2008 Kaplan USMLE Step 1 Home Study Program-Brand New Volume III: Organ Systems Book 1

Contents I: Cardiovascular Section System Chapterl.Embryology. C h a p t e rH2i.s t o l o g y

.....5 .......13

Chapter5.Anatomy....

....19

Chapter4.Physiology,.

.,..51

C h a p t e rP5a. t h o l o g y . . .

....87

Chapter 6. Pharmacology

. .123

Section ll: Respiratory System C h a p t e rEl .m b r y o l o g y C h a p t e rHZi.s t o l o g y C h a p t e rASn.a t o m y . . . .

....141 ......143 ...147

C h a p t e rP4h. y s i o l o g y

.....157

C h a p t e rP5a. t h o l o g y . .

....185

6. Pharmacology Chapter

. . .217

lll: Rena/Urinary Section System l. Embryology . Chapter C h a p t e rH 2 i.s t o l o g y

...227 ......231

iliiitical

vii

Chapter5.Anatomy

......239

Chapter4.Physiology..

...241

Chapter 5. Pathology ...

. . .257

Chapter 6. Pharmacology

. . 281

Section lV:Hematologi{Lymphoreticular System C h a p t le. rH i s t o l o g y

......289

Chapter 2.Anatomy

. . . . . .297

ChapterS.Physiology..

...299

C h a p t e rP4a. t h o l o g y . . .

...303

Chapter 5. Pharmacology

. .327

Section V:Nervous System Chapterl.Embryology. Chapter2. Histology: NerveTissue

.....339

Chapter 5.Histology: Sensory Organs

. .345

Chapter4. Neuroanatomy: lntroduction ,..

...355

Chapter 5.Divisions oftheNervous Sy$em

. . . 559

Chapter 6.Meninges, Ventricular System, andCerebrospinal Fluid 7.Cross Chapter Anatomy oftheSpinal Cord.

viii

ilitstical

...335

. . . . . 561 . . . . . .367

Chapter 8.Spinal Regulation ofSkeletal Muscle Activity Cord

, , . .375

Chapter 9.Functional Anatomy andLesions oftheSpinal Cord.

. .379

Chapter 10.TheAutonomic Nervous Sy$em

. . 389

Chapter ll. ThePeripheral Nervous System

. . .395

B r a iSnt e m C h a p t le2r. T h e

.....401

i ael r v e s C h a p t lesr. C r a n N

......413

Nerves andCranial oftheBrain Stem 14.Lesions Chapter

. .431

Formation 15.Reticular Chapter

. .435

16.TheVestibular System Chapter 17.TheAuditory System Chapter

. . . . .439 . .443

Cerebellum C h a p t le8r. T h e

.....447

19.TheVisual System Chapter

. . .453

Chapter20.TheDiencephalon..

......459

21.TheThalamus Chapter

. . 461

22.TheHypothalamus Chapter

. . 465

.. andSubthalamus 25.TheEpithalamus Chapter

. . .471

24.TheLimbic System Chapter

. . .473

25.TheMotorSystem Chapter

. . .479

.. Hemispheres Anatomy oftheCerebral 25.Cross Chapter

. . . . .483

Cortex 27.TheCerebral Chapter

. .491

to theBrain 28.BloodSupply Chapter

. . 501

Chapter2g.Physiology.

...507

C h a p t e r 5P0a. t h o l o g y . .

...555

. . . 585 Nervous System theAutonomic Drugs Affecting 51.Pharmacology: Chapter Nervous System. . . . . 607 Affecting theCentral Drugs Chapter 52.Pharmacology: Drugs Psychoactive 53.Pharmacology: Chapter lndex

. . . . .643 ....653

ifitshical

ix

I SECTION

System Cardlovascular

Embryology Cardiovascular Allof these andlymphatic vessels. Thecardiovascular system consists of theheart, bloodvessels, isoutlined inthischapter. arederived frommesoderm;their development structures

PRIMITIVE VASCULAR SYSTEM A. Blood islands. During the third week of development, mesenchymal cells associatedwith the yolk sac,chorion, and connecting stalk form clusters called blood islands, which acquire lumina and fuse to form endothelium-lined capillary plexuses.Peripheral cells of the islands become angioblasts that give rise to the endothelial cells of the vessels,whereas centrally located cells become embryonic hemoblasts that give rise to primitive blood cells. 1. Certain capillaries enlargeto form the major blood vessels:vitellinevessels are formed in the yolk sacwall and umbilical vesselsare formed in the vascular chorion. 2. Extraembryonic blood vessels join with intraembryonic blood vesselsformed from splanchnic mesoderm and the primitive vascular systemis established. B. Hematopoiesis first occurs within the islands of the yolk sac.Later, blood cells are formed in the liver (1-7 months), spleen and lymphatic organs (2-4 months), and bone marrow (after 4 months).

Cardiovascular System

PRIMITIVE HEART TUBE FORMATION The pericardial cavity of the coelom lies cephalic to the buccopharyngeal membrane and neural plate in the embryonic disk Mesenchymeclusters in this region form a pair of endothelium-lined heart tubes on either side of the midline. With transversefolding of the embryonic disk, thesetubes fuse to form the single median primitive heart tube. A. Rotation. Cephalocaudal folding of the embryonic disk causesthe pericardial cavity and heart tube to rotate 180' along a transverseaxis and become located ventral to the foregut and caudal to the buccopharyngealmembrane. 1. The heart tube bulges into the pericardial cavity and becomestransiently suspendedfrom its dorsal wall by the dorsal mesocardium. 2.1\e mesoderm adjacent to the heart tube thickens to form the epimyocardial mantle; mantle cells differentiate into muscle cells of the myocardium and mesothelial cells of the epicardium. B. Early differentiation. The cephalic,or arterial, end of the heart tube is continuous with the aortic sac,while the caudal, or venous,end receivesthe vitelline veins from the yolk sac,the umbilical veins from the placenta,and the common cardinal veins from the body wall. The heart tube expands and differentiates to form, in a cephalocaudal direction, the bulbus cordis, primitive ventricle, primitive atrium, and sinus yenosus. 1. The aortic arches connect the truncus to the paired dorsal aortae, which arise from the aortic sacand lie dorsolateral to the foregut. 2. The distal portion of the bulbus, the truncus arteriosus, becomesthe proximal part of the aorta and pulmonary artery. 3. The sinus venosus eventually forms a major part of the wall of the right atrium and the coronary sinus. C. Loop formation. Becausethe bulbus cordis and the ventricular parts of the heart grow more rapidly than the pericardial caviry elongation of the heart tube is accomplishedby the formation of a dorsoventral cardiac loop, which has its convexity directed anteriorly and to the right. 1. In the resulting S-shapedheart, the expanding atrium lies cranial to the ventricle and bulbus cordis, on either side of the truncus arteriosus, and the passagebetween the atrium and ventricle narrows to form the atrioventricular canal. 2. Thesechangesin position are accompaniedby a caudal migration of the pericardium and heart tube from the level of the third and fourth somites to the level of the seventeenthto the rwentiethsomites(FigureI-1-1).

Embryology

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SEPTUM FORMATION A. Primitive atrium 1. At the end of the fourth week, the septum primum grows from the roof of the primitive atrium towards two mesenchymal cushions, the endocardial (atrioventricular; AV) cushions, which appear in the ventral and dorsal walls of the AV canal. a. The transient opening between the septum primum and endocardial cushions is known as the interatrial foramen primum. b. The endocardial cushions gradually extend along the edge of the primum, thereby obliterating the foramen primum.

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System Cardiovascular

c. Prior to its closure,the central portion of the septum primum perforatesto form the interatrial foramen secundum, which insures free blood flow from the right to left primitive atrium. 2. As the sinus venosusbecomesincorporated into the right atrium, the septum secundum grows from the ventral cranial wall of the atrium towards the endocardial cushions. a. The lower edgeof the septum secundumenclosesthe foramen secundum in the septum primum but does not extend firlly towards the endocardialcushions.The opening it leavesbetween the right and left primitive atria is known as the foramen ovale. b. The upper part of the septum primum disappears,but the lower part becomesthe valve of the foramen ovale, which allows blood from the vena cava to pass from the right to left atrium. B. Primitive ventricles

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1. The ventricle beginsto dilate by the end of the fourth week. 2. The expanding walls of the apposing ventricles approach each other medially and fu1e to form the muscular interventricular septum. 3. The interventricular foramen, which lies between the muscular interventricular septum and the endocardialcushionsand permits communication betweenthe two ventricles,is eventually closedby the membranous interventricular septum. C. Ttuncus arteriosus. During the fifth week, the right superior and left inferior bulbar ridges appearin the cephalicportion of ttre truncus arteriosus. 1. The right superiorbulbar ridge grows distally to the left, and the left inferior bulbar ridge grows distally to the right. 2. The bulbar ridges twist around each other and fuse to form the aorticopulmonary septum, which divides the truncus arteriosusinto aortic and pulmonary passages.

VALVES OFCARDIAC FORMATION A. Aortic and pulmonic valves 1. The semilunar valves of the aorta and pulmonary arteries develop following the formation of the aorticopulmonary septum. 2. Three swellingsof endothelium-coveredloose connectivetissue form at the orifices of both the aorta and pulmonary artery. These swellingsbecome hollowed at their uPper surfacesto form semilunar valves. B. Atrioventricular (AV) valves 1. The AVvalves form after the endocardialcushionsfuse. 2. Each atrioventricular orifice becomessurrounded by endocardium-coveredconnective tissueswellings,which hollow on their ventricular surfacesto form valves. a. Two valve leaflets, the bicuspid (mitral) valve, are formed in the left atrioventricular canal. b. Three valve leaflets, the tricuspid valve,are formed in the right atrioventricular canal. 3. The valvesremain connectedto papillary musclesin the wall of the ventricle by meansof chordae tendinae.

6

Embryology

ARTERIAT SYSTEM A. Formation of the aortic arch arteries 1. The aortic arch arteriesarise during the fourth week from the aortic sac,the most distal part of the truncus arteriosus. 2. Eachof the six pairs of arteriesis embeddedin the mesenchymeof its correspondingpharyngeal arch and terminatesin the paired dorsal aortae. 3. The dorsal aortae fuse by the fifth week to form the descendingthoracic aorta and the abdominal aorta with branchesto the embryo, yolk sac (vitelline arteries),and allantois (umbilical arteries).

Flashbackto GeneralPrinciples Nowmaybea goodtimeto review thepharyngeal arches andtheirderivatives inthe lastEmbryology chapter of Book2 Ceneral Principles ftolumell). a o(" ( o <( - I ( ' ?

B. Aortic arch derivatives 1. First aortic arch. The persisting portion becomes the maxillary artery, which supplies the derivatives of the first pharyngeal arch. 2. Second aortic arch. The persisting portion becomes the hyoid artery and stapedial artery, which supply derivatives of the secondpharyngeal arch. 3. Thhd aortic arch. It gives rise to the common carotid artery and the first part of the internal carotid artery (the remainder is formed from the cranial portion of the dorsal aorta); the externalcarotid artery branchesfrom this arch. 4. Fourth aortic arch. The left side forms part of the arch of the aorta betweenthe left common carotid and left subclavianarteries.The right side forms the proximalportion of the right subclavian artery (distal portion is formed from the right dorsal aorta and the seventh intersegmentalartery). 5. Fifth aortic arch. It involutes and disappears. 6. Sixth aortic arch. This is the "pulmonary arch." a. The proximal portions become the proximal left and right pulmonary arteries. b. The right distal portion degenerates.

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C. Developmental changesin the aortic arch system 1. There is obliteration of the carotid duct, the portion of the dorsal aorta betweenthe third and fourth arches.

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2. Disappearanceof the right dorsal aorta occurs betweenthe origin of the seventhintersegmental artery and the junction with the left dorsal aorta.

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D. Branches of the dorsal aortae 1. Dorsal intersegmental arteries (30 pairs) arise from each side of the fused dorsal aortae from the baseof the skull to the sacrum.

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a. Dorsal ramus suppliesthe spinal cord, meninges,skin, and musculatureof the back. Longitudinal anastomosesgive rise to vertebral arteries,which fuse with the single basilar artery. The basilar artery fuses with the internal carotid artery to form the cerebralarterial circle (of Willis). b. Ventral ramus. Each fuseswith its partner at the ventral body wall, giving rise to the intercostal,limb, and lumbar arteries.

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2. Laterulsplanchnic arteries arise from each side of the dorsal aorta. They supply intermediate mesodermand derivativesand give rise to renal, suprarenal,phrenic, and testicular or ovarian arteries. 3. Ventral splanchnic arteries

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a. Vitelline arteries originate asa number of paired vesselsrunning to the yolk sac.They eventually fuse to form the celiac artery to the foregut, superior mesenteric artery to the midgut, and inferior mesentericartery to the hindgut.

vii( i I

b. Umbitical arteries originate as paired ventral branchesto the placentain association with the allantois. ( 1) During the fourth week,eachartery becomesconnectedwith the dorsal aorta via the common iliac artery. ri"'

(2) After birth, the umbilical arteriesgive rise to the internal iliac arteries,proximally, and the medial umbilical ligaments,distally.

VENOUS SYSTEM At five weeks,the embryo has three major pairs of veins. A. Viteltine (omphalomesenteric)veins drain the yolk sacand carryblood around the duodenum and through the septum transversumto the sinusvenosus. l. The vitelline veins cephalicto the liver becomethe hepatocardiacchannels,which enter the sinusvenosuswith the right channelbecoming the first segmentof the inferior vena cava. 2. Caudal to the liver, the vitelline veins anastomoseand atrophy to form the singlehepatic portal vein of the portal systemthat drains the viscera. B. Umbilical veins. After atrophy of the right vein and the left vein proximal to the liver, the remaining left vein carriesblood from the placentato the liver. 1. The ductus venosus, a direct connection through the liver to the right hepatocardiac channel,is formed. This preventsdepletion of oxygenand nutrient-rich blood in the hepatic sinusoids.

Bridgeto Anatomy is Theligamentum venosum remnant ofthe thefibrous ductus venosus. lt runsina of fissure onthevisceral surface theliverandisattached onone endtotheleftbranch ofthe portalvein andontheother venacava. endtotheinferior Theligamentum teresisthe fibrous remnant ofthe in umbilical vein.lt islocated thefreemargin ofthe falciform ligament. 8

2. After birth, the ductus venosusbecomesobliteratedand is fibrosedto form the ligamentum venosum. The left umbilical vein forms a similar ligament, the ligamentum teres, in the free margin of the falciform ligament. C. Cardinal veins 1. The anterior cardinal veins drain the cephalicend of the embryo, and the posterior cardinal veins drain the caudalend of the embryo. Thesejoin to form the common cardinal veins,which enter the horns of the sinus venosus. 2. By the seventhweek, the subcardinalveins, which drain the kidneys, the sacrocardinal veins, which drain the lower extremities,and the supracardinalveins, which drain the body wall via intercostalveins,are formed. 3. The vena cava system is formed by anastomosesbetweenthe right and left sidesof the cardinal systemsuch that blood from the left is channeledto the right side. a. Anastomosisbetweenthe anterior cardinal veins forms the left brachiocephalicvein during the eighth week. b. The superior vena cava is formed from the proximal right anterior cardinal vein and the right common cardinal vein.

Embryology

c. Anastomosisbetweenthe sacrocardinalveins forms the left common iliac vein. The right sacrocardinalvein becomesthe sacrocardinalsegmentof the inferior vena cava. 4. The fourth to eleventh right intercostal veins empty into the right supracardinal vein, which joins the posterior cardinal vein to form the azygosvein. The fourth to seventhleft intercostal veins enter the left supracardinal vein (hemiazygosvein), which empties into the azygosvein.

LYMPHATICS Development of this systemparallelsthat of the veins.It beginswith six primary lymph sacs, which later form a network of lymphatic vessels.Aggregatesof lymphatic tissue, or lymph nodes,form in this network shortly before or after birth.

CIRCUTATION OFBLOOD A. Fetal pattern (Figure I-I-2) 1. In the fetus, blood is oxygenatedat the placenta and travels via the umbilical vein, most of it bypassingthe liver through the ductus venosus, to the inferior vena cava. a. There,it mixes with deoxygenatedblood from the lower body and hepaticportal system and, subsequently,entersthe right atrium. b. The valve at the orifice of the inferior vena cava directs most of the flow out of the right atrium, through the foramen ovale,into the left atrium. c. From the left atrium, the oxygenatedblood, plus some deoxygenatedblood from the lungs, passesinto the left ventricle and, hence,into the ascendingaorta toward the brain, heart, and upper extremities. 2. Deoxygenatedblood from the head and upper extremitiesreturns to the right atrium via the superior vena cava,and passesthrough the tricuspid valveto the right ventricle.From there, most of it is short-circuited awayfrom the inactive lungs by the ductus arteriosus into the descendingaorta to supply the trunk and lower extremities. 3. Since the right ventricle must pump blood againstthe relatively high resistanceof the unexpandedlungs and through the ductus to the generalcirculation, pressureon the right side of the heart is greater than on the left. Thus, prior to birth, the thickness of the right ventricle wall is similar to that of the left. 4. Blood in the aorta travels to the placentavia the umbilical arteries,which now arise from the internal iliac arteries. B. Changesat birth. Cessationof placental blood flow at birth and an increasein flow through the lungs causethe pressurein the right atrium to decrease,while that in the left rises.As a result, the septum primum is apposedto the septum secundum,and the foramen ovale is closed functionally. Fusion occurs in about one year.

System Grdiovascular

Ductus arteriosus

Superior vena cava Foramen ovale In fe ri o r vena cava Portalvein

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Figure l-1-2.Fetal circulation.

ITAIMATFORMATIONS CONGEN A. Tetralogy of Fallot is a common abnormaliry which consistsof pulmonary stenosis,right ventricular hypertrophy (secondaryto pulmonary stenosis),interventricular septal defect, and an overridingaorta.

ln a Nutshell Tetralogy of Fallot . Pulmonary stenosis . Right ventricular (RVH) hypertrophy . Interventricular septal defect . Overriding aorta

1. It is a result of asymmetricaldevelopmentof the truncus arteriosusseptumto form a very small pulmonary artery and a very large aorta. Unoxygenatedblood is shuntedto the left side and blood flows from both right and left ventricles into the enlarged aorta with little reachingthe lungs. 2. This abnormaliry,compatiblewith life, is the most important causeof neonatalryanosis. B. Transposition of the great vesselsis an anomaly in which the aorta emergesfrom the right ventricle and the pulmonary artery from the left ventricle. It is thought to be due to failure of the bulbar septum to spiral. C. Patent ductus arteriosus is a failure of anatomic obliteration that allows orygenated blood from the aorta to be shuntedback into the pulmonary artery. D. Atrial septal defects (ASD) are the failure of the septaprimum and secundum to form. The most common form is a patent foramen ovale,resulting from incompleteadhesionbetween the septum primum and septum secundum.

t0

Embryology

E. Ventricular septal defects (VSD) are usually due to malformation of the membranous interventricular septum. F. Persistent truncus arteriosus is a failure of the partitioning of the truncus arteriosus into the aorta and pulmonary artery. G. Pulmonar'' valvular atresia is an unequal division of the truncus arteriosus such that the pulmonary trunk has no lumen or orifice at the level of the pulmonary valve.

Bddget9 Patrology These congenital abnormalities andmore arediscussed in detailin theCardiovascular Pathology chapter.

H. Aortic coarctation is a narrowing of the aorta just above or below the ductus arteriosus.

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Histology Cardiovascular Thecardiovascular isa closed, fortheseparate system doublepathway circulation of bloodto the lungsandtheperipheral tissue. lt consists of a four-chambered heartanda system of vessels for (arteries (veins) delivery andcapillaries) andsubsequent return ofthebloodto theheart. This chapter willreview thedifferent tissue typesfoundin eachof thesecomponents, andhowthese tissues fortheirspecific arespecialized functions.

MUSCTE CARDIAC CEttS A. Cardiac muscle cells are elongated,branching fibers that exhibit transversebanding patterns like that of skeletalmuscle. 1. They possessone or two centrally placednuclei. 2. Individual cells are surrounded by a delicate connectivetissue containing an abundant capillary network. 3. Cardiac myofibers are joined together by extensive junctional structures called intercalated disks. 4. Unlike skeletalmuscle, cardiac muscle cells are electrically coupled to each other through gap junctions located in the disks. B. Cardiac muscle sarcomeres are similar to those found in skeletalmuscle. Their filaments, however,are not segregatedinto discretemyofibrils but are found in continuous fields that are partially divided by portions of sarcoplasm.Actin filaments attach to the intercalateddisks at the ends of the cells. C. Control of cardiac muscle. Cardiac muscle does not require neural input for activation, but its activity is modulated by the sympathetic and parasympatheticdivisions of the autonomic nervous system(ANS). 1. Specializedmuscle cells in the right atrium, the sinoatrial (SA) node, spontaneously depolarize rhythmically to initiate each heart beat. 2. Electricalcoupling via gapjunctions at the intercalateddiskscausesdepolarization,which is initiated at the SA node and spreadsthrough the atria. a. The impulse reachesthe atrioventricular (AV) node and is delayedthere for approximately 0.1 seconds. b. From the AV node, specializedconduction fibers in the bundle of His and its branches transmit the impulse to the ventricular muscle.

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System Cardiovascular

3. The large-diameterconducting fibers are modified muscle cells called Purkinje fibers, which have few myofibrils and abundant sarcoplasm containing mitochondria and glycogen.

HEART The heart is a muscular organ, composedprimarily of cardiacmuscle tissue,which contracts rhythmically to pump blood throughout the body. A. Structure of the heart wall. The walls of the heart are constructed in layersthat are similar to those of the major blood vessels.

In a Nubhell + outside lnside Endocardium + myocardium -+ epicardium

1. Endocardium is the innermost layer of the heart and is lined with endothelium. Veins, nerves,and components of the impulse conducting systemare presentin the subendocardial connective tissue layer. 2. Myocardium is composedof branching, anastomoticcardiac myocytesattachedto one another by intercalated disks. Most of these cells are involved in the pumping function of the heart; others are specializedfor the control of rhythmicity (impulse conducting system) or secretion(myocardialendocrine cells). 3. Epicardium is a serousmembrane that forms the viscerallining of the pericardium. Its externaimesothelium is supported by a loose connectivetissuesubepicardiallayer. B. Cardiac skeleton is composedmainly of denseconnectivetissueand consistsof the annuli fibrosi, the trigonum fibrosum, and the septum membranaceum. C. Cardiac valvesare composedof densefibrous tissuecoveredby endothelium.

ln a Nutshell Venacavae + RA+ tricuspid valve+ RV+ pulmonic valve + pulmonary artery+lungs+pulmonary vein+ LA+ mitralvalve-> LV+ aorticvalve+ aorta

1. Unidirectional flow is maintained from the: a. Right atrium to the right ventricle (tricuspid valve) b. Right ventricle to the pulmonary artery (pulmonic semilunar valve) c. Left atrium to the left ventricle (mitral/bicuspid valve) d. Left ventricle to the aorta (aortic semilunar valve) 2. Tricuspid and mitral valves are attached to papillary muscles by cords of fibrous connectivetissue(chordaetendineae)and prevent reflux of blood into the atria during ventricular contraction (systole). 3. Semilunar valves (aortic and pulmonic) prevent reflux of blood back into the ventricles during ventricular relaxation (diastole). D. Impulse conducting system of the heart consists of specialized cardiac myorytes that are characterizedbyautomaticity and rhythmicity (i.e.,they are independentof nervous stimulation and possessthe ability to initiate heart beats).Thesespecializedcellsare located in the sinoatrial (SA) node (pacemaker),internodal tracts,atrioventricular (AV) node,AV bundle (of His), left and right bundle branches,and numerous smaller branchesto the left and right ventricular walls (Figure I-2-l).Impulse conducting myocytesare in electricalcontact with eachother and with normal contractile myocftes via communicating (gup) junctions. Specializedwide-diameter impulse conducting cells (Purkinje myocytes), with greatly reduced myofilament components,are well adaptedto increaseconduction velocity. They rapidly deliver the wave of depolarization to ventricular myocytes.

t4

Histology

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E. Myocardial endocrine cells are also specializedmyocytes found mainly in the atria. These cellscontain numerous secretorygranules,which contain atrial natriureticpeptides (ANP). When releasedinto the blood, thesehormones play rolesin the regulation of blood pressure and blood volume.

ARTERIES

Note There arethreetypesof heart cells: . Contractile . lmpulse conducting (Purkinje) . Endocrine (ANP)

Arteries are classifiedaccording to their size,the appearanceof their tunica media, or their major function. A. Large elastic conducting arteries include the aorta and its large branches.Unstained, they appearyellow due to their high content of elastin. 1. The tunica intirna is composed of endothelium and a thin subjacent connective tissue layer.An internal elastic membrane marks the boundary between the intima and media. 2. The tunica media is extremely thick in large arteries and consistsof circularly organized, fenestratedsheetsof elastictissuewith interspersedsmooth muscle cells.Thesecells are responsiblefor producing elastin and other extracellularmatrix components.The outermost elastin sheet is considered as the external elastic membrane, which marks the boundary between the media and the tunica adventitia. 3. The tunica adventitia is a longitudinally oriented collection of collagenousbundles and delicate elasticfibers with associatedfibroblasts. Large blood vesselshavetheir own blood

In a Nubhell -+ outside lnside Intima+ media-+ adventitia

Note Vasa vasorum isLatinfor "vessels of thevessel."

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Cardiovascular System

supply (vasavasorum), which consistsof small vesselsthat branch profusely in the walls of larger arteries and veins. B. Muscular distributing arteries are medium-sized vesselsthat are characterizedby their predominance of circularly arranged smooth muscle cells in the media interspersedwith a few elastin components.Up to 40 layersof smooth muscle may occur. Both internal and external elastic limiting membranes are clearly demonstrated.The intima is thinner than that of the large arteries. C. Arterioles are the smallestcomponents of the arterial tree. Generally,any artery lessthan 0.5 mm in diameter is consideredto be a small artery or arteriole.A subendotheliallayer and the internal elasticmembrane may be present in the largestof thesevesselsbut are absentin the smaller ones.The media is composedof severalsmooth muscle cell layers,and the adventitia is poorly developed.An external elasticmembrane is absent.

CAPITTARIES Capillaries are thin-walled, narrow-diameter, low-pressure vesselsthat generally permit easy diffi.rsion acrosstheir walls. Most capillaries have a cross-sectionaldiameter of 7-12 pm. They are composed of a simple layer of endothelium, which is the lining of the entire vascular system,and an underlying basallamina. They are attachedto the surrounding tissuesby a delicate reticulum of collagen.Associatedwith thesevesselsat various points along their length are specializedcells called pericytes. These cells, enclosedwithin their own basal lamina, which is continuous with that of the endothelium,contain contractileproteins and thus maybe involved in the control of capillary dynamics. They may also serve as stem cells at times of vascular repair. Capillaries are generally divided into three types, according to the structure of their endothelial cell walls. A. Continuous (muscular, somatic) capillaries are formed by a single uninterrupted layer of endothelialcellsrolled up into the shapeof a tube and can be found in locationssuch asconnectivetissue,muscle,and nerve. B. Fenestrated (visceral) capillaries are characterizedby the presenceof pores in the endothelial cell wall. The pores are coveredby a thin diaphragm (exceptin the glomeruli of the kidney) and are usually encounteredin tissueswhere rapid substanceinterchangeoccurs (e.g.,kidney, intestine,endocrine glands).

Note . Morethan700/o of total bloodvolume isfoundin thevenous system atany onetime. . Return bloodflowto the heartisaidedbytheaction and ofsmooth muscle special unidirectional valves inthewallsofveins themselves, aswellasbythe action ofadjacent skeletal muscles.

t6

C. Sinusoidal capillaries can be found in the liver, hematopoietic and lymphopoietic organs, and in certain endocrine glands.Thesetubes with discontinuous endothelial walls have a larger diameter than other capillaries(up to 40 pm), exhibit irregular cross-sectionalprofiles, have more tortuous paths, and often lack a continuous basallamina. Cells with phagocytic activity (macrophages)are presentwithin, or just subjacentto, the endothelium.

VEINS Veins are low-pressurevesselsthat have larger lumina and thinner walls than arteries.In general, veins have more collagenousconnective tissue and less muscle and elastic tissue than their arterial counterparts.Although the walls of veins usually exhibit the three layersdescribedabove, they are much less distinct than those of the arteries. Unlike arteries, veins contain one-lrray valves composedof extensionsof the intima that prevent reflux of blood a\ ray from the heart. Veins can be divided into small veins or venules,medium veins, and large veins. A. Venules are the smallest veins, ranging in diameter from approximately 15-20 pm (postcapillary venules) up to 7-2 mm (small veins). The walls of the smaller of these are structurally and functionally like those of the capillaries; they consist of an endothelium

Histology

surrounded by delicate collagen fibers and some pericytes. In those vesselsof increased diameter, circularly arranged smooth muscle cells occur surrounding the intima layer, but unlike in the small arteries, these cells are loosely woven and widely spaced.Venules are important in inflammation becausetheir endothelialcellsare sensitiveto histamine released by local mast cells.This causesendothelial cells to contract and separatefrom each other, exposing a naked basement membrane. Neutrophils stick to the exposed collagen and extravasate(i.e.,move out into the connectivetissue).Histamine also causeslocal arterioles to relax, affectinga rise in venouspressureand increasedleaking of fluid. This producesthe classicsignsof inflammation: redness,heat, and swelling. B. Medium veins in the range of t-9 mm in diameter have a well-developed intima, a media consisting of connective tissue and loosely organized smooth muscle, and an adventitia (usually the thickestlayer) composedof collagenbundles,elasticfibers,and smooth muscle cells oriented along the longitudinal axis of the vessel.Venous valvesare sheet-like outfoldings of endothelium and underlying connectivetissue that form flaps to permit unidirectional flow of blood.

Note Themajorityof veins(withthe exception ofthemaintrunks) aresmall ormedium-sized.

Note . Artery-media is thickest layer . Vein-adventitia is thickest layer

C. Large veins, such as the external iliac, hepatic portal, and vena cavae,are the major conduits of return toward the heart. The intima is similar to that of medium veins.Although a network of elasticfibers may occur at the boundary betweenthe intima and media, a typical internal elasticmembrane as seenin arteriesis not present.A tunica media may or may not be present.If present,smooth muscle cellsare most often circularly arranged.The adventitia is the thickestlayer of the wall and consistsof elasticfibers and longitudinal bundles of collagen.In the vena cava,this layer also containswell-developedbundles of longitudinally oriented smooth muscle.

TYMPHATIC VESSETS Lymphatic vesselsare discussedin the Histology chapter of the Heme/Lymph Systemsection in this book.

t7

Anatomy Cardiovascular portion cavity known asthemediastinum. This inthemiddle ofthethoracic Theheartislocated anatomy thestructures located in themediastinum aswellasthegross of the chapter willreview andazygos vein. andthebranches inferior venacava, heartitself oftheabdominal aorta,

MEDIASTINUM Located between the pleural cavities,the mediastinum is divided into inferior and superior parts by a plane passingfrom the sternalangle anteriorly,to the intervertebraldisc betweenT4 and T5 posteriorly. The inferior mediastinum is classicallysubdivided into middle, anterior, and posterior parts (FiguresI-3-1 andl-3-2). A. Middle mediastinum. This sectioncontainsthe pericardium, phrenic nerves,and heart. 1. Pericardium is the outer fibrous sac; it is lined by a double-layeredserousmembrane that enclosesthe pericardial cavity betweenits parietal and viscerallayers. a. Transversepericardial sinus is a spaceposterior to the ascendingaorta and pulmonary trunk and anterior to the superior vena cava. b. Oblique pericardial sinus is a blind, inverted,U-shapedspaceposterior to the heart and bounded by reflection of serouspericardium around the eight vesselsentering and leaving the heart. 2. Phrenicnerves a. Phrenic neryesarisefrom the ventral primary rami of cervicalnerves3, 4, and 5. b. They are the sole motor supply of the diaphragm and convey sensoryinformation from the central portion of both the superior and inferior portions of the diaphragm. c. Both phrenic nerves passthrough the middle mediastinum lateral to fibrous pericardium and anterior to the root of the lung. 3. The heart (discussedseparatelybelow)

ClinicalCorrelate

isa lifeCardiac tamponade resulting threaten ingcondition in compression oftheheart of dueto anaccumulation fluidinthepericardial excess cavity. Thefluidmustbe bypericardiocentesis removed to relieve thepressure. is Pericardiocentesis performed byinserting a needle theskinand through tissues along subcutaneous theunderside ofthexiphoid process, inward and directed toward thepericardial upward, the sac(alternatively, pericardial saccanbe approached fromthe angles, xiphocostal orthrough space). thefifthleftintercostal Withdrawal of evena small offluidcanrestore amount in many function cardiac cases. Caremustbetakento access thepericardium to the"barearea" through avoid violation ofthe pleura. costal

t9

System Cardiovascular

Anterior

Figure l-3-1. Divisions of the mediastinum.

Mnemonic

B. Anteriormediastinum. This section contains fat and areolartissue.

C3,C4,andC5keepthe alive! diaphragm

C. Posterior mediastinum. This section contains many of the samestructuresas the superior mediastinum. 1. Thoracic (desceneg) aorta

Mnemonic Thefourbirdsin thethoracic caSe: . Va-goose . Azy-goose . Esopha-goose . Thoracic duck

20

a. The most important branchesof the thoracic aorta are the bronchial, esophageal, and posterior intercostalarteries. b. It terminatesat vertebrallevel T12, where it passesthrough the aortic orifice between the two crura of the diaphragm. 2. Esophagus a. The esophagusis related anteriorly to the anterior esophagealplexus,which is derived mainly from the left vagus.

Anatomy

\

a tr

\, !

I

Aortic valve

Pulmonary valve

J

;

t I

t,

Tricuspid Mitral valve valve

Figure l-3-2.Surface landmarks and auscultation points.

b. The esophagusis related posteriorly to the posterior esophagealplexus, which is derived mainly from the right vagus. c. The esophagusterminates at vertebral level T10 by passingthrough the esophageal hiatus in the right crus of the diaphragm. 3 . Thoracic duct a. The thoracic duct lies betweenthe esophagusand the thoracic aorta. b. It arisqsfrom the cisterna chyli in the abdomen at vertebral level L1-L2 and entersthe thorax through the aortic orifice of the diaphragm.

Mnemonic "LARP" Esophagus: (leftanterior, rightposterior)

4. Azygous systemof veins (Figure I-3-3) a. The posterior thoracic and abdominal walls are drained by the arygossystemof veins. b. The azygous vefn may arise from the posterior aspectof the inferior vena cavain the abdomen; the hemiarygos vein often arisesfrom the left renal vein. Theseveins often ascend to the thorax throug\ the aortic orifice of the diaphragm. Alternativgly, the arygosand hemiarygos veins may arise from the ascendinglumbar veins and ascend behind the diaphragm. c. The azygosveintermillqtes by arching over the root of the right lung to empty into the superior vena cava. d. It receivesblood djlgctly from the right posterior intgrcostal veins and indiregtly via the left-sided tributaries of the hemiarygos and accessoryhemiarygosveins and the left posterior intercostalveins.

2l

Cardiovascutar System

Ir , , .

Superior venacava

Leftsuperior intercostaf vein

Accessory hemiazygos vein Hemiazygos vein

Inferior vena cava Ascending lumbarvein

Figure l-g_9.The azygos

system of veins.

5. Sympathetic trunks a' The sympathetic trunks are located paravertebra[y, just outside the posterior stinum.

media-

"fJ::i',:Tril:i.f::"'fji:':ffi

::.#:#.h:*':,pregangrionicsympathetic mediallv *" posterior runningbr.n.i., of thesympatherijl;,i,lrll meairrti'um ", D superior,il"$::SffiJH:,,'"T*:n contains manvstru*ures, someof whicharearso l. Thymus (or remains) 2. Superiorvenacaya

" ffi:'ffi',T#l:dffi:1,?ffiX*lffitheright sternocostar junction bythe union 22

Anatomy I

la'

I t

Left vagus nerve (X) Right vagus nerve (X) Rightsubclavian artery and vein

l;

Right brachiocephalic vein Brachiocephalic artery

Rightphrenic nerve

'' t,.'...' ," "',--.

Left vein brachiocephalic Left phrenicnerve

Superior venacava

Figure l-3-4. Structures of the superior mediastinum.

Bridgeto Embryology b. It returns blood from the head, neck, and upper extremities to the right atrium of the heart. 3. Arch of aorta a. The aortic arch begins and ends at the level of the sternal angle. b. There are three branches:the brachiocephalic trunk, the left common carotid artery, and the left subclavian artery. +. Right and left vagus nerves contribute to the pulmonary and cardiac plexuses. a.@rvegivesrisetotherightrecurrentlaryngealnerve(intherootof the neck), which passesunder the righf subClavianartery to ascend in the groove between the esophagusand the trachea to reach the larynx. b. The left vagus nerve gives rise to the left recurrent laryngeal nerve, which passes under the aortic arch and ligamentum arteriosum to ascendto the larynx (ligamentum arteriosum).

lqryUqql nerve -gb!tqgUtrent "recurs" around thederivative ofthefou4lfaodicareh (proximal portion ofsubclavian grtery); re_current'tecurs" left around thederivative ofthe sixt!-ggrtrc arch(igamentum arteriosr,rm), ClinicalCorrelate Hoarseness asa result of compromise oftheleft nerve recurrent laryngeal may pressure indicate froman aortic aneurysm.

2t

Grdiovascular System

ClinicalCorrelate Therightprimarybronchus is straighter andwiderthanthe left;aspirated objecbtherefore lodgemorefrequently inthe rightbronchus thanin theleft.

Superior Mediastinum (remains) Thymus SVC Aortic arch Vagus nerves Trachea Bophagus

Thoracic duct InferiorMediastinum

rv\ Anterior Fatand areolar tissue

|

a. The tracheaext€ndsftom the levelofthe cricoid cartilage(vertebrallevelC6) to bifurcation (behindthe sternalangle)to form the primary bronchi. b. At the bifurcation is a ridge calledthe carina whosernucosais very sensitiveto external stimuli.

6. Esophagus a. The esophagusextendsfrom the level of the cricoid cartilage(vertebrallevel C6) and passesthrough the esophagealhiatus of the diaphragm (Tt0).

In a Nutshell

/

5. Trachea

\

Middle Posterigt Pericardium Descending Heart aorta Phrenic Esophagus nerves Thoracic duct Azygos system Thoracic splanchnic

u"ffil:'*" and Denvatives: anterior and posterior esophagal plexuses, left recunent laryngeal nerve

b. It lies to the right of the thoracic duct in the superior mediastinum. 7. Thoracic duct a. The thoracic duct is the largest lymphatic channel in the body. b. It returns lymph to the venous circulation at the junction of the left internal jugular vein and the left subclavianvein (beginning of left brachiocephalictrunk).

THEHEART A. Borders of the heart 1. The right border is formed by the right atrium. 2. The inferior border is formed by the right ventricle and the apex of the left ventricle. 3. The left border is formed by the left ventricle and the auricle of the left atrium. 4. The superior border is formed by the right and left auriclesplus the conus arteriosusof the right ventricle. 5. The apexis the tip of the left ventricle. 6. The baseis oppositethe apex,formed mainly by the surfacewhere pulmonary veins enter the heart (left atrium) and by part of the right atrium. B. Surface projections of the heart may be traced on the anterior chestwall. 1. The right border extends from the margin of the third right costal cartilage to the sixth right costalcartilagejust to the right of the sternum. 2. The inferior border extendsfrom the sixth right costalcartilage to the fifth left intercostal spaceat the midclavicular line. 3. The left border extendsfrom the fifth left intercostalspaceto the secondleft costalcartilage. 4. The superior border extendsfrom the inferior margin of the secondleft costalcartilage to the superior margin of the third right costalcartilage.

24

Anatomy

ClinicalConelate Ligamentum arteriosum

Valve

Leftpulmonaryartery

Right pulmonary

Pulmonary trunk

artery

Left atrium

Right pulmonary

Pulmonary L 2nd intercostal space Aortic

R2nd interco$al space

Mitral

L 5th intercostal space

Tricuspid

Xiphisternal function

Left pulmonary veins

verns

Left ventricle Right

atrium

Areaof Auscultation

Right ventricle Figure l-3-5. Sternocostal view of the heart.

C. Chambers of the heart 1. Right atrium receivesvenous blood from the entire body with the exception of blood from the pulmonary veins. a. Auricle is derived from the fetal atrium; it has rough myocardium known as musculi pectinati. b. Sinus venarum is the smooth-walled portion of the atrium, which receivesblood from the superior and inferior venaecavae. c. Crista terminalis is the vertical ridge that separatesthe smooth from the rough portion of the right atrium; it extends longitudinally from the superior vena cava to the inferior vena cava. d. In the fetus, the fossa ovalis was the foramen ovale, an opening in the interatrial septum to allow blood entering the right atrium from the inferior vena cava to passdirectly to the left side of the heart. e. Right atrioventricular (AV), or tricuspid, valve communicates with the right ventricle. 2. Right ventricle receivesblood from the right atrium via the tricuspid valve; outflow is to the pulmonary trunk via the pulmonary semilunar valve. a. Trabeculae carneae are ridges of myocardium in the ventricular wall.

ClinicalCorelate Themostexposed chamber fromananteriorprojection is right the ventricle. Thisisthe mostfrequently chamber damaged infrontal trauma, i.e.,stabwound.

Flashback to Embryology venarum Thesinus is derived fromthefetalsinus venosus, which isdiscussed intheCardiovascular Embryology chapter.

b. Papillary muscles project into the cavity of the ventricle and attach to cuspsof the AV valve by strands of chordae tendineae.

25

Cardiovascular System

c. Chordae tendineae pull cuspsof the valve together during contraction of the ventricle.

ClinicalCorrelate Mitralvalveinsufficiency leads to a backup of bloodin the leftatrium; theresultant enlargement ofthischamber mayexertpressure onthe esophagus. Symptoms of dysphagia, therefore, may indicate a problem withthe functioning ofthemitral valve.

Ftashback to Embryology

d. Infundibulum valve.

is the smooth area of the right ventricle leading to the pulmonary

3. Left atrium receivesoxygenatedblood from the lungs via the pulmonary veins. a. There are four openings for the upper right and left and the lower right and left pulmonary veins. b. The left AV orifice is guarded by the mitral (bicuspid) valve; it allows oxygenated blood to passfrom the left atrium to the left ventricle. 4. Leftventricle. Blood enters from the left atrium through the mitral valve and is pumped out to the aorta through the aortic semilunar valve. a. Tiabeculae carneae. The myocardium is normally three times thicker than that of the right ventricle. b. Papillary muscles, usually two large ones, are each attached by chordae tendineae to both cuspsof the bicuspid valve.

Theaortic ve$ibule and c. Aortic vestibule leadsto the aortic semilunar valve and ascendingaorta; right and left infundibulum oftheright coronary arteries originate from the right and left aortic sinusesat the root of the ventricle arederived fromthe ascendingaorta. fetalbulbus cordis, asdiscussed D. Arterial supply of the heart intheCardiovascular Embryology chapter. 1. Right coronary artery

Bridgeto Physiology Thecoronary arteries fillduring diastole.

a. The right coronary artery arisesfrom the ascendingaorta and runs in the coronary (AV) sulcus. b. The right coronary artery suppliesthe right atrium, the right ventricle, the sinoatrial (SA) and AV nodes,and parts of the left atrium and left ventricle. c. Important branches are the SA nodal artery, the a-v nodal arte\, the right marginal artery and the posterior interventricular artery. 2. Left coronary arter'' a. The left coronary artery arisesfrom the ascendingaorta. It divides into two branches, the anterior interventricular (left anterior descending) artery and the circumflex artery. b. The left coronary artery supplies most of the left ventricle, the left atrium, and the interventricular septum. E. Venous drainage of the heart l. Coronary sinus is the main vein of the coronary circulation; it travels in the posterior coronary sulcus.It drains to an opening in the right atrium. 2. Greatcardiac vein travels in the anterior interventricular sulcus. It is the main tributarv of the coronary sinus. 3. Middle cardiac vein travels in the posterior interventricular sulcus.It joins the coronary sinus. 4. Venae cordis minimae (thebesian veins) and anterior cardiac veins open directly to the chambers of the heart.

26

Anatomy

F. Conducting system of the heart (seeFigure I-2- 1) 1. SA node a. The SA node initiates the impulse for contraction of heart muscle (and is therefore termed the "pacemaker"of the heart). It is located at the superior end of the crista terminalis, where the superior vena cavaenters the right atrium. b. The SA node is supplied by the SA nodal branch of the right coronary artery.

Bridgeto Physiology

c. Impulse production is speededup by sympatheticnervousstimulation; it is slowedby parasympathetic(vagal) stimulation.

Astheimpulse travels through theAVnode,it slovrs. This corresponds to thePRinterval onanelectrocardiogram.

2. Nl node receivesimpulses from the SA node. The AV node is located in the interatrial septum near the opening of the coronary sinus. 3. Bundle of His originatesin the AV node. It distributesto the right and left ventricles. a. In the right ventricle, the moderator band (septomarginaltrabecula) contains the right bundle branch. b. Impulses passfrom the right and left bundle branchesto the papillary musclesand ventricular myocardium. G. Innervation. The cardiac plexus is a combination of sympathetic and parasympathetic (vagal) fibers. Sympathetic stimulation increasesthe heart rate; parasympatheticstimulation slowsthe heart rate.

BRANCHES OFTHEABDOMINAI AORTA AND INFERIOR VENA CAVA A. The abdominal aorta first passesthrough the aortic orifice of the diaphragm at vertebral level T12 (Figure I-3-6). It ends atL4, where it forms the paired common iliac arteriesand single small median sacralartery. The branchesof the abdominal aorta include the following: 1. Three visceral unpaired branches a. Celiactrunk b. Superior mesentericartery c. Inferior mesentericartery 2. Three visceral paired branches a. Renalarteries b. Suprarenalarteries c. Gonadal arteries 3. Five paired parietal branches a. Inferior phrenic arteries b. Four pairs of lumbar arteries c. A fifth pair of lumbar arteriesarisefrom the median sacralartery. B. The inferior vena cava begins at vertebral level L5 from the joining of the two common iliac veins. It terminates in the right atrium after passing through the caval orifice of the diaphragm at vertebrallevel T8. 1. The azygosvein interconnectsthe superior and inferior venaecavae.It drains the posterior intercostalveins of the thoracic wall and the posterior abdominal wall.

27

Grdiovascutar System

2' The renal veins lie superficial to the corresponding arteries. The left renal is longer becauseit must cross the aorta and vertebral column to reach the inferior vena cava. 3' Right gonadal vein is a direct tributary of the inferior vena cava.(The left gonadal drains to the left renal vein.) 4' Right suprarenal vein is a direct tributary of the inferior vena cava.(The left suprarenal drains to the left renal vein.) 5. The lumbar veins drain the posterior abdominal wall. 6. The inferior phrenic veins drain the diaphragm. 7' The hepatic veins open into the inferior vena cava just before it passesthrough the diaphragm. They return blood from the liver to the systemiccirculation.

fnferiorphrenic--'

Superiormesenteric

Gonadal Lumbars

Mediansacral

Commoniliac

Internaliliac Externaliliac

Figure l-3-0. Branching of the abdominal aorta. C' Azygosvein arisesin the abdomen, usually from the inferior vena cavaor ascendinglumbar vein' It ascendsto the posterior mediastinum and terminates in the superior vena cavajust before the superior vena cavaenters the pericardium. 1' The hemiazygos vein drains the lower left inferior posterior intercostal veins (T9-T12). It joins the azygosvein.

28

Anatomy

2. The accessoryhemiazygos vein receivesblood from the left posterior intercostal veins from T5 to T8. It joins the azygosvein.

Left suprarenalvein

suprarenal vein Right renal vein Right gonadalvein

Left renal vein Left gonadalvein

Figurel-3-7.Inferiorvenacava(lVC)and tributaries.

29

Physiology Cardiovascular q6tem,consi$ing Thecardiovascular functions oftheheartandvessels, inthedistribution of essential fromthetissues. sub$ances tothetissues andtheremoval byproducts ln addition, of metabolic the provides for homeo$atic including bod support mechanisms, temperature regulation, humoral l6tem communication, andadju$ment oftheoxygen andnutrient supply. Thischapter willreview thebasic processes functions and associated withthedifferent components ofthecardiovascular system.

MYOCARDIAT ETECTROPHYSIOTOGY A. Anatomyof the conduction system (Figure I-4-l)

Superior i venacava\-\- i -\ Sinoatrialnode (SA node)

Atrioventricularnode (AV node)

Pulmonary veins His bundle Left ventricle

Rightatrium

Bundle branches

Rightventricle Inferior _/-' vena cava' : Purkinje fibers

Figure l4-1.The cardiac conduction system.

5l

Cardiovascular System

1. The electrical impulse that depolarizes the heart normally originates in the sinoatrial (SA) node, a spindle-shapedstructure 10-20 mm long and,2-3 mm wide, located at the junction of the superior vena cavaand right atrium, 1 mm below the epicardial surface. a. The SA node is richly innervated with postganglionic sympathetic (adrenergic) and parasympathetic(cholinergic) nerve terminals. b. Sympathetic stimulation produces acceleration of the SA node discharge rate, while parasympathetic stimulation slows it down. 2. The depolarizing impulse travels from the SA node concentrically through the atrial myocardium, eventually reaching the atrioventricular (AV) node, which lies just beneath the right atrial endocardium,anterior to the ostium of the coronary sinus. 3. In the AV node, the impulse is conducted very slowly, delaying the impulse and allowing atrial contraction to be completed before ventricular depolarization and ventricular contraction begin. a. The AV node has a rich supply of sympathetic and parasympathetic fibers. b. Parasympatheticstimulation slows AV conduction and prolongs AV nodal refractoriness,while sympathetic stimulation speedsAV conduction and shortensrefractoriness. 4. From the AV node, the depolarizing impulse enters the His bundle, where conduction becomesrapid again. 5. The His bundle penetratesthe interatrial septum, and after approximately I cm it divides into a right bundle branch (RBB) and a left bundle branch (tBB), which also conduct rapidly. a. The RBB is a relatively thin bundle that travels along the endocardial surface of the right side of the interventricular septum. b. The LBB is a thicker bundle that travelsalong the endocardialsurfaceof the left side of the interventricular septum. After approximately I to 2 cm, the LBB divides into a thin left anterior division and a broad left posterior division. 6. The RBB and the divisions of the LBB arborize into a fine network of Purkinje fibers, which also conduct rapidly. The Purkinje fibers penetrate the ventricular myocardium and function to depolarize the ventricular muscle cells. 7- The term His-Purkinje system or ventricular conduction system is used to describethe His bundle, bundle branches,and Purkinje fibers together. It consistsprimarily of rapidly conducting cells called Purkinje cells.

In a Nutshell NormalCardiac Conduction -+ -> SAnode atrialmuscle AVnode+ Hisbundle and bundle branches + Purkinje fibers + ventricular muscle

B. Electrophysiologic categories of cardiac cells 1. Cardiac cellscan be divided into two electrophysiologiccategories: a. Fast fibers: atrial and ventricular muscle cells,Purkinje cellsof the His-Purkinje system b. Slow fibers: SA node, AV node 2. Fast fiber versus slow fiber terminology is based primarily on the velocity at which the electricalimpulse is conducted. C. Basic cellular electrophysiology 1. The phospholipid bilayer of the myocardial cell membrane, particularly its hydrophobic core' servesasan insulator that allows the cell to maintain a potential differencebetweenits interior and its exterior. This potential differenceis generatedby:

t2

Physiology

a. Net movement of ions (i.e., electrical current) across the cell membrane through transmembrane protein "openings" in the phospholipid bilayer, called channels. Channelsare usually selectivefor a specific ion (Na*, K*, Ca2*,or Cl-) and are controlled by protein gates,whose conformation (open or closed) may depend on the potential difference acrossthe cell membrane. b. Exchange of ions along their concentration gradients via protein transmembrane transport systems c. Active transport of ions against their electrochemical energy gradients by special transmembranepumps, which may be electrogenic(i.e., effect net chargemovement acrossthe membrane) 2. Adjacent myocardial cells are connectedend-to-end by a thickened portion of the cell membrane, called the intercalated disk. The nexus, or gap junction, is a region in the intercalated disk that provides a low-resistanceelectrical connection and allows movement of ions betweenadjacentcells. D. Resting membrane potential (RMP). The RMP is -90 mV in fast fibers (atrial and ventricular musclecells,Purkinje cells)and {0 to-7O mV in slowfibers (SA node,AV node), with the inside of the cell being negativewith respectto the outside. 1. Two characteristicsof resting cardiaccellsare important for establishingthe RMP: a. Differences in composition between the extracellular fluid (ECF; often abbreviated as o = outside) and intracellular fluid (ICF; often abbreviatedas i = inside): most importantly [K*], >> [Kn]. and [Na+]">> [Na*J,. b. The selectivepermeability of the cell membrane: most importantly, the K+ permeability (P") >> Na* permeability (P*"). 2. Given thesetwo characteristics,the RMP originatesas follows: a. Due to the high P*, K+ movesfrom ICF to ECF along its concentrationgradient,leaving an excessof anions (many of which are too large to diffirse out of the cell along with K+) in the ICF and creating a negative transmembrane potential (TMP). This negativeTMP tends to slow the further efflux of K+. b. If the cell were permeable only to K+, an equilibriurn would be establishedin which the negative TMP created by K* efflux would exactly balance the tendency of K+ to leavethe cell along its concentration gradient. The negativeTMP at equilibrium would then equal the K+ equilibrium potential (V*), as calculated by the Nernst equation for K+: V r = 6 1 .5l o g ([K+ ]./[K + ],)mV c. However, due to the small P*u,Na+ moves from ECF to ICF along its concentration and electrical gradients,making the actud RMP lessnegativethan V* and allowing for a continued small K+ efflux. Thus, at the RMR there is a small outward K+ current balancedby a small inward Na+ current. d. Slow fibers have a somewhat greater PN"/PKratio than fast fibers and therefore a less negativeRMP. 3. The RMP can be changedby: a. Changes in the K+ concentration gradient. For example, a decrease in the K+ concentration gradient decreasesthe tendency of K+ to leavethe cell along its concentration gradient, resulting in a less negative RMP. (1) Hyperkalemia (increased[K"].) reducesthe magnitude of the gradient.

,,

System Cardiovascular

(2) Myocardial injury or ischemia can result in a local decreasein the magnitude of the gradient. b. Changes in the ionic permeabilities. For example, an increase in K" permeability increasesthe tendencyof K* to leavethe cell along its concentration gradient, resulting in a more negative RMP. Acerylcholine hyperpolarizes cardiac cells by this mechanism. E. Cardiac action potentials (APs). When a resting cardiac cell is depolarized to a certain critical potential, the threshold potential, an AP is initiated. The APs in fast fibers (fast responseAPs) differ from the APs in slow fibers (slow responseAPs) (Fig:ureI-4-2, Thble

r_4_1):

20 0 o -20 = o -40 = -60 -80 -100

20 0 a -20 = o -40 = -60 -80 -100 0,1 0.2 Seconds

0.3

0.1 0.2 Seconds

0.3

Figurel-4-2.Fastresponseand slow responsecardiacactionpotentials.

Thble I-4-f . Comparison of fast and slow response cardiac action potentials. Parameter

Fast ResponseAP

Slow ResponseAP

Resting membrane potential (RMP)

-90 mV

-60 to -70 mV

Threshold potential

-60 to -70mv

-30 to -40mV

Rapid inward Na+ current 100-130mV 200-1,000mV/sec

Slow inward Ca2+ current 35-75 mY 1-10 mV/sec

0.3-3.0 m/sec

0.01-0.10m/sec

Phase0 Primary current Amplitude Slope Conduction velocity

1. Fast responseAPs. The fast responseAP can be divided into four phases(Figure l-4-3, Table I-4-2), which are causedby passiveion fluxes along their establishedchemical and electrical gradients,primarily through ion-specific channels. The rapid, spike-like depolarization (phase0) is followed by a gradual repolarization (phasesf to 3) back to the RMP (which is commonly referredto asphase4).

,4

Physiology

?able l-4-2. The phasesof the fast response action potential. Phase

Description

0

Rapid depolarization,which determinesconduction velocity of action potential

1

Early repolarization

2

Plateau

3

Late repolarization

4

Resting potential

Nrc'hcLcx

{< c[tex '*[trl,r Ca

K "llt'.^

g E

Figure l-4-3. Conductances of Na+,Ca2*,and K+ during the phases of the fast response action potential.

a. Phase 0 is causedby an increasein Na* permeability, or conductance,resulting in a Na* influx that depolarizes the cell to = +20 mV. This increasein Na* permeability can be attributed to the activation of the voltage-gatedNa* channels, which are rapidly activated when the fast fiber is suddenly depolarized to its threshold potential. The Na* influx is termed the rapid inward Na* current. (1) The Na* channelscan be blocked pharmacologicallyby the classI antiarrhythmic drugs, such as procainamide, quinidine, and lidocaine. (2) The Na* channelsare inactivated if the RMP becomesless negative (e.g.,due to hyperkalemia, myocardial injury or ischemia) or if the fast fiber is gradually (rather than suddenly) depolarized to its threshold potential. b. Phase l, the initial repolarization phase,is especiallyprominent in Purkinje fibers. It is causedby the termination of the rapid inward Na* current, due to inactivation of the Na* channels (thus, the phase0 depolarization approaches,but never reaches,the Na+ equilibrium potential of +40 mV), a transient efflux of K+, and possibly a transient influx of Cl-.

Bridgeto Pharmacology These drugsarereviewed in detailin theCardiovascular Pharmacology chapter.

55

Cardiovascular System

Note Inatrial andventricular phase muscle, 2 Caz* isresponsible fortriggering therelease of largeramounts of Ca2*from reticulum thesarcoplasmic (Ca2*-induced Ca2*release).

c. Phase2,the plateau, is the longest phaseof the AP and is characterizedby an increase in Ca2*permeability, resulting in a Caz+influx. This influx of Ca2ndoes not causethe transmembrane potential to become more positive becausethe K* permeability, which decreasedduring phase0, is sufficiently large to allow K* efflux. This increasein Ca2* permeability can be attributed to the activation of the voltage-gated L-type 662* channels, which are slowly activated when the fast fiber is depolarized to a transmembrane potential of = -60 to -70 mV (i.e., the activation of the Ca2+channels actually begins during phase 0, but since the activation is slow, the Ca2+influx is delayed).The Ca2*influx during phase2 is termed the slow inward Ca2*current. (1) The Ca2* channels can be blocked pharmacologically by the Ca2* channel blockers, such asverapamil and diltiazem. (2) Caz*influx through the Ca2*channels is increasedby sympathetic stimulation (B, receptors)and inhibited by parasympatheticstimulation (M, receptors). (3) The phase2 Caz*influx is responsiblefor triggering the releaseof larger amounts of Ca2*from the SR (Cah-induced Cah release). d. Phase3, the final repolarization phase,is causedby the termination of the slow inward Ca2*current, due to the inactivation of the Ca2*channels,and an increasedK* efflux, due to the return of K* permeability to its high resting value. At the end of phase 3, the potential returns to the RMP (i.e., the hyperpolarization seen at the end of the nerve AP is not observed). The phase 3 slope is an important determinant of the action potential duration (APD), i.e., the width of the AP (phases0 through 3). (1) The typical APD in cardiaccellsis 200 to 300 msec,markedly longer than the I to 2 msecAPD observedin nerve and skeletalmuscle. (2) Purkinie fibers havethe longestAPDs, while atrial muscle fibers havethe shortestAPDs. (3) The APD varies with the heart rate: the faster the rate, the shorter the APD. (a) The APD varies with the temperature hypothermia increasesthe APD. 2. Slow responseAPs. The major differencesbetween fast responseAPs and slow response APs are summarized in Thble I-4-1. The most significant differencesinvolve phase 0: a. The phase0 slope and amplitude are reduced in slow fibers. b. Phase0 depolarization is accomplishedby the slow inward Ca2*current (rather than the rapid inward Na* current) in slow fibers. In fact, slow response APs can be observedin fast fibers if the rapid inward Na* current is blocked by inactivating the Na* channels. Such inactivation can be achievedpharmacologically(procainamide, quinidine,lidocaine) or by making the RMP lessnegative(hyperkalemia,myocardial injury or ischemia). The conduction velocity refers to the speed of impulse propagation and is determined by various characteristics of the cell and also by the phase 0 slope and amplitude. 1. A decreasein fiber diameter increasesthe resistanceto current flow and slows conduction. The siow conduction observedin the AV node can be attributed in part to the small diameter of AV nodal cells. 2. A decreasein contractile protein content reduces the resistanceto current flow and speeds conduction. The rapid conduction observed in the Purkinje cells of the HisPurkinje systemcan be attributed in part to a reduced contractile protein content. 3. A decreasein electrical resistance of junctions between adjacent cells speedsconduction. The rapid conduction observedin the Purkinje cells of the His-Purkinje systemcan be attributed in part to their long,low resistancenexus (gap) junctions.

56

Physiology

4. Conduction velocity is directly proportional to the phase 0 slope and amplitude. Thus, conduction velocity in fast fibers is markedly greater than that in slow fibers (Table I-a-l); in fact,the fast fiber-slow fiber terminology wasoriginally developedto emphasize this difference in conduction velocity. G. Excitability refersto the ability of cardiac cellsto respond normally to electrical stimulation. During the AP, cardiaccellsare refractory to excitation,i.e.,they cannot be excitedby electrical stimulation in the normal way. The effective refractory period (ERP) is the interval during which a propagatedAP cannot be elicited, no matter how strong the depolarizing stimulus.The relative refractoryperiod (RRP) is the interval during which a propagatedAP may be elicited,but only if the depolarizingstimulus is strongerthan is neededto initiate an AP when the excitability is normal (Figure I-4-4).

In a Nubhell Conduction Velocities > Purkinje fibers> ventricles AVnode

1. In fast fibers, the ERP starts at the beginning of phase0 and typically lastsuntil repolarization reachesa transmembranepotential of = -50 mV. The RRP startsat the end of the ERP and typically lastsuntil the end of phase3. As repolarizationproceedsduring phase 3, increasingnumbers of Na* channelshaverecoveredand are readyto be reactivatedby the next stimulus. Thus, the later the cell is stimulated in the RRP,the greaterthe phase0 slope and amplitude, and hence conduction velocity, of the resulting AP. Conduction velocity is constantand maximal once the cell is completelyrepolarized.

Fast response

40

Slow response 2

0 I

E*o =

-80 -'120 ttl

0 A

100 200 300 Time(msec)

0 B

100 200 Time (msec)

Figure l-4-4. Refractory periods in fast and slow fibers. (ERP = effectiverefractoryperiod;RRP = relativerefractoryperiod.)

2. ln slowfibers, the ERPis much longer than in fast fibers and typically extendsbeyond phase 3, i.e.,evenwhen the slow fiber is completelyrepolarized,it may not be ableto respondnormally to electrical stimulation. Thus, the RRP extendsinto phase4. Theselong refractory periods account for the increasedlikelihood of conduction blocks in slow fibers (e.g.,the AV node). H. Automaticity refers to the ability of some cardiac cells to automatically depolarize toward thresholdduring phase4. Suchcellsdo not exhibit a constantRMR but insteaddisplaygradual phase4 depolarization (Figure I-4-5). 1. Automaticity normally occurs in the cells of the SA node, AV node, and His-Purkinje system. The mechanism for automaticity involvesa gradual increasein Na* influx during phasea (the pacemakercurrent), due to the activation of a specialpopulation of Na* channels;in the SA node and AV node, a gradual increasein Ca2*influx and a gradual decreasein K* eflux are important.

Note Automaticity isdefined asa gradual depolarization phase during 4.

17

Cardiovascular System

In a Nutshell Pacemaker Cells . SAnode . AVnode . Purkinje fibers > rate AV SA rate> Purkinje rate

2. If phase4 depolarization is not interrupted before the threshold is reached,an AP will be initiated spontaneously. Thus, cells that possessautomaticity can function as pacemakers, i.e.,sourcesof APs that can propagatethrough the remaining myocardialtissue. Normally, the SA node is the dominant pacemaker becauseit depolarizes more rapidly and becauseof what is known as overdrive suppression, the slowing of other pacemakers roughly in proportion to the duration and rate of stimulation of the dominant pacemaker (e.g.,the fasterthe SA node dischargerate, the slower the rate of the AV node and His-Purkinje system pacemakers).Clinically, the use of percutaneouspacemakersto terminate arrhythmias takesadvantageof overdrive suppression. 3. The pacemaker firing rate, and therefore the heart rate, is determined by: a. The rate of phase4 depolarization,i.e.,the phase4 slope. (1) Sympathetic stimulatiot (F, receptors) and fever increasethe phase 4 slope, thereby increasingthe heart rate (Figure I-4-5). (2) Parasympatheticstimulation (M, receptors)and hypothermia decreasethe phase 4 slope,there\ decreasingthe heart rate (Figure I-4-5). b. The threshold potential c. The transmembrane potential at the start of phase4 (maximum diastolic potential). Parasympatheticstimulation causeshyperpolarization of the cell membrane, i.e., a more negative maximum diastolic potential, which contributes to its abiliry to decreasethe heart rate (Figure I-4-5).

mV

t

Sympathetic stimulation

mV

Figure l-4-5. Automaticity in SA nodal cells, illustrating the effect of sympathetic and parasympatheticstimulation on heart rate.

MYOCARDIAL CONTRACTION Note T tubules facilitate action potential transmission intotheinterior ofthefiber. Theyarewelldeveloped intheventricles.

58

A. Mechanism of excitation-contraction coupling. As in skeletal muscle, Ca2+ions mediate myocardial excitation-contraction coupling. 1. During phase 2 of the action potential, Ca2nions enter the cell through voltage-gated L-type Ca2*channels (slow inward Ca2*current). At the Z line of each sarcomere,the sarcolemma invaginates to form the system of T tubules, thus ensuring that the action potential spreadsinto the interior of the myocardial fiber. 2. Although the Ca2*ions that enter the cell during phase2 are not sufficient to activatethe contractile mechanism of the myocardial cell, their entry causesthe releaseof a much

Physiology

larger number of Ca2*ions from the sarcoplasmic reticulum (SR), an intracellular Ca2* storage reservoir that consists of a network of anastomosingtubular structures surrounding each myofibril. This Ca2*-induced Ca2*release provides a sufficient amount of Ca2*to initiate contraction. a. Sac-like cisternae, or lateral sacs,of the SR are found adjacent to the T tubules and surfacesarcolemma. b. The Ca2*ions entering during phase2 releaseCa2*from the SR by binding to Ca2+ releasechannels (also known as ryanodine receptors) on the cisternaeof the SR. 3. The amount of Caznreleasedfrom the SR, and hence the number of activatedcontractile sites and the force generatedby the contraction, is determined by the amount of extracellular Ca2*entering the cell during phase2, the time that has elapsedsincethe previous action potential (which, in turn, determineswhether the Ca2*releasechannelshave recovered their ability to respond to Ca2*),and the sizeof the SR Ca2*stores. 4. The amount of extracellular Ca2nentering the cell during phase2 is directly proportional to the: a. ExtracellularCa2*concentration b. Number of open Ca2*channels c. Duration of the action potential d. Number of action potentials 5. Sympathetic stimulation (p, receptors) and p-receptor agonists increasethe force of myocardial contraction by increasingthe probability that a given Ca2*channel is open, thereby increasing Ca2*influx. B. Mechanism of myocardial contraction I. Caz*binds to troponin C, causing the troponin complex to undergo a conformational change,which in turn causestropomyosin to move deeperinto the groove betweenthe two actin strandsof the thin filament. 2. The movement of tropomyosin into the grooveuncoversthe myosin binding siteson the actin strands, allowing the myosin headsto bind to the thin filament. 3. The myosin headundergoesa changein shape,which causesthe myosin head to move the thin filament (power stroke),thereby shorteningthe sarcomere. C. Mechanism of myocardial relaxation 1. The influx of extracellularCa2*stopsat the end of phase2 of the action potential. reducing the intracellular Ca2*con2. The SR actively accumulatesCa2*via a Ca2*-ATPase, centration and removing Ca2*from troponin. 3. The regulatory proteins troponin and tropomyosin now assume their inhibitory conformation, preventing cross-bridging between actin and myosin and resulting in myocardial relaxation. D. Differences between cardiac and skeletal muscle contraction 1. Prolongedtetanic contraction, possiblein skeletalmuscle,cannot occur in the myocardium, becausethe efifectiverefractory period of the myocardial fiber extendsbeyond phase 2 of the action potential; thus, relaxation is part of the contractile rycle triggeredby each action potential.

T9

Cardiovascular System

In a Nutshell . Skeletal muscle: changes in contractile forcearedueto changes inthenumber of fibersactivated . Cardiac muscle: changes in forcearedueto contractile inconFactility changes offiben

2. Forceofcontraction a. In skeletalmuscle, each activated fiber generatesa maximum force and any variation in the total force generatedby the skeletalmuscle is therefore due to changesin the number of fibers activated. b. In cardiacmuscle,all fibers are activatedwith eachcontraction; any variation in the force of contraction is therefore due to changesin the contractile properties,or contractility, of the individual fibers rather than to changesin the number of fibers activated.

THECARDIAC CYCTE The concurrent electricaland mechanicaleventsoccurring during the cardiacrycle are shown in Figure l-4-6 (the Wiggers diagram). In the following description of the cardiac rycle, the eventson the left side of the heart will be emphasized. A. Atrial systole ( 150 milliseconds). The atria contract,accomplishingthe final = 20o/oof ventricular filling (atrial kick) (Figure l-4-7). 1. On the ECG, the P wave (atrial depolarization) startsjust before the beginning of atrial systole,triggering atrial muscle contraction. 2. Left atrial pressure increasesasthe left atrium contracts,causingthe a wave. 3. Left ventricular pressure increases,paralleling the a wave,but remains below left atrial pressure. Thus, the pressuregradient for ventricular filling is maintained. The left ventricular pressureat the end of atrial systolerepresentsthe left ventricular end-diastolic pressure. 4. Leftventricular volume increases= 20o/oto its maximum value during the cardiac rycle (= 120 ml), the end-fiastolic volume. Left atrial volume falls. 5. The fourth heart sound (Sn)occurs during atrial systole,but typically is audible only in pathologicalconditions that result in a more forceful atrial systole(e.9.,a reduction in left ventricular compliancedue to hypertrophy or infarction).

40

Physiology

lso. Filling Atrial lso. Ejection systole Vol. Rapid RedrcecVol, Rapid Reduced Col RIX R ,B\

Q

---_r{

120

b

6;100

I

,

I

I

E g80 E = o

ECG

-....E

- Left ventr'icular presriure

Aortic pressure

$60

(L

40

Atrial p ressure I

" t , " I" f ' f

20

8 4oo-J-

c-' . . X

a

500-1

t t

o

a

i

\-V a

! zoo-lP 1oo f roo-J€ 80 sJ

l \

^.'(

Mitral Aortic Tricuspid PulmonaryI

1t

,,i,

lntri,:ularoutflow

f-:\

l_ 4th

i4,

\I

. a ' \

E soo-l€rzo

\ t

(

Ar Jtr

2nd I

Left ventricular volume Atrial volume

'\--

Heart sounds

3rd

E Open valves I Closed valves

I 0 . 1 5 0.06 0 . 1 1 0 . 1 7 ).0t 0 . 1 1

0.20

Time (sec) Figure l-4-6. Concurrent electrical and mechanical events during the cardiac cycle.

4l

Cardiovascular System

Figure l-4-7. Atrial systole. B. Ventricular systole(300 milliseconds). The contraction of the ventriclescanbe divided into threephases: 1. Isovolumetric contraction (50 milliseconds).The left ventricle contracts at a constant volume,sinceboth the mitral and aortic valvesare closed(FigureI-4-S).

Figure l-4-8. lsovolumetric contraction. On the ECG, the QRS complex (ventricular depolarization) starts just before the beginning of isovolumetric contraction, triggering ventricular muscle contraction. b. Left ventricular pressure rises above the left atrial pressure,closing the mitral valve; in fact, mitral valve closure defines the beginning of isovolumetric contraction. Left ventricular pressurecontinuesto rise at an increasinglyrapid rate until aortic pressure is reached. Note that mitral valve closure occurs very shortly before tricuspid valve closure. c . Left atrial pressure increasestransientlydue to the bulging of the mitral valveinto the

left atrium at the beginning of isovolumetric contraction, causingthe c wave.

42

Physiology

d. teft ventricular volume remains constant at its maximum value (end-diastolic volume); isovolumetric contraction causesonly a shape change and a rise in left ventricular pressure.

I

L .

r.i+

. . t t t

e. The first heart sound (S,) coincideswith AV valve closure (mitral, then tricuspid). S, is the loudest and longestheart sound and can continue into early ejection. 2. Rapidventricular ejection (100 milliseconds). The aortic valve is open and most of ejection occurs (Figure I-4-9).

('z

-- t

Figure l-4-9. Rapid ventricular ejection. a. Left ventricular pressure rises above the aortic pressure,opening the aortic valve; in fact, aortic valve opening defines the beginning of ventricular ejection. Left ventricular pressurecontinuesto rise at a slower rate until maximum left ventricular pressure(= 120 mm Hg) is reached. Note that aortic valve opening occurs after pulmonic valveopening; thus, isovolumetric contraction is longer in the left ventricle.

. r-P

b. t€ft ventricular pressure decreasesrapidly, then more slowly. c. Aortic pressure risesrapidly, sincethe rapid ejection of blood into the aorta exceeds the drainageof blood into the peripheral arteries.

.

ft.>(t

''

g-

f-,i,..r'

a .,'

d. Left atrial volume begins to increaseas the left atrium is refilled by the pulmonary veins whiie the mitral vaive is closed,causingthe v wave.

--y

tso '-

':r , r_

['r/-'

Jft

'.-' ,-

'tt,

e. On the ECG, the isoelectricST segmentand the beginning of the T wave (ventricular r epolarization) are recorded. 3. Reducedejection (150 milliseconds). Ventricular ejection slows. a. Left ventricular pressure decreasesdue to relaxation of the left ventricular muscle until aortic pressureis reached. b. Left ventricular volume decreasesmore slowly, reaching its minimum value (= 40 ml), the end-systolic volume. c. Aortic pressure decreasesbecausethe drainageof blood into the peripheral arteries exceedsthe ejection of blood into the aorta.

4t

I

System Grdiovascular

d. teft atrial pressure continues to increasedue to continued refilling of the left atrium, increasingthe magnitude of the v wave. e. On the ECG, the end of the T wave is recorded. t 1 ' t . 1 . , ' i i, ' . t ' 1 ( r I

, 5.r'' i 1

I

, !\t

'

(i

L ' ( t J f r r ' r r

I

C. Ventricular diastole (duration dependson heart rate). The relaxation of the ventricles can be divided into four phases. 1. Isovolumetric relaxation (50 milliseconds). The ventricle relaxesat a constant volume, sinceboth the mitral and aortic valvesare closed(Figure I-4-10).

Figure l-4-10. lsovolumetric relaxation.

a. Ieft ventricular pressure falls below aortic pressure,resulting in closure of the aortic valve; in fact, aortic valve closure defines the beginning of isovolumetric relaxation. Left ventricular pressurecontinues to fall, due to the continued relaxation of the left ventricular muscle. Note that aortic valve closure precedespulmonic valve closure; thus, ventricular ejection is longer in the right ventricle. b. I€ft ventricular volume remains constant at its minimum value (end-systolicvolume). c. Aortic pressure shows a dip, the incisura, when the aortic valve closes,followed by a small pressureincrease. This is due to a short period of backward flow of blood immediately prior to aortic valve closure that is interrupted by the closure. d. Left atrial pressure continues to increasedue to continued refilling of the left atrium, reaching its maximum value, the peak of the v wave, at the end of this phase. e. The secondheart sound (Sr) coincideswith semilunar valve closure.Two S, sounds can be heard: aortic valve closure(4) followed by pulmonic valve closure(Pr). f. On the ECG, the beginning of the isoelectricTP segment is recorded.

2. Rapid ventricular filling (100 milliseconds).The mitral valve is open and most (= 80o/o) of ventricular filling occurs (Figure I-4-11).

u

Physiology

Figure l-4-11. Rapid ventricularfilling.

a. I,eft ventricular pressure falls below left atrial pressure,opening the mitral valve; in fact, mitrd valve opening definesthe beginning of ventricular filling. Left ventricular pressurecontinues to fall in parallel with left atrial pressure. b. I^eft ventricular volume increasesrapidly as the left ventricle fills. c. Ieft atrial pressure starts at the peak of the v wave,then falls as blood flows into the left ventricle (the y descent). Left atrial pressureremains above left ventricular pressure,maintaining a pressuregradient for ventricular filling. d. Aortic pressure decreasesslowly due to the drainage of blood into the peripleural arteries. e. The third heart sound (Sr) coincideswith rapid ventricular fillitg. S, can be a normal finding in children and young adults,but in adults over 30 to 35 yearsof age,it usually is audible only in pathologic conditions. f. On the ECG, the isoelectricTP segment is recorded. 3. Diastasis (duration dependson heart rate) is the period of slow ventricular filling.

In a Nutshell

a. Left ventricular pressure and left ventricular volume slowly increase,due to the slow filling. b. Left atrial pressure slowly increases,due to continued left atrial filling from the pulmonary veins. c. Aortic pressure decreasesslowly, due to the continued drainage of blood into the peripheral arteries. d. On the ECG, the end of the isoelectricTP segment is recorded. 4. Atrial systole. The rycle begins again.

Left MiFal Aortic \ftnthhr Vahe Valve Volume bo,ofum€fic closed closed <+ contaction Ejection

closed oPen

.,

lsorclume0ic closed closed <+ relaxation Venbicular open closed T filling

D. Normal pressures. Thble l-4-3 shows the normal pressuresin the right and left sidesof the heart.

45

Physiology

C. Third heart sound (Sr) 1. 53, or the ventricular gallop sound, is synchronous with rapid ventricular filling. S, *r,epresents vibiations of the left ventricular structures and bloildrnaiis as the iapid fiflow of blood is limited to the left ventricular diastolic expansion. 2. S, is a normal finding in children and young.adults.In 3{ults over 30 to 35 yearsof age, the presenceof an S, usually reflects significant global ventricular dysfunction and is frequently associatedwith ventricular dilatation and increa-sedleft ventricular end-diastolic volume and pressure. 3. S, may also be a sign of diastolic volume overload without significant abnormalities of systolic ventricular function. S, can, therefore, be present in mitral regurgitation, severe aneTrar or jhyrotoxicosis. D. Fourth heart sound (Sn) 1. 54,or the atrial gallop sound, is synchronouswith atrial systole. Sinceatrial contraction is requiied to generateSn,it is never heard in atrial fibrillation. 2. Sufrequently occurs in conditions associatedwith decreasedleft ventricular compliance, or i4-c1e_ased stiffness,such as systemichlryertension,aortic stenosis,idiopathic hypertrophic subaortic stenosis,acut6myocardialischemiaor infarction.

ClinicalCorrelate S,andSoarelow-frequency sounds andarebestheard withthebellof the placed stethoscope atthe leftventricular apexwiththe patient in theleftlateral position. decubitus

MURMURS A murmur is a sound associatedwith turbulent flow. Murmurs can occur when an excessof blood flows through a normal-sizedvalve(high output), when a normal amount of blood flows through a small or stenotic valve,or when blood leaksbackrvardsthrough a regurgitant (incompetent) valve.Sometimesthey occur when blood flows through an inappropriate opening,asin septaldefects. A. Systolic murmurs can be divided into two categories:ejection murmurs and pansystolic (or holosystolic) murmurs. The intensity of systolic murmurs varies with respiration. Murmurs originating on the right side of the heart generally increasewith inspiration and those from the left side decreasewith inspiration becauseinspiration increasesvenous return. 1. An ejection murmur startsafter S,,crescendosto reacha peak in early or middle systole, and tapeTsto a closebefore Sr.

Bridgeto Pathology Valvular disease isdiscussed indetailintheCardiovascular Pathology chapter,

a. Ejection murmurs originate from the outflow tracts of the right and left ventricles. They can usually be well heard in the neck. b. Conditions usually associatedwith systolicejection murmurs are: (1) Valvular aortic stenosis (2) Idiopathic hypertrophic subaortic stenosis (3) Pulmonic stenosis (4) Atrial septaldefect c. The term functional or flow murmur is used to describe an ejection_murmur produced by increasedejection velocity acrossa normal aortic or pulmonic valve in various pathologically or physiologically altered states.This type of a murmur can be heard in -fevet anemia, during exercise,pregnancy,or in conditions in which stroke volume d itrge ie.g., bradycardiu,.o-plete heart block, aortic regurgitation).

47

Grdiovascular System

In a Nubhell . Systolic ejectionmurmurs - Aorticstenosis - Pulmonic stenosis - ASD . Pansystolic murmurs - Mitralregurgitation - Tricuspid regurgitation

-ry

. Diastolic murmurs - Aortic regurgitation - Pulmonic regurgitation - flitralstenosig - Tricuspid stenosis

2. A pansystolic murmur starts with S, and continues on through Sr.It is a longer -ur-u, and frequently obscuiesS, and Sr.The prominent gap betweenthe murmur and S, heard with ejection murmurs is not present. Conditions usually associatedwith pansystolic murmurs are: a. Mitral regurg{4ti_on b. Tiicuspid regurgitation c. Ventricular septaldefect (some of the loudest murmurs encountered) B. Diastolic murmurs also can be divided into two categories: regurgitant murmurs of aortic and pulmonic regurgitation and ventricular filling murmurs. 1. In aortic regurgitation, the murmur starts in early diastole,usually immediately after Sr. This murmur is typically_blowing,decrescendo,high-pitched, and pandiastolic and is best heard at the upper right sternal border with the patient leaning forward at full expiration 2. ln mitrd stenosis, the murmur is loudest when the flow across the mitral valve is maximal: during rapid filling in early diastole and then again during atrial systolein late diastole. It may be p.recededby an audible opening snap of the stiffened mitral valve and -followedby a loud S,.

Note Thecardiac indexisequal to thecardiac output divided bythebody's surface area. It represents cardiac outputnormalized for bod sizeandisuseful in comparing function cardiac of different individuals.

In a Nubhell

' S V =rn ft =EDV-ESV

. EF=ffx roovo (normal= 55-800/o)

(CO) GARD|AC OUTPUT Cardiac output is the volume of blood pumped by either of the ventriclesper minute. Cardiac output usually representsleft ventricular output, but in the absenceof pathologic intracardiac shunts, the outputs of both ventricles are obviously closely matched. The range of normal resting cardiac output is 4-8 liters/min, depending on body size,and it can increasefive or six times during exercise. A. Definitions 1. Stroke volume (SV) representsthe volume of blood pumped by the ventricle per beat. SV can be calculatedby dividing the CO by the heart rate or as the difference between ventricular end-diastolicvolume (EDV) and end-systolicvolume (ESV). In the absenceof pathologic intracardiac shunts and valvular regurgitation, the stroke volumes of both ventricles are closelymatched. If valvular regurgitation is present,the total stroke volumes of the two ventricles may differ greatly. 2. Ejection fraction (EF) representsthe fraction of the blood in the ventricle at the end of diastole that is ejected during systole.EF can be calculatedby dividing the SV by the ventricular EDV and is typicallyerpressedasa percent.The normal resting EF is 55 to 80o/o. a. If valvular regurgitation is present,a distinction must be made between the total, forward, and regurgitant EF: Total EF = forward EF + regurgitant EF b. Note that even when there are no pathologic intracardiac shunts or regurgitant valvular lesions,the EFs of the two ventricles may be different. c. Although EF is affectedby the ventricular preload and afterload, it is the best clinical index of myocardial contractility. B. Measuring cardiac output. The Fick oxFgen rnethod is based on the principle of the conservation of mass. Thus, the total uptake of oxygen by the lungs per minute must equal the product of the pulmonary blood flow per minute and the difference in the oxygen concentrations in pulmonary venous (systemic arterial) and pulmonary arterial (systemic mixed

48

Physiology

venous) blood. If there are no pathologic intracardiac shunts, the pulmonary blood flow equals systemicblood flow, and the Fick method allows the measurement of systemic cardiac output.

t.. "

./ :'

{

1. Since pulmonary venous blood cannot be easily sampled,the orygen concentration of systemic arterial blood is used in the calculation of cardiac output by the Fick method. Pulmonary arterial blood is also difficult to sample,but complete mixing of venous blood is accomplishedonly in the pulmonary artery. 2. Becausebronchial and thebesian(small cardiac) veins drain directly into the left ventricle (the physiologic intracardiac shunt), the orygen concentration of systemicarterial blood is generally 2 to 5o/olower than that of pulmonary venous blood. This results in a small and usually not clinically significant overestimation of the cardiac output. The total error of the Fick method is approximately 10olo.

t:'lf: i

3. The Fick method is most accuratewhen the cardiac output is low and the arteriovenous difference in orygen concentration is high.

DETERMINANTS OFCARDIAC PERFORMANCE The performance of the heart is determined by three factors: preload, afterload, and inotropic state (contractility). A. Preload. A fundamental property of cardiac muscle is that the force of contraction is determined by the initial stretch on the myocardial fibers, or preload. When applied to the whole heart, this relationship between the force of contraction and preload is referred to as the Starling law of the heart and is best illustrated by plotting ventricular peak systolic pressureas a function of ventricular end-diastolic volume (EDV), to give the peak systolic pressure-volume curve (Figure I-4-12).

ln a Nubhell Strengh of contraction isrelated to muscle fiberstretch.

Peak systolic pressure- volumecurue

o l

a o o (L

50 100 150 End-diastolic volume(ml) Figure a-4-1 2. Ventricular pressure-volume curves. 1. Note that the ventricularpeaksystolicpressurerisessharplyuntil the ventricularEDV becomesgreaterthan a certaincriticalvalue,and then plateaus.

49

System Cardiovascular

Note lengh Optimal sarcomere corresponds to optimal overlap ofthickandthin filamen6.

a. Ultrastructurally, the steeply ascendingportion of the peak systolic pressure-volume curve corresponds to increasesin the length of individual sarcomeresuntil the optimal overlap of the thick and thin filaments in the sarcomereis achieved,typically at a sarcomerelength of 2.0 to 2.2 p. b. In the intact heart, the myocardial fibers cannot be stretched much beyond the sarcomere length corresponding to optimal filament overlap, due to the extreme stiffnessof cardiac muscle at longer fiber lengths. This stiffiressis evident in the steep rise of the diastolic (resting) pressure-volume curve at high EDVs (Figure l-4-I2). c. The steeply ascendingportion of the peak systolic pressure-volumecurve can be attributed not only to optimization of the overlapof the thick and thin filaments,but also to an increasedaffinity of troponin C for Ca2+as sarcomerelength increases (length-dependent activation). 2. This "longer is stronger" property of cardiac muscle is important to the function of the intact heart becauseit provides a mechanism for adjusting the force developedduring contraction with the volume filling the ventricle just prior to the contraction (EDV). In effect, the greater the venous return to the heart, the greater the EDV which in turn increasesthe force of contraction, thereby increasing the cardiac output. 3. Becausethe aortic pressureis typically lower than the peak systolicpressurecorresponding to a given left ventricular EDV in normal cardiac contractions the peak systolic pressureis not attained. Instead, as soon as the left ventricular pressureexceedsthe aortic pressure,the aortic valveopensand blood is ejected. Thus, the cardiaccycleforms a loop on the pressure-volumegraph, calledthe PV loop (Figure I-4-13).

Peak systolic pressure- volumecurve

o

= (t, o o (L L

pressure- volumecurve ESV

EDV V ol ume

Figure l-4-13. A typical cardiac cycle illustrated as a PV loop on the pressure-volumegraph. (1 = isovolumetriccontraction; 2 = ventricularejection;3 - isovolumetricrelaxation;4 = ventricularfilling; EDV= end-diastolic volume;ESV = end-systolic volume.)

4 . PV loops can be usedto illustrate how an increasein preload (EDV) resultsin an increase in strokevolume (SV), a manifestationof Starling'slaw of the heart (Figure I-4-I4).

50

Physiology

Peak systolicpressurevolumecurve

Afterload (constant) Diastolicpressurevolumecurue

ESV

EDVI

EDVz

Figure l-4-14. The effect of changing preload (EDV)on SV.

5. The EDV is directly related to the duration of ventricular filling, the pressuregradient betweenthe atrium and the ventricle,the rate of venousreturn, the effectiveness of atrial contraction (the atrial kick), and the integrity of the AV valve. B. Afterload. The force of contraction is determined by the wall tension or pressurethat the ventricle must generateto ejectblood, commonly termed the afterload.The bestindex of left ventricular afterload is left ventricular systolic wall stress,but aortic pressure is a satisfactory index that is more readily measured.

Note lncreased heartratewill decrease diastolic filling timeandtherefore decrease EDVandSV.

1. PV loops can be used to illustrate how a decreasein afterload results in an increasein strokevolume (SV) becauseit is easierto ejectblood if the pressurethat the ventricle must developis reduced(FigureI-4-15).

Afterloadl Afterload2

ln a Nutshell ESV2 ESVI

EDV (constant)

Figure l'4-15. The effect of changing afterload on SV.

2. Mitral regurgitation,patent ductus arteriosus,septaldefects,and arteriovenousfistulaeall representconditions in which the left ventricular afterload is reduced,resulting in an increasedstroke volume. The inverse relationship between afterload and stroke volume provides the rationale for vasodilator therapy in congestiveheart failure.

3 . Systemichypertensionand aortic stenosisrepresentconditions in which the left ventricular afterload is increased.In theseconditions, the left ventricular and diastolic volume generallyincreases,which in many casesallows a normal or near normal stroke volume to be maintained.

. Preload = ventricular end (EDq= 1l0* diastolic volume muchbloodtheheartis receiving fromvenous system; howmuchit needs to pump. preload. Venodilators decrease . Afterload = aorticpressure; affected byhowmucharterial resistance theheartispumpingagainst. Vasodilators decrease afterload. . Stroke volumeisincreased by preload increasing or decreasingafterload.

5l

System Cardiovascular

C. Inotropic state (myocardial contractmat'). Cardiac performance is determined not only by the preload (or EDV) and afterload (or aortic pressure),but alsoby the degreeof activation of the fibers. In skeletal muscle, contractile force is regulated by varying the number of fibers that are completely activated.In cardiac muscle, contractile force is regulatedby varying the degree to which all fibers are activated. The term inotropic state, or myocardial contractility, is used to describe the degree to which the fibers are activated at a given preload and afterload. 1. The peak systolic pressure-volume curve can be used to illustrate the effect of changesin myocardial contractility on cardiac performance. Any agent or condition that shifts this curye upward and to the left (so that the same or greater peak systolic pressurecan now be generated at a smaller preload or EDV) is called a positive inotropic agent. Conversely,any agent or condition that shifts this curve downward and to the right is called a negative inotropic agent. For a given preload (EDV) and afterload, positive inotropic agentswill result in an increasedstrokevolume, while negativeinotropic agents will result in a decreasedstrokevolume (Figure I-4-16).

Peak systolic - volume curve 1 Afterload (constant)

Diastolic pressure- volume curve

ESV2 ESV

EDV(constant)

Figure l-4-16. Effect of changes in inotropic state (myocardial contractility) on the peak systolic pressure-volumecurve and the stroke volume.

2. Mechanisms for changesin inotropic state (contractility) a. Changes in troponin sensitivity to Ca2*.The binding affinity of troponin C for Ca2* can be influenced by mechanismsthat usually involve phosphorylation processes. Changesof this type permit the activation of more actin activesitesat lower intracellular concentrationsof Ca2*as a positive inotropic mechanism;the conversenegative inotropic potential is also present. b. Changesin Ca2*-inducedC,a2*release. A small amount of Caznentersthe myocardial cell during phase2 of the action potential,though not enough to initiate cardiacmusclecontraction. However,this phase2 Caz*influx causesthe releaseof a much larger amount of Ca2*from the sarcoplasmicreticulum (SR). The amount of Ca2*releasedfrom the SR, and hencethe force generatedby the contraction, is determinedby the amount of extracellular Ca2*entering the cell during phase2, the time that haselapsedsincethe previous action potential (which, in turn, determineswhetherthe Ca2*releasechannelshaverecovered their ability to respondto Ca2*),and the sizeof the SR Ca2+stores.

52

Physiology

c. Regulation of the sarcoplasmic reticulum Ca2*AIPase. The Ca2*releasedduring the activation process(and bound to troponin C) is removed from the cytoplasm and returned to storagesitesin the SR by the SR Ca2*ATPase. (1) This ATPaseconsumesapproximately20o/oof the heart's energy,or an amount about equal to that expendeddoing mechanicalwork, i.e.,pumping blood. (2) The rate of Ca2*uptake can be regulated,so that the rate of removal of cytoplasmic Ca2*can be adjusted. (3) This ATPaseis probably concentration-gradientdriven and may automatically operatefasterwhen more Ca2*is releasedfrom the SR. d. Changesin Na*-Ca2*exchange(the Ca2*turret pump). To prevent an increasingaccumulation of Caz*in the cell, the small amount of Ca}*that entersthe fiber during phase 2 of the action potential must be removed from the cytoplasm. This Ca2*removal is accomplishedprimarily by a passiveNa+-Ca2+ exchangemechanism,locatedin the sarcolemma in proximity to the activeNa*-K* ATPase. (1) The Na*-K+ATPasecorrectsthe minor Na* and K* concentration changesarising from the ion fluxesthat occursduring the action potential, by removing Na* from the cell and returning K* to the cell. (2) The Na* gradient createdby the Na*-K* AIPase drives the Na*-Ca2*exhange mechanism, which exchangesthree extracellular Nan ions for one intracellular Ca2*ion, thereby removing the small amount of Ca2*that entersthe cell during phase2 of the action potential. (3) Cardiac glycosides such as digitalis inhibit the Na*-K* AIPase, thereby decreasing the Na* gradient and inhibiting Na+-Ca2+ exchange. The intracellular Caz* concentration therefore rises slightly. 3. Positive inotropy is most commonly relatedto increasedavailabilityof intracellular Cazn. Positiveinotropic agentsinclude: a. Epinephrine, norepinephrine, and other B,-receptor agonists, which increase the probability that a given Ca2*channelis open, resultingin increasedCa2*influx during phase2 of the action potential. b. Increased concentration of extracellular Ca'*,which causesan increasein Ca2*influx during phase2. c. Cardiac glycosides such as digitalis, which inhibit the Na*-K* ATPase.Digitalis causes an increasedconcentration of intracellular Ca2*by reducing the Na* gradient that normally drivesthe passiveNa+-Ca2+ exchangemechanism.

Bridgeto Pharmacology glycosides Thecardiac havea positive inotropic effect.

d. Increasedheart rate, which increasesCaz*influx by increasingthe number of phase 2s per minute 4. Negative inotropy is most commonly relatedto decreasedavailabfity of intracellular Ca2*. Negativeinotropic agentsinclude: a. Ca2*channel blockers, such asverapamil and diltiazem b. Acidosis, which decreasesthe affinity of troponin C for Ca2n c. p,-Receptor antagonists, which decreasethe probability that a given Ca2*channel is open, decreasingCa2*influx d. Myocardial ischemia

55

Grdiovascular System

e. Alcohol f. Decreasedheart rate, which decreasesCa2*influx by decreasingthe number of phase 2s per minute g. Acetylcholine, which decreasesCa2*influx in the atria, but not in the ventricles D. Interactions between cardiac function and vascular function in regulating cardiac performance are best analyzedusing the cardiac ouput-venous return graph, on which the cardiac output curve and the venous return curve are plotted (Figure I-4-17). 1. Cardiac output curyes a. On the pressure-volumegraph (Figure I-4-I2), an index of performance (e.g.,peak systolicpressure)is plotted as a function of an index of filling (e.g.,EDV). Similarly, on the cardiac ouput curve, an index of performance, the cardiac output, is plotted as a function of an index of filling, the right atrial pressure(Figure I-4-l7A). b. Like the peak systolic pressure-volume curve, the cardiac output curve illustrates Starling'slaw of the heart.

21

.F 21

21

18 c

5ru

@ Inotropy,decreased afterload.or increased heart rate

d,lz :J

E

818

3.18 E >15 E

T

E rs o f

en o

Rtz g tt,

be

3 e c

o9 .o

E (UD

= Eo6

o

o

Inotropy,increased afterload, or decreased heart rate

A

024681012 Venousfillingpressure (mmHg)

B

o o

3

.q3 p

(! C)

024681012 Venous filling pre$sure (mm Hg)

C

024681012 Venous filling pressura (mm Hg)

Rr .^f, rat prtgg , Hez.^'!q9le*,irL; 1,^1 p, r i.,.

Figure l-4-17. The cardiac output-venous return graph. (A, cardiac output curve; B, venous return curve; C, interactionof cardiac output and venous return curves)

c. The cardiac output curve is shifted upward and leftward by positive inotropic agents, decreases in afterload,or increasesin heart rate, all of which increasethe cardiacoutput at a given right atrial pressure.Conversely,it is shifted downward and rightward by negative inotropic agents,increasesin afterload, or decreasesin heart rate, all of which decreasethe cardiac output at a given right atrial pressure. 2. Venous return curves a. On the venous return clrrve, the venous return (i.e., the flow of blood returning to the heart from the venous system) is plotted as a function of the right atrial pressure (Figure l-4-178). Note that in contrastto cardiacoutput, venousreturn decreases as venous filling pressure increases. The shape of the venous return curve can be explained as follows:

54

Physiology

(1) x-Intercept. If the heart were stopped,the venous return (and cardiacoutput) would equal zero and the pressurethroughout the entire cardiovascular system would be the same. Hence, the x-intercept, which is equal to the right atrial pressure when venous return = 0, is also equal to this uniform vascularpressure, commonly termed the mean systemic filling pressure (MSFP). The normal MSFP is = 7 mm Hg. (2) Downsloping region. If the heart now starts to pump, it removesblood from the venous system (and adds it to the arterial system), thereby lowering right atrial pressure(and increasingarterial pressure).The harder the heart pumps, the more it lowers the right atrial pressure on the filling side of the heart. A decreasein right atrial pressurefaciliatesvenous return to the heart; the lower the right atrial pressure,the greater the venous return. (3) Plateau. If the heart pumps hard enough, it eventually removesenough blood from the venous system to decreasethe right atrial pressureto zero (compared with atmospheric pressure). At a right atrial pressure of zero, any further increasein pumping tends to collapsethe venae cavae,and there will be no further increasesin venousreturn. b. The venous return curve is shifted upward and rightward by increasesin MSFP and downward and leftward by decreasesin MSFP. The MSFR in turn, is affected by changesin blood volume and vascularsmooth muscletone, commonly referredto as vasomotor tone (Figure I-4-l7B). (1) Blood volume. The MSFP representsthe uniform vascularpressuremeasured when the heart is stopped and therefore is increasedby expanding the blood volume (e.g.,blood transfusion) and decreasedby a loss of blood volume (e.g., hemorrhage). (2) Vasomotor tone. The MSFP is increased if the vesselwalls become stiffer (increasedvasomotor tone) but are filled with the same blood volume. The MSFP is decreasedif the vesselwalls become less stiff (decreasedvasomotor tone) with a constant blood volume. The MSFP is most sensitiveto changesin the stifftressof the veins,i.e., changesin venomotor tone becausethe veins contain = 75o/oof the total blood volume; making the arteries stiffer won't significantly affect the MSFP at a given blood volume. c. The venous return curve is rotated rightward, without changing MSFR by decreasesin vascular resistance and rotated leftward, without changing MSFP, by increasesin vascular resistance. ( 1) Many interventionsthat changevascularresistancealsochangeMSFP.For example, vasoconstrictordrugs generallyincreasevascular resistanceand venomotor tone; therefore,such a drug would causean upward and rightward shift and leftward rotation of the venousreturn curve. (2) A small number of interventions changevascularresistanceonly. For example, increasesin blood viscosityincreasevascularresistancewithout changingMSFP. A large but localized flow obstruction in a large vessel(e.g., a clot or tumor obstructing the vena cava) could increasevascular resistancewith only a negligible effect on MSFP.

3 . Interaction between the cardiac output curve and venous return curve. The cardiac output curve illustrates the relationship between cardiac output and venous fi.lling pressure in a given physiological state. The venous return curve illustrates the relationship between the venous return and venous filling pressure in a given physiologic state.

55

Cardiovascular System

Obviously, in a given physiologic state,the cardiac output must equal the venous return with a single venous filling pressureat steady state; these steady state values for cardiac output, venous return, and venous filling pressureare given by the intersection point of the cardiacoutput and venousreturn curvesfor that physiologicalstate(Figure I-4-l7C).

THEPERIPHERAT CIRCUTATION A. Hemodynamic parameters. Severalparameters are used to characterizethe flow of blood through the different parts of the circulatory system. 1. Blood flow (Q) is the volume of blood that passesa given point in the circulation per unit time (liters/min or mUmin). Blood flow may be laminar (in layeredstreamlines)or turbulent (chaotic). a. Laminar flow. Blood flows in concentric layerswithin the vessel,with the velocity of flow being zero at the vesselwall and maximal along its central axis. Becauseof the zero velocity layer, there is no friction at the vesselwall, only within the molecular structure of the blood. b. Turbulent flow. Blood flows chaotically in the vessel,continuously mixing. Flow tends to become turbulent when blood flows at high velociry passeshighly irregular surfaces,or makes a sharp turn. The tendency toward turbulent flow is expressedby the Reynold's number (RE): RE = vdp/r] where v is the mean velociry d is the tube diameter, p is the fluid densiry and 11is the fluid viscosity. (1) When RE is greaterthan 200, turbulent flow occurs at the branching points of blood vessels. (2) When RE exceeds2000, turbulent flow occurs even in the smooth portions of vessels,where laminar flow would normally occur. (3) The flow is alwaysturbulent in the proximal aorta and pulmonary artery but is almost never turbulent in small vessels. 2. Pressure(P) in the circulation is the force applied by the blood to a unit areaof the walls of the heart and blood vessels.A pressure gradient is required for flow to occur. a. Arterial pressure. In the arterial part of the circulation, blood pressurevaries during the cardiac rycle. ( 1) Systolic pressure is the peak pressureduring the cardiac cycle,occurring early in ventricular systole. (2) Diastolic pressure is the lowest pressure during the cardiac cycle. The arterial pressuredrops throughout ventricular diastoleand reachesits lowest value iust prior to the opening of the aortic valve. (3) PulsePressureis the differencebetweenthe systolicand diastolicpressures. b. Pressure waves are transmitted from the left ventricle to arteries down to the arterioles and capillaries.Pressurewavestravel fasterthan blood itself. The velocity of the pressurewaveincreasesin smaller and stiffer (e.g.,atherosclerotic)vessels. c. Shapeof the pressurecurve is alteredin certain pathologic states(Figure I-4-18). For example, in aortic stenosis,arterial pressurerises more slowly, and the pulse pressure is reduced.The shapeis a function of:

56

Physiology

( 1) Rate of rise of ventricular pressure. The faster the ventricle contracts, the steeper the rise in arterial pressure. (2) Stroke volume. The larger the stroke volume, the larger the increment of arterial volume and the larger and steeperthe rise in arterial pressure. (3) Arterial elasticity. The lesscompliant the arteries,the larger and steeperthe rise in arterial pressure for a given stroke volume; this is one of the reasonsblood pressurerises with age. (a) Blood viscosity. The higher the viscosity of the blood, the more difficult flow becomes,and the higher the pressurerequired to pump a given stroke volume. d. Mean arterial Pressure is the area under the arterial pressure curve for a single cardiac qcle, divided by the duration of the cycle.As long as the heart rate is between 60 and 100 beats/min, the mean arterial pressurecan be accurately approximated by the equation: P = ll3 systolicP + 213diastolic p.

In a ilrfthell = Meanarterial pressure + 2/J dia$olic. l/3 systolic

C',

r

E E

160

g 120 o o

$Bo 120

0.4

0.8

1.2 1.6 Seconds

2.0

2.4

Figure l-4-18. Normal and pathotogic aortic pressure curves. e. Indirect measurement of arterial blood pressure is routinely accomplished by the auscultatory method using a sphygmomanometer, a pneumatic device that allows a controlled occlusion of the underlying artery (usually the brachial artery). f. Direct measurement of arterial blood pressure involves the insertion of a needle or a plastic cannula into a large artery (usually, the radial or femoral artery); this cannula is connected via fluid-filled plastic tubing to an electronic transducer, which converts changesin pressureinto electricalsignalswhosemagnitude is proportional to the blood Pressure. g. fu the distance from the aortic valve increases,the peak systolic pressurein the large arteries becomesgreater,but the mean pressuredeclines becausethe pressureenergy is gradually dissipated by vascular resistance.The mean pressure drops slightly in smaller arteries, and then falls steeply acrossthe arterioles, the major site of vascular resistance.

57

Cardiovascular System

3. Resistance(R) representsthe viscous opposition to the flow of blood. a. Resistancecannot be measured directly, but for a given segment of the circulation, resistanceis defined as the ratio of the mean blood pressure gradient across that segmentto the mean blood flow through it:

Nole

R = AP/Q

A decrease invessel (e.g., diameter via atherosclerosis) can greatly increase resistance.

b. Resistanceis directly proportional to the length of the vesseland inversely proportional to the fourth power of the vesselradius. R = 8rlVnl where 4 is the viscosity of the blood, I is the length of the vessel,and r is the radius. This called Poisenille's law. Although strictly this equation applies only to laminar flow through a rigid blood vessel,it is useful for understanding the factors that affect the resistanceto blood flow. c. Viscositl' (n) is a measure of the resistanceof a fluid to flow. Among other factors (e.g.,temperatureand velocity of blood flow), the viscosityof blood is a function of:

Note ^ n: Q:

AP : e

8ql t t r o, therefore

APtrt{

8nl

Flowisdependent on. . Vessel (direct) diameter . Viscosity (inverse) . Vessel lengh(inverse)

(l) Hematocrit. Hematocrit is the most important determinant of viscosify;when the hematocrit is greaterthan 600lo(e.g.,in primary polycythemia), blood viscosity is more than twice its normal value (2) Concentration of proteins in plasma. For example,when there is marked overproduction of immunoglobulins in multiple myeloma or Waldenstrom's macroglobulinemia,blood viscositymay rise sharply. 4. Velocity (v) of blood flow in each part of the circulation is inversely related to its total cross-sectionalarea: v=Q/A The segmentof the circulation with the largesttotal cross-sectionalareais the capillarybed (2,500 cm'). Therefore, the velocity of blood flow in the capillaries is slower than anywhere elsein circulation, allowing adequatetime for transcapillary exchange. 5. Bernoulli's principle is basedon the observation that the total energy of laminar flow is constant anywherein the vessel.As the diameter and therefore cross-sectionalarea of the vesseldecreases,the velocirf of flow increases.A greater fraction of the fluid's energy therefore becomeskinetic energy,and the amount of energy availableto distend the vessel decreases,causing the transmural distending pressureto fall. B. Venous portion of the circulation. Compared with the arterial part of the circulation, the venous systemis characterizedby much lower pressuresand much higher compliances. The systemicveins return blood to the heart and serve as capacitance vessels,containing up to 75o/oof the systemicblood volume at rest. 1. Venous compliance is under the control of the sympathetic nervous system (cr receptors), with sympatheticstimulation resulting in a prompt increasein venous return. 2. Blood from all of the systemic veins returns to the right atrium. The mean right atrial pressure,also referred to as the central venous pressure, is normally 0 to 3 mm Hg. 3. Pressurein peripheral veins is greatly affectedby gravity, reaching 90 mm Hg in the lower extremities in the upright human. This is not usually a factor in the circulation of blood becausethe hydrostatic pressureadded to the venous blood is also added to the arterial side, and the gradient for circulation is unafifected.However, the venous side is very compliant, and sudden changesin position allow the blood in the peripheral veins to stretch

58

Physiology

the vesselwalls and transiently pool, thereby decreasingvenous return to the heart. Three main mechanismsare involved in maintaining venous blood flow toward the heart: a. Abdominothoracic pump of inspiration. When inspiration occurs, intrathoracic pressuredecreasesand abdominal pressureincreases,favoring the flow of blood from the abdominal vena cavainto the thoracic vena cava,and hence the heart. b. Musclepump of skeletal muscle aaivity. During activiry skeletalmuscle contraction causescompressionof thin-walled veins,preventingbackflow of blood and enhancing venousreturn. c. Venous valves allow venous blood to flow only toward the heart. If the pressureand volume in the venous side are sufficiently elevated,the vesselsmay become so dilated that the valveswill not reach acrossthe functional diameter of the vessels.Suchvenous dilation and valvular incompetencemay occur during prolonged upright posture or when the central venouspressureis elevated(e.g.,in right heart failure). 4. Becauseno valvesseparatethe right atrium from the venae cavae,the right atrial pressure wavescan be seenin the jugular vein, particularly when the right atrial pressures are elevated. a. Prominent cannon jugular venous a waves are present in patients with AV dissociation (e.g.,due to third-degreeAV block), and are causedby the right atrium contracting againsta closedtricuspid valve. b. Prominent v waves are present in patients with tricuspid regurgitation, representing transmitted right ventricular systolic pressures.

Note waves Cannon areseenin (complete) third-degree AVblock.

C. Microcirculation 1. Arterioles branch extensively,each supplying 10 to 100 capillaries. a. Arterioles have a circumferential continuous smooth muscle coat. b. In some tissues,the arterioles give rise to smaller metarterioles, which have smooth muscle fibers encircling them at various points. c. At the junction between an arteriole or metarteriole and capillary, a circumferential band of smooth muscle, the precapillary sphincter, can open or closethe entrance to the capillary, regulating the flow of blood into the capillary. d. The resistanceof arteriolesand metarteriolesaccountsfor approximatelyone-half of the resistanceof the entire systemic circulation; correspondingly, the pressure drop acrossthe arterioles and metarterioles is the largest of any type of vessel,decreasing from = 85 mm Hg at the arterial end to = 30 mm Hg at the capillary end. 2. The capillary wall consists of a single layer of endothelial cells, resting on a thin basement membrane.The capillary endothelialcellscan be: a. Continuous, as in skeletal muscle capillaries, allowing only smaller molecules (e.g., water, electrolytes,glucose) to travel acrossthe capillary wall b. Fenestrated, with perforations piercing the cytoplasm of endothelial cells, as in glomerular capillaries and capillaries of most endocrine organs, allowing larger molecules(e.g.,myoglobin, small peptides)to be transportedpassivelyacrossthe capillary wall c. Discontinuous, with large gaps between endothelial cells, as in hepatic sinusoids, allowing largeproteins (e.g.,albumin) to enter and leavethe capillaries(hepatic sinusoids also are fenestrated)

59

System Cardiovascular

3. Venules a. Postcapillaryvenules have no smooth muscle coat and allow some exchangebetween the blood and surrounding cells. b. Collecting venules have an incomplete muscle coat and drain the capillary system. c. Muscular venules contain a continuous smooth muscle coat and may serveas postcapillary resistancevesselsas well as active capacitancevessels. 4. Regulation of capillary blood flow. Contraction of the smooth muscle in the walls of arterioles and metarterioles can change the diameter of these vesselsand therefore the amount of blood flow to the correspondingcapillary bed. a. Nervous mechanisms. Arterioles are denselyinnervated by the sympathetic nervous system. (1) Stimulation of cr receptors resultsin arteriolar constriction. (2) Stimulation of p, receptors producesarteriolar dilatation. (3) Metarterioles and precapillary sphinctersare sparselyinnervated and therefore are primarily under the control of various local mediators. b. Localmechanisms.Variousfactorsrelatedto local tissuemetabolism (e.g.,phosphate, pH, K*, lactate, and ATP) can produce dilatation of metarterioles and precapillary sphincters,leading to an increasein blood flow through the appropriatecapillary bed. c. Humoral mechanisms. Chemical agents(such as angiotensin,bradykinin, serotonin, histamine,and various prostaglandins)can affect arteriolar smooth muscletone and, in some situations,capillary permeability. 5. Transcapillary exchange. The capillary bed is the site of nutritive exchangebetween the body's tissuesand blood. The capillary wall acts as a semipermeablemembrane, allowing water and small solute molecules to travel passivelyacrossthe capillary wall. a. The net flow of fluid across the capillary wall (Q) is governed by the Starling equation: Q=K[(P.-P,)-1n.-n,)J ( 1) The capillary filtration coefficient (K) is a measureof capillary permeability. (2) The capillary hydrostatic pressure (P.) dependson the hydrostatic pressuresin the feeding arteriole and draining vein and the precapillary and postcapillary resistances. P. is largeston the arteriolar end of the capillary (= 30 mm Hg) and decreases(to = 15 mm Hg) at the venous end. P. tends to drive fluid out of the capillary and into the interstitial space. (3) The interstitid fluidhydrostaticpressure (P,) dependson the stateof hydration (i.e., interstitial fluid volume) and tissue compliance.P, is difficult to measure directly,but its magnitude is thought to be small (= 2 mm Hg). (a) The capillary oncotic pressure (n.) is a function of the concentration of nondiffusible molecules in plasma,especiallyalbumin. n. keepsfluid in the capillary and averages28 mm Hg. (5) The interstitial fluid oncotic pressure (n,) is determined by the interstitial protein concentration.It is of small magnitude (= 5 mm Hg) and draws fluid out of the capillary and into the interstitial space. b. At the arteriolar end of the capillary, the pressuresdriving fluid out of the capillary (primarily P.) are greater than the pressureskeeping it in the capillary, resulting in a

60

Physiology

net outflow of fluid. At the venular end of the capillary P. is much lower and is exceededby the other pressurestending to pull fluid into the capillary (primarily n.), resulting in net inflow of fluid (Figure I-4-19). Net outflow normally exceedsnet inflow, and the excessfluid is returned to the intravascular spaceby the lymphatics.

ln a Nubhell . P,-drives fluidoutof capillaries . P,-drives fluidinto capillaries . n,-pullsfluidintocapillaries . lq-pullsfluidoutof capillaries

Figure l-4-19. Transcapillaryfluid flow. c. Small solutes (e.g.,ions, glucose,urea) are carried with the fluid flowing acrossthe capillary wall (bulk flow). d. Large molecules must be transported acrossthe capillary wall by membrane-bound carriersor by vesiculartransport.

Atthearteriolar end,P. dominates andthereisa net fluidoutflow intothe interstitial space. Atthe venular endofthecapillary, n, dominates andpullsthe fluidbackintothecapillary.

6. Lymphatics a. The lymphatic systemreturns excessfluid and solutesfrom the interstitial spaceto the intravascular space. (1) AX of the lyr,tph from the lower part of the body and from the left side of the head, left arm, and left chest drains into the thoracic duct, which empties into the venous system at the junction between the left internal jugular and subclavianveins.

Bridgeto Heme/Lymph Lymphatic vessels are discussed intheHeme/Lymph Histology chapter of thisbook.

(2) The ly*ph from the right side of the upper body drains into the right ly-ph duct, which empties into the venous system at the junction between the right internal jugular and subclavian veins. b. In any part of the body, ly-ph has the samecomposition asthe correspondinginterstitial fluid. On the average,lyotph contains 2 g protein per 100 ml fluid. Ly-ph protein concentration is higher in the lymphatics draining the gastrointestinaltract. c. The rate of lyotph flow is approximately 120 mUhr, most of it (approximately 100 mUhr) draining into the thoracic duct. Factorsthat increasethe rate of lymph flow are: (1) IncreasedP. (2) Decreasedn. (e.g.,hypoalbuminemia) (3) Increasedcapillary permeabiliry K (4) Increasedn, (5) Muscular activity d. When the net movement of fluid out of the capillaries exceedsthe maximum rate of lymphatic drainage in a particular area of the body, edema develops. D. Coronarycirculation. Under normal physiologic conditions, the contracting heart receives 60 to 90 ml of blood per minute per 100 g of myocardium, or approximately5o/oof the total cardiacoutput.

Bridgeto RenafUrinary Thepathophysiology of edema isdiscussed in detail intheRena[Urinary Physiology chapter ofthis book.

6l

Cardiovascular System

Flashback to Anatomy Youmaywantto takea few minutes to review the anatomy ofthecoronary arteries intheCardiovascular Anatomy chapter.

ln a Nutshell . Mostcoronary bloodflow occurs during diastole. . lncreased heartrate decreases diastole more thansystole andcan compromise coronary bloodflow.

I

l. Regulation of coronary blood flow. The flow through the coronary circulation, as through any vascular bed, dependson the perfusing pressure gradient and the vascular resistance. a. Perfusing pressure gradient. In the coronary circulation, the perfusing pressuregradient is the pressuregradient between the coronary arteries and the coronary sinus. (1) Coronary artery pressure. During systole, the coronary artery pressure is slightly below aortic pressurebecauseof the rapid flow past the coronary ostia (Bernoulli's principle). During diastole, if the aortic valve is competent,aortic diastolic pressureis transmitted into the coronary arteries without significant diminution. In conditions associatedwith decreaseddiastolic blood pressure (e.g.,aortic regurgitation, arteriovenousfistula), coronary blood flow may also be decreased. (2) Coronary sinus pressure. The pressure in the coronary sinus equals the right atrial pressureand varies little during the cardiac cycle relative to the changesin the coronary arterial pressure. b. Coronary vascular resistance (CVR) (1) Variations in CVR during the cardiac cycle. Becauseof high compressiveforces within the myocardium during systole,a large portion of intramyocardial (particularly endocardial) vesselsare collapsed shut, and the systolic CVR is high. Intramyocardial pressuredrops during diastole, allowing intramyocardial vessels to reopen, accounting for the much lower diastolic CVR. Consequently,a large proportion of coronary blood flow (particularly endocardial) occurs during diastole. Thchycardia, in addition to increasing myocardial oxygen demand, decreasesthe duration of diastole more than the duration of systole and may causea decreasein coronary blood flow. (2) Variations in CVR due to local metabolic factors. Severalmetabolic factors may have a role in regulating CVR via their effects on coronary vascular tone. For example, a reduction in intracellular AIP can activate the K^". channels in coronary vascular smooth muscle. The activation of these channels,in turn, resultsin K+ efflux,leading to hyperpolarization,smooth musclerelaxation,and a decreasein CVR. Under ischemic conditions, the nucleoside a@p,osine, a potent coronary vasodilator, may have a role in regulating CVR. The concentration of adenosine,a breakdown product of AIP metabolism, increaseswhen cardiac metabolic activity increases, and the resulting vasodilation (and decreasedCVR) ensuresthat coronary blood flow increasesto support this increasedmetabolic activity. Local metabolic factors also ensurethat changesin regional coronary blood flow resulting from fluctuations in systemicblood pressure are transitory, i.e., they account for the autoregulation of coronary blood flow. Only when the perfusion pressure falls below 50 mm Hg is coronary autoregulation lost, so that coronary blood flow becomespressure-dependent. Local metabolic factors also allow coronary flow to rise as much as four- to fivefold to match increasedmyocardialoxygendemand,e.g.,during exercise.

i' i

(3) Neural effects on CVR. The coronary arteries are richly innervated by the sympathetic nervous system.Stimulation of the coronary sympathetic fibers resultsin receptor-mediated vasoconstriction, but this effect normally is overridden by metabolic factors. Specifically,the increasedheart rate and inotropic statecaused by sympathetic stimulation result in an increasedproduction of vasodilator metabolites,and hence a decreasein CVR.

62

physiofogy (a) Pharmacologic effects on cvR. o-receptor agonists cause coronary vasocon-

:H::f;J'"T'il"'$,ffi

channel Lroir.".r, dipvridamore, andprostacycrin Bridgeto pharmacology .

2. Myocardial oxygen requirements and extraction a' under basalconditions, the contracting heart extractsmore than75o/oofarterial oxygen (arterial oxygen exrraction is only ,sii'irrthe rest of the iody). consequently, when myocardial oxygendemand "bo".rt rises,the h.*t.* increase its arteriar oxygenextracUy only a_smallamount, and most of the in Iol

Because nitrates and calcium-channel blockers cause coronary vasodilation, theyareusedin the treatment of angina.

(ttq Ihas tobematch ediv in.r.*.,i, .o,o,,"ry'lil:: TJIT::t* #fil ffnill vasodilation isnotpo-r-Jut., additionar

;;;;ur., in Mvo, may

tl$t."9tr,o.ffi;,:n

b' under normal' nonischemic conditions, fatry acids are the major myocardial €n€rgy ---r source' accounting for 700/o of myocardial consumption. carbohydrate metabolismvia the Krebs cycre "rr:: accountsfor most of the remaining MVor.

,!

i ^ t

i,

NEURAT CONTROT OFTHECIRCUTATION a' The autonomic nervous system pluy: a major role in controlling the circulation regulating the cardiac output, by vascular resistance,and venous capacitance.Neural

ct'

;:ff:l,T:*J:iil:j|,'ff:,1"Ti'krv ;;; po'",tulv,"l"*i"g rorrapid changes in

1. Role of the sympathetic nervous system a' Preganglionicfibers originate from cell bodiesin the intermediolateral columns in the thoracic and lumb", ,.!ior,, of the ,pirJ.o.d and ild; ;; sympatheticganglia. Postganglionictttu'o"'-innervate effector sites such as the heart and blood vessers. Preganglionic neurons release acetylcholine and- postganglionic neurons almost always releasenorepinephrine (exceptions: acetylcholi.rJ is i.l..r.d by sympathetic postganglionicneuronsin most sweatglandsand some skeletJmuscle blood vessers). b' The adrenalmedulla receives preganglionicsympatheticinnervation and respondsby secretingepinephrine (along with sm-all of norepinephrine) into the tion. circula"-o.r.rt,

t

cr,,G2'andB,receptors. Epinephrine srimutates ITtdtl.t:.li*:.stimulates o,, G, F,,

d' stimuration of the sympathetic nervous systemresurtsin: (1) constriction of skin and splanchnicvesselsvia cx,receptors (2) Dilatation of skeletal musclebrood vessers via B, receptors (3) Venoconstrictionvia clr receptors (4) Increasedheart rate' conduction velocify (particularly in the AV node), and inotropic statevia p, receptors 2. Role of the parasympathetic nervous system a' Parasympatheticoutflow to the heart originates in the dorsal motor vagarnucleus and nucleus ambiguus in the brain stem and is transmitted to the heart via the vagus nerye.

ff:3#H:6':

##'r:rotransmitter

in both preganglionic and postgangrionic

6t

J

Grdiovascular System

b. Stimulation of the vagus results in decreasedheart rate, AV node conduction velocity, and inotropic stateof atrial musclevia M, receptors. B. Baroreceptors are stretch receptorsthat provide afferent impulses to the cardiovascularcenters in the CNS. The baroreceptorsare situated in the carotid sinus and aortic arch (arterial baroreceptors) and in the heart and lungs (cardiopulmonarybaroreceptors). 1. Arterial baroreceptors a. The nerve endings in the arterial baroreceptorsare activated by stretching of the arterial wall secondaryto elevation of arterial pressure. (1) Afferent impulses from the carotid sinus travel in CN IX (glossopharyngeal nerve),while those from the aortic arch travel in CN X (vagusnerve). (2) The rate of firing of arterial baroreceptorsis affectedboth by the magnitude and rate of stretch; i.e., the rate of firing is affected by both the mean arterial pressure and the pulse pressure. b. The function of arterial baroreceptors is to reduce acute fluctuations in blood pressure. Arterial baroreceptorsdischargeat a baselinerate even when blood pressureis normal; the rate of firing varies slightly with normal pulsatile pressure,increasing in systoleand decreasingin diastole. (1) A decreasein systemic arterial pressure producesa decreasein baroreceptor firing, which leadsto an increasein sympathetic tone and a decreasein parasympathetic tone. This results in vasoconstriction and increased heart rate. (2) An increase in systemic arterial pressure stretchesthe arterial wall, resulting in an increasein the rate of baroreceptorfiring, which leadsto a decreasein sympathetic tone and an increasein parasympathetictone. This resultsin vasodilation and decreasedheart rate. The increasein arterial baroreceptor firing is also proportional to the rate of rise of the arterial pressure.

ln a Nutshell Baroreceptor Reflex . JBP+lsympathetic

(3) In normotensivesubjects,maximal arterial baroreceptorfiring occurs when the arterial pressureis = 180mm Hg. Arterial baroreceptorsensitivityis decreasedin exercise,hlpertension, heart failure, and with aging.

J parasympathetic . tBP+Jsympathetic t parasympathetic

2. Cardiopulmonary baroreceptors. The function of the cardiopulmonary baroreceptors is lessunderstood.The atrial receptors, located at the junction of the right atrium and the venae cavaeand of the left atrium and the pulmonary veins, are activatedby atrial filling and contraction.Activation of the atrial receptorsresultsin: a. Increasedheart rate (the Bainbridge reflex) r'

b. Increasedsecretionof atrial natriuretic factor (ANF), a polypeptide hormone that c. Decreasedsecretionof antidiuretic hormone (ADH) (also known asvasopressin),a polypeptide hormone that regulatesurine concentrationby its action on the kidney

ETECTROCARDIOGRAPHY Nole Traditionally, therehave notbeenthatmanyECC questions onStep 1 oftheUSMLE. il

A. Electrocardiography is a technique for studying the electrical potentials generatedby the heart during the cardiacrycle. In contrastto the electricalpotentials discussedearlier in the study of cardiac action potentials, which represent transmembrane potential differences, the electrical potentials studied in electrocardiography represent potential differences between specificpoints on the surfaceof the body. The electrocardiogram (ECG) represents a plot of thesepotential differences(y-axis) as a function of time (x-axis).

Physiology

1. In the absenceof electrical activity within the myocardium (e.g., asystoleor death) or skeletalmuscle (e.g.,absenceof voluntary contractions or shivering),the surfaceof the body is uniformly positive at all points, the potential difference befween any two points is zero, and the ECG records a flat line (isoelectric segment) along its baseline. 2. Once an action potential is generatedand depolarizationspreadsthrough the heart, distribution of electricalchargeon the surfaceof the body is no longer uniform, differences in electricalpotential are generatedbetweendistinct points on the skin, and a deflection is recordedon the ECG tracing. 3. The ECG is recordedon l-mm graph paper,with darker grid lines every 5 mm. a. On the 7-axis, a l-mm deflectioncorrespondsto a voltageof 0.1 mV. b. On the r-axis at a standardrecording speedof 25 mm of recording paper per second, each mm correspondsto a time interval of 0.04 seconds,so that the 5-mm grid lines indicate time intervals of 0.20 seconds. B. Electrocardiographic leads.An ECG consistsof 12leads,each of which recordsthe potential difference along an axis connecting two specific points on the surfaceof the body. Six of these leads record potential differencesalong axesin the frontal plane of the body and six record potential differencesalong axesin the transverse, or horizontal, plane of the body. By convention, a depolarization wave advancing toward the positive end of each axis is recordedas an upward deflection,while a depolarizationwave advancingtoward the negative end of eachaxis is recordedas a downward deflection. 1. The six frontal plane leads,or limb leads, can be subdivided into three bipolar leads (I,II, III) and three unipolar leads (aVR, aVL, aVF). The limb leadsrecord potential differences along the axesillustrated in Figure l- -2},using electrodesattachedto the arms and legs.

Note . Toward (+) endof leadaxis (+) + upstroke . Toward (-) endof leadaxis (-) + downstroke

aVR

1180'

+ +

Figure l-4-20. Orientations and polarities of axes of the limb leads.

a. The bipolar leads I,II, and III measurepotential differencesbetweenthe right arm (RA),left arm (LA), and left leg (LL): (1) Lead I recordsthe potential differencebetweenthe LA and RA and is positive at 0 and negativeat 180 degrees.

65

Cardiovascular System

(2) Lead II records the potential difference between the LL and RA and is positive at +60 and negativeat -120 degrees. (3) Lead III recordsthe potential differencebetweenthe LL and LA and is positive at +I20 and negativeat -60 degrees. b. The unipolar leads aVR, aVI" and aVF measurepotential differencesbetween eachlimb and an electricallyderived zero potential level,correspondingto the centerof the chest. (l) Lead aVR is positiveat -150 and negativeat +30 degrees. (2) Lead aVL is positiveat -30 and negativeat +150 degrees. (3) Lead aVF is positive at +90 and negativeat -90 degrees. 2. The six transverseplane leads,or precordialleads, designatedV, throughVu, record potential differencesalong the axesillustrated in Figwe l-4-21A. The precordial leadsmeasure potential differencesbetween each of six points on the chestwall (Figurel-4-2lB) and an electricallyderived zero potential level,correspondingto the center of the chest.

A

Figure l-4-21. A, orientations and polarities of axes of the precordial leads; B, electrode placement for the precordial leads: (V1: rightfourthintercostal space,V2: left fourth intercostalspace,V3: midway betweenV2 and V4, V4: left fifth intercostalspace at midclavicularline,V5: midwaybetween V4 and V6;V6: leftfifth intercostalspace at midaxillaryline)

C. Complexes and intervals on the ECG. A rypical ECG tracing recorded by one lead is illustrated in Figure l-4-22. Although depolarizationof the SA node initiates overall depolarization of the heart, this initial depolarizationis too small to be detectedby electrodeson the surfaceof the body and thereforeis not recordedon the ECG tracing.

66

Physiology

l)'f

0.2

0.4 Time(sec)

Figure a-4-22.Normal complexes and intervals on the ECG.

1 . The P wave representsthe depolarization of the atria. Normal P wavesare: a. No more than 2.5 mm (small boxes)in amplitude b. Gently rounded in contour c. No more than 0.10 secondsin duration d. Upright in leadsI, II, aVF,and Vn through Vu e. Inverted (negative)in lead aVR

2. The PR segment is measuredbetween the end of the P wave and the beginning of the QRS complex. It reflectsthe depolarization of the AV node, the bundle of His, bundle branches,and Purkinje fibers and is normally isoelectric, as thesedepolarizations are too small to be detectedby electrodeson the surfaceof the body. 3 . The 3&intsr*val is measured from the beginning of the P wave to the beginning of the QRS complex,i.e.,it includesthe P waveplus the PR segment.It reflectsthe time it takes for the depolarizingimpulse to travel from the SA node to the ventricles.The normal PR interval: a. Is 0.12to 0.20 secondsin duration F''\'1

'41

decreases(due to more rapid conduction b. Ygftglgtttt ]regt rate, e.9., the PR interval through aha-Avnode) at faster tates 4. The QRS complex, the most important component of the ECG, representsthe spread of depolarizationthrough the ventricles. a. The deflections in the QRS complex are labeled according to the following rules: (1) If the first deflection is downward (negative),it is a Qwave. (2) The first upward (positive) deflection is an R wave, regardlessof whether it is precededby u Q wave.Subsequentupward deflections are labeled successivelyR', R" , etc. (3) A downward deflection following an R wave is an Swave. Subsequentdownward deflectionsare labeledsuccessively S', S", etc.

67

Cardiovascular System

(4) If the complex consistsonly of a Q wave,it is described as a QS complex. (5) Uppercaseand lowercaseletters are used when labeling relatively large and small deflections, respectively. b. The normal width of the QRS complex, the QRS interval (or QRS duration), is less than 0.10 seconds.A QRS interval of 0.12 secondsor longer is clearly abnormal and can be causedby: ( 1) Marked slowing of action potential conduction through ventricular muscle, e.g., due to severehyperkalemia or quinidine or procainamide toxicity. (2) Asynchrony of ventricular depolarization, so that the ventricles no longer depoIarizr, almost simultaneously, e.g., due to bundle branch block or ectopic beats that originate in the ventricles, such as premature ventricular contractions. c. The normal sequenceof ventricular depolarization is as follows (Figure I-4-23):

S-A node A-V node

Figure 14-23. Normal sequence of ventricular depolarization.

ln a Nutshell Venfricular Depolarization ventricular free .$tuLwalls

68

(1) The interventricular septum depolarizes first, mainly from left to right because the Purkinje fibers that initiate septal depolarization arborlze from the LBB. Becausethe right side of the septum facessomewhat anteriorly as well as rightward, septaldepolarization spreadsin a generallyrightrvard and anterior direction. (2) The ventricular free walls depolarize next, from endocardium to epicardium becausethe bundle branchesrun along the endocardial surfaceof the ventricles. While the ventricular walls are depolarized approximately simultaneously, the left ventricular free wall is so much thicker than the right ventricular free wall that the electricalpotentials generatedby its depolarization almost totally mask the electrical potentials generatedby the depolarization of the right ventricular free wall. Sincethe left ventricular freewall facessomewhatposteriorly well asleftward, its depolarization spreadsin a leftward and posterior direction. "r The electricalpotentials generatedby Ieft ventricular free wall depolarization are normally the largest electrical potentials generated during the cardiac cycle and therefore are very important in determini.g the morphology of the QRS complex.

Physiology

d. The normal sequenceof ventricular depolarization is perhaps most clearly demonstratedby the QRS complexesin leadsV, and Vu. (1) LeadV, recordsa positivedeflectionwhen depolarizationspreadsanteriorly and a negativedeflectionwhen depolarizationspreadsposteriorly. LeadV, therefore will initially record a positive deflection (r wave), becauseseptaldepolarization spreadsanteriorly. Next, it will record a negativedeflection (Swave), becauseleft ventricular free wall depolarizationspreadsposteriorly. (Note that the electrical potentials generated during left ventricular free wall depolarization are larger than those generatedduring septaldepolarization.) (2) LeadVu recordsa positivedeflectionwhen depolarizationspreadsleftward and a negativedeflection when depolarization spreadsrightward. Lead Vu therefore will initially record a negativedeflection (q wave), becauseseptal depolarization spreadsrightward. Next, it will record a positivedeflection (Rwave), becauseleft ventricular free wall depolarization spreadsleftward. (3) Note that the QRS complex is predominantly negativein lead V, and predominantly positive in lead Vu; i.e., a transition from predominantly negativeQRS complexes to predominantly positive QRS complexes normally occurs when moving from right to left acrossthe precordium. Normally, the transition from negativeto positive is recordedin lead V, or Vn. (4) Note that a small r wave is recorded in lead V, and a large R wave is recorded in lead Vr; i.e., a gradual increasein r wave height normally occurs when moving from right to left acrossthe precordium (normal R wave progression). The largestR wave can be recordedin leadV4,Vs, or Vu. e. Mean frontal QRS axis. The electricalpotentials generatedduring ventricular depolarization produce the largestnet QRS amplitude in the ECG lead whose axis is parallel to the path of depolarization and the smallestnet QRS amplitude in the ECG lead whose axis is perpendicular to its path. To estimatethe net QRS amplitude in a particular lead, the magnitudesof the negativedeflectionsin the QRS complex are subtractedfrom the magnitudes of the positive deflections in the QRS complex. The axis of the limb lead that recordsthe largestnet QRS amplitude represents(at leastapproximately) the mean frontal QRS axis. If a limb lead recordsa net QRS amplitude of zero,the mean frontal QRS axis is perpendicular to the axis of that lead. The mean frontal QRS axis normally lies between-30 and +90 degrees. (1) If the mean frontal QRS axis is further leftward (i.e., more negativethan -30 degrees),abnormal lgft34l*deviation is present.Possiblecausesinclude left ventricular trlpe*qtrophy-andconduction tto.t in the anterior fascicle of ihe LBB (left anterior hemiblock). (2) If the mean frontal QRS axis is further rightward (i.e., more positive than +90 degrees),abnormal right axis deviation is present.Possiblecausesincludeljght ventricular-h)rpertrophy, conduction block in the posterior fascicle of the left The Q$S axis is normally bundle (left posterior hemiblock), and dextrocard_ia. hypertrophy of the right relative the because of deviatedto the right in neonates ventrjcle-. 5. The ST segment is measuredfrom the end of the QRScomplex to the beginning of the T wave.

vt

a. The _STsegmgntis normally isoelectric, correspond-ingtp,the part of the cardiac rycle wlrsn all gf1fu ve_ntricglg muscle cells are depolarized (p-!rar_s_e _2of the a,,cJ_io_n_p*oJenpoints on the surfaceof the body any two between _tiqD,so that the potential difference is zero.

69

Cardiovascular System

b. ST segmentelevation or depression can be seenin numerous pathologic conditions, including myocardial infarction and ischemia,ventricular hlpertrophy, bundle branch block, and electrolyteabnormalities. 6. The T wave representsthe electrical recovery,or repolarization, of the ventricles. a. Normal T waves are:

ln a Nutshell . PWqve =depolarization of atria . PRsegment = conduction through AVnodeandthe Purkinje system ' QRS = complex depolarization of ventricles ' Twave= repolarization ofventricles

(1) Upright in leads with QRS complexesthat are predominantly positive, and inverted (negative) in leads with QRS complexesthat are predominantly negative. However, in leads V, and V, the T wave may be upright even if the QRS complexesare predominantly negative. (2) Slightly rounded and slightly asymmetricalin shape. (3) Lessthan 5 mm in height in the limb leadsand lessthan 10 mm in height in the precordial leads. b. Unusually t"q_T waves ("tented T waves") can be seen in myocardij! ischemia, myocardial infarction, hyperkalemia, and cerebrovascularaccidents. c. Inverted (negative) T waves can be seenin numerous pathologic conditions, including ;yocardial infarction and ischemia, ventricular hypertrophy, bundle branch block,ind electrolyteabnormalities. 7. The QT interval is measuredfrom the beginning of the QRS complex to the end of the T wave;f.e.,liincludes the QRS complex,ST segment,and T wave. The QT interval: a. Varies with heart rate, so that a normal range can be specified only for the ratecorrected QT interval (QT.), defined as QT. : QT/VRR, where RR is the RR interval (seebelow). The normal QT. is 0.35 to 0.44 secondfin duration. b. Varieswith ageand sexof the patient c. Is prolongjd in congestiveheart failure (9HFJ, myocardial infarction, and hypocalcemia,and by quinldgre, procainamide,and triry_clicantldepre$a-lJs.Prolongationis co_ngenitalin some paiients, who are then at higEir risk for vCntricular tactiyatrtt@mias and sudden death. d. Is s"hortenedin hypercalcem.raand by digitalis 8. TbU wave is a small deflection that, when present,follows the T wave and has the same orientation as the T wave. Its magnitude is in hypokalemia. increased 9. The RRinterval is the time interval from the beginning of one QRS complex to the beginning of the next QRS complex and representsthe cardiac cycle length. If the RR interval is measuredin seconds,the heart rate = 60/RR.,Therefore,at a normal heart rate of 60 to 100/min, the RR interval is 0.6 to 1.0 seconds. n. \":+_4_9_Tus rhythm. Under normal conditions, the heart is depolarizedby impulses that o*rlginatein the SA node at a regular (or approximatelyregular) rate of 60 to 100/min and spreadto the remainder of the heart via the cardiacconduction system. This is callednormal sinus rtrythm. Three other sinus rhythms can be identified, which differ from normal sinusrhythm only in their rates;the impulsesstill originate normally in the SA node and are conductednormally to the remainder of the heart via the cardiacconduction system. l. In sinus tachycardia, the rate exceeds100/min. Sinus tachycardia is most commonly cauied by incieased syfrrpathetic stimulation of the heart, as in exercise,feve!, pain, and anterior myocardial infarction.

70

Physiology

2. In sinus bradycardia, the rate is less than 60/min. Sinus bradycardia can be causedby increised paiasymdthetic tone to the heart, as in some young healthy individuals (particularly well-trained athletes) and inferior myocardial infarction. It also can be seen in SA node dysfunction. 3. In sinus arrhythmiS, the rate is irregular, i.e., the_va4qtio" in thg RR interval exceeds0.16 seconds. The most common type of sinus arrhythmia is respirato_rysinusrrrhythmia, in which the rate-inc-r_eaqgs during inspiration a-nddecreasesduring expiration. E. Arrhythmias. The term arrhythmia refers to any cardiac rhythm other than normal sinus rhythm. The arrhythmias can be divided into disturbances of impulse conduction and disturbances of impulse origin.

Nole Arrhythmias aresometimes refened to asdysrhythmias.

* ARRHYTHMIAS l: DISTURBANCES OFIMPUTSE CONDUCTION

/ t--

Delaysor complete failure of conduction can occur in anypart of the cardiacconduction system, producing characteristicchangeson the ECG. The following discussionwill consider conduction disturbancesin the AV node (AV block) and bundle branches(bundle branch block).

L;

-_./ ' ,,.',.

A. AV block 1. First-degree AV block representsa delay in conduction of the impulse from the atria to the ventricles. This delay is most commonly due to abnormalities in the AV node and is reflectedby a prolonged PR interval, usually exceeding0.20 sec.First-degreeAV block may be due to a wide variety of-ggs_es,.including:

li.,t., 'z

)tQl r u /

''

'

7,4 F '-t f

a. lalasympathetic (vagal) stimulation b. Digitalis c. B-rec9-ptorantagonSJs d. Infiltrative or degenerativeconditions (amyloidosis,sarcoidosis,hemochromatosis, l""iil.r .Acification) e. Inflammatory processes(vual mJ.oc_arditis, ankylosing spondylitis, bacterial endo."rditis with myocardial abscess) f. Hypothyroidism g. Duchenne muscular dystropJry h. Congenital conduction systemabnormalities i. Isolated PR interval prolongation in otherwise healthy asymptomatic young adults, which is usually benign Second-degreeAV block representsan intermittent, usually periodic or cyclical,failure of conduction of the impulse from the atria to the ventricles.When the intermittent failure occurs in a regular pattern, it can be described by giving the ratio of the number of P waves (including the nonconducted P wave) to the number of QRS complexesper rycle (e.g.,3:2,4:3,2:l).Two typesof second-degree AV block can be identified: a. Wenckebach,or Mobitz Type I, second-degreeAV block ( 1) Mobitz Type I second-degreeAV block is characterizedon the ECG by (Figure I-4-24): (a) ryqg{ggliveprolongation of the PR interval before failure of AV conduction (i.e.,dropped QRS) occurs.

7l

System Cardiovascular

(b) Progressivediminution of the increment of PR interval prolongation before failure of AV conduction occurs. (c) Progressivediminution of the RR interval before failure of AV conduction occurs.

Progressively longerPR interval

/ P

Droppedbeat

P

P

J

Figure l-4-24. MobitzType lsecond-degree AV block.

(2) Mobitz Type I second-degreeAV block is usually du_eto a problem in the AV node; the tist of possibl. ."rrr., is identical to the list o? causesof first-degtie AV= block but should also include myocardial infarction, especiallyinferior myocard.1alinfarction. (a) Type I second-degreeAV block is usually_asymplom4lc, very rarely progressesto third-degree (complete) AV block, and therefore does not require prophylactic pacemakerinsertion. (b) If symptoms of decreasedcardiacoutput do occur,the patient may respond to atropine or isoproterenol. b. MobitzTlpe II second-degreeAVblock is characterizedon the ECG by a constant PRinterval before failure of AV conduction occurs (Figure I-4-25). The anatomic site of Mobitz Type II second-degreeAV block is almost alwaysbelow the AV node. Mobitz II block is frequently associatedwith bundle branch blocb it often progressesto third-degree(complete)AV block, and prophylactic pacing may be required.

Droppedbeat \ \ P

J\

P

P

I

P

\-

E.

t

Figure l-4-25. MobitzType ll second-degree AV block.

72

I

Physiology

c. In second-degreeAV block with 2:1 conduction, it is not possible to determine whether the block is Mobitz I or Mobitz II. In iqQrior myocardial infarction, Mobitz I is-Uqqfe-likely;in anterior my.ocardialinfarclion or in the pt.r.tt.e of bundle branch block, Mobitz is mgre likelylI 3. Third-degree (complete) AV block representsthe f4ilure of any impulses to be conducted frqm-Ue atrla,tq"the-ventrides. The yelqrcLeq,qrqdepolarized by an AV nodal or ventricular escaperhythm. Thus, third-degree AV block results in AV dissociation, i.e., the indgnendg3t{epolariiqtion of the atria and ventricles(Figure l-4-%).-

Figurel-4-26.Third-degree(complete)AV block.

a. Third-degree AV block must be differentiated from other causesof AV dissociati,on, with an ectopic junctional or ventricular escape such as marked sinuq-b_radyq4rdia pacemakerfiring at a rate faster than the SA node. b. Third-degreeAV block is manifestedby a slow ventricular rate,wi{e_pulsepressgle,a variablefirst heart sound, and prominent jugular venouspulsations,correspondingto right atrial contractions against a llosed tricuspid valve (cannon a waves). It may be causedby: (I) A utg.myocardialinfarction

(usuallyvalvular) tz) O_ry!99_t_95rg.ry (3) Degenerativeconduction systemdisease (+) C_9nggr1t{conduction systemabnormalities (5) Cardiomyopathy insertion to prec. Acquired third-degree AV block virtually dWgySr-e-quires-pacemaker vent CHF or shock secondaryto bradycardia and to prevent ventricular tachyarrhythis frequently asymptomatic, especiallyif the mias. Qo_"ggry!44_tr_4-4egfee,AV_block ventricular rate exceeds50/min. b. Bundle branch block representsfailure of conduction of the cardiac impulse through one of the bundle branches.Depolarization spreadsnormally through the other bundle branch, rapidly activating the corresponding ventricle. The affected ventricle is depolarized much more slowly. For example, in LBB blgck (LBBB), the right v_e_ntriql_q5&pq\,y_izedfirstand the leftventricle later,producing paradoxic4tsplitting of-the se.otrd heait ro.rttd. In the presenceof bundle branch block, the _QR!lnlerval is prolonged (to O.tZ secor longer). The QRS complexesin LBBB and RBBB have characteristic appearances(Figure l-4-27).

7t

System Cardiovascular

Lead I

LeadVu

Lead V.,

LBBB ) V

I

)

A\.,

\\

V

RBBB 1/]

U'-\

|\

/'

! U-.-

Figurel-4-27.TypicalORScomplexesin LBBBand RBBB.

t !

,t'.', \,r r-'

i..: / 1

I

r

(''

ll: DISTURBANCES OFIMPUISE ORIGIN . ARRHYTHMIAS In the disturbancesof impulse origin, the heart (or part of the heart) is depolarized by an impulse that originatesoutside of the SA node, i.e., an ectopic impulse. A beat resulting from an ectopic impulse is called an ectopicbeat. A. Escapebeats and rh)'thms. Under normal circumstances,pacemakercells outside of the SA node (e.g.,in the AV nodal area and His-Purkinje system)are latent: Becausetheir rate of depolarizationis slowerthan the rate of depolarizationof the SA node, they are depolarized by a SA nodal impulse before they can reach threshold and fire spontaneously. If, however, a SA nodal impulse fails to depolarize such pacemaker cells,they may reach threshold and produce an escapebeat or an escaperhythm. 1. Nodal or junctional escapebeats originate in the AV nodal area and reach the ventricles via the normal His-Purkinje system,producing a normal QRS complex. If SA nodal impulsesfail to depolarizethe AV nodal areafor a prolonged period, €.8.,in third-degree (complete) AV block located abovethe AV nodal pacemakers,junctional escaperhythm, typically at a rate of 45-60/min, will be seen. 2. Ventricular escape beats originate in an ectopic ventricular focus (generally in the Purkinje fibers) and produce an abnormal QRS complex that resemblesa PVC. If SA nodal impulsesfail to depolarizethETurkinje fibers for a prolonged period, e.g.,in thirddegree (complete) AV block located below the His bundle, ventricular escaperhythm, fyp,icallyat a rate of 3540lmin, will be seen. B. Supraventricular arrhythmias. Supraventricular arrhythmias originate abovethe ventricles and therefore are typically associatedwith normal QRS complexes. 1. A premature atrial contraction (PAC) occurs when an ectopic atrial pacemaker interrupts the underlying sinus rhythm by inserting an ectopicbeat before the next sinusbeat occurs. a. The P waveis usually abnormal in shapeand is thereforecalled a P'wave. b. The QRS complex is usually normal, but it may be abnormal (as a result of aberrant conduction of the premature atrial impulse) or even absent (if the AV node is still refractory from the precedingsinus beat), dependingon when the PAC occurs. c. PACs typically reset the SA node and are therefore followed by a noncompensatory Pause. d. PACsare usually benign.

74

Physiology

2. Wandering atrial pacemaker. The dominant pacemaker"wanders" from one atrial focus to another and in and out of the SA node. a. When the pacemakeris in the SA node, the P wave and PR interval are normal. Other P wavesare abnormal and vary in configuration; the correspondingPR intervals are usually longer. b. This arrhythmia is usually benign. (PSVT) is a_regulll:Igp-l9lll_9 to 250/min) 3. Paroxysmal suprave;tti;"1.;tachycardia arrhythmia _orry"1lglilgin the atria or AV node, often via a re-entry mechanism. divided into two a. AV nodal re_gntry (70o/oof all PSWs). The AV:n95!9-l!"pa_t_hologieally fun?lional pithways. The impulse proceedsantegradedown the slow pathway and retrograde back up the fast pathway in the majority of cases.The P wave is usually recorded simultaneously with the QRS complex; thus, a rapid ,.q,r.rr.. of normal QRS complextls ii typically seen on the ECG. This arrhythmia is frequently seen in older patients,of whom = 50o/ohave underlying heart disease. b. Atrid re-entry (I0o/oof all PSVTs).The re-entrant pathwayis in the atria. The P wave is recorded before the QRS complex. This arrhythmia is frequently associatedwith organic heart disease. c. Automatic atrial (5o/oof all PSVTs).Often, theseare not paroxysmal,lasting daysto years,and are resistantto treatment.The P wavehas an abnormal configuration. d. Treatment of the re-entry tnres of PSVTs includes stpport of blood pressurewith pressors(e.g.,norepinephrine) and maneuversto re-establish fl11rlgand,if necessary, normal sinus rhythm by interrupting the re-entry pathway: (1) IncreasingAV nodal refractorinesswith vagal maneuvers(e.g.,therelease_ofa Valsalva maneuver, carotid sinus massage),adg4-gqlng,9\.grt-acting acetylinhibitors (e.9.,edrophonium),9ig*i", y-.5rlgqf$ or p-receptor _ch9]!1eg19rase antagonists(e.g.,propranolol) (2)

-Cardioversion (3) Over{rive pacing (saferthan cardioversionif digoxin level is.bigh)

e. Following conversion of PSVT to normal sinus rhythm, the_-ECQ* mgy__qhow widespreadT wave inversion that may take 2 to 7 daysto resolve.It is usually a benign finding. 4. Atrialflutter is a regular,rapid (250 to 350/min) arrhythmia originating in the atria, often as a result of a wave of depolarizationthat propagatescontinuously within a closedcircuit (circus movement). On the ECG,atrial depolarizationis representedby flutterwaves (F waves), which typically have a "sawtooth" appearance, especiallyin leads II, III, and aVF.Becauseof the refractorinessof the AV node, a physiologicAV block is almost always present,and only one-half, or evenone-fourth, of the impulsesare conductedto the ventricles (2:l or 4:1 conduction). a. The degreeof AV block is decreased(i.e.,more of the atrial impulsesare conductedto the ventricles)by: (I) Sy_mpalhetic stimulation, €.g.,exercise (2) Accessorypathwaysbetween the atria and the ventricles,which rypically have shorter refractory periods than the AV node (3) Quini4ine, which slows impulse conduction in_atrial muscle and can lead to a "paradoxic" increasein the number of atrial impulses that passthrough the AV node to the ventricles. The anticholinergic (atropine-like) effectsof quinidine,

75

System Grdiovascular

which can decreaseAV nodal refractoriness,may also contribute to its ability to increasethe number of atrial impulses passingto the ventricles. b. The degreeof AV block is increased(i.e., fewer of the atrial impulses are conducted to the ventiiiles) b/_yagal maneuvers, digoxin, verapamil, and p-receptor antagonists (e.g.,propranolol). c. Atrial flutter should be suspectedwhenever an ECG shows a regular ventricular rate of 125to 150/min. If the patient does not have bruits on auscultation of the ;;bTra arteries,careful carotid sinus massagemay by increasingparasympatheticstimulation of the heart, result in a higher degree of AV block and may reveal the characteristic "sawtooth" pattern on the ECG (FigureI-4-28), which can otherwise be obscured by the QRS complexes.

Figure l-4-28. Atrial flutter.

(1) Atrid contractions are often ineffective in atrial flutter. Adequate cardiae-output .g" b. maintained only if the ventricular rate is sufficiently slow, i.e., if the degree of AV block is high enough. (2) Atrial flutter usually accompaniesorganic heart disease,such as coronary artery or valvular disease. d. The treatment_olatrial flutter should include: (1) Correction of fever, anemia, ischemia, pericarditis, electrolyte abnormalities, hlpovolemia, infections, hyperthyroidism, and valvular disease (2) Drugs and maneuvers that increaseAV block, as they may occasionally convert the rhythm to atrial fibrillation or normal sinus rhythm (3) Quinidine, but only after the AV node is blocked with digoxir_r propt_iiolol 9r (4) If necessary atrial pacing at l25o/oof the atrial rate for_3Q1gqgry\_ Spia (5) If necessarylow-voltage synchroniznd cardioversion 5. Atrial fibrillation is a common supraventricular arrhythmia (and one of the most common of all cardiac arrhythmias). In atrial fibrillation, randomly irregular, rapid (350__to 600/min) impulses from multiple atrial foci depolarize the atria. This chaotic atrial depo-larization is representedon the ECG by irregular, rapid, and continually varying undulations called fibrillatory waves (f waves), which are often most prominent in lead V Normal QRS complexesare recorded at irregularly irregular intervals, as the rapid atriai impulses are randomly conducted through the AV node.

76

Physiology

a. If the ventricula!_t4[e-js.over"200/minand the QRS complexesare abnormal, aberrant condiictio" accessorypathrvayshould be suspelied (e.g.,in Wolff-Parkinson"1" ""

M_t!ry.4fqqr.).

b. Atrial contraction is extremely ineffective in this arrhythmia. As a result, qtlg! fibrillation is usually associatedwith a fall in cardiac output, especiallyin patients who are elderly or-who hir," u noncompliant (stiff) left ventricle (e.g., due to ischemia or chronic hypertension). c. Tieatment of atrial fibrillation invovles the following: (t) Slqulthr-ventricular respensethrough administration of digo{in, a F-receptor antagonist,or yerapamil. (2) Conve_r!the pa!,ientto normal sinus rhythm. If the left atrium is large and the patient hasbeen in atrial fibrillation for a long time, a normal sinusrhythm may be difficult to maintain. The ventricular responseshould be slowed. (3) ,{nticoagulatethe patient iltbgre a{e no contraindicationsand if the atrial fibrillation has been presentfor more than two days. (a) Administer guinidile or procainamide; i! they are i-neffqc_tivg, e_lgctrical cardioversionshould be used. (5) MqLlLt4lItdigoxin plus quinidine or procainamide for 3 to 6 months after cardioversion. 6. Multifocal atrial tachycardia (MAI) is an irregular atrial rhythm in which impulses from multiple foci depolarizethe atria; however,the atrial rate (100 to 250/min) is slowerthan in atrial fibrillation. a. The diagnosticECG criteria (FigureI-4-29) for MAT are:the prese_nce of abnorm4l P waves(P'waves) of at leastthree different morphologies and an irregularly irregular rhythm.

P'waves

Figure 14-29. Murtifocaratriar tachycardia- onset in middre of rhythm strip. b. It is very important to distinguish MAT from wandering atrial pacemaker (a benign arrhythmia) and from atrial fibrillation (MAT does not respond to digoxin). MAT is an arrhythmia secondaryto serious, and not necessarilycardiac, disease.It is seen most commonly in COPD, postoperativesettings,and in elderly patientswith serious illnesses. c. The treatment MAT includes the improvement of the patient's underlying illness of -'- -:-'--(e.g.,correction of hypoxia, acidosis,fever,anemia), ayor.dalce_of aminophylline and sympathomimetics,and the useof verapamil.Note that cardioversionand digoxin are not indicated in the treatment of MAT.

77

Grdiovascular System

pace7. Acceleratedjunctionalrhythm.In acceleratedjunctional rhythm,Ulggally,latent regular, rate area depolarizes at a accelerated of 60 to 150/min. .T{.f_111!_:_AYlg,*al a. The P wavesare typically inverted and may precede,follow, or be hidden within the dnS ;oapieiCi-(Figure I-a-30). However, when the rate of the acceleratedpacemaker is closeto the rate of the SA node, the ectopic impulsesare often conductedto the ventricles only, while the atria remain under the control of the SA node; thus, acceleratedjunctional rhythm gan causeAV dissociation. b. Acceleratedjunctional rhythm is usually 4g._tg digoxin toxicity and may be clinically manifested first by the apparent "regularization" of the ventricular rate in atrial fibrillation. This arrhythmia may also be seenafteiin acute inferior myocirdial infarction. c. Treatment is often expectant;gg9y

should be withheld.

Figure l-4-30. Accelerated junctional rhythm.

C. Ventricular arrhythmias. Ventricular arrhythmias originate in the ventricles and therefore are associatedwith abnormal ("wide and bizarre") QRS complexes. 1. A premature ventricular contraction (PVC) occurs when an ectopic ventricular pacemaker inserts an ectopic beat before the next sinus beat occurs. The ectopic impulse spreadsthrough the ventricles via an abnormal route but is typically not conducted retrograde through the AV node to the atria. a. PVCsare representedon the ECG as shown in Figure l-4-31.

78

Physiology

Figure l-4-31. Premature ventricular contractions (PVCs) in a bigeminy pattern (i.e., each sinus beat is followed by a PVC).

(1) A "wide and bizarre" QRS complex,sincethe ectopicimpulse doesnot follow the normal rapid conduction systembut is conducted slowly through the ventricular myocardium (2) Large deflections in the QRS complex becausethe two ventricles do not depolarize simultaneously.Normally, the simultaneous opposing ventricular depolarizations partially canceleachother and reducethe sizeof the QRS deflections. (3) A compensatorypause following the PVC. The pause occurs because the AV node and/or ventriclesare refractory to the normal SA node impulse that immediately follows the PVC, but the next SA node impulse is conducted normally and produces a normal QRS complex. Thus, the underlyrng sinus rhythm is not disturbed. b. PVCs occur both in normal and in diseasedhearts. (1) In patients with normal hearts, PVCs are not associatedwith decreasedlife expectanry. (2) In patients with heart disease,PVCs may be a marker for a higher risk of other ventricular arrhythmias and sudden death. c. The use of antiarrhythmic drugs to treat PVCs has not been demonstratedto have a clear benefit, in part becausemost of thesedrugs haveproarrhythmic effects. Patients with symptomatic PVCs should be reassured;if necessary a B-receptor antagonist without intrinsic sympathomimetic activity (i.e.,without partial agonistactivity) can be administered. 2. Accelerated idioventricular rhythm (AIVR). In AIVR, a normally latent pacemaker in the ventricles depol arizesat a regular, acceleratedrate of 50 to 100/min. This arrhythmia is seen_mo_st commody _t" F&tr_or myocardial infarction ( Figure l- 4-32).

79

Cardiovascular System

vs

Figure l-4-32. Accelerated idioventricular rhythm.

a. The rate in AIVR is often similar to the sinus rate, so that the ECG may show fusion beats (i.e.,QRS complexesresulting from the simultaneousspreadof the ectopic and sinus impulses) at the onset and termination of AMR. b. If the patient is asymptomatic, no treatment is indicated; atropine may be used to increasethe sinus rate, while lidocaine may be usedto protect againstventricular tachycardia. 3 . Ventricular tachycardia (VT). In VT, ectopic impulsesoriginate in the ventricles at q rggf Iar, rapid rate of 1_00* to 250/min (Figure l-4-33).It is most frequently causedby a re-entry pechanism; in a smill minority of cases,it is causedby the fitiog of an ectopic focus. a. The ECG in VT shows: (l) "Wide and bizarre" QRS complexes,similar to PVCs (2) In some cases,evidencethat the SA node retains control of the atria (AV dissociation), such as fusion beatsand independentsinus P waves

Figure l-4-33. Ventricular tachycardia.

b. VT is usually associatedwith a decreasein cardiacoutput, due to decreasedtime for ventricular filling and absenceof an effective"atrial kick."

80

Physiology

c. Emergency treatment is alwaysindicated in sustained (more than 30 secondsduration) VT. Treatment includes: (1)

-Precordialthump

(2) C_ardiopulmonary.resuscitation (3 ) Synchronlzg{ cardioversion (4) Lidocaine (5) Procainamide

Nolc Torsades dePointes isa form of ventricular tachycardia in whichtheQRS amplitude andaxischange cyclically. It occurs mostcommonly in patients witha prolonged interval. QT

(6) Brerylium (7) B-recgptg*Lqntagonists d. Patients who have experienced repeated episodesof sustainedVT should be treated with an itpt."q{gtttqgt-ty.a_1dia pacemakeror sotalol. e. Patients who have experienced repeated episodesof nonsustained, symptomatic VT can be treatedwith F-receptorantagonists. f. Vag{mgreu_ve1q_hgye no effe-ct-o-n the rate of ventricular tachycardia. 4. Ventricular fibrillation. In ventricular fibrillation, ventricular depolarization is rapid and irregular, due to impulses originating tr multiql_e991opicventricular foci. a. Ventricular fibrillation can be triggered by a !VC- that occurs during the "vulnerable period" at the end of ventricular repolarization (the R-o4-T phenomenon). b. The ECG shows random electrical activity without recognizable QRS complexes (Figure l-434r. c. Emergency treatment of ventricular fibrillation includes: ( I ) Cardiopulmonary resuscitation (CPR) (2) Asynchronous defibrillation (3) Ep_ineph-rine and repeat defibrillation if necessary (4) Lidocaine (5) Procainamide d. Patientswho have experiencedrepeatedepisodesof ventricular fibrillation should be treated with an implanted defibrillator.

Figurel-4-34.Ventricularfibrillation.

8l

System Cardiovascular

(CHF) HEART FATTURE GoNGESTTVE Congestive heart failure may be defined as an inability of the heart to deliver a sufficient cardiac output to meet the metabolic demands of the peripheral tissues,despite normal or elevatedcardiac filling pressures. A. Pathophysiology 1. Initial causesof CHF a. Increased afterload, as in hypertension or aortic stenosis b. Increasedpreload, as with injudicious transfusionsor fluid infusions, or noniatrogenic accumulationof fluid volume (e.g.,due to renal disease) c. Severevalvular disease,which leads either to pressureor volume overloading of the ventricle(s) d. Chronic tachy- or bradyarrhythmias e. Impaired myocardial function (e.g., a large myocardial infarction, viral myocarditis, alcoholic or other cardiomyopathy) 2. Factors involved in the development of chronic CHF a. Sympathetic nervous system. Plasma norepinephrine concentration is commonly elevated in patients with CHR while myocardial tissue levels of catecholaminesare depleted.Systemicvasoconstrictionand tachycardiaare also common findings. b. Renin-angiotensin-aldosterone system. Plasma renin levels are elevated in some patients with CHF. c. Antidiuretic hormone. Antidiuretic hormone levelsare frequently elevatedin CHF. 3. Hemodynamic and hormonal factors contribute to sodium retention by the kidneys and developmentof peripheral and pulmonary edema,which characterizeadvancedforms of CHF. B. Symptoms

Clinical Conelate thedegree of Clinically, is oftenquantified orthopnea of intermsofthenumber pillows patient needs in the orderto sleepcomfortably "three-pillow (e.g., orthopnea").

1. Dyspnea refersto laboredbreathingand the sensationof shortnessof breath. In CHR the elevatedpulmonary capillary pressureand engorgement of the lungs with fluid increase the work of breathing, producing the sensation of effort characteristic of dyspnea. Dyspnea on exertion is usually one of the earliest symptoms of CHF. 2. Orthopnea is the sensation of dyspnea occurring while lying relatively flat in bed. Recumbencyresultsin a rise in the position of the diaphragm and a decreasein ventilatory reserve.More importantly, it causesincreasedvenous return from the dependent portions of the body, augmenting right ventricular output and further increasingpulmonary capillary pressure.Patientswith orthopnea report having to use additional pillows to sleepcomfortably. Orthopnea usually developsat a later stageof CHF than does exertional dyspnea. 3. Paroxysmal nocturnal dyspnea (PND). Patients with PND awake from sleep suddenly with a sensation of severebreathlessnessand gasp for air. They immediately sit up and PND has the same mechanism as may complain of cough as well as breathlessness. orthopnea.It may be a harbinger of impending acutepulmonary edema. a. Weight gain not explained by changesin diet or activity may be the earliest evidence of sodium and water retention associatedwith CHF. Approximately 10 lb of extracellular fluid accumulatesbefore it becomesevident as pitting edema.

82

Physiology

C. Signs l. Cardiac signs. Most patients with chronic CHF have an enlarged heart (cardiomegaly). Examples of relatively unusual conditions associatedwith CHF without cardiomegaly include restrictive cardiomyopathy and constrictive pericarditis. The heart appearslarge on the chestx-ray. The apical impulse is displacedlaterally and may be diffuse and boggy. fu S, gallop due to excessvenous return to the right atrium may be heard if left ventricular dilatation is severe. a. Cardiomegaly (eccentric or volume overload hypertrophy) involves volume overloading and dilatation of the ventricles. The ultrastructure of hlpertrophied fibers in this condition containsnormal distributions of myosin isomers. b. Concentric or pressure overload hlpertrophy is frequently not detectableon radiographs,but can be detectedon the ECG (increasedvoltage of the QRS complexes), which is usually quite sensitive to mass increasein the myocardium. The isomer of myosin produced in this type of hypertrophy is unusual and of a type with intrinsically slow myosin AIPase activity. 2. Vital signs a. Thchycardia is a common finding. Heart rate may be irregular, reflecting atrial fibrillation or frequent PVCs commonly associatedwith longstanding CHF. b. Arterial pressure may be high, normal, or, if cardiac failure is severe,low (shock). Pulsus alternans (variations in blood pressureassociatedwith alternating weak and strong left ventricular contractions) may be present if left ventricular dysfunction is very severe. c. Respiratory rate is commonly elevated. d. Temperature may be markedly below normal if the cardiac output is very low. 3. Pulmonary signs. Persistentlyelevatedpulmonary capillary pressuresresult in transudation of fluid from pulmonary capillaries into the interstitial spacesand, eventually, into the alveolar spaces.When the rate of transudation exceedsthe rate of absorption of the fluid by the pulmonary lymphatics, the accumulated edema results in pulmonary rales, initially heard only in the dependent portions of the lungs (i.e., the posterior bases). Severepulmonary edema may also be associatedwith wheezing secondary to bronchial wall edemaor bronchospasm. 4. Central venous pressure (CVP) is commonly elevated in patients with CHF. Increased CVP may be manifested by: a. |ugular venous distension. The peak of the maximum venous pulsation within the deep jugular venous systemis elevatedmore than 2 cm of vertical distance above the sternal angle when the patient lies in bed with the head elevatedto a 45-degreeangle. b. Positive Kussmaul sign. ]ugular venous pressureincreaseswith inspiration. c. Hepatojugular reflex. |ugular venous pressureincreasesmore than 2 cm after approximately 1 minute of heavy pressureexertedby the examiner's hands over the patient's abdomen while the patient breathesnormally. 5. Hepatomegaly. If right ventricular failure is present,the liver may become congestedand enlarged. The liver edge may be felt well below the costal margin and may be pulsatile if tricuspid regurgitation is present secondaryto right ventricular dilatation. Occassionally, CHF may produce splenomegaly as well as hepatomegaly.

8T

System Cardiovascular

6. Edema. Extracellular fluid initially accumulatesin the most dependent areas:in an ambulatory patient, the feet; in a bedridden patient, the lumbosacral area. a. Edema of CHF is characteristicallypitting: A finger applied against a bony structure produces a dimple or pit, which disappearsin 1 minute. b. Edema involving the entire body is referred to as anasarca. 7. Pleural effrrsions. Bilateral or right-sided unilateral pleural effirsions are common in patients with CHF. They are detectedby finding dullness to percussion in the lower lung fields and on chestx-rays. 8. Ascites. The transudation of fluid can result in its accumulation in the peritoneal caviry or ascites.Ascitesis usually seenin severebiventricular or right-sided heart tailure. 9. Cyanosis. Becausepatients with CHF have inappropriately low cardiac outputs, the flow through the capillarybeds is reducedand oxygenextraction is increased.The increasedconcentration of deorygenatedhemoglobin in the capillary beds results in a bluish hue of the skin, referred to ascyanosis.In contrast to cyanosiscausedby primary pulmonary diseases, the ryanosisof CHF is likely to remain unaffectedby the administration of oxygen. D. Classification of CHF 1. Clinically, CHF is usually classifiedby the severity of impairment of exerciseperformance according to the New York Heart Association Functional Classification: a. Class I: no limitations of activity; no symptoms with ordinary physical activity b. Class II: slight limitation of physical activity; symptoms with ordinary activity c. ClassIII: marked limitation of physicalactiviry; symptomswith lighter-than-ordinary activity d. ClassfV: symptoms presentat rest of circulatory impairment 2. Classificationbasedon more objectivemethods of assessment are also available.

In a Nutshell Strategiesfor TreatingCHF . Reduce (vasodilators) afterload . Reduce preload (diuretia) . Increase contractility (+ inotropes)

E. Principles of treatment. The initial efforts are understandably directed toward reversingthe existing initial causesof CHR such as surgical correction of aortic stenosisor treatment of hypertension, arrhythmias, or the causeof cardiomyopathy. If CHF persists,the goal of the therapy becomesimprovement of the patient's circulatory function. The mainstays of such therapy are: 1. Vasodilators (e.g.,captopril, hydralazine,nifedipine, nitroglycerine) to reduce left ventricular afterload 2. Diuretics (e.g., furosemide, thiazides) to reduce intravascular volume and ventricular preload 3. Positive inotropic agents (e.g.,digoxin, dobutamine) to improve ventricular contractility

84

Physiology

CARDIOVASCUTAR RESPONSE TOEXERCISE A. Definitions (Thble l-4-4) 1. Isotonic or dynamic exerciseis predominantly aerobic,is performed againsta constantload (isotonic), and involves rhythmic contractions of flexor and extensor muscle groups (dynamic). 2. Isometric or static exercise (i.e., weight lifting) refers to activity that is predominantly fueled by anaerobicbreakdown of glucoseto lactate,is performed at a relatively constant musclelength (isometric), and involvesminimal or no movement (static). ?able l-4-4. Overview of cardiovascular effects of exercise. Parameter

Isometric

Isotonic

Minimally increased

Markedly increased ,

Heart rate

Minimally increased

Markedly increased

Blood pressure

Moderately increased

, Systolicincreased, diastolic unchanged, and mean slightly increased

Cardiac index

Minimally increased

Markedly increased

Systemicvascular resistance

Relativelyunchanged

Markedly decreased

' Orygen consumption

I

B. Cardiovascular response to isotonic exercise 1. Initial anticipatory sympathetic outflow occurs even before exercisebegins, resulting in increasedheart rate, increasedcardiac output, and decreasedvenous compliance. 2. Shortly after the beginning of exercise,muscle blood flow increasesup to 15 times its resting value as a result of vasodilatation mediated by local factors such as hypoxia and changesin K*, H*, and AIP concentrations. 3. Circulating catecholaminesand direct sympathetic stimulation of the heart increasethe heart rate and the inotropic state. a. Early in exercise,increasedstroke volume is the most important adjustment. b. Later (beyond 50o/oof maximal work capacity), increased heart rate becomes more important in maintaining the cardiac output. c. At maximum exercisein well-conditioned individuals, cardiac output can be doubled by increasesin stroke volume and tripled by increasesin heart rate.

85

Cardiovascular Pathology

Cardiovascular disease affects a large segment ofthepopulation. Infact,atherosclerosis istheleading cause of deathintheUnited States. Because theeffects of cardiovascular disease arewidespread and potentially lethal, it isimportant to beableto identify themajorriskfactors foreachtypeof disease. Thischapter willfocus onthe$ructural andfunctional changes withdiseases thatoccur oftheheart andvessels, aswellasthemajorriskfactors associated witheachdisease entity. Notethatconduction abnormalities andarrhythmias werereviewed intheCardiovascular Physiology chapter.

CONGENITAL ABNORMATITIES OFTHEHEART A. Overview 1. Etiology a. During cardiacdevelopment,insults must occur before the end of week 16 (completion of heart development)in order for a congenitaldefectto occur. b. Chromosomal abnormalities (e.g.,trisomy 13, 18, 21) may lead to specific cardiac anomalies. c. Mendelian hereditary syndromes (e.g.,Marfan, Ehlers-Danlos) may also be associated with specificcardiacdefectsaswell aswith other developmentalanomalies. d. Environmental causes(e.g., maternal rubella, alcohol, smoking) may have variable effects,dependingon when and how severethe insult is to the mother and fetus. e. Up to 90o/oof congenitalheart diseaseis of unknown etiology. f. Cardiomegily, heart murmurs, and congestiveheart failure g. Chronic ryanosis,which will causepolycythemia, clubbing of fingers and toes, and hlpertrophic osteoarthropathy B. Acyanotic congenital heart disease (left-to-right shunts). In this disease,blood is abnormally shunted from the left to the right side of the heart. This causeschronic right heart failure and secondarypulmonary hypertension as a result of increasedpressureand flow. Right heart pressuremay eventuallyincreaseto becomegreaterthan left heart pressure,and the shunt will reverse,becoming a right-to-left shunt that resultsin late onset ryanosis.

GliniCal COrfelate

1. Ventricular septal defect (VSD) is an abnormal communication betweenventricles,usually at the membranousinterventricular septum.The clinical significancedependson the volume of the shunt. It is often associatedwith other defects.

Someof the loudest murmursareVSDs.

87

System Cardiovascular

Ostium primum

m

)

A. Ostiumprimumdefect

'i:tc

Septumprimum

lVC

Septum secundum Ostium secundum [A Septum primum

B. Ostiumsecundumdefect

Sinusvenosus Rightpulmonary defect veins Leftpulmonary verns Ostium primum

Pulmonary veins

Endocardial cushions lnterventricular septum C. Completeendocardialcushiondefect

Note Inapproximately 250/o of adult hearts, theatrialseptum actually remains open,butis keptfunctionally bythe closed pressure normal differential between therightandleftatria.

D. Sinusvenosusdefect

Figure l-5-1. Common configurations of atrial septal defects.

2. Atrial septal defect (ASD) is an abnormal communication betweenthe atria (Figure I-5-1). The clinical significancedependson the volume of the shunt. a. Ostium primum defects account for approximately 5o/oof all ASDs. The defect is in the lower atrial septum above the atrioventricular (AV) valves.It may be associated with maldevelopedAV valves. b. Ostium secundum defectsaccount for approximately 90o/oof all ASDs. The defect is in the center of the atrial septum at the foramen ovale, resulting from abnormalities of the septum primum, septum secundum,or both. It is not associatedwith maldeveloped AV valves. c. Complete endocardial cushion defect results in an ASD, a VSD, and a common AV canal.

Note pulmonary PDA causes hypertension dueto excess bloodto pulmonary artery (leads pressure). to t 88

d. Sinus yenosus accounts for approximately 5o/oof all ASDs. It causesa defect in the upper part of the atrial septum and may causeanomalous venous return from the pulmonary veins into the superior vena cavaor right atrium. e. Patent foramen ovale is a slit-like remnant of the foramen ovale and is usuallv not of clinical significance. 3. Patent ductus arteriosus (PDA) is a defect in which oxygenatedblood flows from the aorta to the pulmonary artery. This deprivesthe systemiccirculation of orygenatedblood

Pathology

and eventually leads to pulmonary hypertension. Indomethacin can be used to close a PDA, while the prostaglandinPGE can be utilized to keep it open if necessary. C. Cyanotic congenital heart disease (right-to-left shunts). In these diseases,blood is shunted from the right to the left side of the heart, causing poorly orygenated blood to be pumped out to the systemic circulation. This causesimmediate ryanosis and permits paradoxic embolism, in which venous emboli bypassthe pulmonary circulation and directly enter the systemiccirculation (Figure l-5-2).

Aorta

Aorta

Ductus arteriosus

Ligamentum arteriosum

Pulmonary valvular stenosis

ertton"ryf -/

artery

ding Right ventricular hypertrophy

aorta Ventricular septal defect

A. Tetralogyof Fallot

B. Transpositionof the great vessels

Figure l-5-2. Common forms of cyanotic congenital heart disease.

I . Tetralogy of Fallot has four specific anomalies and is the most common cyanotic con-

genital heart diseasein older children and adults. a. The four lesionsare: (1) VSD (2) An overriding aorta that receivesblood from both ventricles (3) Right ventricular hypertrophy ( ) Pulmonic stenosis (right ventricular outflow obstruction) b. The clinical significancedependson the degreeof right ventricular outflow obstruction. c. Deoxygenatedblood is shunted to the left side of the heart through the VSD, and blood flows from both ventricles into the enlargedaorta with little reaching the lungs. d. A PDA permits survival if the pulmonary artery is completely obstructed. 2 . Transposition of the greatvesselsresults from a failure of the truncoconal septum to spiral during development. The aorta arises from the right ventricle, and the pulmonary artery arisesfrom the left ventricle. This is often associatedwith other anomalies.Either PDA, a VSD, an ASD, or a patent foramen ovale mixes venous and systemicblood and, therefore, permits survival.

89

Grdiovascular System

3. Persistent truncus arteriosus is the failure of the aorta and pulmonary arteries to separate. There is also a VSD, usually at the membranous interventricular septum. The truncus arteriosusreceivesblood from both ventricles,so ryanosisresults. D. Obstructive congenital heart disease.This form of developmental defect typically does not causeryanosis. 1. Coarctation of the aorta a. In the preductal (infantile) tfpe, there is narrowing of the aorta proximal to the opening of the ductus arteriosus. b. In the postductal (adult) Qrpe,there is narrowing of the aorta distal to the opening of the ductus arteriosus. This is the most common tfpe, and generally allows survival into adulthood. 2. Pulmonaryvalve stenosisoratresia. This lesion maybe due to an unequaldivision of the truncus arteriosusso that the pulmonary trunk has no lumen or opening at the level of the pulmonary valve. It may causecyanosisif severe. 3. Aortic valve stenosis or atresia a. Complete atresiawill not support neonatallife. b. Bicuspid aortic valvesmaybe asymptomaticbut can lead to infectiveendocarditis,left ventricular overload, and sudden death. This lesion is the most common causeof aortic stenosis,replacingrheumatic fever.

E. Abnormalities associatedwith genetic syndromes 1. Marfan syndrome. One-third of patients have congenitalcardiovasculardiseasecharacterized by aortic dilatation and incompetence,aortic dissection,and ASD. 2. Down syndrome (trisomy 21). Twenty percent of patients may have congenital cardiovasculardisease,characterizedbyan ostium primum type of ASD and a VSD. 3. Turner syndrome patientsfrequently havecoarctationof the aorta and pulmonary stenosis. F. Abnormalities associatedwith perinatal insults 1. Maternal infection with rubella in the fifth to tenth weeks can lead to PDA, ASD, and VSD. 2. Fetal alcohol syndrome can lead to cardiovasculardefects,including VSD. 3. Maternal ingestion of drugs such as trimethadione (antiseizuremedication) and isotretionin (retin-A) can causefetal cardiacdefects.

(rHD) rscHEMrc HEART DTSEASE A. Overview 1. IHD occurs when the oxygen supply does not meet the orygen demand of the myocardial tissue. It is the leading causeof death (along with hypertensive and valvular diseases)in the United States. 2. Ischemiais caused(alone or in combination) by the following conditions: a. Narrowing of the coronary arteries, often precipitated by vasospasmor overlying thrombus is the most frequent causeof cardiacischemia.Most infarctions occur when multiple vesselsare narrowed.

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Pathology

(l) Ninety percent of casesare due to atherosclerosis. (2) The underlying lesion is usually a complicatedplaque,with calcification,ulceration, or overlying thrombus. (3) Less common causesinclude dissecting aortic aneurysm, arteritis, coronary embolism, and cocaine-inducedvasospasm. (4) Perfusionis impaired when the cross-sectionalarea of the lumen is reducedby more thanTlo/o. b. Decreased oxygen-carrying capacity of the blood from anemia, carbon monoxide poisoning, pulmonary disease,or smoking may lead to cardiacischemia,particularly in combination with atherosclerosis. c. Increased myocardial demand from tachycardiaor hypertrophy may also increasethe risk of ischemia.

Note Thepathophysiology of isdiscussed atherosclerosis lateron inthischapter.

3. IHD is categorizedinto four syndromes. a. Angina pectoris is pain due to ischemia.Patientswith angina have an increasedincidenceof myocardialinfarction. b. Myocardial infarction is ischemic necrosisdue to insufficient blood supply. c. Chronic ischemic heart disease may or may not causeangina or myocardial infarction. Somepatientsmerely experienceheart failure. d. Sudden cardiac death is the presentingsymptom in 25o/oof patientswith IHD.

B. Angina pectoris. This syndrome is paroxysmal substernal or precordial chest pain, caused by transient myocardial ischemia without myocardial infarction. Prolonged and repeated angina pectoris may causefocal fibrosis and subendocardialmyocardialvacuolization,indicating gradual loss of myocytes. Angina and its resultant fibrosis are associated with impaired diastolicrelaxation,increaseddiastolicfilling pressure,and subsequentpulmonary congestionwith resultant dyspnea. l. Stable angina pectoris a. Paroxysmsare associatedwith a fixed amount of exertion. b. Typicat attackslast lessthan 10 minutes and are relieved with rest or sublingual nitroglycerin. c. EKG may show ST segmentdepressions(ischemialimited to subendocardium). d. Most angina pectoris is causedby severeatheroscleroticnarrowing of coronary arteries. 2. Prinzmetal angina pectoris (paroxysmal vasospasm) a. Vasospasmcausesdecreasedblood flow through atheroscleroticvessels. b. This form of attack frequently occurs at rest with ST-segmentelevationson EKG. 3. Unstable angina pectoris often leadsto myocardial infarction. a. It can presentwith prolonged chestpain, abnormally severepain, or pain at rest in a person with stableangina. b. It is often unresponsiveto nitroglycerin.

9t

Cardiovascular System

C. Myocardial infarction 1. Overview a. Myocardial infarction is ischemic necrosis of the myocardium, resulting from an abrupt decreasein coronary blood flow or a suddendemand for increasedmyocardial delivery, which cannot be met becauseof coronary artery narrowing. It is more commonly transmural, but can be subendocardial. b. Myocardial infarction is more common in men than women; the highest incidenceof fatal myocardial infarction is from 55 to 64 yearsold. c. Risk factors include hypertension, hypercholesterolemia,cigarette smoking, family history, diabetesmellitus, oral contraceptiveuse,and sedentarylife style. d. Type A personalities(aggressive, compulsive)may have an increasedrisk. e. Regular exerciseand moderate alcohol use (one glassof wine per day) may decrease the risk by raising the level of high-density lipoprotein (HDL). 2. Types of infarcts a. Tiansmural infarcts are infarctions of the fi.rll thickness of the ventricular wall. They are usuallydue to occlusionof vesselsfrom severecoronary atherosclerosis, formation of complicated atheromatous plaques with ulceration or fissure, and thrombosis. Occlusionsoccur most often in the proximal left anterior descending(50olo),right coronary (35o/o),and left circumflex (l5o/o)arteries. b. Subendocardial infarcts are infarctions limited to the inner half of the ventricular wall. The subendocardiumis more vulnerable to generalizedmyocardial hypoperfusion than are other areas,usually becauseof diftrse atherosclerosiswithout thrombosis and resultant borderline ischemia. Infarction occurs when flow is further compromised (e.g., CHF, shock, arrhythmia, vasospasm,severehypertension) or when oxygen demand is increased(e.g.,exertion,tachycardia). 3. Pathology a. Tiansmural infarcts ( I ) Grossly,transmural infarctspresentaccordingto the following scenario.A lesion extendsfrom the endocardium to the epicardium. No grosschangesare evident until 6-12 hours after the onset of myocardial infarction. In 6-24 hours, the myocardium becomesprogressivelypale,ryanotic, and swollen.In 24-48 hours, the infarct is well-demarcated,soft, and pale. In 3-10 days,the infarct becomes soft, yellow, and surrounded by a hyperemic rim. By 2 weeks,the infarcted area is surrounded by granulation tissuethat is gradually replacedby scartissue.By 2 months, the former myocardium is convertedto scartissue(Figure I-5-3).

92

Pathology

Note Wavyfibers+ highly eosinophilic bands of - very necrotic myocytes earlymicroscopic sign of myocardial infarction

Figure l-5-3. Myocardial infarcts (gross).

(2) Microscopically, transmural infarcts presentaccording to the following scenario. Within I hour, there is intracellular edema.Within 6 hours, there is wavinessof myocardial fibers, vacuolar degeneration,and contraction band necrosisat the periphery. Within 2+-72 hours, a neutrophilic infiltrate, increasedcytoplasmic eosinophilia, and coagulation necrosis become evident. Additionally, crossstriations begin to disappear.By the end of the first week, there is increased coagulativenecrosis,the appearanceof a mononuclear infiltrate, and granulation tissue at the margins where new vesselsstart to grow. In 8-10 days,there is an increasein granulation tissuewith ongoing phagocytosisand removal of necrotic myocardium by macrophages.By 4 weeks,collagenis becomingpredominant. By 2 months, there is a densefibrohyaline scarwith occasionallipofuscin-laden macrophages(FiguresI-5-4, I-5-5, and I-5-6). b. Subendocardial infarcts (1) Grossly, subendocardialinfarcts present as multiple small foci (0.5-1.5 cm) of necrosiswithin the inner half of the myocardial wall. (2) Microscopically, they develop like transmural infarcts, only over a longer period of time, causingthe inflammatory reaction to take somewhatlonger to develop.

95

System Cardiovascular

Figure l-5-4.Acute infarct,48 hours (microscopic).

Figure l-5-5. Healing infarct, 10 days (microscopic).

94

Pathology

"fi.t,

fi;r: Figure l-5-6. Healed infarct,3 months (microscopic).

Note 4. Clinical features a. There is acute,severe,crushing chestpain, often radiating to the jaw or left arm. b. The pain is associatedwith diaphoresis,a senseof impending doom, nausea,anxiety, and shortnessof breath. c. ECG abnormalitiesconsistof ST elevationand T-waveinversion (with Q-wave development) and ST depression(without Q-wave development).Q wavesmay develop with transmural infarcts.

presentations of Ml Atypical paincan withlittleor nochest in beseenmostfrequently diabetic women, theelderly, patients. patients, andsurgical

d. Elevatedcardiacenzymes(Figure l-5-7) include: (l) MB isoenzymeof creatinekinase (CK-MB), which is the most sensitivein common use (2) Lactate dehydrogenase(specificallythe LDH I isoenzyme),which is elevated rather specifically in myocardial infarction (3) Serum glutamic-oxaloacetic transaminase (SGOT) or aspartate transaminase (AST), also risesand falls predictably in myocardialinfarction, but may indicate liver damageinstead.

95

System Cardiovascular

Clinical Correlate CK-MB isthestandard enzyme usedto diagnose infarction inthe myocardial laboratory. Approximately 200/o is of CKinthemyocardium restisMM.ln MBtype;the muscle, skeletal only2olo of CKisMBtype.Therefore, to provemyocardial infarction, it isimportant notonlyto quantitate butto show CK-MB thatitsfraction oftotalCK LDHmaybe exceeds 5ol0. forshowing that valuable infarction myocardial occurred risen whenCKhasalready levels. andfallen to normal T isprobably a Troponin testforthisbutis better notwidely available.

(t,

= o

.= .n o tL

Time (hours) Figure l-5-7.Enzymology of myocardial infarction. (CK = creatinekinase;LDH = lactatedehydrogenase; AST = aspartatetransaminase;and SGOT = serum glutamic-oxaloacetic transaminase)

5 . Prognosis a. Suddencardiacdeath,secondaryto a fatal arrhythmia, occursin25o/oof patientswith an acutemyocardial infarction. b. Mortality after myocardial infarction is 35oloin the first year, 45o/oin the secondyear, and 55o/oin the third year. c. Eighty-five to ninety percentof survivors developcomplications. 6 . Complications are listed below in order of frequenry. a. Arrhythmias (ventricular fibrillation is the most serious).Ischemia and necrosisof the AV node and three fasciclesof the conduction systemcan lead to heart block with compromiseof cardiacfunction. b. CHF may be seenwith a loss of 20o/oor more of the ventricular muscle. c. Cardiogenic shock resultswhen there is a loss of 40o/oor more of the left ventricular muscle,resulting in the inability of the heart to maintain an adequateoutput to vital organs.Mortality is greaterthan 80%. d. Thrombus formation, resulting from lack of contractility of the infarcted area and abnormal endothelium, may follow myocardial infarction. This may be a source of systemicor cerebralemboli in large anterior wall infarctions. e. Aneurysm formation (outpouching of noncontractile scar) results in depressionof cardiac output; rupture is uncommon. It may be the site of ectopic ventricular electrical activiry leading to fibrillation. f. Myocardial (ventricular) rupture (l) Patients are most susceptiblel-7 days after infarct, when the myocardium is necrotic but granulation tissueformation has not really begun. (2) Rupture is most common with anteroapicalinfarction and is almost uniformly fatal; it resultsfrom suddenbleeding into the pericardial sacand tamponade. g. Postinfarction pericarditis (Dresslersyndrome) occurs 2-10 weekspostinfarction. h. Acute mitral insufficiency may be caused by papillary muscle infarction with or without rupture.

96

Pathology

7. Treatment and management a. Coronary artery bnrass with saphenousvein or internal mammary artery grafts restorescirculation and eliminatesangina. Grafts last approximately l0 yearsbefore restenosistypically occurs. b. Angioplasty (balloon dilatation) also restorescirculation; half restenosein 1 year.

Bridgeto Pharmacology Smalldailydoses of aspirin have beenshoum to reduce the incidence in men. of reinfarction

D. Chronic ischemic heart disease 1. Pathogenesis.Chronic ischemic heart diseaseresults from prolonged ischemia, most often due to atherosclerosis. 2. Pathology a. Grossly, chronic ischemia presents as a small or sometimes enlarged, brownishcolored heart. b. Microscopically, it presentswith myocyte atrophy and dififrrsefibrosis. 3. Clinical features.It is usuallyasymptomatic(exceptfor angina) until the late stages,when CHF supervenes. E. Sudden cardiac death 1. Overview. Suddendeath is defined as unexpecteddeath of cardiacorigin within t hour of the onset of acutesymptoms;it is usually due to a fatal arrhythmia. 2. Etiology. It is causedby IHD with coronary artery occlusion (most common) or by aortic valve stenosis,myocarditis, mitral valve prolapse, conduction disturbances,or cardiomyopathy. 3. Incidence. Out of 750,000 deaths every year in the United Statesas a result of heart disease,approximately50o/oare due to sudden cardiacdeath.

RHEUMATIC FEVER ANDRHEUMATIC HEART DISEASE A. Acute rheumatic fever (ARF) is a recurrent inflammatory diseasethat typically follows pharyngitis causedby group A B-hemolytic streptococci. l. Incidence. ARF is found mainly in children 5-15 yearsold. There has been a declining incidenceand mortality in the last 40 years,mostly due to penicillin, though the incidence beganto drop evenbefore penicillin was widely used. 2. Pathogenesis.Antistreptococcalantibodies made by the infected host cross-reactwith host connectivetissue(i.e.,cardiac,pulmonary, synovial,peritoneal) antigensand lead to end-organ damageby an immunologic mechanism. 3. Clinical features a. Onset is typically 1-3 weeksafter streptococcalpharyngitis,otitis media, or tonsillitis. b. Major Jonescriteria. In context of prior streptococcalinfection, the presenceof two of five clinical features (major Jones criteria) is sufficient to diagnose ARF. Alternatively,the presenceof one major fones criterion plus two minor |ones criteria (see"c" below) is also highly suggestiveof the disease. (1) Migratory polyarthritis involvesthe larger joints of the extremities,producing red, swollen,and painful manifestations.This featureis more common in adults than children.

Bridgeto Microbiology KeyFeatures of GroupA Streptococci . B hemolytic , HaveM protein thatconfers virulence . Catalase negative . Sensitive to bacitracin . Produce streptolysins SandO

97

System Grdiovascular

(2) Erfthema marginatum is a macular skin rash,often in a "bathing suit" distribution. (3) Sydenham's chorea is involuntary, choreiform movements of the extremities that are seenmore frequently in women. (a) Subcutaneousnodules containing Aschoff bodies. (5) Carditis may affectthe endocardium,myocardium, or pericardium. Myocarditis causesmost deathsduring the acutestage.Chronic scarringof the endocardium and heart valvesmay lead to chronic rheumatic heart disease(RHD). c. Minor Jones criteria include previous rheumatic fever, fever, arthralgias, prolonged P-R interval on ECG, elevatederythrocyte sedimentationrate, leukocytosis,and elevated C-reactiveprotein. 4. Complications. Initial episodesof ARF last weeksto months and often recur into young adulthood. Mortality is low, but the diseaseoften leads to chronic valvulitis of the mitral and aortic valves.

B. Rheumatic heart disease (RHD) causes dysfunctional, deformed heart valves through chronic inflammatory insult, deposition of fibrin and plateletthrombi, and then fibrosis. 1. Clinical features. The patient is usually asymptomatic from puberty until young adulthood. a. Valve leaflets become red and swollen and develop fibrinous, friable vegetations (verrucae)along lines of closure. b. The mitral valve is most commonly (75-80o/o)affected.Next in frequenry is the aortic and mitral valvecombination (20-25olo).The aortic valve alone is involved in 30o/o of patients.The tricuspid and pulmonic valvesare rarely affected. c. Valvedysfunction usuallypresentsasa combination of stenosisand insufficienry with one predominating. d. Fibrosis and deformity lead to "fish mouth" or "buttonhole" stenosisof the mitral valve,which may causethe patient to presentwith cardiacmurmurs,left atrial dilatation, mural thrombi, and right ventricular hypertrophy. e. Chronic valvulitis predisposesto infective endocarditis.CHF is the ultimate result, although it takesyears to develop. 2. Pathology a. Aschoffbodies

In a Nutshell = rheumatic bodies Aschoff heartdisease

(1) Aschoffbodies are pathognomoniclesions,usuallylocatedin interstitial myocardial connectivetissue,especiallynear vessels,but may be found elsewhere(e.g., subcutaneousnodules,pericardium). (2) Aschoff bodies consistof focal collectionsof perivascularfibrinoid necrosissurrounded by inflammatory cells.They contain large histiocytes (Anitschkow cells) with an irregular, ribbon-like nucleus and eosinophilic cytoplasm.These may becomemultinucleated (giant Aschoff cells). (3) Eventually,the Aschoffbody is replacedby a scar. 3. Treatment involves prophylaxis of infective endocarditis, balloon valvuloplasty, or valve replacement.

98

Pathology

HYPERIENSIVE HEART DISEASE Systemichypertension,leadingto left ventricularhypertrophy,produceshypertensiveheartdisease, A. Diagnosis requiresleft ventricular hypertrophy;a history of hypertension;and absenceof vahrllar, congenital,or aortic abnormalities. B. Pathology l. Grossly, this syndrome pres€ntswith cardiomegaly,left ventricular hypertrophy and eventualleft ventricular dilatation. Heartsmayweightwo to threetirnesnormal.

ltf!: Leftventricular trypertroptry canbedetected viax-rayor echocardiagram

2. Microscopically,h1)ertensiv€heart diseaseshowsdiffrrseand scatt€redmyocfte hypertrophy; and eventualfibrosis,atrophy,and degeneration(afteryears). 3. Chronic pressureoverloadresultsin compensatorymyocfte hypertrophy(myocytescannot replicate).Myoc''te hypertroPhyand fibrosis decreasemyocardialcompliance,limit diastolicfilling, increaseoxygendemand,and increasethe risk for myocardialischemia. C. Clinical features.HypertensiveheartdiseaseclinicallypresentsasCHF in onethird of cases, suddencardiacdeath,stroke,or renal failure (alsodue to atherosclerosis and ischemia).

(CHD GoNGESTTVE HEART FATTURE A. Overview 1. CHF is often the final outcomeof many cardiacdiseases, resulting from the inability of the heart to provide adequatecardiacoutput to meetthe body'smetabolicdemands. 2. It is most often due to decreasedmyocardialcontractility (e.g.,myocardialinfarction or fibrosis)or presswe/volume overload(e.g.,hypertension). 3. Compensatorychangesthat increasetle worHoad of the heart and ultimatd result in cHF:

t{ote

b. Tachycardiain responseto decreased strokevolume.

Although CHFispreviously discussed in the Grdiovascular Phpiology chapter, it is soclinically

c. saltandwaterretention, whichcauses anexpansion of bloodvotume.

ffi$::H

a. Hypertrophy and dilatation (Figure I-5-8) of the heart causedby compensationfor increasedworkload or volume.

Hff:ll,ur.

99

Grdiovascular System

Figure l-5-8. Biventricular dilatation (gross).

B. Left-sided heart failure (decreasedsystolic ejection of blood) 1. Etiology. Left-sided heart failure is most often causedby ischemic heart diseaseand valvular disease(particularly aortic stenosisor insufficienry), hypertension,or cardiomyopathy. 2. Clinical features a. Pulmonarycongestion and edema, resulting from pooling of blood in the pulmonary circulation, causeincreasedpulmonary venous pressure.Clinically, patients present with shortnessof breath,orthopnea,paroxysmalnocturnal dyspnea,and cough. b. Renal hypoperfusion stimulates the renin-angiotensin-aldosteroneaxis, causing retention of salt and water. Fluid retention exacerbatesthe pulmonary edema. Hypoperfusion may also causeprerenal azotemiaand acute tubular necrosis. c. Cerebral hypoxia, secondary to decreasedperfusion, nny lead to encephalopathy, stupor, or coma.

C. Right-sided heart failure 1. Etiology. Right-sided heart failure is most often causedby: a. Left-sidedheart failure, causingback pressurethrough the lungs b. Cor pulmonale, valvular disease(particularly pulmonary stenosisor insufficiency), and cardiomyopathy.Mitral stenosisand insufficiency lead to back pressureon the right ventricle. 2. Clinical features. Right-sided failure is characterized by systemic venous congestion, leading to: a. Chronic passivecongestion of the liver (nutmeg liver) with eventual centrilobular necrosis,followed by central hemorrhagic necrosis,and finally, (with fibrosis) cardiac sclerosis b. Renal hypoperfusion with salt and water retention (more severethan in left-sided heart failure) c. Splenomegaly

t00

Pathology

d. fucites, edema,pleural effrrsions,and cerebralhypoxia D. C,orpulmonale is right ventricular failure, resulting specificallyfrom pulmonary hypertension. 1. EtiologT a. Pulmonary parenchymal disease,causing increased pulmonary vascular resistance (e.g.,COPD, TB, pneumoconiosis,or carcinoid)

ClinicalCorrelate Hallmarkof Clinical Failure Right-Sided . Jugular distension venous (JVD)

b. Pulmonary vasculardisease(e.g.,vasculitis,shunts,or multiple emboli)

. Hepatomegaly

c. Restrictive chestwall abnormalities (a rare cause)

. Splenomegaly

2. Types

. Ceneralized edema

a. Acute cor pulmonale is a dilatation of the right ventricles caused by massive pulmonary embolization that may causetricuspid regurgitation. b. Chronic cor pulmonale is a gradual hypertrophy of the right ventricle, usually due to pressureoverload.

SHOCK A. pathogenesis.Shockoccurswhen decreasedblood volume or decreasedcirculation leadsto inadequate perfusion of body tissuesand cells. B. Etiology l. Decreased cardiac function leads to inadequate cardiac output. Myocardial infarction, arrhythmia, tamponade,or aortic stenosisall may lead to reducedoutput. 2. Reduction of blood volume, resulting from hemorrhage, adrenal insuffi.ciency(Addison disease),or fluid loss (vomiting and diarrhea),may lead to poor perfusion evenwith adequate cardiac function. 3. pooling of blood in peripheral vesselsmay occur as a result of the loss of vascular tone causedby bacterialtoxins and vasoactivesubstances(free radicals,anaphylatoxins).This results in loss of vascular volume into the extracellular space. C. Complications. Cellular hnroxia leads to increased anaerobic metabolism and resultant lactic acidosis,causing: 1. EncephalopathY 2. Myocardial necrosisand infarcts 3. pulmonary edemaand "shock lung" (adult respiratory distresssyndrome) 4. Acute tubular necrosisin the renal cortex 5. Various hypoxic injuries to other organs D. Stagesof compensation in shock l. Compensated stage. In this stage,early hypotension leads to reflex tachycardia and to peripieral vasoconstriction, stimulated by the CNS, causing cold, clammy, and pale extremities. 2. Decompensated stage a. Initial compensatory changes become insufficient to maintain adequate cardiac output.

to PhysiologY Flashback and tachycardia Reflex peripheral vasoconstriction viabaroreceptor occur BarorecePtors mechanisms. inthe in detail arediscussed Physiology Cardiovascular chapter.

b. Decreasedblood pressure,increasedtachycardia,metabolic acidosis,respiratory distress,and decreasedrenal output may all eventually occur.

t0l

Grdiovascular System

3. Irreversible stage. The above changes lead to irreversible cellular damage, coma, and death. E. Tr€atment. Corr€ction of the initial metabolic and physiologic derangements (prior to the irreversible stage) permit reversal of organ damage and prevent coma and death.

ENDOCARDITIS A. Infective endocarditis is the colonization of heart valves with bacteria. 1. Pathology a. Grossly, the colonies form large, friable, yegetative masses,overhanging the free margins of the valve leaflet, prosthetic valve, or other cardiac defect, b. Microscopically, a mass of clot, fibrin, and bacteria is seen.In the healing phase,there is fibrosis and calcification. c. Infective endocarditis usually involves the mitral valve. d. It can involve right-sided valves in intravenous drug users,but left-sided valves may be involved as a result of paradoxic embolization or when bacteria flow through the pulmonary capillaries. 2. Etiology

Note . Acutebaclerial endocarditis:

phyIococcu mostlikelySto s . Subacute: morelikely viridons StrEtococcus

a. There may be implantation of colonies ftom transient (i.e., dental procedures, minor skin infections) or persistent bacteremia (i.e., infected intrav€nous cathet€r). b. Strqrtococci cause6570 of infective endocarditis, usually producing a subacute bacterial endocarditis.

c. Staphylococcicause20-30 of infectiveendocarditis,usuallyproducingacutebacterial endocarditis.Intravenousdrug abuseoften causesstaphylococcalinfection ftorn the skin,but th€ spectrumof organisms is wide. d. candida is a causeof endocarditisin intravenousdrug users. e. Risk factors (1) Congenital cardiac anomalieswith high pressur€jet streams (e.9., VSD or stenoses)that produceendothelialinjury. (2) Valvular abnormalities(e.g.,mitral valve prolapse,prostheticvalves,bicuspid aortic valve,and RHD). (3) Immunosuppression,neutropenia,and intravenousdrug abusemay contribute to infectiveendocarditis. f. Bacterial by products are swept off infectedvalves,resulting in the absenceof an inflammatory reaction. This explains how a tfpically nonyirulent organism (e.g., Sfieptococcus vifidans) cancauseprogressivedisease, 3. Tlpes

Clinital Correlate Endocarditis involving therightsideof theheart suSgests intravenous druguse.

t02

a. Acut€bacterial endocsrditis (ABE) (1) Infeaion is usuallycausedby higl y vtulent organismssuchassaphyloacctts and streptococci(35%)' and it is tvpicallv seenin previouslvnorffi?f::l' (2) It oft€n involvesthe tricuspid valvein intravenousdrug users.

Pathology

(3) The acute onset clinically presentswith faneway lesions (erythematous,nontender lesions on palms and soles),representingembolized bacterial colonies, anemia,splinter hemorrhages in the nail beds (also representingemboli), high feverwith chills, hematuria causedby microemboli in the kidney,petechiae,and splenomegaly. (4) Vegetationsmay becomelarge,leading to myocardial abscessformation or systemic septic emboli. Vegetationsmay eat through valve leaflets,producing the suddenonset of valvular incompetenceand a new heart murmur (Figure I-5-9).

ts

'k

Figure l-5-9.Acute bacterial endocarditls, Staphylococcus aureus(gross).

b. Subacutebacterial endocarditis (SBE) ( 1) Etiology. Infection is causedby organismsof low virulence,suchasStreptococcus viridans, Staphylococcusepidermidis, enterococci, or Gram-negative bacilli. Candida infections are rare and are usually associatedwith indwelling vascular catheters. (2) Pathology. It is typically seenon previously abnormal valves.Regionsof turbulent blood flow produced by abnormal valves permit formation of sterile platelet-fibrin aggregateson valve leafletsthat become seededduring transient bacteremia.Vegetationsare lessbulky and lessinvasivethan in ABE. (3) Ctinical features. There is an insidious onset,clinically presentingwith positive blood cultures,Roth spots (retinal hemorrhageswith pale centers),Osler nodes (erythematous,tender lesionson fingersand toes),fatigue,low-gradefeverwithout chills, anemia,splenomegaly,and hematuria. 4. Complications of infective endocarditis a. Cardiacvalveperforation with acuteheart failure in acuteinfective endocarditis b. Myocardial abscessformation with perforation of the septum or involvement of the conductionsystem,leadingto heart block c. Mitral annulus and papillary muscle abscesses, leading to mitral valveprolapse

t05

cardiovroftt Systcm

d. Right-sided septic emboli, causing pneumonia or lung abscess in the brain, spleen,and kidney e. pft-sided septic emboli, causingstrokesand abscesses f. Nephritis may occur bY: (l) Immune complex deposition of IgM, complement component C3, and bacterial antigen in glomerular basementmembranes (2) Septicemboli,leading to renal abscessformation with rupture of the abscessinto renal tubules, causing hematuria B. Nonbacterid thrombotic (marantic) endocarditis l. Irsions are made of fibrin and platelets, producing sterile, small vegetations, loosely adhering along lines of closure of cardiac valves. The mitral valve is most commonly affected.These sterile vegetationsmay embolize, causing systemic infarctions. They may also provide a nidus for infective endocarditis.

t{ot! Marantic andvenucous arerare endocarditis and withacute compared endocarditis. subacute

2. Marantic endocarditis is associatedwith chronic illness (especiallycancer) and disseminated intravascular coagulation (DIC). There is also an increasedrisk with Swan-Ganz catheters,hypercoagulablestates,and starvation. C. Nonbacterial verrucous (Libman-Sacks) endocarditis l. This form of endocarditis typically produces mitral and tricuspid valvulitis in Patients with systemic lupus erythematosus (SLE). 2. Fibrinoid necrosisand subsequentsterile fibrosis of valvesmay occur. Patients may form small, warty vegetationson both sidesof their valve leaflets. 3. Nonbacterial endocarditis of this type rarely provides a nidus for infective endocarditis.

DISEASE HEART VALWLAR A. Mitral vdve prolapse 1. Etiology a. Prolapseof the mitral valve will lead to mitral insufficiency. The mitrd leaflets (usually the posterior leaflets) billow into the Ieft atrium during systole,leadingto insufficiency. b. Some casesmay be due to a defect in connective tissue metabolism. 2. Pathology a. Grossly, it presentsas large ballooning leaflets with elongated,drawn out, and possibly ruptured chordae tendineae. b. Microscopically, degeneration of the outer zona fibrosa and thickening of the inner zona spongiosaare seen. 3. Incidence. Mitral valve prolapse (MVP) is found in7o/o of the United Statespopulation, most commonly in young women; it is seenin most patients with Marfan's syndrome. 4. Clinical features a. Mitral prolapse presents with a characteristic midsystolic click and high-pitched murmgr. Patients are usually asymptomatic but may have dyspnea,tachycardia,chest pain, syncoPe,eventual CHR or, rarely, sudden death'

r04

Pathology

b. Prolapsemay coincidewith tricuspid or pulmonary valvedisease.It may alsobe associated with psychiatric conditions (e.9., anxiety, depression)through an unknown mechanism. 5. Complications include atrial thrombosis, calcification,infective endocarditis,embolization (to brain), rupture of chordae,arrhythmias,and suddendeath.MVP can alsolead to mitral regurgitation/insufficiencyand premature ventricular contractions ( PVCs). B. Mitral stenosis 1. Pathogenesis.Mitral stenosisis due to scarring, caicification, and fusion of the mitral valve, interfering with its opening (FiguresI-5-10 and I-5-11). It is most commonly causedby rheumatic heart disease.

Figure l-5-10.Normal mitral valve (gross).

Figure l-5-11.Mitral valve stenosis: "fish mouth" (gross).

t05

System Grdiovascular

2. Clinical features a. Mitral stenosispresentswith increasedleft atrial pressureand an enlargedleft atrium. Stenosismay be combined with mitral valve prolapse. b. An early diastolic opening snap is characteristic of mitral stenosis. Severemitral stenosiscan lead to backr,vardfailure (e.g.,CHF) if the valve fails to open sufficiently. 3. Complications. Prolonged stenosis,producing left atrial enlargement, may eventually produce chronic atrial fibrillation, which predisposesto atrial thrombosis.

Note = regu rgitation Insufficiency Backflow through theaortic valveleads to 1 LVvolume, t tittingpressure, therefore leading toLVfailure.

C. Aortic valve insufficiency 1. Acute a. It may lead to left ventricular failure due to increasedleft ventricular filling pressure, inadequatestroke volume, decreaseddiastolic filling time (due to reflex tachycardia), and myocardial ischemia. b. Acute insufficiencymay result from perforations or tearsfrom infective endocarditis. 2. Chronic a. The left ventricle will dilate and hypertrophy to accommodatethe gradual increasein regurgitatingdiastolicvolume and to maintain adequatenet cardiacoutput. b. A wide pulse pressure(clinically seenas bounding pulses)causesreflex tachycardia. c. It may be due to a congenitallybicuspid aortic valve,RHD, or syphilis. D. Aortic valve stenosis 1. Etiology a. Calcific (degenerative)heart diseasecauses90o/oof stenoticvalves. b. The aortic valve is affected somewhat lessthan the mitral valve in RHD. c. Congenital heart diseasecausesa higher percentageof stenosissince the advent of penicillin.

2 . Incidence increaseswith age. 3 . Pathology a. It is often associatedwith a congenitallyabnormal (e.g.,bicuspid) aortic valve. b. Grossly,it presentsaslargecalcifiedmasseswith thickening and fibrosis of valvecusps without fusion of valve commissures;rheumatic aortic valve stenosisinvolvesfusion of the valve leaflets. 4. Clinical features a. It presentswith angina, syncope,and CHF; it is often asymptomaticuntil late in the courseof the disease. b. Signsof increasingstenosisinclude decreasingperipheral pulse pressure,slowing of the carotid upstroke,and increasingleft ventricular hlpertrophy as a result of chronic pressureoverload. c. A systolicejection click is characteristicof aortic valve stenosis. 5. Complications. It may lead to sudden death,secondaryto an arrhythmia or CHF. 6. Treatment. Definitive treatment is surgicalreplacementof the aortic valve.

t06

Pathology

the ring of tissue surroundE. Mitral annulus calcification is a deposition of calcium within disorder' noninflammatory ing the baseof the mitral valve.It is a degenerative, mitral valvering to close 1. It may lead to mitral regurgitationbecauseof the inability of the during contraction of the Ieft ventricle' 2. It usually occurs in the elderly and is associatedwith IHD. F. Valve replacement may be indicated in: 1. Both mechanicaland bioprosthetic (usually porcine) valves a. Mitral and aortic valve stenosis b. Mixed mitral valve stenosisand insufficiency c. Mitral and aortic valve insufiiciency (regurgitation) 2. Complications that occur in 100/oof patients a year' include: a. Thromboembolism b. Infective endocarditis by calcification of c. paravalvularleak through the suture line (a problem exacerbated the mitral annulus) RBCs as a result of the d. Microangiopathic hemolysis (mechanicaltrauma to passing fragmented RBCs observing by diagnosed is presence-of u1 artificial valve). This (schistocytes)on the blood smear'

MYOCARDITIS that may lead to necrosis' A. Overview. Myocarditis is an inflammation of the myocardium seenin collagen vascular Noninfectious myocarditis may be due to a hypersensitivity reaction to pathology in viral contribute also may It allergies. diseases,rheumatic fever,SLE,and drug may alsoproduce myocarditis' myocarditis.Tiauma, which producesinflammation or necrosis, B. PathologY four chambers' A diffuse but 1. Grossly, it presentswith dilatation and hypertrophy of all foci of fibrosis can be patchy hemorrhage in the myocardium wiih eventual small,pale seen. lesionswith: 2. Microscopically, myocarditis is characterizedby focal inflammatory or granuloma in bacterial myocarditis a. A neutrophilic infiltrate, abscess, b. A mononuclear infiltrate and necrosisin viral myocarditis formation in Fiedler c. An eosinophilic infiltrate with giant cell and granuloma myocarditis C. Etiology (especially coxsackie B 1. Viral myocarditis is the most common form of myocarditis virus). as etiologic agents' a. Polio, rubella, and influenza viruseshavealsobeen described lead to cardiomyopathy and b. It is usually self-limited, but it may be recurrent and death. myocarditis on autopsy' c. Approximately one-third of AIDS patients show focal

Bridgeto MicrobiologY are B viruses Coxsackie RNA positive-sense to the belonging viruses famitY. Picornavirus

107

Grdiovascular System

2. Bacterial myocarditis may be due to diphtheria, meningococci, or other bacteria. These bacteria may damagethe heart directly or via secretedtoxins, such as diphtheria toxin.

Clinical Conetg-te Romana sign-unilateral swelling oftheeyelid-is a signof Chagas disease.

3. Protozoal etiology a. Trypanosomacruzi causesChagas disease, which is characterized by trypanosomecontaining myocardial pseudocysts,causing myocardial necrosis.Fifty percent of the population is infectedin endemic areasof South America and it is an important cause of congestiveheart failure in that areaof the world. b. Toxoplasmosisalso causesmyocardial pseudocysts. D. Clinical features 1. Myocardial involvement appearsdaysto weeksafter the primary infection. There is a variable severiry depending on the etiology. 2. Myocarditis may be asymptomatic with EKG abnormalities only, or it may present with the acute onset of dyspnea,tachycardia,weakness,or severeCHF. Edema is common to all forms of myocarditis. 3. It may have a protracted or a frrlminant course;most patients recover fully without longterm adverseeffects.

CARDIOMYOPATHY A. Primary cardiomyopathy is associatedwith ill-defined syndromes of unknown origin that may be divided into three subtypes:dilated, hlpertrophic, and restrictive. 1. Dilated (congestive) cardiomyopathy a. Pathology (1) Grossly, dilated cardiomyopathy presents with gradual dilatation of all four chambers,producing cardiomegaly. (2) Microscopic findings are nonspecific, with some patients showing scattered fibrosis and myocyte atrophy. b. Clinical features. There is decreasedcontractility, stasis, and formation of mural thrombi. c. Complications. Death is due to progressiveCHF, thromboembolism, or arrhythmia. d. Possible etiologies include: (1) Pregnancy-inducednutritional, hlpertensive, volume, or metabolic abnormalities (peripartal cardiomyopathy) (2) Alcohol toxicity or associatedthiamine deficiency (3) Geneticdilated cardiomyopathy (4) Poswiral infection

ClinicalCorrelate Young adultathletes whodie duringstrenuous activity are sometimes notedto have hadhypertrophic subaortic stenosis.

r08

2. Hypertrophic cardiomyopathy (idiopathic hlperthrophic subaortic stenosis; IHSS) a. Pathology (1) Grossly, hypertrophic cardiomyopathy presentswith cardiomegaly as a result of myocardial hypertrophy (left ventricle > right ventricle), marked asymmetrical hypertrophy of the ventricular septum, causingobstruction of the left ventricular outflow tract that is rarely clinically significant, endocardial thickening in the

Pathology

ventricular outflow tract (which may be a nidus for infective endocarditis), a thickened mitral valve, and dilated atria. (2) Microscopic findings include myofiber hlpertrophy, disorganization of septal myofibrils, and diffirse fibrosis. (3) A hypercontracting heart with diminished ventricular volume and decreased cardiac output may causedyspnea,angina, atrial fibrillation, syncope,sudden death,mural thrombus formation and embolization,infective endocarditis,and CHF. b. Clinical features. There is a variable clinical course, and patients may be asymptomatic. c. Possibleetiologies include: (1) Genetic (50oloof hypertrophic cardiomyopathyis transmitted in an autosomal dominant pattern) (2) Catecholaminehypersensitivity

Note Thegeneforhypertrophic cardiomyopathy ison chromosome 14q, whereit encodes a peptide inthe heavy chain of myosin.

(3) Myocardial ischemiacausedby abnormal intracardiacarteries (4) Primary collagendisorder,causingmyocardialfibrosis 3. Restrictive (infiltrative) cardiomyopathy and subtypescausemyocardial disease,leading to restriction of ventricular inflow and reducedcardiacoutput. a. Cardiac amyloidosis cardiomyopathy can occur in isolation or in association with systemicamyloidosis. It often occurs in the elderly and may also induce arrhythmias. b. Sarcoidosis/granulomatous cardiomyopathy is associatedwith systemicsarcoidosis. It often occursin the young (<25 years). B. Secondary cardiomyopathy. Myocardial diseasemay be associatedwith well-defined syndromes or settings,from metabolic disorders,such as diabetes,to nutritional deficiencies, such as scurvy.

PERICARDITIS A. Overview. Pericarditisis inflammation of the pericardium, usually as a result of local spread from adjacentmediastinalstructures(myocardial infarction, trauma, surgery,infections,or tumors). Primary pericarditis is usually due to systemicviral infection; uremia and autoimmune diseasesare also common causes. B. Fibrinous (serofibrinous) pericarditis is the exudation of fibrin and other plasma proteins with clumping of fibrin deposits.It is the most frequent form of pericarditisassociatedwith myocardial infarction. It may also be due to trauma, rheumatic fever,radiation, SLE, and infrequently, infections. Clinically, it may present as a loud pericardial friction rub with chestpain, fever,and, occasionally,symptoms of CHF.

Note lf yousee/hear the "friction words rub," thinkpericarditis.

C. Serous pericarditis is due to a small amount of exudative effusion with few inflammatory cells.It is usually causedby a nonbacterial,immunologic reaction (e.g., rheumatic fever, SLE),tumor, uremia, or a viral infection (e.g.,coxsackievirus),or it may be idiopathic. It is usually asymptomaticbut may clinically presentas a persistentdull chestache. D. Suppurative pericarditis is a purulent exudate with erythema of the serosa.Organization leadsto constrictivepericarditis and cardiac insufficiency.It is usually causedby bacterial, fungal, or parasitic infection and may clinically present with systemic signs of infection (fever,malaise)and a soft friction rub.

r09

System Cardiovascular

Note lf youseecaseous, thinkTB.

E. Hemorrhagic pericarditis is an exudate of blood, mixed with suppurative or fibrinous material. It is usually associatedwith tuberculosisor a malignant neoplasm;organization may lead to constrictive pericarditis. F. Caseous pericarditis usually develops into fibrocalcific constrictive pericarditis and is usually causedby tuberculosis. G. Chronic/resolved pericarditis and subtypes 1. Adhesive mediastinopericarditis causesobliteration of the pericardial sac by fibrous organization of suppurative or caseouspericarditis. The parietal layer of the heart becomesfusedto the inner layer of the pericardium, causingincreasedcardiacworkload, and leading to cardiachypertrophy and dilatation. 2. Constrictive pericarditis is a restrictive diseasecausedby thick fibrosis and scarring of the pericardialspace.The heart is unable to hypertrophy becauseof the surrounding scar tissue.Cardiac output diminishes as a result of decreasedfilling during diastole (right ventricle is unable to expand),and heart sounds are diminished.

PERICARDIAT EFFUSION Pericardialeffusion is leakageof fluid (transudateor exudate)into the pericardialspace.It may result in cardiactamponade,in which the collection of fluid compressesthe heart, limiting filling during diastole,and decreasingcardiacfilling. A. Serous effr,rsion results from hypoproteinemia or CHF. It usually develops slowly, rarely causingcardiaccompromise. B. Serosanguineouseffusion is usually due to trauma (e.g.,cardiopulmonary resuscitation), tumor, or TB. It rarely causescardiaccompromise. C. Chylous effusion is due to lymphatic blockage.It rarely causescardiaccompromise.

Clinical Conelate Hemopericardium canbea complication of vigorous CPR.

D. Cholesterol effusion is either idiopathic or due to myxedema;it is very uncommon. E. Hemopericardium occurs when blood flows into the pericardial sac as a result of trauma, ventricular rupture (after myocardial infarction), or aortic rupture. There is no inflammatory infiltrate. This condition can quickly causecardiactamponadeand death.

CARDIAC NEOPTASMS A. Primary cardiac tumors are rare. Eighty percent are benign. 1. Myxomas (atrial mlxoma). A myxoma is a benign tumor derived from multipotential mesenchymalcells.It is the most common primary cardiactumor in adults. a. Clinical features. Most tumors occur in the left atrium and are usually single.They may be any size,sessileor pedunculated. b. Complications include: (1) Ball-valve obstructions of the mitral valve,resulting in syncope,shock,or death (2) Impact trauma as a result of tumor movement during heart contraction (3) Embolization of the myxoma or its fragments 2. Rhabdomyomas are benign tumors derived from striated muscle. They are the most common primary cardiactumor in children (especiallythosewith tuberous sclerosis).

il0

Pathology

3. Angiosarcomas, rhabdomyosarcomas, mesotheliomas, lipomas, and papillary fibroelastomasare much lesscommon. B. Metastasesto the heart. Most metastasesto the heart come from bronchogeniccarcinoma and lymphoma from regionalnodes.They involve the pericardium more than the myocardium, and may interfere with the conduction systemor causepericardial effusions.

TRAUMATIC HEART INIURIES A. Penetrating injuries. In wounds causedby low-velocity penetration (e.g., knife wound, shrapnel,medical procedures),the damagefollows the path of the penetrating object. In high velocity (..9., bullet) wounds, damagefollows the path of injury, but tissueat a distance from the path of injury is also affectedas a result of releasedenergy. B. Nonpenetrating accidents,such as sudden deceleration,explosion, or compression,injure the heart by forcing contact with adjacentstructures. C. Automobile accidents are the most common causeof cardiac trauma. Compression,false aneurysm (occlusion of aorta due to blood accumulation in the adventitia),anterior right ventricular contusion, and anterior descending coronary artery damage may all occur. Compressioninjuries may exacerbateunderlying cardiacdisease,such as mitral valve prolapseor IHD. D. Bullet and knife wounds may causecardiac tamponade, hemopericardium, and myocardial rupture. During healing,thesemay developarteriovenousfistulas.

CONGENITAT ABNORMAIITIES OFVESSETS A. Berry aneurysms are focal weakeningsin cerebral vesselwalls, resulting in an outpouching. They are most common at branch points in the anterior circleof Willis and at the bifurcation of the middle cerebral artery. Symptoms are rare before age 20, after which time they may burst and causea subarachnoidhemorrhage. B. Arteriovenous (AV) fistula is a rare abnormal communication between a vein and an artery. 1. By diverting blood from the arterial to the venous circulation, it increasesvenousreturn, increasesthe workload to the right heart, and may, therefore,causeright heart failure. 2. AV fistulasmay also form as a result of trauma.

ARTERIAT HYPERTENSION A. Clinical features l. Arterial hypertension is defined as a consistentdiastolic pressureover 90 mm Hg (for adults over 18 yearsof age) or a systolicpressureover 140 mm Hg, or both on repeated determinations. 2. Hypertension causeshlpertensive heart diseasewith progressivethickening of the left ventricle,myocyte dropout, fibrosis,and eventualheart failure. B. Morbidity and mortality 1. Hypertensionis the secondleadingcauseof cardiacmortality after ischemicheart disease. 2. Hypertensionis stronglyassociated with both strokeand myocardialinfarction.It may also lead to CHR renal failure, coronary and peripheral artery disease,and aortic dissection.

ill

Cardiovascular System

3. Mortality hasbeendeclining asa result of early recognition,antihypertensivetherapy,and control of obesity. C. Essential (primary) hypertension is idiopathic and accounts for approximately 90o/oof cases.The pathophysiologyis unknown, but it may be due to geneticor environmental factors, most likely resulting in increasedsystemicvascularresistanceor increasedcardiacoutput. Type A personaliry obesiry stress,high-salt diet, and oral contraceptivesincreasethe risk; it is most common in African American malesaround 40 yearsof age. D. Secondary hnrertension is hypertension resulting from other diseases,most commonly renal disease.

ATHEROSCTEROSIS Atherosclerosisinvolves the progressiveformation of elevated fatty plaques (atheromata) in the intima of large-and medium-sizedmuscular and elasticarteries.The atheromatacausenarrowing of the vessellumen, weakeningof the media, and possiblyprogressionto ulceration,calcification, thrombosis,intralesionalhemorrhage,or aneurysmformation. This disorder affects primarily the coronary, cerebral,and iliac arteries and the aorta. It accountsfor 50oloof all deathsin the United States.Death occursmainly from myocardialor cerebralinfarcts. A. Pathology 1. Grossly, atherosclerosis presentswith: a. White or pale yellow plaques0.5-1.5 cm in diameter bulging into the lumen with a soft "gruel-like" center b. Lesions occur (in order of frequency) in the abdominal aorta, coronary arteries, popliteal arteries,descendingthoracic aorta, internal carotid arteries,and circle of Willis 2. Microscopically, atherosclerosis presents(from inside the lumen to the outer vesselwall) as:

Note = macrophages Foam cells afterlipidingestion

a. A fibrous cap composed of smooth muscle cells,collagen,connectivetissue matrix, and scatteredleukocftes b. A cellular zonecomposedof smooth muscle cells,macrophages,and lymphocytes c. A central core composedof necrotic cells,cholesterolclefts,lipid-filled foam cells,and plasmaproteins d. Proliferating capillarieswhen lesionsare well-advanced 3. Complicated plaques are seen in advanceddisease.They arise when calcification and thickening causeischemia of the intima. Fissure,ulceration, and rupture of atheromas into the lumen may cause: a. Thrombus formation with occlusionof the vessel,leading to infarction of the tissueit supplies b. Cholesterolemboli c. Hemorrhageinto the lesion d. Aneurysmal dilatation 4. Fatty streaks have the following characteristics. a. They are elevated,poorly demarcated,yellow intimal lesionslessthan 2 mm wide and 1 cm long.

il2

Pathology

b. They may be present in children asyoung as 1 year old and may or may not evolveinto atheromas. c. They are composedof lipid-containing cells(macrophagesand smooth musclecells), collagen,elastic fibers, proteoglycans,and extracellular lipid. d. They are most common in the thoracic aorta (<1 year) and coronary arteries. B. Etiology of atheromatous plaques 1. Responseto injury a. Endothelial injury may be due to hypertension, hyperlipidemia, chemicalsin tobacco smoke, diabetic angiopathy, and gross physical or chemical injury. b. Injury may lead to increased permeability of plasma proteins, platelet and inflammatory cell adherence,and thrombus formation at the site. c. Chemical mediators from the above cells may induce migration and proliferation of smooth muscle cells from the media into the intima. d. Production of abundant connective tissue matrix (collagen, elastic fibers, proteoglycans) by smooth muscle cells follows with ingrowth of intimal capillaries from the vasavasorum for nourishment. This may lead to subsequentleakageof more plasma proteins, finally resulting in the deposition and accumulation of lipid in the plaque. 2. The loss of growth control hypothesis suggeststhat smooth muscle proliferation in the media may be the initial event. C. Risk factors 1. Hlpertension. The risk of atherosclerosiscorrelatesmore closelywith diastolic than with systolic pressure. 2. Cigarette smoking. The death rate from ischemic heart diseaseis70-200o/ohigher in men who smoke at leastone pack per day than in nonsmoking men. 3. Hlperlipidemia a. Elevated serum cholesterol levels,especiallylow-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) b. Hyperlipidemia may be due to genetic (e.g.,familial hypercholesterolemias), dietary (e.g., high cholesterol and saturated fat intake), other clinical conditions (e.g., nephrotic syndrome, hypothyroidism), or a sedentarylifestyle. c. Elevatedhigh-densitylipoproteins (HDLs) may decreaserisk becauseHDL transports cholesterol out of tissuesback to the liver, while LDL transports cholesterol from the liver to the tissues. 4. Diabetes causesdamage to arterioles by depositing hyaline material in their walls and reducing blood flow. 5. Increasing age. Significant atherosclerosisis rarely seenin patients younger than 30 years of age;it becomessymptomatic in patients in their fifties and sixties. 6. Incidence is higher in men, in postmenopausalwomen, and in individuals with a positive family history. 7. Sedentary lifestyle, obesiry oral contraceptives, stress, and a compulsive, workaholic behavior pattern (tfpe A personality) increasethe risk. "U

il5

System Cardiovascular

D. Clinical features 1. Atherosclerosismay be asymptomaticfor decades. 2. Ischemia due to gradual vesselocclusion (e.g.,gangreneof the lower extremities,intermittent claudication) may eventuallydevelop. 3. Infarction due to sudden occlusion by thrombosis or embolization (e.g., myocardial infarction, renal artery occlusion) is the most dramatic sign. Twenfy-fivepercentof cases presentwith sudden death. of coronary atherosclerosis 4. Aneurysm formation with subsequentrupture (e.g., abdominal aortic aneurysm) may alsobe a presentingsign.

ARTERIOIOSCIEROSIS Note Thekidneyis particularly to vulnerable arteriolosclerosis.

Arteriolosclerosisis a diffrrsethickening of arteriolesand small arteries,resulting in narrowing of the lumen and ischemiaof involved tissue. A. Hyperplastic arteriolosclerosis is associatedwith malignant hypertension or necrotizing vasculitisand is characterizedby "onionskin hyperplasia,"i.e., concentric thickening of the intima, deposition of basophilicground substance,smooth muscleproliferation, and hypertrophy of the adventitia. B. Hyaline arteriolosclerosis is associatedwith diabetes,hpertension, and old age.It is characterized by hyaline thickening of arteriolesthat nanows the vessellumen. This form of arteriolosclerosisis further characterizedby eosinophfic material (thickenedbasementmembraneof endothelial and smooth muscle cells)in the intima and media and is a degenerativeprocess.It is best recognizedin the arteriolesof adiposetissue,where the vesselwalls appearasthick asthe diameter of the lumen.

Figure l-5-12.Coronary artery atherosclerotic occlusion, old (microscopic).

il4

Pathology

EMBOTISMS Embolisms may arise from solid, liquid, or gaseousmassestransported within the vesselsand originating from thrombi (98olo),fat (bone fractures), atheromas,gos€s(deep seadivers), or amniotic fluid (pregnanry). A. Emboli arising from the venous circulation involve the pulmonary circulation (pulmonary emboli). Thesemay paradoxicallyinvolve the systemiccirculation via a right-to-left cardiac shunt (e.9.,atrial septaldefect),which was not previously known to exist. B. Emboli arising from the arterial circulation involve nonpulmonary structures. 1. Seventy-fivepercent arise from cardiac mural thrombi due to myocardial infarction. Grossly, mural thrombi appear gray-red with alternating light and dark lines (lines of Zahn), which representclotted plasmaand red blood cells(RBCs),respectively. 2. Arterial emboli most commonly involve the legs,then the brain, other viscera,and the arms.

ANEURYSMS Aneurysmsare focal, abnormal, dilatations of arterial vesselsas a result of wall weakness.They may lead to rupture, which is a recognizedcauseof suddendeath,compressionof nearbystructures, and thrombus formation and embolism, which may causeinfarction of distal organsor structures. A. Atherosclerotic aneurysms are secondaryto atheroma formation. They usually occur in the abdominal aorta below the renal arteries,are associatedwith hypertension,and are found in men over 50 years of age.Fifty percent of atherosclerotic aneurysms over 6 cm in diameter will rupture within 10 years. B. Syphilitic aneurysms are due to chronic damageto the vasavasorum of the aortic media by syphilitic aortitis. This damage results in obliterative endarteritis, ischemia,and smooth muscle cell atrophy.It usually occursin the ascendingaorta and may impinge on the aortic valve, causing aortic insufficiency due to dilatation of the valve ring. C. Microaneurysms may appearin cerebralvesselsasa result of hlpertension and in retinal vesselsas a result of diabeticvasculitis. D. Dissecting aneurysms are due to degeneration of the tunica media, which allows blood from the lumen to enter an intimal tear and dissect through the layers of the media. They most frequently occur in the aorta. 1. They may progressivelyspreadinto aortic branches(e.g.,renal or coronary arteries),leading to compressionand obstruction of the lumen of the branch. 2. Etiology is unknown, but hypertensionand Marfan diseaseare predisposingfactors. E. Berry aneurysms are previously discussed.

VASCUTITIS

Bridgeto Biochemistry ln Marfan disease, thereisa defect inthegeneforfibrillin onchromosome l5q.Fibrillin isa rSO-kD a molecule, glycoprotein present in particularly connective tissue, thesuspensory ligament of thelens, thewallsof blood vessels, andtheskin.

Vasculitisis an inflammation of the vesselsthat may be localized (due to trauma, infections, toxins) or systemic.Multifocal vasculitismay lead to widespread,patchy necrosisand thrombi formation and is usually due to an immune reaction. A. Polyarteritis nodosa (PAN) is a systemicnecrotizing vasculitis of small- and medium-sized muscular arteries(often at bifurcations).

il5

System Cardiovascular

Bridgeto lmmunology (Ag-Ab) Antigen-a ntibody precipitate complexes onto vessel walls, where theyfix complement andattract neutrophils bymeans of gradients of C5afragments, phagocytose Neutrophils the complexes anddischarge granules lysosomal that destroy smooth muscle and fibers. elastic

1. Etiology a. Hepatitis B antigenemiacan be demonstratedin 30o/oof cases. b. Essentiallyall casesof PAN are thought to be due to antigen-antibody complexes. c. Autoantibodies may also play a role when they form complexeswith self-antigens. P-ANCA (perinuclear antineutrophil cytoplasmic autoantibodies) are frequently observedin PAN and may correlatewith diseaseactivity. 2. Pathology a. Grossly,PAN presentsas up to 1-cm segmentalaneurysmaldilatationsin vessels.It is seenpredominantly in the kidneys, heart, and gastrointestinaltract; the pulmonary circulation is spared. b. Microscopically, there are three different stages,the lesions of which may be all be presentsimultaneously. (1) Acute lesions havesharply demarcatedfibrinoid necrosisof the vesselwall and a neutrophilic infiltrate. (2) Healing lesions havea proliferation of fibrobiastsand a mononuclear infiltrate. (3) Healed lesions have fibrotic thickening, loss of elastictissue,and possibleaneurysmal dilatations.The loss of the internal elasticlamina is an excellentclue that old vasculitis is present. 3. Clinical features a. Symptoms depend on the systeminvolved. Patientsmost commonly have low-grade fever,weakness,and weight loss.They may alsohaveabdominal pain, hematuria,renal failure, hypertension,and leukocytosis. b. PAN is most common in young aduits. 4. Diagnosis is made by arterial biopsy. 5. Prognosis. Mortality is decreasedwith immunosuppressivetherapy. B. Churg-Strauss syndrome (allergic angiitis) is a variant of PAN that involves small and medium-sizedmuscular arteriesaswell asveins and venules.It involvesthe lung and spleen with intra- and extravasculargranulomasand is also associatedwith bronchial asthma and eosinophilia.

ln a Nutshell + tenderness Headache at = + elevated temples ESR temporal arteritis. Temporal arteritis hasbeena long-time USMLEfavorite.

C. Temporal (giant-cell) arteritis is a granulomatous inflammation of small- and mediumsizedarteries,particularlyextracranial arteries (especiallythe temporal artery). This is perhaps the most common form of vasculitis.Etiology is unknown. l. Pathology. Microscopically, this disorder presentsas a continuum of: a. Focal areasof multinucleatedgiant cells,forming granulomaswith fragmentedinternal elasticlamina b. Generalinflammation of vesselwalls with neutrophils,eosinophils,and lymphocytes c. Fibrosisof the intima with lumenal narrowing 2. Clinical features a. Giant cell arteritis occursin both malesand females,usually greaterthan 50 yearsold, and affectsmainly the cranial and most commonly the temporal arteries. b. It clinically presentswith:

il6

Pilrology

(1) Headache and facial pain (the most common symptoms) (2)Fever,malaise,weightloss,muscleaches,anemia,claudicationofthejaw,visual disturbancesin 40o/oof cases,and tender, firm temporal arteries (3) Elevated ESR, as in all inflammatory diseases (a) Bhndness,if not treated early (due to occlusion of ophthalmic artery)

,

3. Diagnosis. Temporal arteritis is diagnosed by arterial biopsy, usually of the superficial temporal artery. 4. Treatment. Patientsare treated with steroids, which usuallyproduce a dramatic response. D. Hypersensitivity (leukocytoclastic) angiitis affects small vessels(i.e., arterioles, venules, capillaries)predominantlyintheskin.Itmayalsoaffectvessels,lungs,kidneys,andother organs simultaneously and may causecrescenticglomerulonephritis. Hypersensitivity angiitis may be distinguished from PAN by the involvement of smaller vessels.Lesions are usu.lly.ll in the same stageat the sametime. 1. Etiology. Immune complexesare thought to be involved becauseit is often precipitated by a specific antigen, such as bacteria (e.g., Streptococcus),drugs (penicillin), tumor antigens,or serum sickness.The diseaseremits if the ofifending agent is removed. 2. Pathology. MicroscopicallR leukocytoclastic angiitis presentswith neutrophilic inflammation with or without fibrinoid necrosis. 3. Clinical features a. Hypersensitivity angiitis is often associatedwith well-defined clinical sfndromes that are thoughttoinvolvehypersensitivityreactionstoanapparentexogenousantigen. ( 1) Henoch-Schitnlein purpura is a diseaseof children that is characterizndby nonthrombocytopenic purpura, skin lesions, joint involvement, coliclcy abdominal pain, and renal lesions. (2) Vasculitides associatedwith infectious disease,neoplasms,and connectivetissue disorders all may have a common mechanism but obviously different antigens. b. Hypersensitivity angiitis clinically presentswith:

l

( I ) Purpura, petechiae,and necrotic ulceration predominantly on the skin of the feet and ankles (2) Fever,myalgia, anorexia,arthritis, and renal involvement E. Thromboangiitis obliterans (Buerger disease) is a recurrent acute and chronic inflamma-

In a ill6tfcll

tory disorderof smalland medium-sizedarteriesandveins,causingsegmentalthrombosis that occursin the extremitiesand may also affectadjacentnery€s.It occursalmost exdu-

lf youseegangrene in a

sivelyin cigarette smokers lessthan 35 years of age.

-r think youngsmoker

1. Etiology. Possiblecausesinclude a genetic predisposition, an immunologic reaction, and a direct toxic response(tobacco).

Buergerdisease'

2. Pathology. Microscopically, it presents with a neutrophilic inflammatory infiltrate, occlusiveormuralthrombosiswithmicroabscessesandgiantcells,andeventually,fibrous encasementof the artery vein, and nerye. 3. Clinical features include severe pain in the affected extremity, ulcers, gangrene, and thrombophlebitis. 4. Prognosis. Remission correlatesvery well with abstinencefrom smoking.

il7

System Cardiovascular

l{Ote ifyou OntheUSMLE, encounter a patientwith lung,sinus,andkidney disease, thinkWegener granulomatosis

F. Wegenergranulomatosisconsistsof a triad of necrotizingvasculitisof lungs and airways' xecrotizing granulomasof the upper respiratory tract, and necrotizing glomerulitis. It occurs in men more often than women. Patientsare usually older than 50 yearsof age. Etiology is unknown' 1. pathology,Microscopically, it presentsasregionsof necrotizingvasculitisand granuloma formationwith areasof fibrosis. 2. clinical features.Wegenerclinically presentswith cavitary pulmonary lesions,chronic ulcerations' sinusitis,renaldisease,nasophatyngeal 3. Prognosis.Thereis a poor prognosiswithout treatment,but mostPatientshavecomPlet€ drugs' remissionwith immunosuppressive G. Tak yasus arteritis (pulselessdisease)is a granulomatousinflammation of medium-tolargearteries,often branchesof the aortic arch. 1. Etiology. The causeis unknown. 2. Pathology a. Grossly,it presentswith: (1) Irregular fibrous thickeningof the wall of the aortic arch with narrowing of the orificesof the major branch arteries,leadingto weakpulsesin the carotids of cases (2) Involvementof the pulmonary arteriesin 50026 b. Microscopically,it pr€sentswith;

Gliniol Conelah thebloodpressure Check ln botharmsinyoung Asianwomento identt{y pressure dif{erences Takayasu suSSesting arteritis.

(1) Arl early mononuclearcell infiltrate ofthe vasavasorumand mediawith occasionalgranulomaformation (2) Massivefibrosis of the media 3' clinical features arteritis is most common in women (15-45 years)and in Asians. a. T?rkayasu as: o' ll crmcary Presenrs (1) Ocular disturbanc€s(visual abnormalities, retinal hemorrhages),neurologic abnormalities,and weakpulsesin the upper extremities (2) Weakness, fever,malaise,and arthralgias (3) Spontaneousremission for limited periods of time but relapsesif untreated (steroids) H. Kawasakidisease(mucocutaneouslymph node syndrome)wasfust describedin Japanand is still morecommonthere. 1. Epidemiology.The diseaseis usuallyseenin young children,but adult patientshavebeen described(rare). 2. Etiology. The causeis unknown.An RNA-dependentDNA polymerasehasbeenfound in somelesions,suggestinga viral etiology' 3. Pathology.Microscopically, it presentswith inflammation and necrosisof the entire vesselwall and possibleaneurysmformation. 4, Clinical f€atures,Kawasakidiseaseis an acutesyndromeconsistingof: a. Fever,conjunctivitis,erfthema and erosionsof the oral mucosa,a generalizedmaculopapularskin rash,and adenopathy

il8

Pathology

b. A mortality rate of l-2o/o as a result of coronary vasculitis or coronary aneurysm, thrombosis,or rupture c. Self-limited course

VENOUS DISEASE A. Thrombophlebitis is inflammation and thrombus formation of the veins.Ninety percentof casesoccur in the deep veins of the leg (i.e., deepvenousthrombosis). l. Pathology. Factors involved in thrombus formation (Virchow triad) are endothelial injury, alterationsin blood flow, and hlpercoaguabiliryof blood. Thrombi grosslyappear blue-red. 2. Clinical features a. Thrombophlebitis may be associatedwith or may be secondaryto: (1) Clotting disorders (deficiencyof antithrombin III, protein C, or protein S). In thesedeficiencies,normal clot dissolution (fibrinolysis) is abnormally slow. (2) Heart disease(CHR myocardialinfarction, valvular disease),leadingto sluggish flow

Bridgeto Heme/lymph Theroles of antithrombin lll, protein C,andprotein S in enhancing clotdissolution are discussed intheHematologic/ Lymphoreticular Physiology chapter.

(3) Immobilization (including bed rest), slowing venous flow (a) Neoplasia,sometimesproducing enzFmesthat promote clotting (5) Advanced agewith sclerotic veins and slow flow (6) Pregnanrywith obstruction of pelvic veins (7) Oral contraceptives,which activatesome clotting factors (8) Tissueinjury (postoperativecourse,trauma), which alsoactivatesclotting, sometimes systemically b. Thrombi may cause: (1) Embolization, particularly to the lungs (2) Bacterialsuperinfection,producing a septicnidus (3) Postphlebiticsyndrome (predisposition of recurrent thrombosis due to loss of venousvalves) (4) Recanalizationof the thrombus, restoring more normal flow c. Clinically, thrombophlebitis presentsinsidiously with few symptoms (localizedpain, erythema, and edema). It often presentsinitially as a pulmonary embolism or as multiple emboli; a large embolus may causesuddendeath. B. Venous occlusion may occur as a result of thrombophlebitis, deep venous thrombosis, or obstruction of outflow (pregnancy). C. Varicoseveins are dilated, tortuous veins,most likely resulting from increasedintraluminal pressureand inadequateexternal support. They occur most frequently in the superficial veins of the lower extremities.They are more common in women.

Note Some ofthevasculitides theveinsandvenulesaffect on seetheprevious section Vasculitis.

1. Pathogenesis.Varicoseveins are associatedwith the venous stasisof pregnanry,obesity, compressionby tumors, prolonged immobility of legs,and congenitaldefectsin venous walls (including valves).They may result in venousthrombosis and valvedamage.

I t9

Cardiovascular System

2. Clinical features.Varicositespresentwith edema,thrombosis,stasisdermatitis,and ulcerations. Unlike venous abnormalities of the deep veins of the lower extremities,varicose veins are rarelv a sourceof emboli.

VASCUTAR NEOPTASMS Vascularneoplasmsinclude all of the neoplasticgrowths of the vascularendothelialcells,forming well-defined endothelial-linedvascularchannelsin benign tumors, or ill-defined massesof anaplasticendothelialcellsin malignant tumors. A. Benign tumors 1. Hemangiomas a. Capillary hemangiomas form unencapsulatedwell-defined massesof capillarieswith a small amount of connectivetissuethat usually occur in the skin and mucous membranes. b. Cavernous hemangiomas form sharply defined, sponge-like tumors composed of large, dilated, cavernousvascular spaces.They usually occur on the skin, mucous membranes,and visceraand are rarely clinically significant exceptfor their cosmetic effects. c. von Hippel-Lindau disease is a syndrome of multiple cavernous hemangiomas involving the cerebellum,brain stem, liver, pancreas,and eyes.It is associatedwith renal rystsand renal cell carcinoma.This diseaseis transmitted via an autosomaldominant pattern with the genelocalizedto chromosome3p. 2. Vascular ectasias (telangiectasias)are actually a developmental abnormality but can closelymimic benign vascularneoplasms.They may be composedof abnormal aggregations of arterioles,capillaries,or venules. a. Nevus flammeus is a flat birthmark on the head or neck that usually spontaneously regresses. b. Port wine stain may grow proportionately with the child and may be associatedwith Sturge-Webersyndrome, a nevus formation in the skin supplied by the trigeminal nerve and associatedwith glaucoma,meningealangiomas,and mental retardation. c. Spider telangiectasias are a radial array of tiny arterioles, commonly occuring in pregnant women and patientswith hepatic cirrhosis. In men, they may be relatedto elevatedestrogenlevelsoccurring as a result of liver disease(e.g,alcoholism). B. Malignant tumors 1. Hemangiosarcomas are growths of atypical, anaplastic endothelial cells that usually metastasizeand are associatedwith a high mortality. a. Gross pathology. Hemangiosarcomasmost commonly occur in skin, breast,liver,and soft tissues.They are usually sharply defined red nodules,which become large,pale, soft masses. b. Microscopic pathology. Hemangiosarcomasshow varying degreesof anaplasiaand vesselsof different sizesand shapes.Vesselsare often merely slit-like spaces. 2. Hepatic angiosarcomasare tumors causedby toxic exposures. 3. Kaposi sarcoma was once a rare, slowly progressivediseaseseen in older men of Mediterranean or African descentor immunosuppressedtransplant patients. It is now

r20

Pathology

seen in one third of AIDS patients, most frequently in homosexual males. This form of the diseasemay be more aggressiveand frequently disseminates. a. Pathology (1) Grossly, it presentsas multiple violaceous nodules that may remain confined to the skin or may disseminate. (2) Microscopically, it presentsas a proliferation of endothelial cells, spindle cells, and inflammatory cellswith RBCs scatteredthroughout slit-like vascular spaces. (3) It has been shown to be causedby human herpesvirusrype S (HHVS). b. Prognosis. Kaposi sarcomararely causesdeath in otherwisenormal patients responsive to chemotherapyand interferon-cr (INF-cr), but it usually spreadsrelentlesslyin AIDS patients.

l2l

Cardiovascular Pharmacology Although manydrugsexertaneffectonthecardiovascular system, thefivegroupsof drugsdiscussed inthischapter actspecifically ontheheartorareuseful intreating cardiac disease: antihypertensives, glycosides, antiarrhythmis, cardiac antianginal agents, andantilipid agents. Thrombolytic agents are introduced, butarediscussed in moredetail intheHeme/Lymph Pharmacology chapter.

ANTIHYPERTENSIVES Antihypertensivesrepresenta categoryof agentsthat span severalclassesof drugs. They share the common feature of decreasingvascular tone, intravascular volume, or cardiac contractility. Vasculartone is modified by agentsthat alter CNS sympatheticoutflow, block sympathetic tone at the arterial smooth muscle receptor,or act directly to relax vascular smooth muscle. Their respectivepropertiesare summarizedlater in ThbleI-6-1. A. Central-acting sympatholytic agents 1. Clonidine a. Pharmacologic properties. Clonidine stimulates central and peripheral o2-adrenergic receptors and diminishessympatheticoutflow. An intravenousinjection or overdosecan causea transient initial increasein blood pressureasa result of stimulation of peripheral postsynapticvasoconstrictivecr2receptors.Fifty percentof the drug is metabolizedin the liver, and 50% is excretedunchangedby the kidney. b. Indications for use include moderate-to-severeessential(i.e., idiopathic) hypertension. Clonidine can also be used during narcotic withdrawal, as adjuvant therapy in ethanol withdrawal, and for the diagnosisof pheochromocytoma.It is frequently used in patients with renal hypertension. c. Side effects and toxicity. Clonidine causessedation and dry mouth (xerostomia) in more than half of patients and can also causeinsomnia, nightmares,and depression. Orthostatic hypotension and fluid retention can be alleviatedby adding a diuretic to the treatment regimen. Rebound hlpertensive crisis can occur after abrupt withdrawal. d. Drug interactions ( 1) Tricyclic antidepressantsand clonidine (methyldopa) canceleach other's effect. Antidepressantsincreasesympathetic activity by blocking reuptake of norepinephrine, whiie crr-agonistsare antihypertensiveby lowering it. (2) Ca2+channelblockers also decreaseheart rate and contractibility and will have additive effectto the cardiosuppressioninduced by ar-agonists.

Note Clonidine decreases sympathetic outflowcentral ly. It alsoactsperipherally by presynaptic q stimulating receptors, inhibiting thereby norepinephrine release and decreasing vascular toneand heartrate.

Note Methyldopa isconverted to cr-methyl NE,which stimulates cx,-adrenergic receptors andinhibits sympathetic outflow in a manner analogous to clonidine.

12,

System Grdiovascular

Note caninduce a Methyldopa positive direct Coombs butdoesnotseemto reaction, (seepenicillin) actasa hapten orbindto RBGasanimmune (seequinidine). complex

2. Methyldopa a. Pharmacologic properties. Methyldopa is structurally related to the catecholamine neurotransmittersand is convertedto cr-methylnorepinephrine.Its site of action is believed to be in the CNS, stimulating central cr2-adrenergicreceptors and inhibiting sympathetic outflow. Methyldopa is clearedpredominantly by renal excretion. b. Indications for use include moderate essential hypertension. Methyldopa usually requires concomitant diuretic therapy and is the drug of choice for hlpertension in pregnancy. Side effectsfrequently limit its use. c. Side effectsand toxicity include sedation,dry mouth, headaches,nightmares (especially in the elderly), depression,postural hypotension,salt and water retention (if a diuretic is not given), impotence,dr.tg feverwith or without Iiver involvement,positive direct Coombs reaction rn l0-20o/o(hemolysisis rare), lactation (in both sexes),and hepatitis (can lead to hepatic necrosisupon re-exposureto the drug).Rebound hypertension following sudden withdrawal may occur (lessoften than with clonidine).

ClinicalCorrelate Nonselective B blockers not be should usedin patients lungdisease withsevere because blockade can B, cause lifethreatening p,bronchoconstriction. selective antagonists should be usedinstead.

Mnemonic 'ABEAM" ofprblockers: Acebutolol Betaxolol Esmolol Atenolol Metoprolol ClinicalCorrelate lntravenous are B blockers oftenusedto treat hypertensive crises.

3. Guanabenzhas properties,indications,and side effectssimilar to clonidine. B. Agents acting at peripheral adrenergic receptors 1. Beta-adrenergic blockers (e.g., propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol,acebutolol,esmolol,betaxolol) a. Pharmacologic properties. The mechanism of action is related to blockade of peripheral sympathetic p receptors. The role of the central receptors is unclear. Antihypertensiveaction is thought to be secondaryto decreasedcardiacoutput in the faceof a normal vascularresistance.Inhibition of renin secretionmay alsoplay a role. Despite differences,all gr blockers have the same antihypertensive efficacy.Atenolol, acebutolol, esmolol, betaxolol, and metoprolol have cardioselectiviryi.e., they are relativelyselectivein the blockadeof Fr receptors.Other agentsblock both B1and B2 receptors. Pindolol and acebutolol have intrinsic sympathomimetic activity (ISA) and thereforehavelessnegativeinotropic and chronotropic effects.Thesedrugs may be preferred in patients with decreasedcardiac functioning or a tendenry for bradycardia. Drugs with ISA do not increaseserum triglycerides or decreaseHDL lipids. Labetalol is unique in that it is a mixed antagonist; it blocks both p and ct,receptors. It decreasesperipheral vascularresistancewithout a concomitant reflex tachycardia. It also has some intrinsic sympathomimetic activity at p2 receptors,which may contribute to vasodilatation. c. Indications for use. Beta blockers are indicated for mild-to-severe essentialhypertension (alone or in combination with diuretics or vasodilators),supraventricularand ventricular tachyarrhythmias, treatment of angina, acute myocardial infarction (reducedrisk of reinfarction and death),hypertrophic cardiomyopathies(to decrease ventricular outflow obstruction), hyperthyroidism (propanolol), anxiety states(e.g., stagefright), migraine headache(prophylaxis),glaucoma(timolol and betaxolol ophthalmic solutions to reducesecretionof aqueoushumor), hypertensiveemergencies, and pheochromocytoma(labetalol). d. Side effects and toxicity (1) Side effects related to B blockade at nonvascularsites include bronchospasm (contraindicated in patients with reactive airway disease),masking of the sympathetic responsesto hypoglycemia (contraindicated in patients with diabetes mellitus), a negativeinotropic effect (exacerbates or precipitatescongestiveheart failure), an increaseor precipitation of heart block or bradycardia,and aggra'vation of vasospasm.

124

Pharmacology

(2) Hallucinations,nightmares,depression,and impotence (lesswith lipid-insoluble agents)can also occur.

ln a Nutshell

(3) Rebound hypertension,angina,or rarely evenMI, may occur after abrupt withdrawal.

areusedto: B blockers . Treathypertension

(4) Gastrointestinaleffectsinclude nausea,diarrhea,or constipation. (5) There is a decreasedmetabolism of B blockers with cimetidine and chlorpromazine.

. Decrease postMl mortality (withaspirin andnitrates) . Control tachyarrhythmias

(6) Increasedtriglyceride levelsand decreasedHDL cholesterollevelsare also seen (exceptwith drugs with intrinsic sympathomimetic activity).

. Treat glaucoma . Treathyperthyroidism

2. Alpha-adrenergic blockers a. Prazosin, terazosin, ifld doxazosin (a, selective)

. Treat pectoris chronic angina . Treat migraine headache

(1) Pharmacologic properties include blockade of vasoconstrictivecr-adrenergic type 1 recePtors (predominantly postsynaptic) on vascular smooth muscle. Thesedrugs relax both arteriolar and venoussmooth muscleand do not increase the heart rate during long-term therapy.

. Treat (e.9., anxiety stage fright) phobias andsocial (propanol)

(2) Indications for use include mild-to-moderate essentialhypertension (usually used with a diuretic or p blocker), CHF (preload and afterload reduction), pheochromocytoma (prazosin), and benign prostatic hypertrophy (reduces symptoms).

In a Nutshell

(3) Side effects and toxicity include severepostural hypotension and reflex tachycardia (usually after the first dose), dizziness(commonly seenwith prazosin), sedation,and headache. b. Phentolamine, tolazoline, and phenoxybenzamine (nonselective cr-blockers) (1) Pharmacologicproperties include blockadeof peripheralvascularo-adrenergic receptors(both cr1and o2). Phentolamineand tolazoline are administeredintravenously,and phenoxybenzamineis administered orally or intravenously. (2) Indications for use include diagnosisof pheochromocytoma (phentolamine), hypertensiveemergenciesdue to pheochromocytoma,peripheral vasculardisease (tolazoline), Raynaud'sphenomenon (phenorybenzamineand tolazoline), and autonomic hyryerreflexiaas a result of spinal cord lesions.Phentolamine is used to prevent dermal necrosisand sloughing from infiltrated drugs, such as norepinephrine. (3) Side effects and toxicity include sedation, miosis, postural hypotension, and reflex tachycardia. C. Adrenergic neuron blockers 1. Reserpine a. Pharmacologic properties include blocking the uptake of neurotransmitters into their storagevessicles,leading to depletion of catecholamineand serotonin storesin the brain, adrenalmedulla, and periphery.It alsodecreases cardiacoutput and peripheral vascularresistance. b. Indications for use include mild-to-moderate hypertension,though it is rarely used clinically becauseof its side effects.

areused with Bblockers caution in patients with reactive ainruay disease, diabetes mellitus, and congestive heartfailure. ln a Nutshell cr,-Blockers . Block a,-mediated vasoconstriction anddecrease afterload andpreload . Promote relaxation of urethra andtrigone anddecrease the urinary retention seenin patients prostatic withbenign hypertrophy

Note Phentolamine andtolazoline arecompetitive ct,antagonists. Phenoxybenzamine is noncompetitive because it bindsto cr receptors irreversibly.

125

System Cardiovascular

Note and reserpine Although mayshowupon guanethidine Stepl, youwon't USMLE themonthewards. encounter Note requires Cuanethidine 'l uptake to enternerve thatblock Drugs terminals. (e.g., tricyclic uptake willinterfere antidepressants) action. withguanethidine Note prevent blockers Canglionic reflexes. baroreceptor

c. Side effects and toxicity include sedation, bradycardia, vasodilatation (causing nasal congestion,flushing, conjunctival congestion),diarrhea,and depressionwith high suicide risk (contraindicatedin patientswith a history of depression). 2. Guanethidine a. pharmacologic properties. Guanethidine inhibits the releaseof stored norepinephrine from stimulated peripheral sympathetic nerve endings. It also can deplete peripheral norepinephrinestoresbut doesnot crossthe blood-brain barrier (no CNS effects). b. Indications for use include severe hlpertension, although it is rarely used today becauseof its side effects. c. Side effects and toxicity include severeorthostatic hlpotension, sexual dysfunction (delayedor retrogradeejaculation),and fluid retention. D. Ganglionic blockers include hexamethonium, trimethaphan, and mecamylamine. These ug.ni, block sympatheticand parasympatheticoutflow by blocking the nicotinic receptorsof the autonomic ganglia.They havebeen used as antihypertensivesin the past but are seldom used clinically for the treatment of hypertension today; the exception is the use of trimethaphan in the treatment of hypertension secondaryto acutedissectingaortic aneurysm. Thesedrugs are describedin greaterdetail in the Nervous SystemPharmacologychapter. E. Agents acting directly on vascular smooth muscle 1. Hydralazine

Correlate Clinical Hydralazine/nitrate isusedasan combination in to ACEinhibitors alternative CHF. treating Note lf youseea lupus-like witha positive syndrome patient an taking ANAin a think antihypertensive, is lf thepatient hydralazine. anantiarrhythmic, taking thinkprocainamide.

Bridgeto Pathology antibody antihistone Specific orantism thandsDNA rather SLE. arefoundin drug-induced

t26

a. Pharmacologic properties. Hydralazine causes the direct relaxation of vascular smooth muscle (possiblyvia nitric oxide) but has a greatereffecton arteriolesthan on venules. It is extensively conjugated by N-acetylation by the liver in the first pass. Bioavailability varies with individual rates of acetylation. Rapid acetylatorshavelower bioavailability than slow acetylators. b. Indications for use include moderate-to-severeessentialhypertension (used with p blockers to prevent reflex tachycardia and with a diuretic to prevent salt and water retention), and CHF (usedin combination with oral nitrates). c. Side effects and toxicity include reflex tachycardia,increasedmyocardial orygen consumption (which can be avoidedby adding a p blocker to the regimen),and headache and flushing relatedto vasodilatation,nausea,dizziness,and diaphoresis.A lupus-like syndrome with positive antinuclear antibody (ANA) is seenprimarily in slow acetylators (usually Caucasians).Salt and water retention occurs as a result of increased renin secretion,which can be avoidedby adding a diuretic to the treatment. 2. Minoxidil a. Pharmacologic properties. Minoxidil causesvasodilation by opening potassium channels,thereby hyperpolar izing and relaxing vascular smooth muscle. b. Indications for use include therapy for severehypertension refractory to conventional regimens.Minoxidil should be usedin combination with a p blocker and diuretic. c. Side effects and toxicity include salt and water retention, reflex tachycardia,hypertrichosis,and pericardial effi'rsion.

Pharmacology

3. Diazoxide a. Pharmacologic properties. While diazoxide is structurally similar to the thiazide diuretics,it causessodium and water retention, not diuresis.The mechanismof action is vasodilatation(via K- channelopening) of resistancevessels,primarily arterioles.It produceshyperglycemiaby inhibiting insulin release. b. Indications for use include hypertensiveemergencies,such asmalignant hypertension (contraindicatedif coronary artery disease,pulmonary edema,aortic aneurysm,or intracranial hemorrhageare present)and hyperinsulinemia(notably in insulinomas). hypotensionfollowing intravenousadminc. Sideeffectsand toxicity include excessive istration (true for all antihlryertensivesgiven intravenously);salt and water retention; hyperglycemia;reflex sympathetic activity, which can result in angina (should be administeredwith a B blocker in patientswith coronary artery disease);tissueirritation if extravasationoccurs;and hirsutism with prolonged administration.

Clinical Correlate Because minoxidil wasnoted to cause hypertrichosis, it was developed intoa topical formale-pattern treatment baldness. Bridgeto Endocrinology Diazoxide minoxidil opensATPdependent K*channels onB cellsofthepancreas, hyperpolarizing thecells and preventing release. insulin

4. Sodium nitroprusside a. Pharmacologic properties. Sodium nitroprusside directly relaxesvascular smooth muscle.It actson both arteriolar and venoussmooth muscle.Becauseof its very short half-life, it is administeredas a continuous intravenousinfusion. Sodium nitroprusside interactswith sulfhydryl groups in RBCsto produce a cyanideanion and nitric oxide (vasodilator).The ryanide is then metabolizedin the liver to thiocyanateand is slowly clearedby the kidney (half-life is 4 days). acuteCHF (preload and afterb. Indications for use include hlryertensiveemergencies, pulmonary mitral regurgitation with congestion.Sodium load reduction), and severe nitroprusside is used only in well-monitored, intensivecare settingsand for a short time becauseof ryanide toxicity. c. Side effects and toxicity include excessivevasodilatation that may produce hypotension, nausea,headache,palpitations,diaphoresis,and anxiety.The effectsof thiocyanate poisoning (i.e.,nausea,psychosis,musclespasm,tissuehypoxia) can alsooccur. F. Calcium-channel blockers (verapamil,diltiazem, nifedipine, nicardipine, and nimodipine) l. Pharmacologic properties. Thesedrugs block Ca2+entry into cells and mobilization of Ca2+from intracellular stores,thereby inhibiting excitation-contractioncoupling of the vascular smooth muscle (and smooth muscle in certain other sites). The result is a decreasein peripheral vascularresistance.Diltiazem and verapamil also slow conduction through the atrioventricular (AV) node. 2. Indications for use include mild-to-moderate hypertension(particularly if either angina or supraventriculartachyarrhythmia is also a problem), coronary vasospasm,supraventricular tachyarrhythmias (verapamil, diltiazem), migraine prophylaxis, esophageal spasm,and Raynaud'sphenomenon. 3. Side effects and toxicity include dizziness,headache,nausea,heart block (especially verapamil), exacerbationof CHR and hypotension (negative inotropy, especiallywith verapamil).

ClinicalCorrelate Thehyperglycemic sideeffect of diazoxide issometimes fortreating insulinomas. useful ln a Nutshell . Sodium nitroprusside directly relaxes vascular smooth muscle vianitric oxide. ' Nitricoxide stimulates guanylate cyclase+ tcCMP-+ vasodilatation. . lt isbestusedin hypertensive emergencies.

Clinical Correlate toxicity management Cyanide requires nitrites to begiven to reduce hemoglobin to methemoglobin whichbinds cyanide{orming This cyanomethemoglobin. prevents oxidase cytochrome inhibition intheelectron chain. Cyanomethtransport (Hb)isreconverted emoglobin to metHbbyadministering to allowexcretion of thiosulfate asthiocyanate cyanide (although alsohighly toxic!).

127

Cardiovascular System

Note blockers Calcium-channel differin theirclinical effects: . Nifedipine, nicardipine, and primarily nimodipine peripheral decrease resistance + decrease bloodpressure. . Verapamil anddiltiazem primarily reduce AVnode conduction.

Bridgeto General Principles Themechanisms ofaction of theangiotensins and bradykinin arediscussed inthe Autacoids chapter ofthe Pharmacology section of Principles Book2 Ceneral (Volume ll). Note "Captopril isthought cough" to becaused byirritation from increased bradykinin, an inflammatory mediator. Note ACEinhibitors are in patients contraindicated with renalartery where stenosis, physiologic angiotensin || isneeded to preserve renal function.

t28

G. Antagonists of the renin-angiotensin system 1. Captopril a. Pharmacologicproperties. Captopril inhibits angiotensin-convertingenzyme (ACE), which convertsangiotensinI to angiotensinII (a potent vasoconstrictor).ACE inhibitors also decreasebradykinin inactivation, thereby potentiating the vasodilatory effectsof bradykinin. It decreasesperipheral resistanceby lowering angiotensin II levels and increasingbradykinin levels.The decreasein angiotensin II also leadsto a reduction of aldosteronelevels.Becausevasodilatationof renal efferentarteriolesis greaterthan afferent arterioles,filtration pressureand the glomerular filtration rate (GFR) are reduced. Fifiy percent is metabolizedto inactive compounds. Both captopril and its metabolites are renally excreted. b. Indications for use include CHF (reducesboth preload and afterload) and mild-tomoderate essentialhlryertension;origin"lly, it was introduced for high-renin states, but it is now used with normal renin levels.It is often used in conjunction with a thiazidediuretic. Studieshave shown that the ACE inhibitors decreaseproteinuria and the rate of progressionof renal failure in diabetics. c. Side effectsand toxicity include distortion or loss of tastesensation(most common side ef[ect),dty cough, angioedema,dizziness,orthostatic hypotension,renal damage in patientswith preexistingrenal disease,proteinuria, rash,pruritus, eosinophilia,rare bone marrow toxicity (e.g.,agranulocytosis),and renal damagein the fetus. 2. Enalapril a. Pharmacologic properties. Enalapril is a prodrug ACE inhibitor with a spectrum of activity and mechanism of action identical to captopril. It is hydrolyzed to enalaprilat, the activecompound that persistsin plasmalonger and is more potent than captopril. b. Indications for use are the same as captopril, but enalapril is also availablein intravenousform for use in intensivecare settings. c. Side effectsand toxicity are similar to captopril, but enalapril showslesseosinophilia and a lower incidenceof tastedisturbance. H. Diuretics are used extensively in the treatment of hypertension (reduce intravascular volume). They are discussedin detail in the RenalPharmacologychapterin this book.

Pharmacology

Table I-5- l. Antihypertensive agents. Category

Agents

Mechanism of Antihypertensive Action

Central-acting sympatholytic agents

Clonidine, methyldopa, and guanabenzreceptors

Decreasesympathetic outflow by stimulating central crr-adrenergic

Peripheraladrenergic blockers

Alpha blockers: Phenoxybenzamine,phentolamine, tolazoline,prazosin,and terazosin

Block vasoconstrictivecr receptors

Betablockers: Propranolol, nadolol, timolol, pindolol, acebutolol,metoprolol, atenolol and esmolol Mixed antaeonists: Labetalol, carvedilol

Block peripheral p receptors

Block both a and p receptors

Adrenergicneuron blockers

Reserpineand guanethidine catecholamines

Reduceamount of circulating

Ganglionic blockers

Hexamethonium,trimethaphan, and mecamylamine

Block sympathetic and parasympathetic outflow

Direct vasodilators

Hy dr alazine,minoxidil, diazoxide, and sodium nitroprusside

Act directly to relax vascular smooth muscle and induce vasodilatation

Calcium-channel blockers

Nifedipine, verapamil,and diltiazem

Block Ca2*mobilization and entry into cells;dilate vesselsby inhibiting vascularsmooth muscle contraction

ACE inhibitors

Captopril and enalapril

Inhibitors of ACE; block synthesis of angiotensinII, a potent vasoconstrictor;increase circulating bradykinin

ANTIARRHYTHMICS Antiarrhythmic drugs affect the action potential and its conduction in many ways. Clinically, this is reflectedin alterationsof pulse rate and blood pressure,as well as changesin the ECG. The most widely used antiarrhythmic agents can be grouped into various classesby their electrophysiologic effects (Table l-6-2). Antiarrhythmic agents have proarrhythmic effects as well as antiarrhythmic effects.

129

Grdiovascular System

ln a Nutshell l-Na*channel blockers Class Class ll-B blockers Class lll-prolong action potential lV-calcium-channel Class blockers

Flashbackto Physiology Thephases ofthecardiac potential action aredescribed in detail in theCardiovascular Physiology section.

Thble l-6-2. Categories of drugs based on electrophysiologic effects. Category

Electrophysiologic Effect

ClassI

through Na+ Drugs that decreasemembrane responsiveness channelblockade Drugs that inhibit sympatheticactivity through B-adrenergicblockade Drugs that prolong the action potential (by blocking potassiumchannels) Drugs that block the slow inward calcium current

ClassII ClassIII ClassIV

A. ClassIA agents.ClassIA agentsdecreasethe rate of cardiacconduction by slowing the rate of phase 0 depolarization, slowing conduction, and prolonging repolarization.This is primarily due to the blockade of activatedNa* channels. 1. Quinidine a. Pharmacologicproperties. Quinidine is the dextrostereoisomerof quinine. It is given by the oral route, where it is rapidly absorbed,metabolizedby the liver, and excreted by the kidney. BesidesNa+ channel blockade, quinidine blocks muscarinic and ct, receptors. b. Electrophysiologic effects. Quinidine blocks Na+ channels and slows the phase 0 upstroke.At therapeuticlevels,quinidine prolongs the action potential conduction in the bundle of His and Purkinje fibers.It also decreases the automaticity of ventricular tissue.The resultant ECG showsprolongation of the QRS and QT intervals (torsade de pointes). It can increaseAV nodal conduction (vagolytic) in low dosesand thus increasethe ventricular rate during atrial flutter.

Note quinidine Before using totreat youmust anatrial arrhythmia, pretreat withanagent to slow ventricular response.

c. Indications for use include atrial arrhythmias, i.e., premature contractions, flutter, fibrillation, and ventricular arrhythmias, including ventricular ectopic beats.The patient must be pretreatedwith digitalis,a p blocker,or a Ca2+-channel blockerto avoidthe possible increasein ventricular responseto atrial dysrhythmias. This can be causedby a vagolytic effect of quinidine at the AV node. Quinidine can decreaseatrial fibrillation and flutter suchthat 1:1conductionthrough the AV node can occur. d. Sideeffectsand toxicity include severeprolongation of the QT and QRS intervals,SA nodal arrest,a high degreeof AV block, ventricular tachyarrhythmias,asystole,shortened AV nodal delay,and conversionof atrial fibrillation to ventricular fibrillation. Hypotensioncan alsooccur becauseof crblockade.Other effectsinclude nausea,vomiting, diarrhea(common), immunologic effects(e.g.,drug fever,anaphylaxis, autoimmune thrombocytopenia),cinchonism (e.g.,tinnitus, blurred vision), and delirium. e. Drug interactions. Barbiturates,phenytoin, primidone, and rifampin can increasethe metaboiism of quinidine. Cimetidine decreasesthe metabolism of quinidine. An increasedquinidine effect is seenwith amiodarone.Quinidine increasesthe effectsof warfarin and neuromuscular blockers, and the serum levels of digoxin and digitoxin. Quinidine is a weakbase;therefore,antacidsincreasesits absorption,increasingthe risk of toxicity. 2. Procainamide a. Pharmacologic properties. Procainamideis derived from procaine.It is given orally, intravenously, or by intramuscular injection. It is rapidly absorbed orally and is

tI0

Pharmacology

metabolized in the liver by acerylation to N-acetylprocainamide (NAPA). The rate of acetylation (genetically determined) is inversely related to the likelihood of developing a lupus-like syndrome. Both NAPA and procainamide are renally excreted. Its electrophysiologiceffects are similar to quinidine. b. Indications for use are similar to quinidine (either may work even if the other is ineffective), although procainimide seemsto be better for ventricular dysrhythmias and blocks muscarinic and c receptorsto a lesserdegree. c. Side effects and toxicity include a high degreeof block and bradyarrhythmias, conversion of atrial fibrillation to ventricular fibrillation, hypotension, a syndrome similar to lupus erythematosus,gastrointestinal disturbances (but not as common as with quinidine), and fever. 3. Disopyramide a. Pharmacologic properties. Disopyramide is well absorbed orally. The parent compound and metabolites are renally excreted.The hepatic first-pass effect metabolizes about half of the drug. b. Electrophysiologic effects are similar to quinidine and procainamide, though there is little effect on conduction velocity through the His-Purkinje system. c. Indications for use. Disopyramide's major role is in treatment and prevention of ventricular tachycardiaand ventricular ectopic contractions. d. Side effects and toxicity include a strong negative inotropic effect (can precipitate CHF), vasoconstriction,and anticholinergiceffects(e.g.,urinary retention, constipation, closed-angleglaucoma).

B. Class IB agents.The classIB agentsdecreasethe action potential duration by shortening the phase 3 repolarization. They have little effect on depolarization. Becausethey block inactivated sodium channels, they are usefrrl in disorders in which the myocardium becomes hlpoxic or dqnlarized (e.g.,post MI, digitalis toxicity). 1. Lidocaine a. Pharmacologic properties. Lidocaine is an amide local anestheticgiven by the intravenous or intramuscular routes. It is de-ethylated in the liver with a 90olofirst-pass effect; thus, the dosagemust be adjusted in patients with hepatic insufficiency. b. Electrophysiologic effects. Lidocaine decreasesautomaticity in Purkinje fibers and ventricular tissue.It has no effecton sinus node automaticity or AV node conduction. It can causeprolongation of PR interval, QRS interval, or worsening of dysrhythmias. c. Indications for use include primary therapy for ventricular arrhythmias (intravenous only). Lidocaine is also used as a local anesthetic. d. Side effects and toxicity are predominantly CNS related (e.g.,drowsiness,disorientation, seizures,psychosisin the elderly and those with CHF). Lidocaine can cause hlpotension. Cimetidine and propranolol increaselidocaine toxicity. Overall,it is one of the least cardiotoxic agentsof classI. 2. Tiocainide and mexiletine are newer class IB drugs with actions and effects similar to those of lidocaine. They are indicated for use in treating ventricular arrhythmias and causeCNS (e.g.,dizziness,tremor), gastrointestinal(e.g.,anorexia,nausea,vomiting), and hematologicside effects.

tIl

Cardiovascular System

C. Class IC agents (flecainide,encainide,propafenone,and moricizine). The classIC agents induce considerablephase 0 depressionby strongly binding to Na+ channels.They slow impulse conduction in all cardiac tissue, especiallyin the His-Purkinje system.They have little effect on repolarization. 1. Pharmacologic properties. Flecainide and encainide are well absorbed orally and are metabolizedby the liver. Encainideundergoessignificant first-passmetabolism. 2. Indications for use. Current use of all drugs in this classis limited to life-threatening ventricular arrhythmias that do not respond to drugs of the IA and IB classes. 3. Side effects and toxiciry These drugs can precipitate cardiac arrest and sudden death in patientswith preexistingcardiacabnormalities. D. Class II agents (B-adrenergic blockers). The antiarrhythmic efficacy of these agentsstems from their suppressionof phase4 depolarization and their inhibition of AV node conduction. They also decreasemyocardial contractility. Beta-adrenergic blockers used as antiarrythmics include propranolol, acebutolol,esmolol,and sotalol. l. Pharmacologic properties. These drugs are highly protein bound, metabolized in the liver, and excretedin urine. 2. Electrophysiologic effects. B blockers decreasethe automaticity of the SA node and Purkinje fibers, prolong conduction through the AV node, and increasethe R-R interval (i.e.,decrease the heart rate). 3. Indications for use include supraventricular tachyarrhythmias (slow ventricular rate by prolonging conduction through the AV node), atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia,postmyocardial infarction (decreasesrisk of reinfarction and suddendeath), and acutemyocardialinfarction (in some situations). 4. Sideeffectsand toxicity relatedto B blockadeat nonvascularsitesinclude bronchospasm in asthmatics(risk reducedwith B1-selective agentssuch as metoprolol); exacerbationof peripheral vascular disease;masking the sympatheticresponseto hypoglycemiain diabetics;a negativeinotropic effectleadingto exacerbationor precipitation of CHF (maybe less severewith an agent such as pindolol, which has some intrinsic sympathomimetic activity); heart block; gastrointestinaleffects (e.g., nausea,diarrhea, constipation); and CNS efFects(e.g., hallucinations,nightmares,depression,impotence). E. Class III agents are all capableof prolonging the action potential duration and increasing the effectiverefractory period (ERP), i.e., the period during which an action potential will only be stimulated via a strong impulse. They block K+ channels and prolong repolarization. They haveno effect on phase0 depolarizationor the resting membrane potential. 1. Bretylium

ClinicalCorrelate Bretylium causes aninitial worsening ofventricular because anhythmias of the catecholamine release. Thisis whyit isonlyusedafterlA andlBdrugs fail.

lt2

a. Pharmacologic properties. The ammonium salt of bretylium is an adrenergic neuron blocker.It is administeredparenterallyand is excretedunchangedin the urine. b. Electrophysiologic effects include an increasein the action potential duration and the ERP.There is no effect on automaticiry responsiveness, or conduction. c. Indications for use include ventricular arrhythmias in intensivecare or arrest situations when drugs of the IA and IB classesare not successfrrl. d. Side effects and toxicity include hlpotension (from blockade of efferent limb of baroreceptorreflex),nausea,vomiting, vertigo, and dizziness.Hypertensionis seenin the presenceof sympathomimeticamines.

Pharmacology

2. Amiodarone a. Pharmacologicproperties. Amiodarone is structurally similar to thyroxine.After oral administration, 2-4 weeksare neededto achievesteadystate.It is metabolizedby the liver. The half-life rangesfrom 20-100 days. b. Electrophysiologic effects.Amiodarone prolongs the action potential and refractoriness in atrial and ventricular Purkinje fibers, slows spontaneoussinus node dischargerate (automaticity),and can causesinusbradycardia. c. Indications for use include refractory atrial or ventricular tachyarrhythmias(uselimited by toxicity). It is used for life threateningconditions that do not respondto conventional agents.

Note Because amiodarone's half-life issolong,loading doses haveto beusedfor upto threeweeks.

d. Side effects and toxicity include pulmonary alveolitis or fibrosis, gastrointestinal disturbances(e.g.,vomiting, nausea,anorexia),hyper- and hypothyroidism, hepatotoxicity, and corneal microdeposits. It may increaselevels of digitalis, quinidine, procainamide, and diltiazem. Photosensitivity and bluish skin deposits ("gray man syndrome" or "smurf skin") are also seen. 3. Sotalol a. Pharmacologic properties. Sotalol is a nonselectiveB-adrenergicblocking agent, which uniquely possesses both class II and class III antiarrhythmic characteristics. The bioavailabiliry of oral sotalol approaches100o/o,and the drug is not protein bound. It undergoesnegligible first-passhepatic metabolism with 75o/oof the dose excretedunchangedin the urine. b. Indications for use. Sotalol is approved only for use in the acute and prophylactic managementof life-threateningventricular tachyarrhythmias.It has also been used for the treatment of stableand unstableangina and hypertension. c. Side effectsand toxicity include new or worseningof ventricular arrhythmias,which occur in approximately4o/oof patients.The most prominent adverseeffectsare those related to B blockade (e.g.,fatigue,bradycardia,dyspnea,asthenia,dizziness).Sotalol is hydrophilic and has a low CNS penetration and central effects. F. Class IV agents. The Ca2+-channelblockers increase the conduction time through the AV node by blocking the slow calcium channels.They are used for treatment of supraventricular tachycardia(they protect ventriclesfrom fast atrial rates). 1. Pharmacologic properties. Verapamil is completelyabsorbedby the oral route but has substantialfirst-passmetabolismby the liver.Up to 70o/ois excretedby the kidneys. 2. Electrophysiologic effects include inhibition of the slow inward current of phase0 and phase2 of the action potential in slow fibers, and the prolongation of conduction time and ERP through the AV node. 3. Indications for use include paroxysmalsupraventriculartachycardiaand atrial fibrillation and flutter. 4. Side effectsand toxicity include hypotension,asystole,and AV block. Verapamil and diltrazemhave a negativeinotropic effect and should not be used in patientswith compromised cardiacfunction.

Note Verapamil, diltiazem, and bepridil aretheonly Ca2*-channel blockers used asantiarrhythmia. Bepridil's useislimited because it causes torsades depointes.

Clinical Correlate Verapamil should notbeused in patients withatrial fibrillation whoalsohave Wolff-Pa rkinson-Wh ite syndrome. Anincrease in conduction through the (bypas$ accessory tractcan leadto increased ventricular response andpossible ventricular fibrillation.

l15

System Cardiovascular

GTYCOSIDES CARDIAC A. Overview. Certain steroidsand their glycosideshave a characteristiceffect on the electrophysiologyof the heart.The digitalis leaf is the sourceof the cardiacglycosides,digoxin and digitoxin. 1. Pharmacologic properties

ln a Nutshell isvia inotropy Increased calcium 1 intracellular ("direct" effect)

Note glycosides Thecardiac produce theirantianhythmic of viaenhancement actions ("indirect" vagal activity effect).

a. Cardiac glycosidesinhibit the Na+-K+ ATPase in cell membranes. The inhibition of the Na+-K* po-p diminishes the Na+ gradient, which in turn decreases5t+-g^2+ exchange,thus leading to intracellular Ca2+ accumulation. This increasesthe Ca2+ available to the Ca2+-dependentcontractile proteins of the cardiac muscle cells. Contractile force increases,causinga positive inotropic effect. b. At the AV node, the glycosidesprolong the ERP and diminish the rate at which supraventricularimpulses are transmitted to the ventricles.The mechanism of this effect involvesenhancementof vagal activity and diminution of the sensitivityof the AV node to sympatheticinput. c. Bioavailabilityof oral preparationsis extremelyvariable,requiring monitoring of the serum levels of the drug. d. Absorption is retardedby food in the gastrointestinaltract, delayedgastricemptying, malabsorption,and antibiotics. 2. Indications for use include CHF (due to their positive inotropic effect), AV nodal depressionto control the ventricular responseto paroxysmalsupraventriculartachycardia, and atrial fibrillation or atrial flutter. Becauseof the tendenry of classI antiarrhythmics to increaseAV nodal conduction, glycosidesmay be usedbefore or in conjunction with classI antiarrhythmic agentsfor control of chronic atrial tachyarrhythmia. 3. Side effects and toxicity a. Life-threatening cardiac arrhythmias, such as ventricular ectopy,ventricular dysrhythmias,paroxysmaiatrial tachycardiawith block, and second-and third-degree(complete) heart block, all require that patientsbe closelymonitored.

Note produces asmany Digitalis The asit treats. arrhythmias indexisl-2. therapeutic Note should cardioversion Electrical withdigitalis beavoided because intoxication fibrillation canbe ventricular of induced asa result a threshold. reduced fibrillation due isdepolarized Thetissue to thepumpblock.

t54

b. Other side effectsinclude gastrointestinal(e.g.,anorexia,nausea,vomiting, abdominal pain), CNS (e.g.,fatigue, neuralgias,delirium, hallucinations), and visual disturbances (e.g.,abnormalcolor perception). c. Toxicity can be precipitated by hypokalernia, alkalosis,hypoxia, hypercalcemia,hyPomagnesemia,hypothyroidism, hyponatremia.Certain drugs increasetoxiciry including verapamil, quinidine, corticosteroids,thiazides, and other K+-wasting diuretics. d. Therapy for digitalis intoxication includes discontinuation of the drug, potassium supplementation (if hypokalemia is present), arrhythmia control (with phenytoin, lidocaine,or procainamidefor tachyarrhythmia).Bradyarrhythmiasmay be controlled with atropine and pacing;in casesof severetoxiciry antidigoxin immunoglobulin is administered. B. Specific agents 1. Digoxin, the most commonly used preparation, is 25o/oprotein bound, excretedmostly unchanged in urine (dosagemust be reduced in renal failure), and has a half-life of approximately 36 hours. An increaseddigoxin effect is seenwith verapamil, nifedipine, amiodarone, quinidine, tetrarycline, diazepaln, erythromycin, and hypothyroidism. A decreaseddigoxin effect is seen with antacids, prednisone, rifampin, and hyperthyroidism.

Pharmacology

2. Digitoxin is over 900/oprotein bound and is metabolizedby hepatic microsomal enzymes (one metabolic product is digoxin). Enzyme induction by drugs such as phenytoin, phenobarbital, rifampin, and phenylbutazoneincreasesdigitoxin metabolism. Tirere is significant enterohepaticcirculation, resulting in a half-life of 4-7 days.

ANTIANGINAT AGENTS Antianginal agentsinclude drugs that dilate coronary arteries,decreaseheart rate,decreasecardiac contractiliry decreasewall tension,or decreasevenousresistance. A. Organic nitrates (nitroglycerin) l. Pharmacologic properties a. Pharmacokinetics. Organic nitrates are well-absorbedorally but rapidly denitrate and inactivate through a first-pass effect in the liver. To remedy this, they are often given by the sublingual route. Oral preparations are also available,which are lessvulnerable to denitration (e.g.,isosorbidedinitrate). Nitrate toleranceoccurs secondary to sulfhydryl group depletion. This is best avoidedby a dosing regimen that allows a nitrate-freeinterval of at least l2 hours. b. Mechanism of action includes coronary vasodilatation and systemicvenouspooling to reducepreload.Vasodilatationis believedto be secondaryto the metabolismof nitrates to nitric oxide, which can activateguanylatecyclaseand increasecGMp; cGMR in turn, leadsto dephosphoryiationof the myosin light chain and inhibition of vascularsmooth musclecontraction. 2. Specific agents include nitroglycerin (sublingual, intravenous, transcutaneous,transbuccal), isosorbide dinitrate (oral preparation), and amyl nitrate (a volatile liquid administeredby inhalation). Toleranceto continuous useis a problem. 3. Indications for use include angina, coronary vasospasm,Prinzmetal's angina, CHF (afterloadreduction), and short-term managementof hypertension. 4. Side effectsand toxicity include postural hypotension,reflex tachycardia,and headache. B. Calcium-channel blockers l. Pharmacologicproperties. Ca2+-channelblockersinterferewith Ca2+influx required for excitation-contraction coupling in smooth and cardiac muscle, resulting in vasodilatation. The net effect is reduction in systemicvascular resistance,reduction in coronary vasospasm,and decreasedmyocardial oxygen demand. Effects on the cardiac HisPurkinje system result in a decreasedventricular responseto supraventricular tachyarrhythmias. 2. Indications for use include angina as a result of vasospasm(nifedipine, diltiazem), exertional angina, hypertension in patients also suffering angina, supraventricular tachyarrhythmias (especiallyverapamil), idiopathic hypertrophic subaortic stenosis(IHSS), and migraine headacheprophylaxis (verapamil). 3. Side effects and toxicity include hlpotension, AV nodal block, bradycardia,asystole, CHR dry mouth, and constipation.Digitalis toxicity is also increasedwith verapamil. C. Beta-adrenergicblockersrelieveanginaby modifring sympathetictone and, thereby,reducing heart rate and cardiaccontractility. The mechanismof action is relatedto the blockade of cardiacsympatheticB, receptors.Drugs have variablehalf-lives and cardioselectiviry(p1 versusB2).

Flashbackto Pathology Thepathophysiology of angina isdiscussed inthe Cardiovascu larPathology chapter.

ClinicalCorrelate AnginaSymptoms . Crushing pain;may chest radiate to leftarmor neck . Canalsoseeshortness of breath, nausea and vomiting, diaphoresis Response to sublingual nitroglycerin ishelpful indiagnosing and treating angina.

In a Nutshell Uses ofBBlockers in Cardiac Patients . Hypertension-decreases cardiac output andrenin secretion . Arrhythmias-especially SW (prolongs conduction through AVnode) . Angina-reduces heartrate andcontractility . PostMl-reduces riskof reinfarction anddeath

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Cardiovascular System

ANTILIPID AGENTS A. Nicotinic acid (niacin) 1. Pharmacologicproperties. Niacin is structurally relatedto the pyrimidines. It is available as an oral or parenteralpreparation. Nicotinic acid decreasesVLDI production by the liver by working multiple mechanisms,including inhibition of lipolysis,decreasedhepatic esterificationof triglycerides,and increasedlipoprotein lipase activity. It is used as a cofactorafter conversionto nicotinamide and nicotinamide adeninedinucleotide (NAD), which is unrelatedto its antihyperlipidemic action. 2. Indications for use include all hyperlipidemias excepttype I. It is especiallyuseful for type IIb, prevention of pellagra(lower doses),and peripheralvascularinsufficienry (causesperipheralvasodilatation). 3. Side effects and toxicity include cutaneous effects (e.g., pruritus, flushing, which is decreasedby taking aspirin), gastrointestinaleffects(e.g.,vomiting, diarrhea,dyspepsia), hyperpigmentation,increasedliver enzymelevels,hyperuricemia,and hyperglycemia. B. Clofibrate 1. Pharmacologic properties. Clofibrate is a fibric acid derivativethat increasesthe activity of lipoprotein lipase, which breaks down triglycerides(in VLDL) into fatty acids.It decreasesVLDL, has no effect on HDL, inhibits cholesterolsynthesisin the liver, and increasesits excretionin bile. 2. Indications for use include patientswith increasedVLDL and LDL levelswho havefailed to respondto diet therapy.It is especiallyuseful for type III hyperlipoproteinemia. 3. Side effects and toxicity include nausea,diarrhea, alopecia,rash, impotence, myalgias with elevated SGOT and CPK, cholelithiasis,cholecystitis,arrhythmias, angina, cardiomegaly,and thromboembolic disease.It is contraindicatedin pregnancyand in renal or hepatic insufficiency. Clofibrate displacesother drugs from plasma albumin and increasestheir effects,for example,phenytoin, tolbutamide, and warfarin. There is a need to monitor the prothrombin time in patients on both warfarin and clofibrate. C. Gemfibrozil 1. Pharmacologic properties. Gemfibrozil is a fibric acid derivativeand an analog of clofibrate. It lowersVLDL and raisesHDL levels. 2. Indications for use are similar to clofibrate. 3. Side effects and toxicity include mild gastrointestinalupset, abdominal pain, nausea, eosinophilia, and rash. Gemfibrozil may enhancegallstoneformation and may have a mild hyperglycemiceffect.It alsopotentiateswarfarin activity. D. Cholestyramine and colestipol l. Pharmacologicproperties. The mechanismof thesecompounds involvesbinding to bile acids in the gut and increasingtheir excretionin feces.The result is increasedconversion of cholesterolinto bile acidsand decreasedplasmacholesterol. 2. Indications for use include type IIa and IIb hyperlipidemias.They are often used with niacin.

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Pharmacology

3. Side effects and toxicity include nausea,abdominal cramps, constipation, steatorrhea, and impaired absorption of fat-solublevitamins. They also increaseVLDL synthesisand should be usedwith niacin and avoidedin patientswith hypertriglyceridemia.Drug interactions include binding to certain drugs (e.9.,tetrarycline, phenobarbital, digitoxin) if given simultaneously. E. Lovastatin and mevastatin 1. Pharmacologic properties. These drugs inhibit HMG CoA reductase, the enzyme that catalyzesthe rate-limiting step in cholesterolsynthesis.The decreaseof cholesterolsynthesis resultsin an increasedbreakdown of circulating LDL and an increasein HDL. These drugs are excretedthrough bile and feces. 2. Indications for use include typesIIa and IIb hyperlipoproteinemiaand secondaryhyperlipoproteinemia (e.g.,nephrotic syndrome,diabetes). 3. Side effects and toxicity include gastrointestinal symptoms, headache, and rash. Asymptomatic increasein liver enzymesmay occur.Liver function should be monitored, and the drug discontinuedif abnormalitiesarise.An increasein muscleCPK is also seen; rhabdomyolysis may occur.

THROMBOTYTIC AGENTS Thrombolytic agents include streptokinase, urokinase, and tissue plasminogen activator (t-PA). All three agentsact by promoting the conversionof plasminogento plasmin. Plasmin, in turn, actsto cleavefibrin and to dissolveclots. Besidestheir other indications,theseagents are used in the treatment of acutemyocardialinfarction. Thrombolytic agentsare describedin detail in the Hematologic/LymphoreticularPharmacologychapter of this book.

lt7

Respiratory Embryology Therespiratory in thefourthweekof development grove, system appears asthelaryngotracheal a median diverticulum inthecaudal groove endofthepharyngeal floor. Theendodermal liningofthis gives riseto theinternal epithelium ofthelarynx, trachea, bronchi, andlungs. Lateral margins ofthe groove fusein a caudal-to-cranial direction to formthelaryngotracheal tube,whichcommunicates withthepharynx viathelaryngeal orifice behind thecopula. Atthesame time,thedorsal lumenof thelengthening foregut narrows to formtheesophagus. Therespiratory diverticulum becomes separated fromthedorsal foregut bythetracheo-esophageal septum.

LARYNX A. Cartilage and musculature originate from the fourth and sixth pharyngeal arch mesenchyme. Laryngeal muscles are innervated by the vagus nerve. Derivatives of the fourth pharyngeal arch are innervated by the superior laryngeal nerve, and derivativesof the sixth arch are innervated by the recurrent laryngeal nerve. B. Laryngeal orifice becomes T-shaped as mesenchyme proliferates to form the thyroid, cricoid, and arytenoid cartilages. C. Falseand true vocal cords differentiate from tissue folds in the laryngeal epithelium.

TRACHEA, BRONCHI, ANDTUNGS A. Conductitg airways. The laryngotrachealtube grows caudally into the splanchnic mesoderm of the ventral foregut, where it divides into a midline trachea and right and left lung buds. 1. The right lung bud divides into three lobes and the left into two, correspondingto the number of main bronchi and lobes in the fi.rlly developedlung. 2. The bronchi divide repeatedlyin a dichotomous processthat continues after birth to form bronchioles. 3. Distal expansionsof terminal bronchiolesform alveoli. B. Respiratoryairways 1. Respirationis possibleby the seventhmonth, as the cells of the respiratory bronchioles becomeassociatedwith the endothelium of the capillariesto form primitive alveoli. 2. TWokinds of alveolar epithelial cells line the terminal sacs.

t4l

Respiratory System

a. Tlpe I pneumocytes are squamousepithelial cellsthat form the alveolar gasexchange surface. b. Type II pneumocytes are plump cuboidal-like cells that produce surfactant.

PIEURAICAVITIES As the lungs grow caudolaterallyinto the pericardioperitonealcanals,they penetratethe part of the intra-embryonic coelom that becomesthe pleural cavities.The lungs acquire a visceral pleura coveringderived from splanchnicmesoderm,and the body wall becomeslined by parietal pleura derived from somatic mesoderm.

CONG ENITAIABNORMALITI ES A. Esophagealatresia (closure)may be causedby posterior deviation of the tracheoesophageal septum.In the embryo, this preventsswallowingof amniotic fluid and resultsin fluid accumulation and an enlargeduterus.When an afflicted newborn attempts to feed,fluid overflows into the trachea,causingaspiration pneumonia. B. Tracheoesophagealfistula usually occurswith esophagealatresiaand consistsof an abnormal passagebetweenthe distal part of the esophagusand the tracheajust abovethe bifurcation. As a result, acidic gastric contents may passinto the lungs and causeseverechemical pneumonitis. Movement of air into the stomach also may causedilatation of the stomach, elevationof the diaphragm, and hamperedrespiration. C. Congenital cystsof the lungs are saccularenlargementsof terminal bronchiolesthat can be solitary or multiple. If not removed,they may result in chronic infection becauseof poor drainage. D. Prematurity l. Before 25-28 weeks,the fetal lungs cannot provide adequategasexchange,and the fetus is not viable.After that age,the alveolarsurfaceareaand the associatedcapillary network are developedenough to support life. 2. Between24 and 28 weeks,alveolarepithelial cells produce surfactant, a phospholipidcontaining substance that is necessaryfor effective ventilation. Surfactant overcomes surfacetensionwithin the alveoliand, thus, preventstheir collapsewhen the intra-alveolar liquid is replacedby air. 3. In premature infants, lack of surfactantcontributes to hyaline membrane diseaserespiratory distresssyndromeof the newborn. When an afflictednewborn takesthe first breath in responseto the anoxia produced during delivery and cutting of the umbilical cord, the alveoli do not remain patent, and the lungs are underinflated.

142

Histology Respiratory permits airandblood dioxide between Therespiratory system theexchange of oxygen andcarbon capillary membrane, thatseparates bloodfrom byproviding a thincellular deepinthelungs, portion (nasal pharynx, cavity, larynx, trachea, air.Thesystem isdivided intoa conducting alveolar thatcarries during inspiration andexpiration anda respiratory bronchi, bronchioles) thegases (alveoli) portion forgasexchange between airandblood. thatprovides

NASAL CAVITIES The nose contains the paired nasal cavitiesseparatedby the nasal septum. Anteriorly, each cavity opens to the outside at a nostril (naris), and posteriorly, each cavity opens into the nasopharynx. Each cavity contains a vestibule, a respiratory area, and an olf4ctory area, and eachcavity communicateswith the paranasalsinuses. A. Vestibule is locatedbehind the naresand is continuous with the skin. 1. Epithelium is composedof stratified squamous cellsthat are similar to the contiguous skin. 2. Hairs and glandsthat extendinto the underlying connectivetissueconstitutethe first barrier to foreign particlesentering the respiratorytract. 3. Posteriorly,the vestibular epithelium becomespseudostratified,ciliated, and columnar with goblet cells (respiratory epithelium). B. Respiratory area is the major portion of the nasal cavity. 1. Mucosa is composed of a pseudostratified, ciliated, columnar epithelium with numerous goblet cells and a subjacentfibrous lamina propria that contains mixed mucous and serous glands. 2. Mucus produced by the goblet cellsand the glandsis carried toward the pharynx by ciliary motion. 3. The lateral wall of each nasal cavity contains three bony projections, the conchae, which increasethe surfaceareaand promote warming of the inspired air. This region is richly vascularizedand innervated. C. Olfactory area is located superiorly and posteriorly in eachof the nasalcavities. 1. The pseudostratified epithelium is composedof bipolar neurons (olfactory cells),supporting cells,brush cells,and basalcells. The receptor portions of the bipolar neurons are modified dendriteswith long, nonmotile cilia. 2. Under the epithelium, Bowman's glands produce serousfluid, which dissolvesodorous substances.

Note Thereceptor cellsinthe pathway olfactory arethe olfactory cells epithelial themselves. cellsare Thebasal stemcells thatcontinuously turnoverto replace the Thisis olfactory receptor cells. animportant inthe example adulthuman neurons where arereplaced.

t4t

Respiratory System

ln a Nutshell Sinus Cavities . Frontal . Maxillary

D. Paranasal sinuses are cavities in the frontal, maxillary ethmoid, and sphenoid bones that communicate with the nasal cavities. 1. The respiratory epithelium is similar to that of the nasal cavities except that it is thinner. Few glands are 2. Numerous goblet cellsproduce mucus, which drains to the nasalpassages. found in the thin lamina propria.

. Ethmoid . Sphenoid

NASOPHARYNX ANDTARYNX A. Nasopharynx is the first part of the pharynx.

Note

l. It is lined by a pseudostratified, ciliated, columnar epithelium with goblet cells.

Theciliated cells'ciliabeatand protect theconducting and respiratory airways by propelling particles inhaled andsecretions toward the oropharynx.

2. Under the epithelium, a gland-containing connective tissue layer rests directly on the periosteum of the bone. 3. The cilia beat toward the oropharynx, which is composed of a stratified, squamous, nonkerati nized epithelium. 4. The pharyngeal tonsil, an aggregateof nodular and diffrrselymphatic tissue,is located on the posterior wall of the nasopharynx subjacent to the epithelium. Hypertrophy of this tissue as a result of chronic inflammation results in a condition known as adenoiditis. B. Larynx is a passagewaythat connectsthe pharynx to the trachea and contains the voicebox. Its walls are composed of cartilage held together by fibroelastic connective tissue. 1. The mucous layer of the larynx forms two pairs of elastictissue folds that extend into the lumen. The upper pair are called the vestibular folds (or falsevocal cords), and the lower pair constitute the true vocal cords. 2. The epithelium of the ventral side of the epiglottis and of the vocal cords is composedof stratified, squamous,nonkeratinized cells.The remainder of the larynx is lined with ciliated,pseudostratified,columnar epithelium. 3. All cilia, from the larynx to the lungs, beat upward toward the nasopharynx.

TRACHEA The trachea,a hollow cylinder supportedby 16-20 cartilaginousrings, is continuous with the larynx above and the branching primary bronchi below.

ln a Nutshell Trachea . Lined withciliated pseudostratified columnar epithelium . Supported by16-20 rings C-shaped cartilaginous

A. Mucosa of the tracheaconsistsof the typical respiratoryepithelium,an unusuallythickbasement membrane,and an underlying lamina propria that is rich in elastin.The lamina propria containslooseelastictissuewith blood vessels,lymphatics, and defensivecells.The outer edge of the lamina propria is defined by a densenetwork of elastic fibers. B. Submucosaconsistsof denseelasticconnectivetissuewith seromucousglandswhose ducts open onto the surfaceof the epithelium. C. Cartilage rings are C-shaped hyaline cartilage pieceswhose free extremities point dorsally (posteriorly). They are coveredby a perichondrium of fibrous connectivetissuethat surrounds each of the cartilages. Smooth muscle bundles (trachealis muscle) and ligaments span the dorsal part of eachcartilage. D. Adventitia consists of peripheral dense connective tissue that binds the trachea to surrounding tissues.

IM

Histology

BRONCHI PRIMARY

Note

The tracheabranchesat its distal end into the two primary bronchi. Short extrapulmonary segments of the primarybronchi existbeforethey enter the lungs at the hilus and then branch further. The histologic structure of the walls of the extrapulmonary segment of the primary bronchi is similar to that of the trachealwall.

isat Therightmainbronchus position than a morevertical particles, theleft.Inhaled tendto betrapped therefore, intherightlungmoreoften thanintheleft.

TUNGS A. Intrapulmonarybronchi. The primarybronchi give rise to three main branchesin the right lung and two branchesin the left lung, eachof which supply a pulmonary lobe. Theselobar bronchi divide repeatedlyto give rise to bronchioles. 1. Mucosa consistsof the typical respiratory epithelium and an underlying lamina propria similar to that of the trachea.However, alayer of looselywoven smooth muscle (muscularis mucosae),which separatesthe lamina propria from the submucosa,is present. 2. Submucosaconsistsof elastictissuewith fewer mixed glandsthan seenin the trachea. 3. Anastomosingcartilage plates replacethe C-shapedrings found in the tracheaand extrapulmonary portions of the primary bronchi. Theseplatesbecomeprogressivelysmalleras airway diameter decreases. B. Bronchioles do not possesscartilage,glands,or lymphatic nodules;however,they contain the highestproportion of smooth musclein the bronchial tree. Bronchiolesbranch up to 12 times to supply lobules in the lung, which are bound by connectivetissuesepta.The smallest conducting bronchiolesare calledterminal bronchioles. 1. Bronchiolesare lined by ciliated,simple, columnar epithelium with nonciliated bronchiolar (Clara) cells.Goblet cellsare presentin largebronchioles. 2. A smooth muscle layer interlacesthe elasticfibers of the lamina propria. The musculature of the bronchi and bronchioles contracts after stimulation by parasympathetic fibers (vagusnerve) and relaxesin responseto sympatheticfibers. 3. Terminal bronchiolesconsistof low-ciliated epithelium with bronchiolar cells. C. Respiratory bronchioles are areasof transition (hybrids) betweenthe conducting and respiratory portions of the airways.In addition to the rypical bronchiolar epithelium of the contain outpouchings of alveoli, which comprise terminal bronchioles,these passageways the respiratoryportion of this system.

ln a Nutshell Bronchioles . Contain noglands, or lymphatic cartilage, nodules . Scattered goblet cells . Abundant muscle smooth . Contract with parasympathetic stimulation Note contain bronchioles Terminal to secrete cellsknown Clara glycosami nsthat noglyca probably protect the lining. bronchiolar

1. Terminal bronchiolesgive rise to respiratorybronchioles. 2. Respiratorybronchiolesbranch to form two to three alveolarducts,which are long sinuous tubes. 3. Alveolar sacsare spacesformed by two or more conjoined alveoli.They are lined by the simple squamousalveolarepithelium. D. Alveoli are the terminal, thin-walled sacsof the respiratorytree that are responsiblefor gas exchange.There are approximately 300 million alveoli per lung, each one 200-300 pm in diameter. 1. Blood-air interface. Oxygen in the alveoli is separatedfrom hemoglobin in the red blood cells of alveolar capillaries by five layers of cellular plasma membrane and two layers of extracellularmembrane:the alveolarepithelial cell (apical and basalmembranes)and its basal lamina, the basal lamina of the capillary and its endothelial cell (basal and apical membranes),and the erythrocfte membrane. The total thicknessof all theselayerscan be asthin as 0.5 pm.

t45

Respiratory System

In a Nubhell TypeI Pneumocytes . Account for970/o of alveolar surface . Areextremely thin;asthin as25nm . Provide minimal barrier to facilitate diffusion of gas Typell Pneumocytes . Account for3olo of alveolar surface . Secrete pulmonary surfactant, whichreduces tension in alveoli surface

ClinicalConelate . Airin pleural space + pneumothorax . Bloodin pleural space + hemothorax

t46

2. Alveolar epithelium contains two cell types. a. Type I cells completely cover the alveolar luminal surface and provide a thin surface for gasexchange.This simple squamousepithelium is so thin (-25 nm) that its details are beyond the resolution of the light microscope. b. Type II cells are rounded, plump, cuboidal-like cellsthat sit on the basallamina of the epithelium and contain membrane-bound granules of phospholipid and protein (lamellarbodies).The contentsof theselamellar bodies are secretedonto the alveolar surfaceto provide a coating of surfactant that reducesalveolar surfacetension. 3. Alveolar macrophages (dust cells) are found on the surface of the alveoli. a. Derived from monocytes that extravasate from alveolar capillaries, alveolar macrophagesare part of the mononuclear phagocyte system. b. Dust cells,as their name implies, continuously remove particles and other irritants in the alveoli by phagocytosis.

E. Pleura 1. Visceral pleura is a thin serous membrane that covers the outer surface of the lungs. A delicate connective tissue layer of collagen and elastin, containing lymphatic channels, vessels,and nerves,supports the membrane. Its surfaceis coveredby simple squamous mesothelium with short microvilli. 2. Parietal pleura is that portion of the pleura that continuesonto the inner aspectof the thoracic wall. It is continuous with the visceralpleura and is lined by the samemesothelium. 3. Pleural @vity is a very narrow fluid-filled spacethat contains monocytes located between the two pleural membranes.It containsno gasesand becomesa true cavity only in disease (e.g.,in pleural infection, fluid and pus may accumulatein the pleural space).If the chest wall is punctured, air may enter the pleural space(pneumothorax),breaking the vacuum and allowing the lung to recoil.

Respiratory Anatomy Theanatomic $ructures thatplaya central roleintherespiratory system arelocated intheheadand neckaswellasthethorax. Thischapter reviews these structures inturn,starting withthenasal cavities andending withthelungs.

NASAL CAVITIES A. Nasal cavities are separatedby the nasal sqrtum, which consistsof the vomer, the perpendicular plate of the ethmoid bone, and the septal cartilagewith small contributions from the maxilla and palatine bone. The lateral wall of each nasal cavity featuresthree scroll-shaped bony structures called the nasal conchae. The nasal cavities communicate posteriorly with the nasopharynx through the choanae. Each spaceinferior to each concha is called a meatus. The paranasalsinusesand the nasolacrimal duct open to the meatus. The inferior concha is a separatebone, and the superior and middle conchaeare parts of the ethmoid bone. 1. Inferior meatus. The only structure that opens to the inferior meatus is the nasolacrimal duct. This duct drains lacrimal fluid (i.e., tears) from the lacrimal sacat the medial aspect of the orbit to the nasal cavity.

ClinicalCorrelale Themaxillary mu$drain sinus gravity upward again$ because themaxillary o$iumislocated highonthemedial wallofthe sinus. This isoneofthe reasons maxillary sinus infections areoften difficult totreat.

2. Middle meatus a. The hiatus semilunaris contains openings of frontal and maxillary sinusesand anterior ethmoidal air cells. b. The bulla ethmoidalis contains the opening for the middle ethmoidal air cells. 3. Superior meatus contains an opening for the posterior ethmoidal air cells. 4. Sphenoethmoidal recessis located above the superior concha and contains an opening for the sphenoid sinus.

ClinicalCorlelate

B. Innervation 1. Somatic innervation. General sensory information from the lateral wall and septum of the nasal cavity is conveyedto the CNS by branches of V, and Vr. 2. Autonomic innervation. Preganglionic parasympathetic fibers destined to supply the glands of the nasal mucosa and the lacrimal gland travel in the nervus intermedius and the greater superficial petrosal branchesof the facial nerye (CN VII). Thesefibers synapse in the pterygopalatine ganglion, which is located in the pterygopalatine fossa. Postganglionic fibers traveling to the mucous glands of the nasal caviry paranasal air sinuses,hard and soft palate, and the lacrimal gland follow branches of V, and in some casesV, to reach their destinations. 3. Special sensory innervation. The olfactory mucosa of the upper nasal cavity is supplied by afferent fibers of CN I.

Insomeindividuals, theroots ofthemaxillary molar teeth protrude wellintothe maxillary sinus. Because these teeth andthesinus share a common innervation sensory viaV,,it isoften difficult to distinguish between a dental abscess anda maxillary sinus infection.

147

SYstem Respiratory

Bridgeto HistologY wallconsists Thepharyngeal laYer, a fibrous of a mucosa, which anda muscularis, is ofaninner composed layer(i.e., longitudinal stylopharyngeus, palatopharyngeus, andan salpingopharyngeus) layer(i.e., outerctrcular inferior middle, superior, muscles). constrictor

Correlate Clinical the Wheninflamed, areknown pharyngeal tonsils enlarged These asadenoids. tissue of lymphoid clumps thechoanae, mayblock to become thepatient causing a "mouthbreather."

Correlate Clinical of theremoval Tonsillectomy, is tonsils, thepalatine bythefactthat complicated havea veryrich thetonsils Theyreceive bloodsupply. bloodfrombranches arterial ascending ofthefacial, maxillary, pharyngeal, lingual, arteries. andpalatine

AREAS ANDRELATED PHARYNX sharedby the digestiveand respiratory systems.It haslateral,posA. The pharynx is a passageway (nasopharynx, terioi and medij *a[s throughout but is open anteriorly in its upper regions wall of The anterior cavity. oral the oropharynx), communicating with the nasal cavity and the laryngopharynx is formed by the larfnx' cavity. It B. Nasopharynx is the region of the pharynx located directly posterior to the nasal communicateswith the nasalcavity through the choanae(i.e.,posterior nasalapertures). 1. The torus tubarius is the cartilaginousrim of the auditory tube' tubarius; 2. The pharyngeal recessis the spacelocated directly above and behind the torus tonsil. nasopharyngeal it contains the salpin3. The salpingopharyngeal fold is a ridge consisting of mucosa and the underlying tubarius' the torus from pharynx the gopharyng.u, -,m.le, which runs down the wall of It comC. Oropharynx is the region of the pharynx located directly posterior to the oral cavity. by are bounded fauces The fauces. the called a space through carrity oial municates with the pillars. posterior and anterior the as known muscle, and mucosa of two folds, consisting the 1. The anterior pillar of the fauces, also known as the palatoglossal fold, contains palatoglossusmuscle. the 2. The posterior pillar of the fauces, also known as the palatopharyngealfold, contains palatopharyngeusmuscle. 3. The tonsillar bed is the spacebetween the pillars that housesthe palatine tonsil. from the D. Laryngopharynx is the region of the pharynx that surrounds the larynx.It extends piriform the as known are extensions Its lateral .oriil"g.. cricoid tip of ihe epiglottis to the recess. to the E. Oral cavity. The portion of the oral cavity that is posterior to the lips and anterior and mylohyoid the by formed teeth is called the vestibule. The oral cavity proper has a floor buccithe of consisting walls, geniohyoid muscles,which support the tongue. It has lateral the nator musclesand buccal mucosa,and a roof formed by the hard palate anteriorly and the to an opening by soft palate posteriorly. Its posterior wall is absent and is replaced oropharynx, which is flanked by the pillars of the fauces. 1. The palateseparatesthe nasaland oral cavities' plate a. Hard palate is formed by the palatine processof the maxilla and the horizontal V2. CN from fibers sensory of the palatinebone. Its mucosais supplied with b. Soft palate consistsof a fibrous membrane, the palatine aPoneurosis,coveredwith mucosa.The portion that hangsdown in the midline is the uvula, which containsthe musculusuvulae.Two additional muscles(i.e.,levator palati, tensor palati) insert into the palatine aPoneurosis. ante2. The tongue is a mobile, muscular organ necessaryfor speech.It is divisible into an terminalis. sulcus the by third one posterior a rior two thirds and (i.e., a. Muscles of the tongue. These include the intrinsic and extrinsic muscles palatoglossus,styloglossus,hyoglossus,genioglossus).All of the musclesare innervated by CN XII except the palatoglossus,which is supplied by CN X'

t48

Anatomy

b. Arterial supply. The tongue is supplied by the lingual branch of the external carotid artery. c. Venousdrainage.The lingual veins,which lie on the undersurfaceof the tongue,drain to the internal jugular veins. d. tymphatic drainage. The tip of the tongue drains to the submental nodes,and the remainder of the lateral margins of the anterior two thirds drains first to submandibular, then to deep cervical nodes. The posterior one third drains directly to deepcervicalnodes(FigureII-3-I). e. Innervation (1) Generalsomatic innervation of the anterior two thirds is by the lingual branch of the mandibular nerve (Vr).

ClinicalCorrelate Thelingual veins are conspicuous under thevery thinmucosa ofthe undersurface ofthetongue. Nitroglycerin, a treatment for pectoris, angina isplaced under thetongue intablet formfor rapidabsorption into thebloodstream through these veins.

(2) Thsteinnervation of the anterior two thirds is by the chorda tympani of the facial nerve (\III). (3) Thsteas well as general sensationof the posterior one third is via the lingual branch of the glossopharyngealnerve (IX). (4) Motor innervation of the whole tongue is provided by the hypoglossalnerve (XII).

To deep cervicalnodes

To deep cervicalnodes

ClinicalCorrelate Thelymphatia fromthe portion middle ofthetongue drainbilaterally to deep cervical nodes. Thisfactis important when to remember tracing thespread of cancer fromthecentral regions ofthe tongue.

To submandibular nodes

To submental nodes Figurell-3-1.Lymphaticdrainageof the tongue.

t49

Respiratory System

F. The larynx is the voicebox. It also maintains a patent airway and acts as a sphincter during lifting and pushing (Figure II-3-2). 1. Skeleton of the larynx a. Three laryngealcartilagesare unpaired (i.e.,thyroid, cricoid, epiglottis),and three are paired (i.e.,arytenoid, cuneiform, corniculate). b. The fibroelastic membranes include the thyrohyoid membrane and the cricothyroid membrane (conuselasticus).The free,upper border of the latter is specializedto form the vocal ligament on either side.

Thyroidcartilage Vocalismuscle Vocalligament Thyroarytenoid

muscle(J tension)

Lateral arytenoid muscle

Posterior cricoarytenoid muscle

Action of posterior cricoarytenoidmuscle (abductionof vocal ligament)

Action of lateral cricoarytenoidmuscle (adductionof vocal ligament)

Hyoidbone Corniculate cartilage Thyroid cartilage

Arytenoid cartilage

Transverse arytenoid muscle

Cricoidcartilage

Cricothyroid muscle(l tension)

Posterior cricoarytenoid muscle

Trachea

Lateral

Posterior

Figure ll-3-2.The larynx.

r50

Anatomy

2. Muscles of the larynx (TableII-3-l)

ClinicalCorrelate

Thble II-3-f .Intrinsic musclesof the larynx.* Muscle

Primary Function

Posteriorcricoarytenoid

Abducts vocal fold

Lateral cricoarftenoid

Adducts vocal fold

Cricothyroid

Tensesvocal fold

Thyroarytenoid (including vocalis)

Relaxesvocal fold

Thyroepiglotticus

Opens laryngealinlet

Aryepiglotticus

Closeslaryngealinlet

Oblique and transversearytenoids

Closeslaryngeal inlet

Croup, or laryngotracheal bronchitis, isa common ailment of infants and children. lt iscaused bythe inflammation andswelling of "false" thesubmucosa ofthe vocal folds, thevestibular folds thatarelocated superior to the "true"vocal foldscontaining thevocalis muscle. Thevirus responsible forcroupisthe parainfluenza virus.

*Note that the cricothyroid is innervated by the external laryngeal nerve, a branch of the superior laryngeal branch of the vagus nerve. All other intrinsic laryngeal muscles are supplied by the recurrent laryngeal branch of the vagus nerve.

3. Arterial supply. The superior and inferior laryngealarteriesarise from the superior and inferior thyroid arteries, respectively. 4. Venous drainage. The superior and inferior laryngeal veins drain to the superior and inferior thyroid veins, respectively. 5. Lymphatic drainage. Lymph from the larynx drains to the deep cervical nodes. 6. Innervation. The superior laryngeal nerve, a branch of the vagus nerve, divides to form the internal laryngeal nerve, which conveys sensory information from the laryngeal mucosa above the vocal folds, and the external laryngeal nerve, which supplies motor fibers to the cricothyroid muscle.The remaining laryngealmucosa and intrinsic muscles are supplied by the recurrent laryngeal nerve.

Note Theinternal laryngeal nerve plays animportant roleinthe cough whichkeeps reflex, the interior freeof ofthelarynx foreign material.

t5l

Respiratory System

CAVITIES ANDPIEURAI PLEURA Parietalpleura lines the inner surfaceof the thoracic cavity;visceralpleura follows the contours of the lung itself (FigureII-3-3).

Rightlung

Left lung

Superiorlobe

Superiorlobe

Middlelobe lnferiorlobe

Inferiorlobe

Costodiaphragmatic recesses

Diaphragm

Mediastinum

Figure ll-3-3.Pleural cavities and mediastinum.

Note oftheparietal Theboundaries pleura approximately extend tworibslowerthanthe ofthe corresponding areas lungs themselves.

A. Pleural cavity 1. The pleural cavity is the spacebetweenthe parietal and viscerallayersof the pleura. It is a sealed,blind space.The introduction of air into the pleural cavity may causethe lung to collapse(pneumothorax). 2. It normally containsa small amount of serousfluid elaboratedby mesothelialcellsof the pleural membrane. B. Pleural reflections are areaswhere the pleura changesdirection from one wall to the other. 1. The sternal line of reflection is where the costalpleura is continuous with the mediastinal pleura behind the sternum (from costal cartilages 24). The pleural margin then passes inferiorly to the level of the sixth costal cartilage.

t52

Anatomy

2. The costal line of reflection is where the costalpleura becomescontinuous with the diaphragmaticpleurafrom rib 8 in the midclavicularline, to rib 10in the midaxillaryline, and to rib 12lateralto the vertebralcolumn. C. Pleural recessesar€ potential spacesnot occupiedby lung tisue exceptduring deepinspiration. 1. Costodiaphragmaticrecesscsare spacesbelow the inferior borders of the lungs where costaland diaphragmaticpleuraare in contact. 2. Costom€diastin l recessis a spacewherethe left costaland mediastinalparietal pleura meet,leayinga spacedue to the cardiacnotch of the left lung. This spaceis occupiedby the lingula of the left lung during inspiration.

9f!if!...Co-ryqfala Painresulting from inflammation of thecentral ponronof thediaphragmatic pleuramaybereferred to the shoulderregion(C3-G dermatomes).

D. lnnervatiol ofthe parietal pleura 1. The costaland peripheral portions of the diaphragmaticpleura are suppliedby intercostalnerves. 2. The centralportion of the diaphragmaticpleura and the mediastinalpleuraare supplied by the phrenic nerve.

TUNGS A. Regions(FigureII-3-4) l. The costalsurhce is a largeconvenarearelatedto the inner surfaceof the ribs. 2. The rnediastinalsurfaceis a concavemedial surface. a. The left lung hasa deepcardiacimpression. b. The mediastinalsurfacecontainsthe root, or hilus, of the lung. c. The pulmonary ligamentis a doublefold of pleurahanginginferior to the root of rhe lung. The layersenclosethe costodiaphragmatic recess.

Oinital Conelate Because of theprotrusion of thecupolaof thelungthrough thesuperior thoracic aperture, it is oossible for a stabwound at therootof theneckto resultin a collapsed lung'

3. The diaphragmeticsurface (base)is r€latedto the convexsurfaceof the diaphragm.It is more concaveon the right due to the presenceof the liver. 4. The apex (cupola) protrudes into the root of the neck. It is crossedby the subclavian artery anteriorly. 5. The hilus is the point of attachmentfor the root of the lung. It containsthe bronchi, pulmonary and bronchialvessels, lymphatics,and nerves.

r55

System Respiratory

t\,

Anteriorview

;

.'.

i

\l t

I I

1

'l ii

t\

Costodiaphragmatic reoess Fosterior view

ClinicalConelate Bronchopulmonary segments aresignificant because each and hasis ownbronchial arterial supply andcanbe removed withminimal involvement ofadjacent segments. Flashback to Embryology between theleft Running pulmonary artery andthe aorta isafibrous cordcalled lt theligamentum arteriosum. isa remnant ofthefetal ductus arteriosus, which provided forblood ashunt ofthe fromtherightventricle thelungs. fetalheartto bypass

t54

Figure ll-3-4. Lungs and pleura. B. Lobes and fissures 1. The right lung is divided by the oblique and horizontal fissuresinto three lobes: superior, middle, and inferior. 2. The left lung has only one fissure, the oblique, which divides the lung into upper and lower lobes. The lingula of the upper lobe corresponds to the middle lobe of the right lung. C. Bronchopulmonary segments of the lung are supplied by the segmental (tertiary) bronchus, artery and vein. There are 10 on the right and eight on the left. D. Arterial supply 1. Right and left pulmonary arteries arise from the pulmonary trunk. The pulmonary arteries deliver deorygenatedblood to the lungs from the right side of the heart. 2. Bronchial arteries supply the bronchi and nonrespiratory portions of the lung. They are usually branches of the thoracic aorta. E. Venous drainage 1. There are four pulmonary veins: superior right and left and inferior right and left. Pulmonary veins carry oxygenatedblood to the left atrium of the heart.

Anatomy

2. The bronchialveins drain to the arygos system.They share drainage from the bronchi with the pulmonary veins. F. Lymphatic drainage 1. Superficial drainage is to the bronchopulmonary nodes; from there, drainage is to the tracheobronchialnodes. 2. Deep drainage is to the pulmonary nodes; from there, drainage is to the bronchopulmonary nodes. 3. Bronchomediastinal lymph trunks drain to the right lymphatic duct and the thoracic duct. G. Innervation of lungs. Anterior and posterior pulmonary plexuses are formed by vagal (parasympathetic)and sympatheticfibers. 1. Parasympatheticstimulation has a bronchoconstrictiveeffect. 2. Sympatheticstimulation has a bronchodilator effect.

t55

Respiratory Physiology Therespiratory system isstructurally andfunctionally adapted fortheefficient transfer of gases between theambient airandthebloodstream aswellasbetween thebloodstream andthetissues. Themajorfunctional components oftherespiratory system aretheainruays, alveoli, andblood vessels ofthelungs; thetissues of theche$wallanddiaphragm; thesystemic bloodvessels; red plasma; bloodcells and andrespiratory control neurons inthebrainstem andtheirsensory and motorconnections. Thischapter revievvs ventilation andthemechania bloodflowinthepulmonary of breathing, circulation, andtheexchange of gases between airandbloodandbetween bloodandtissues. principles problems Application ofthephysiologic to specific clinical includes discussion of pulmonary pulmonary obstructive andrestrictive disorders, sleep apnea, edema, andadaptation to highaltitude andexercise.

INTRODUCTION TOLUNG FUNCTION A. Provision of O, for tissue metabolism occurs via four mechanisms. 1. Ventilation-the alveoli

transport of air from the environment to the gasexchangesurfacein the

2. Ordiffusion from the alveolar air spaceacrossthe alveolar-capillary membranes to the blood 3. Tfansport of Orby the blood to the tissues 4. Ordiffusion from the blood to the tissues B. Removal of CO, produced by tissuemetabolism occursvia four mechanisms. 1. CO2diffrrsion from the tissuesto the blood 2. Transport by the blood to the pulmonary capillary-alveolar membrane 3. COrdifftrsionacross the capillary-alveolar membrane to the air spacesof the alveoli 4. Ventilation-the

transport of alveolar gasto the air

C. Functional components 1. Conducting airways (conducting zone; anatomic dead space) a. These airways are concerned only with the transport of gas, not with gas exchange with the blood.

r57

Respiratory System

b. They are thick-walled, branching, cylindrical structures with ciliated epithelial cells, goblet cells,smooth muscle cells,C1aracells,mucous glands,and (sometimes)cartilage. 2. Alveoli and alveolar septa (respiratory zoneilung parenchyma) a. Theseare the sitesof gasexchange. b. Cell types include: Type I and II epithelial cells,alveolar macrophages c. The blood-gas barrier (pulmonary capillary-alveolar membrane) is ideal for gas exchangebecauseit is very thin (<0.5 pm) and has a very large surfacearea (5G-100 m2). It consistsof alveolarepithelium, basementmembrane, interstitium, and capillary endothelium.

LUNG VOTUMES ANDCAPACITIES A. Lung volumes (Figure II-4-1)-There are four lung volumes, which when added together, equal the maximal volume of the lungs. 1. Tidal volume (%) is the volume of one inspired or expired normal breath (average human = 0.5 liters per breath). 2. Inspiratory reserve volume (IRV) is the volume of air that can be inspired in excessof the tidal volume. 3. Expiratory reserve volume (ERV) is the extra amount of air that can be expired after a normal tidal expiration. 4. Residual volume (RV) is the volume of gasthat remains in the lungs after maximal expiration (averagehuman = l.2liters). B. Lung capacities(Figure II-4- 1) are composedof two or more of the lung volumes. 1. Total lung capacity (TLC) is the volume of gas that can be contained within the maximally inflated lungs (averagehuman = 6 liters). 2. Vital capacity (VC) is the maximal volume that can be expelled after maximal inspiration (averagehuman = 4.8 liters). 3. Functional residual capacity (FRC) is the volume remaining in the lungs at the end of a normal tidal expiration (averagehuman = 2.2liters). 4. Inspiratory capacity (IC) is the volume that can be taken into the lungs after maximal inspiration following expiration of a normal breath. C. Residual volume cannot be directly measured by spirometry. Because FRC and TLC include the residual capaciry they cannot be directly measuredby spirometry either. Helium dilution techniques or the application of whole body plesthygmography are used to determine thesecapacities.

t58

Physiology

1 I

1I I

I

I

Inspiratory reserve Inspiratory volume capacity

Total lung capacity Vital capacity

I =o J

Tidal volume

Expiratory. reserve volume Residual volume

/l\

Functional residualcapacity

Figure ll-+1. Lung volumes and capacities as measured by spirometry.

D. A forced vital capacity (FVC) is obtained when a subject inspires maximally and then exhalesas forcefully and as completely as possible.The forced expiratory volume (FEV,) is the volume of air exhaledin the first second.Typically, the FEV, is approximately 80o/oof the FVC (FigureIl-4-2). 1. In obstructive lung diseases,such as bronchial asthma,the FEV, is reducedmuch more than the FVC, producing a low FEVr/FVC.

Clinical €orrelate . Obstructive airway ratio diseasesJ FEV,:VC . Restrictive airuaydiseasesnoreduction of FEV,:VC ratio

2. In restrictive lung diseases,such as pulmonary fibrosis, both the FEV, and the FVC are reduced.This characteristicallyproducesa normal or increasedFEV,/FVC.

4 Lung 3 volume change 2 (liters)

1234 Seconds Figure ll-4-2.Recordings made during a forced vital capacity maneuver.

t59

Respiratory System

NOMENCTATURE PHYSIOTOGY OFPUTMONARY A. Measurementsandtheir symbols: p = pressure;C = concentration;V = volume of gas;F = fractional concentration;Q = volume of blood; S = saturation. B. A dot over a symbol indicatesa time derivative:V= gasflow or ventilation (L/min); Q = blood flow (ml/min). C.Sitesandgassamples:I=inspired;e=alveolar;p=deadspace;n=expired;t=tidal. D. Sitesandbloodsamples: a = arterial;v = venous;v= mixedvenous;g = pulmonarycapillary. Thble II-4-f . Examples of symbol use. Symbol

Meaning

Units

Pto, VA Poo, P"o,

Partial pressureof O, in inspired gas Alveolar ventilation Partial pressureof O, in alveolar gas Partial pressureof O, in arterial blood

mm Hg L/min mm Hg mm Hg

GASLAWS ASAPPTIED TORESPIRATORY PHYSIOTOGY A. Dalton's law: In a gasmixture, the pressure(P) exertedby eachgasis independentof tle pressureexertedby the other gases.The total measuredpressureis the sum of that er<erted ry all of the gases: P,r,= PH,o+ Po, + Pcoz+ PN" A consequence of this is asfollows: partial pressure= total pressurex fractional conc€ntratiotr l. This equationcanbe usedto determinethe partial pressureof oxygenin the atmosphere. Assumingthat the total pressure(or barometricpressure[P"]) is atmosphericpressureat sealevel(760mm Hg) andtheftactionalconc€ntration of 02 is 2lyo,or 0.21: lofg PaltialPressures of Ol at Sea lorcl (NormalValues) Atmospheric Po,= 160mmHg lnspired orygen(Ft^) = 150mmHg AlveolaPo,(P6,) = 100mmHg Arterialpo,(paor)= l0ommHg MixedvenousPo,(Pp,)= 40 mmHg

po, = 760mm Hg x o.2t = 160mm Hg 2. As air movesinto the airways,the partial pressuresof the variousgasesin atmosphericair are reducedbecauseof the addition of water vapor (47 mm Hg)IThe partial piessureof inspired orygen canbe calculatedasfollows: Io,= (P,*d- PH,o)xEroz= Q60- 47\x 0.21= 150mm Hg B. Henr/s law statesthat the concentrationof a gasdissolvedin liquid is proportional to its partial pressureand its solubifity coefficient((). Thus,for gasX, txl =\xpx lhe useof this law is d€monstratedlater in this chaPter. C. Fick'slaw statesthat the volumeof gasthat diftrsesacrossa barrier per unit tirne is givenby:

%"r=f"ox(P,-Pr)

r50

Physiology

where A and T are the areaand thicknessof the barrier, P, and Prare the partial pressruesof the gason either sideof thebarrier, and D is the diffirsion constantof the gas.D is directlyproportional to the solubility of the gasand inverselyproportional to the squareroot of its molecular weight.

VENTITATION A. Tiotalventilation (Vr, minute ventilation) is the total gasflow into the lungs per minute. It is equal to the tidal volume (Vr) x the respiratory rate (n). Total ventilation is the sum of dead spaceventilation and alveolar ventilation. B. Anatomic dead spaceis equivalentto the volume of the conducting airways(150 mL in normal individuals), i.e.,the tracheaand bronchi up to and including the terminal bronchioles. Gas exchangedoes not occur here. Physiologic dead spaceis the volume of the respiratory tract that doesnot participate in gasexchange.It includesthe anatomic dead spaceand partially functional or nonfunctional alveoli (e.g.,becauseof a pulmonary embolus preventing blood supply to a region of alveoli). In normal individuals, anatomic and physiologic dead space are approximately equal. Physiologic dead space can greatly exceedanatomic dead spacein individuals with lung disease. C. Dead spaceventilation (Vo orVp x n) is the gasflow into dead spaceper minute. Alveolar ventilation (Ve orVe x n) is the gasflow entering functional alveoli per minute. D. Therefor., Vr = VR + Vp. E. AlYeolar ventilation

Note

l. It is the singlemost important parameterof lung function.

Thealveolar ventilation equation isuseful topredict

2. It cannot be measureddirectly. 3. It must be adequatefor removal of the CO, produced by tissuemetabolism.If it is not, alveolar and, therefore, arterial, Pco,increases,asshown by the alveolar ventilation equation: \bo, Po.o, =

Jt

(Vco, = rate of CO, production by tissues)

(andPa6sr) Pn66, when alveolar ventilation changes. (normally Forexample, P066, 40mmHg)willdouble to g0 mmHgbyhalving ventilation (hypoventilation).

4. Po.o,is an indication of the adequaryof alveolarventilation. a. Po.o,is impossible to measureclinically.

Note

b. Pa.o,is a closeestimateof Pl.o,.

. Poo, = 150mmHg= 40mmHg/0.8 100mmHg

5. Pe.o.and Pa.o.are better indications of Vo than is alveolar Por. 6. Whereasthe partial pressureof inspired O, is 150 mm Hg, the partial pressureof O, in the alveoli is typically 100mm Hg becauseof the displacementof O, with COr. Poo.cannot be measureddirectly but can be estimated with the alveolar gas equation: PA.o. Poo,

Pto, -

a. R is the respiratory exchange ratio (Vcor/Vo)

. Thishypoventilating person wouldhavea Pn of 50 mmHg: 1 5 0m mH g= 50mmH8 B0mmHg/0.8

-

and is equal to CO, production/O,

con-

sumption. R is typically 0.8 in the resting individual; it can approach 1.0 with exercise.

t6l

SYstem RespiratorY of P'l'or' b. Note that Pe.or,and therefore Pu.or,is used for the estimation Pa.o,is used to estimats PAcoz' c. Pao,cannot be used to estimate PRo,in the way that

AIRFIOW rower pressure just as fluids do' A A. Air moves from areas of higher pressure to areas of pressuregradient needsto be establishedto move air. when the musclesof inspiration B. Alveorar pressurebecomesressthan atmosphericpressure pressure. Intrapleural pressure enlarge the chest caviry thus lowering the intrathoracic of intra-alveolar pressure' The decreases,causing etp"nsion of the alveoli and reduction air into the airways' The drives alveoli pressure gradient-between the atmosphere and the opposite occurswith exPiration' (ml/min). c. Air travelsin the conducting airwaysvia bulkflow its velocity. velocity representsthe D. Bulk flow may be turbulent or laminar, depending on flow: speedof movement of a single particle in the bulk Velocity (cm/sec)=

Flow (cm3/sec) Cross-sectional area (cm2)

transitional flow is likely to At high velocities, the flow may be turbulent. At lower velocities, (streamlined).Reynold's number predicts occur.At still lower velocities,flow may be laminar will be turbulent' the air flow. The higher the number, the more likely the air

TRANSITIONAL

TURBULENT

ooocoo-o

ol-) c_c^taq^f \, \J'.)'t o a LAMINAR

ln a Nutshell theLung AirFlowthrough . Conducting zone:bulkflow . Respiratory diffusion zone:

Figure ll-4-3. Patterns of air flow'

into the lungs becauseof the E. The veloclty of particle movement slows as air moves deeper

areadue to branching. Diffusion 1sthe primary mechenormous increasein cross-sectionar alveoli (the respiratory zone)' anism by which gasmoves between terminal bronchioles and produce gasflow (V) is directly F. Ainvay resistance.The pressuredifference (Ap) necessaryto walls' airway related to the resistancelR; ."ut.d by friction at the l.

AP=VR

be describedby Poiseuille's law' 2 . The pressure-flow characteristicsfor laminar flow can

t62

Physiology

p - -

8nlV . TCr4

where Tl = viscosity of the gas,I = length of the airway, and r = radius of the airway. 3. The resistancecan be easily calculated using this relationship in conjunction with AP = \lR to give: R=

Srll nr4

Note the importance of the airway radius: if the radius is halved, resistanceincreasesby 16fold and air flow decreases by 16-fold. 4. Medium-sized ainvays (>2 mm diameter) are the major site of airway resistance.Small airways have a high individual resistance.However, their total resistanceis much less becauseresistancesin parallel add as reciprocals. 5. Factors affecting airway resistance a. Bronchoconstriction (increasedresistance)can be causedby parasympatheticstimulation, histamine (immediate hypersensitivityreaction), slow-reactingsubstanceof anaphylaxis(SRS-A= leukotrienesCn,Dn,En;mediator of asthma),and irritants.

Flashback to Cardiovascular Notethattheparameters defining airflowarethesame onesdiscussed in relation to bloodflowinthe Cardiovascular Physiology chapter.

b. Bronchodilation (decreasedresistance)can be causedby sympathetic stimulation (via beta-2 receptors). c. Lung volume also affects airway resistance.High lung volumes lower airway resistancebecausethe surrounding lung parenchymapulls airwaysopen by radial traction. Low lung volumes lead to increasedairway resistancebecausethere is lesstraction on the airways.At very low lung volumes, bronchioles may collapse. d. The viscosity or density of inspired gasescan affect airway resistance.The density of gasincreaseswith deepseadiving,leading to increasedresistanceand work of breathing. Low-density gaseslike helium can lower airway resistance. e. During a forced expiration, the airways are compressedby increased intrathoracic pressure.Regardlessof how forceful the expiratory effort is, the flow rate plateausand cannot be exceeded.Therefore, the air flow is effort-independent; the collapseof the airways is called dynamic compression. Whereasthis phenomenon is seenonly upon forced expiration in normal subjects, this limited flow can be seen during normal expiration in patientswith lung diseasewhere there is increasedresistance(e.g.,asthma) or increasedcompliance(e.g.,emphysema).

Clinical Conelate

MECHANICS OFBREATHING A. Muscles of respiration l. Inspiration is alwaysan active process.The following musclesare involved: a. The diaphragm is the most important muscle of inspiration. It is convex at rest and flattens during contraction, thus elongating the thoracic cavity.

Patients withemphysema exhale with"pursed" or partially closed lipsto increase backpressure through the ainruays, whichhelps maintain theirpatency

b. Contraction of the external intercostals lifts the rib cage upward and outward, expanding the thoracic cavity.Thesemusclesare more important for deep inhalations. c. Accessory muscles of inspiration, including the scalene (elevate the first two ribs) and sternocleidomastoid (elevate the sternum) muscles, are not active during quiet breathing but become more important in exercise.

t65

Respiratory System

2. Expiration is normally a passiveprocess.The lung and chestwall are elastic and naturally return to their resting positions after being actively expanded during inspiration. Expiratory musclesare used during exercise,forced expiration, and certain diseasestates. a. Abdominal muscles (rectus abdominis, internal and external obliques, and transversus abdominis) increaseintra-abdominal pressure,which pushesthe diaphragm up, forcing air out of the lungs. b. The internal intercostal muscles pull the ribs downward and inward, decreasingthe thoracic volume. B. Elastic properties of the lungs 1. The lungs collapseif force is not applied to expand them. Elastin in the alveolar walls aids the passivedeflation of the lungs. Collagen within the pulmonary interstitium resistsfurther expansion at high lung volumes. 2. Compliance is defined as the changein volume per unit changein pressure(AV/AP). 3. In vivo, compliance is measured by esophagealballoon pressureversus lung volume at many points during inspiration and expiration. Each measurementis made after the pressure and volume have equilibrated, so this is called static compliance. The compliance is the slope of the pressure-volume curve (Figure II-4-4).

1.0 o .= 0.75 o E

= 0.50

o

0.25

10

20

30

Pressure(cm HrO) Figure L-4-4. Pressure-volume relationships in a lung inflated and deflated with air or with saline. 4. Severalobservations can be made from the pressure-volume curve. a. Note that the pressure-volume relationship is different with deflation than with inflation of air (hysteresis). b. The complianceof the lungs is greater(the lungs are more distensible)in the middle volume and pressureranges. c. At high volumes and expanding pressures,the compliance is lower (the lungs are stiffer). d.'Evenwhen the lung has no expandingpressure,some air remainsin the lungs. e. When saline is used to fill the lung, compliance is much greater (small pressure changesbring about large changesin volume). With saline inflation, there is little differencein the pressure-volume relationship with inflation or deflation. This indicates that the differencesseenbetween inflation and deflation of air must be due to surface forces in the air-liquid interface of the alveoli.

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Physiology

5. Causesof decreasedcompliance a. Pulmonary fibrosis b. Pulmonary venouscongestionand edema c. Deficiencyof surfactant 6. Causesof increased compliance a. Emphysema b. Age

Emphysematous lung

(D

(D

E

E

I

I

o

E f

5

f

Pressure

I

Pressure

II

I

Pressure

Figure ll-4-5.Pressure-volume relationships (compliance) in a normal lung, a lung with increased connective tissue ("stiff"), and in an emphysematous lung.

C. Surface tension forces 1. In a liquid, the proximity of adjacentmoleculesresultsin large,intermolecular,attractive (Van der Waals)forcesthat serveto stabilizethe liquid. The liquid-air surfaceproduces an inequality of forcesthat are strong on the liquid sidebut weak on the gassidebecause of the greater distancebetween moleculesin the gas phase.Surface tension causesthe surface to maintain as small an area as possible.In alveoli, the result is a spherically curved, liquid lining layer that tends to be pulled inward toward the center of curvature of the alveolus.The spherical surfaceof the alveolarliquid lining behavesin a manner similar to a soapbubble. The inner and outer surfacesof a bubble exert an inward force that createsa greater pressureinside than outside the bubble. The pressuredifference causedby the curved alveolar surfacecan be determined from LaPlace'slaw for a sphere, where AP is the pressuredifferenceacrossthe surface(dynes/cm'),T is the surfacetension (dynes/cm),and r is the radius of curvature of the surface(cm): LP = 2Tlr 2. Interconnectedalveoli of different sizescould lead to collapseof smaller alveoli (atelectasis) into larger alveoli (Figure II-4-6). Becauseof surfacetension, the pressureinside the smaller alveolus(smaller radius of curvature) is greaterthan that of the larger alveolus. Without surfactant, gas would therefore move from smaller to larger alveoli, eventually producing one giant alveolus.

r65

System Respiratory

P t= " 1r, Pr=2'lr,

Figure ll-4-6. Effects due to LaPlace's law on adiacent alveoli of different radii in the absence of surfactant. Pressurein the smalleralveolus(r = 1) would be twice the pressurein the largeralveolus(r = 2).

3. Pulmonary surfactant a. Pulmonary surfactant is a phospholipid (comprised primarily of dipalmitoyl phosphatidylcholine) synthesizedby type II alveolar epithelial cells. b. Surfactantreducessurfacetension,thereby preventingthe collapseof small alveoli. c. Surfactantincreasesthe complianceof the lung and reducesthe work of breathing.

ClinicalCorrelate infants before Premature the may 35thweekof gestation neonatal experience distress respiratory syndrome (NRDS), which is bya lackof characterized pulmonary surfactant production intheimmature lungs. NRDS canbescreened forbysampling theamniotic fluidforthelecithin to ratio, sphingomyelin whichis less than1.5in NRDS. usually

t66

d. Surfactant keepsthe alveoli dry becausealveolar collapsetends to draw fluid into the alveolarspace. e. Surfactantcan be produced in the fetus as early as gestationalweek 24but is synthesized most abundantly by the 35th week of gestation. Neonatal respiratory distress syndrome can occur with premature infants and results in areasof atelectasis,filling of alveoli with transudate, reduced lung compliance, and V/Q mismatch, leading to hypoxia and CO, retention.

THORACIC WALIMECHANICS The chestwall tendsto passivelyspring outward. The lungs recoil inward. Theseopposingrecoil forcescreatea negativepressure(-3 to -5 mm Hg) within the intrapleural spaceat rest.At equilibrium, when the elastic recoil of the lungs is balancedby the tendenry of the chest wall to spring out, the lungs are at FRC.With the expansionof the chestwall during inspiration, a more negativeintrapleural pressureis generated.This negativepressureactsto expandthe lungs. Less negativeintrapleural pressure(aswith relaxation of the musclesof inspiration) allowsthe passive recoil of the lungs and expiration. The introduction of air into the intrapleural space (pneumothorax) causesthe intrapleural pressureto become equal to atmospheric pressure. This causesthe lungs to naturally recoil (collapse)and the chestto naturally spring out.

Physiology

P=0 P=-5

Normal

P nneeuum moot thhoor ar ax x

Figure ll-4-7.Intrathoracicand lung pressures in the normal"resting" state and with pneumothorax (air in the intrathoracic space). Note that with a pneumothorax,the lung collapsesand the chestwall "springs"outward.

DIFFUSION OFGASACROSS A BARRIER A. Principles of gas diffusion (FiclCslaw of diffirsion) 1. V gas = A D( P r-P2 )/T whereVg",= volume of gasmoving through the barrier per unit time, A = areaof the barrier, P, -Pr= partial pressuregradient acrossthe barrier, T = thicknessof the barrier, D = diftrsion constanto solubilitv/VMw. 2. The amount of gas (Vgur)that moves acrossa barrier, such as the blood-gas barrier, is dependentupon the following: a. The surfaceareafor diffusion (-70 m' in the adult lungs) b. The reciprocalof membrane thickness c. A diffi,lsion constant,which is directly proportional to solubiliry and inverselyproportional to the squareroot of the molecular weight of the gas (1) COris more highly solublein tissuefluid than is O, andthus diffirsesmore rapidly acrossthe blood-gas barrier. d. The partial pressuregradient acrossthe blood-gas barrier is the driving force for gas movement. This gradient between alveolar gas and mixed venous blood is much greaterfor O, (60 mm Hg) than for CO, (6 mm Hg). This greaterpartial pressuregradient for O, offsets the solubility advantagefor CO, at sealevel, but the advantageis lost at higher altitudes,at which Poo,ir diminished.

r67

System Respiratory

CAPIIIARY ATTHEPULMONARY GASEQUIUBRATION A. The transit time through the pulmonary capillary is = 0.75 seconds. B. Normally, the equilibration of O, and CO, is completeby 0.3 seconds. C. Exercisereducesthe time availablefor equilibration, but there is still ample reservefor a healthy individual. For O, this reserveis reducedat high altitude becauseof a smaller partial pressuregradient. D. Thickening of the alveolar-capillarymembrane slowsdiffusion so that equilibration may not be complete.Exerciseaccentuatesthis effect. E. Perfusion-limited and diffrrsion-limited exchangeof gases l. Gasesthat equilibrate betweenthe alveolargasand the pulmonary capillariesare called perfusion-limited gases.This is becausethe amount of gastaken up by the blood is not dependenton the propertiesof the blood-gas barrier. However,the uptake of the gascan be increasedif blood flow increases.Examplesof gasesthat are perfusion limited are O, (under normal conditions), nitrous oxide (NrO)' and COr. 2. Gasesthat do not equilibrate betweenthe alveolargasand the pulmonary capillariesare said to be diffusion-limited gases.In other words, the uptake of gasinto the pulmonary capillaries is limited becauseof diffusion properties of the blood-gas barrier, not the amount of blood perfusing that region. a. O, canbe diffusion-limited under certainconditions.If the blood-gasbarrier is thickened (e.g.,fibrosis) or if there is a decreasein the surfaceareaover which gasexchange can occur (e.g.,emphysema),O, may not fully equilibrate.The diffusion limitation therebydecreasing will be evenmore apparentwith exercise(cardiacoutput increases, the equilibration time) or with the breathing of a low-O, mixture (decreasingthe O,

ClinicalCorrelate (DL)can capacity Diffusing with: decrease . Thickening oftheblood-gas (e.g., fibrosis dueto barrier berylliosis, sarcoidosis, or idiopathic asbestosis, fibrosis) . A decrease inthesurface banier area oftheblood-gas (e.9., emphysema, pneumonecomy, space lesion ofthelung) occupying . A decrease intheabilrty ofO, of to bindwithHbbecause pulmonary blood decreased (e.g., of occlusion volume Hb blood flow)orabnormal (e.g., anemia) states

driving force). b. Carbon monoxide (CO) is considered diffusion limited. CO binds so avidly to hemoglobin that there is very little increasein the partial pressureof CO in the blood after inhalation of CO. As a result,CO is usedto measurethe diffrrsing capacity of the lung.

IN BTOOD GASTRANSPORT A.O, 1. In solution a. The solubility coefficientfor O, isvery low (0.003mL/100 mL blood ' mm Hg). b. Thus, in arterialblood (Pao: 100mm Hg), the amount of O, carriedin solution is: (0.003mL o,/100 mL blood ' mm Hg) x (100mm Hg) = 0'3 mL o2l100mL blood 2. lncombination with hemoglobin (Hb) a. 1.34mL O, combineswith 1 g Hb b. Normal Hb is -15 g Hb/100 mL blood c. Thus, the amount of O, that can be carried by Hb (O, capacity) is: 1.34mL Orlg Hb x 15 g Hb/100 mL blood = 20 mL O2l100mL blood

t68

Physiology

3. Tiotaloxygen content of the blood equals the dissolvedO, plus the O, bound to Hb: 1.34mL O g Hb ' 100 mL blood

0.003mL O

X PO, 100 mL blood ' mm Hg PO,

roo I

mL O'

=-roo ,r* utooa TOTAL

BOUND

DISSOLVED

-x gHb x

-l Tosat

4. The hemoglobh-O, dissociation curve (Figure II-4-8) a. The amount of O, carried by Hb increasesnonlinearly with increasingPo, due to changesin affinity as more O, is bound (cooperativrty).

Note exhibits TheHbmolecule positive the cooperativity; of O, binding ofa molecule atonehemegroupincreases affinity of the theoxygen groups. otherthreeheme

O, combined with Hb b. O" saturation =

Orcapacity

x 100

c. In arterial blood, the Po, is typically 100mm Hg. At this partial pressure,Hb is 97.5o/o saturated.In venous blood, the Po, is typically 40 mm Hg, and Hb is 75olosaturated. d. The Pro,or the Po, at which Hb is 50olosaturated,is typically 27 mmHg. e. At a high Por,asoccursat the pulmonary capillaries,large changesin Po,produce only small changesin Hb saturation,so that the O, content of arterial blood can remain relatively constantdespitewide fluctuations in inspired Po,. f. At a low Po, Q040 mm Hg), as occurs in the tissues,large amounts of O, can be deliveredto the tissuesbecausesmall changesin Po,produce large changesin Hb-O, binding. A small decreasein Po,can releaselarge amounts of O, to the tissues. g. The curve shifts to the right (Prois increased)when the Hb-Oraffinity is decreased. This facilitates O, unloading and occurs with the following conditions: (1) IncreasedPco, (which leadsto decreasedpH) causesmore O, deliveryto the tissues(Bohr effect) (2) Increased temperature (3) Increased2,3-diphosphoglycerate(DPG) is produced by RBCsduring anaerobic glycolysis An easywayto rememberthis is that exercisingmuscles(which require more Or) produce more CO, tend to be acidic (becauseof the CO, and lactic acid), are hot, and rely more on anaerobicrespiration,thus generating2,3-DPG.

ln a Nutshell to therightintheHbShifts curve: 0, dissociation . Reflects thatthereislower between HbandO, affinity . Proisincreased, andO,is fromarterial unloaded bloodto thetissues. . lncreases in Pco,, temperature, and2,5-DPC ina concentration result shiftto theright. . A decrease in in pHresults right. a shiftto the

r69

Respiratory System

100 90 *

80

c rl -9 o) o

70

60 E 50 t p H o s I P"o, o 40 I opo c o

E 5 (d

a

lpx t P.o, I onc

30 I temp 20 10

I temp

0 0 10 20 30 40 50 60 70 80 90 100 Figure ll-&8.The oxygen-hemoglobin dissociation curve. Effectsof pH, temperature,PCO2,and 2,3-DPGare shownby the arrows.

In a ltubhell to theleftin theHb-O, Shifts dissociation curve:

h. The curve shifts to the left (Prois decreased)when the Hb-O, affinity is increased. This facilitates Or loading in the lungs and makesO, unloading in the tissuesmore difficult. This occurs under the following conditions: ( 1) Low Pcor,high pH, low temperature, and low 2,3-DPG

. LowP.or, lowtemperature, low2,3-DPG, highpH

(2) Fetal hemoglobin (hemoglobin F) has a lower affinity for 2,3-DPG than does adult hemoglobin, thus causing a left-shift of the curve.

. ln thefetus,HbF(whichhas affinity for0, than a higher Hb)allows doesregular 0, to beextracted from maternal Hb.

(3) Carbon monoxide, which has a 240x greater affinity for Hb than does O, competeswith O, for binding sites on Hb. The remaining sites on Hb have a higher affinity for O, than normal. Carbon monoxide poisoning is very dangerous becauseit lowers the O, content of the blood and produces a left-shift of the hemoglobin-O, dissociation curve, thus impairing the ability of bound O, to dissociate.

. ln COpoisoning O,isnot fromHbto the released resulting intissue tissues, hypoxia.

ilote (Q for Thesolubility constant C0,isabout20x thatof 0,.

B. CO2 l. Dissolved a. Solubility coefficient= 0.06 ml/mm Hg Pco, ' 100 mL blood b. In arterial blood, Pco, = 40 mm Hg: 0.06 mL CO,

2.4 mL CO,

X 40 mm Hg COrmm Hg CO, ' 100mL blood 100mL blood 2. Bicarbonate (major form: 9oo/oof total COr)

COr+Hro 5

H2co3€H*+

HCoy

a. CO, diftrsesfrom the tissuesinto the RBCsand plasma.

t70

Physiology

b. Carbonic anhydrase (CA), which is present in RBCs, catalyzes the formation of H2CO3from CO, andHrO.H2CO3thendissociates to form HCO,- (bicarbonateanion) and H*. c. HCOr- diffirsesinto plasma,and Cl- diffirsesinto RBCsto maintain electroneutraliw. This movement of Cl- is called the chloride shift. d. RBCsare permeableto anionsbut not to cations.The H* left behind in the RBC is better bufferedby deoxyhemoglobinthan by oxyhemoglobin.Therefore,the unloading of O, is advantageousfor CO, loading (Haldane effect).

COzascarbamino Hb

C O z+H zO* H zC Og+H * + H C Os-

Figure ll-4-9.CO2transport in blood.

3. CO2combineswith terminal amine groups on Hb to form carbamino Hb. This reaction is chemically different from O, binding by Hb. CO, binds to the deoxygenatedform of Hb. So again,the unloading of O, helps with the loading of COr. 4. In the lungs, all of the abovereactionsoccur in reverse.Cl- movesout of the RBC. HCO3re-entersthe RBC and combineswith H* to make H2CO3.H2CO3dissociatesto CO, and HrO, and the CO, is exhaled.

ln a Nubhell . ln thetissues, Cl-shiftsinto RBCs. . Inthelungs, Cl-shifts out OfRBG.

HYPOXEMIA ANDHYPERCAPNIA A. Hlpoxemia. Pao,(85 mm Hg when breathing atmosphericair. 1. Possiblecauses a. Decreasedinspired Por,aswith high altitude or anestheticmismanagement b. Alveolar hnroventilation, where reduced Pao,is accompaniedby increasedPa.or.This may be due to pulmonary or neuromusculardisease,CNS depression(e.g.,becauseof sedativeihypnoticsor opiates),or inadequateventilation during anesthesia. c. Right-to-left shunts occur in which venous blood blpassesthe alveoli and "dilutes" the oxygenatedblood returning to the left heart. Congenital heart diseaseor atelectasis (alveolar collapse) with continued blood flow cause shunting. Hnroxemia due to shunting is not completely correctable by breathing l00o/oOr. This is becausethe shunted blood is never exposedto the high Po, and continues to depressthe arterial Or.

l7l

Respiratory System

!_ote Administration of 100o,o, inthe canreverse hypoxemia C8se of V/Qmismatch butnot ;nthecaseol ananatomic shunt

d. Under certaincircumstanc€s, Pao,do€snot fully equilibratewith P,ro,.In other words, (e.9., o, is diftrsion-limited becauseofa thickenedblood-gasbarrier seenwith fibrosrs,' e. Ventilation/perfusion mismatch is the mostcommoncauseof hpoxemia and occurs in manytypesof pulmonarydisease. B. Hlaercapnia.IncreasedPaco,to levels>42 mm Hg. l. Possible causes a. Hnroventilrtion-rernember tlnt Pa.o,is the bestindicator of alveolarventilation,so it mak€ssensethat inadequatealveolarventilation would be the most probablecause of hnrercapnia.

Gliniol GOffelan. Theventilatory driveof patients withchroniclung disease is primarily dueto urErr rryPuxcrrrrd' rdurer urdrr pH. levels CO, or Administration of a highO, mixtureto relievethe hvDoxemia iscontraindicted

b. VerF*severe ventilationy'perfusionmismatch is capableof causinghypercapnia(see 2. IncreasedPa"o,is the major stirnulusfor increasingventilation. If hypercapniaexists,it is highly likely that the respirator)'muscl€sand lungswill not be ableto respondadequately to restorePa.o,' 3. With adaptationto chronichypercapnia, decreased Pa^ canbecomethe majorstimulus for increasingventilation. If sucha iatient is givenOr,"iespiration,nay fail if ventilatory assistance is not givenat the sametime.

SPECTATFEAIURESOFTHEPUTMONARYCIRCULATION becausethisremovesthe hypoxic drive,leadingto severe hypoventilation.

A. pressure,flo-' end r€sistanc€ t. The right ventricle is normally a low-pressure,high-volumepump. It pumps the sarne volume of blood asthe left ventricle,the cardiacoutput (CO), but at a much lower pressure(20-25% of the pressureof the left ventricle). a. The systolicpressureis 25 mm Hg; the diastolicpressureis 8 mm Hg. b. The shapeof the right ventricleis adaptedfor low-pressure,high-volurnepumpinga'wide-bore, short-stroke"purnp. 2. Pulmonary arteries are large-diametervesselswith thin walls,making them distensible and collapsible(compliant). a. They havelesssmooth musclethan systemicaderies. b. Theyreceivethe entir€ cardiacouq)ut,yet the meanpulmonary arterialpressureaverages17mm Hg and dropsoff rapidly in distal pulmonary arteries. l. The differencein meanpressure(AP) from the pulmonary artery to the left atrium (171 mm Hg) is much lessthan that in the systemiccirculation (100-4 mm Hg). L The reasonfor the low pressurein the pulmonary circulation ascomparedwitl the systemic circulation is its much lower resistance(R):

= = R(pulmonary) :## #

R (systemic)=

172

Ap CO

=

98 mm Hg 5 Lhrrir,

= 3 mmHg/(L/min)

= 19 mm Hg/(L/min)

Physiology 5' Furthermore' as flow in the pulmonary circulation increases(increased cardiac output, co)' the resistancecan decreaseto even lower levelsbecause of two mechanisms: a' Distension of individual vesselsproduces larger vessel radii and thus reduces resistance. b' Recruitment of previously collapsed vessels (especially at the top of the lungs) increasesthe total cross-sectional area through which blood is flowing and th-us reducesresistance. 6. Effects of lung inflation on pulmonary vesselradius and resistance a' Small vesselsadjacent to alveoli ("alveolar vessels")are compressedat high lung volumes by the air pressureinside the alveoli. b' Large extra-alveolar vesselsare expanded during inspiration by the reduction of intrathoracic pressureand by radial traction on tl"r.lressels by ih" expanding lung parenchyma. c' Pulmonary resistanceis high at low lung volumes because of narrowing of the extraalveolar vessels.Resistanceis lowest at;iddle lung volumes, but at high lung volumes' resistanceis increasedagain becauseof narrowing of alveolar u.Jsels (rigures I I - 4- 10a n d II-4 -1l ).

extra-alveolar vessels

extra-alveolar vessels

4 alveolar vessel

alveolar vessel

alveolar vessel

LOW LUNG VOLUME

MEDIUMLUNG VOLUME

HIGHLUNG VOLUME

Figurell-+10. Effectsof expandinglung volumeon diameters of atveolar and extra-alveolarblood vessels.

o o c (d .(t, o

E

(d J

o

U'

Lungvolume

Figurell-4-11.Biphasicchangesin pulmonaryvascularresistance with expandinglung volume.

t7,

Respiratory System

7. Effects of gravity-induced hydrostatic pressure on blood flow at different lung levels in the upright human (Figure II-4-12) a. Blood flow is greatestin the lowestportions of the lung (zone 3) becausepulmonary arterial, venous, and capillary (alveolar vessel)pressuresare largest in this lowest region, distendingthe blood vesselsand lowering vascularresistance(P. > Pv > PA). b. Blood flow is intermediatein the middle portions of the lung (zone 2).ln this zone, alveolargaspressureis greaterthan that in pulmonary capillaries,causingnarrowing of thesevessels, thus increasingvascularresistance(P") Po> Pu).In zone 2, blood flow is intermittent. During systole,P" exceedsPo, producing a blood flow that is determined by P"- Po(not the typical P"- Pv).During diastole,P" falls below Po,causing blood flow to cease. c. Blood flow is lowest in the upper portions of the lung (zone f ). A situation can occur in which there is no blood flow becausethe alveolarpressureis greaterthan the arterial and venouspressures,leading to collapseof the capillaries(Po > P" > Pv). Zone I doesnot existunder normal conditions becausethe pulmonary arterial pressureis just sufficient to perfusethe top of the lung. This zone may be presentif the arterial pressure is abnormally low (e.g.,becauseof hypotension due to hemorrhage) or if the alveolarpressureis abnormally high (e.g.,with positive-pressureventilation). d. Theseeffectsdescribean upright individual at rest.An individual in a supine position would have fairly uniform blood flow from the apex to the base(although posterior blood flow would exceedblood flow in anterior regions). Exerciseincreasescardiac output, resulting in a more uniform distribution of blood flow in the lung.

PotP">Pv

No flow is possible. Pnis sufficientto collapsecapillaries.

P">PA>Pv Intermittentflow. Flow is driven by Pu- Podifference. P">Pv>PA Flow always possible.Flow is driven by P"- Pu difference. Figure ll-4-12.Blood flow at three zones in the upright lung.

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Physiology

B. Regulation of pulmonaryblood flow 1. Hypoxic vasoconstriction results from a low alveolar Por. a. In contrastto systemicarteriolar smooth muscle,which relaxesin responseto low Po, alveolar hypoxia causesconstriction of small pulmonary arteries. This responseis adaptive in that it shunts blood flow away from poorly ventilated alveoli (e.g., after bronchial obstruction). b. Fetal lungs exhibit hypoxic vasoconstrictionproducing a low pulmonary blood flow. There is a sudden rise in Pao, with the first breath, leading to a marked decreasein pulmonary vascularresistance.This allows the entire cardiacoutput to flow through the pulmonary vasculaturewithin severalbreaths. c. A generalizedhypoxic vasoconstrictionoccursat high dtitude. This is not an advantageous responsebecausethe increased pulmonary arterial pressure can lead to increasedwork and hypertrophy of the right heart.

ln a Nubhell Alveolar hypoxia causes local vasoconstriction in Pulmonary bloodflowThisresponse is opposite to thesystemic vascular response to hypoxia, whichisvasodilatation. The pulmonary vascular vasoconstriction isimportant because it diverts bloodaway frompoorlyventilated areas of thelungandtoward well ventilated areas.

d. Hypoxic vasoconstriction occurs in experimentally denervatedlungs and in transplanted lungs and is therefore not dependent on an intact nerve supply. Local chemical mediators or a direct effect of low alveolar Po, are implicated. C. Pressure measurements in the pulmonary circulation 1. All vascular pressuresin the pulmonary circulation can be measuredclinically with a b alloon -tipped catheter,the Swan-Ganz catheter. a. The Swan-Ganzcatheter has two lumens-an air-fi.lled lumen and a saline-filled lumen. (1) The heparinized,saline-filledlumen can be attachedto a pressuretransducerfor pressuremeasurementor can be usedfor blood samplingby withdrawal of blood into a syringe. (2) The air-filled lumen can be attachedto an air-filled syringethat is usedto inflate a balloon surrounding the tip of the catheter. 2. The Swan-Ganzcatheteris flow directed. a. Inserted into a systemicvein with the balloon collapsed,it can be passedto the right atrium. b. With the balloon inflated, it is then swept along through the right atrium, acrossthe tricuspid valve into the right ventricle, then acrossthe pulmonic valve into the pulmonary trunk, and onward into a small pulmonary artery where the balloon becomes lodged or "wedged."The saline-filledlumen no longer measuresthe pulmonary arterial pressurebecausethe blood previouslyflowing in this small artery hasbeen diverted to other small pulmonary arteriesin parallelwith it. The saline-filledlumen is now in a position to measurepressure(the pulmonary wedge pressure) in the vessels downstream from the catheter tip, which ultimately reflects the left atrial pressure.

THEMATCHING OFVENTITATION ANDPERFUSION A. The total minute ventilation and the cardiac output in adults are both approximately 5-6 L/min. Therefore,the overall ventilation/perfusion (VCD is approximately r. n VQ raiio of I is ideal for maximal exchangeof O, and COr. B. However,in eachlung compartment, the VQ can vary from 0 to oo.

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Respiratory System

C. If an alveolus or group of alveoli are servedby an obstructed airway, the local ventilation may be 0. VA/Q: 0. The Po, and P"o, of the alveolar gas and pulmonary capillary blood approach that of mixed venous blood (Figure II-4-13). This is called a physiologicshunt. D. If an alveolusis being ventilated but hasno blood supply, ascould happen with a pulmonary embolus, V^/Q = -. The Po, and P.o, of the alveolar gas approach that of inspired air. The ventilation of these alveoli is wasted producing physiologic dead space.

Oz = 150 mm H g

n ) I\ co2-o

ln a.Nubhell . Normal V/Qratio-t . Airwayobstruction -+ = o. lf thereis ventilation bloodflow,V/Q=g. normal Pno,andPno,approaches venous thevalueof mixed blood. . Bloodflowobstruction -> V/Q- infinity. Nogas Pno, exchange occurs. and Pn.o,approach thevalueof inspired air.

@

Il

v v v , (o,=o\

\

obstruction of ventilation

or=fo(

c o 'o = + o L

oz=1oo \ \

normal ventilation

/*\

t ( o r = 1 s o\ \

obstruction of arterialvessel

Figure ll-4-13. The effects of altering ventilation or perfusion in the lung.

E. Neither ventilation nor perfusion are uniform throughout the lung. 1. Ventilation. Upright individuals have the greatest ventilation in the lower regions of the lungs. This is becauseintrapleural pressureis more negativesurrounding the apical portions of the lung, so that apical alveoli are more distended.Thesealveoli are stiff and difficult to distend further to ventilate them. Basal alveoli are lessdistended, more compliant, and easier to ventilate. With each inspiration-expiration rycle they exchangemore gas. 2. Perfusion. Perfusion is also greatest in basal areasof the lung becauseof the higher vascular pressuresdue to gravity (seeFigureII-4-12). 3. Ventilation increasesslowly from the apex to the base of the lung. Perfusion increases more rapidly from the apex to the baseof the lung. As a result, the ventilation/perfusion ratio is highest at the top of the lung and lowest at the bottom (Table lI-4-2).

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Physiology

Thble ll-4-2.Ventilation Rib Number

and perfusion (L/min) at various levels of the l ntg.

Blood Flow (L/min)

I (top) 2 3 4 5 6 (bottom)

Ventilatio n (o/olung vol)

Ve/Q

0.045

3.20

0.014 0.02 0.05 0.07 0.08 0.1

0.035 0.05 0.0s 0.055 0.06

r.75 1.00x

0.7r 0.69 0.60

Note that blood flow increasesmore sharply from top to bottom of the lung than does ventilation. Thus, below rib 3, perfusion is lessthan ventilation ana V^lQ is lessthan l; at the level of about rib 3, ventilation and perfrrsion are equal and Volq = 1*; at higher levels,ventilation is greater than perfusion andVo/Q is greaterthan l.

F. The baseof the lung has a lower Po, becauseof its lower V/Qratio. Becausea disproportionate amount of blood comes from the base,there is a slight depressionof arterial Por. This contributes to the alveolar-arterialO, differenceof about 4 mm Hg io the normal individual.

VA/eINEeuAury tNpATHorocrc srATEs A. The degree of V^/Q inequality (with increasesin both high and low VQ alveolar units) increasesdramatically in various pulmonary diseases,reducing the efficiency of gas exchange.

ClinicalCorrelate Theapexofthelunghasa higherPo,because of its higherV/Qratio.Reactivation tuberculosis tends to involve thelungapices because Mycobacteriun tubercuI osis requires O,to grow.

B. Causesof lowVo/Q 1. Airway obstruction impairs alveolar ventilation. a. Physicalobstruction (e.g.,mucus or object) b. Bronchoconstriction 2. Decreasedlung compliance impairs alveolar ventilation. a. Pulmonary edema"stiffens" the lung, decreasingalveolarventilation aswell asimpairing gastransport from alveoli into the blood. b. Pulmonary fibrosis decreaseslung compliance, impairing ventilation; also,thickening of the blood-gas barrier impairs gastransport from the alveoli to the blood. C. Causesof highVn/a l. Pulmonary embolism (impairs circulation) 2. Hemorrhage (impairs circulation) 3. Positive-pressureventilation (can impair circulation by collapsing pulmonary blood vessels) 4. Anesthesia(can impair circulation) D. Pulmonary responsesthat normally minimize U/a mismatch 1. Hypoxic vasoconstriction. Constriction of small pulmonary arteries in responseto alveolar hypoxia reducesflow to hypoxic alveoli. 2. Hypocapnic bronchoconstriction. IncreasedVQ leads to reduced Pr.o^, causing local bronchial smooth muscle contraction.

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Respiratory System

CONTROT OFBREATHING A. Central control of breathing 1. Medullary respiratory center a. The dorsal respiratory group is responsible for inspiration and for generating the basic rhythm of breathing. This cell group receivesinformation from peripheral chemoreceptors,baroreceptors,and various lung receptorsvia the glossopharyngeal and vagus nerves.It outputs via the phrenic nerve to the diaphragm. b. The ventral respiratory group is inactive during quiet breathing but is involved in regulatingbreathing when ventilation is greaterthan normal (e.g.,during exercise).It is particularly important in sendingexpiratory signalsto the abdominal musclesduring active expiration. 2. The apneustic center, located in the lower pons, causesdeep and prolonged inspiratory gasps (apneuses).It is unclear whether this functions in normal breathing,but apneuses interrupted by brief expirations are seenin some types of brain injury. 3. The pneumotaxic center,located in the upper pons, actsprimarily to inhibit inspiration. This can increasethe respiratory rate. 4. The cerebral cortex plays a role in voluntary breathing. Hyperventilation is easier to accomplish voluntarily than is hypoventilation. B. Efferent pathways 1. Phrenic nerve to diaphragm 2. Motor neurons to intercostalmusclesand abdominal muscles

ln a Nubhell

C. Afferent systems 1. Chemoreceptors for CO,

CentralChemoreceptors . Aresensitive to CSFpH. . Increases in P.o. and[H.] stimulate breathing rate. Decreases in P.o,and[H.] inhibit thebreathing rate.

a. Medullary CO, receptors actuallyrespondto H'. CO, passesthrough the blood-brain barrier into cerebrospinalfluid (CSF) and reactswith HrO to form H2CO3HCOr- and H* are subsequentlyproduced, and the H* stimulatesthe chemoreceptors.Increases h P.o, and [H.] in the CSF stimulate breathing, ord decreasesin Pco, and [H*] inhibit breathing. Theseare the most important receptorsthat respond to changesin CO, levels.

. Hypoxia doesnot$imulate central chemoreceptors atall.

b. Peripheral CO, receptors are located in the carotid and aortic bodies. Increasesin P.o, lead to increasesin ventilation. (1) Quantitatively,peripheral CO, receptorsare not as important as their central counterparts. (2) This responseis potentiatedby decreases is Pao,(FigureII-4-14).

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Physiology

ln a NuGhefl

P?or= 100 mm Hg Alveolar ventilation (Umin)

. Increases in P.o,in arterial peripheral bloodstimulate thus chemoreceptors, therateof increasing breathing. . Theperipheral arenotas chemoreceptors asthecentral important in chemoreceptors in to changes responding P.o,. arterial

Pa6er(mmHg) Figure ll-rt-l4. Influence of Pagron chemorcceptor responsiveness to Pa6qr.

2. Chemoreceptors for O, a. Peripherd O, receptors are located in the carotid and aortic bodies. Decreasesin Po, lead to increased ventilation. (1) However, Poz must fall to fairly low levels (below 6G70 mm Hg) to have an effect. (2) This responseis potentiatedby increasesis Pa.o" (Figure II-4-15). 3. Chemoreceptors for pH a. Peripheral pH recePtorsare located in the carotid bodies. b. Decreasesin pH lead to increasedventilation.

In a Nubhell Po,, Decreases in arterial below70mmHg, especially theperipheral stimulate andincrease chemoreceptors rate.These thebreathing receptors aretheonly to onesthatrespond (J hypoxia Po).

In a NuBhell . Anincrease in [H*] (decrease in pH)stimulates body carotid to increase chemoreceptors rate thebreathing in ofchanges independent level. P.o,

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Respiratory System

80 70 60 Alveolar 50 ventilation (Umin)

40

P".or= 50 mm Hg

30 20

P^"or= 45 mm Hg

10

P^"or= 38 mm Hg

60

80

100

120

P""o, (mmHg) Figure ll-4-15.Response to hypoxia. Note the nonlinearresponseto hypoxia as comparedwith the linearresponseto hypercapniain Figurell-4-14.Note also the relativeinsensitivityof this systemas comparedwith the CO2system.

4. Other sensory receptors a. Stretch receptors in smooth muscle of airwaysrespond to increasedbronchial wall distention. Steadylung inflation leadsto an increasein the duration of expiration (HeringBreuer inflation reflex). Conversely,marked deflation of the lung leadsto a decreasein the duration of expiration (Hering-Breuer deflation reflex). Thesereflexesare largely inactive until tidal volumes exceed1 liter, aswould occur in exercise. b. Irritant receptors, located between epithelial cells in the airways, respond to noxious gases,smoke, particulates, and cold air. Afferent signalstravel up the vagus nerve and result in bronchoconstriction,coughing,and mucus secretion. c. J (juxtacapillary) receptors are located in the lung parenchyma near capillaries.They are stimulated when pulmonary capillaries become engorgedwith blood or as a result of interstitial edema.They are thought to causerapid, shallow breathing and dyspnea as seenin patients with left heart failure and interstitial lung disease. D. Role of the respiratory system in acid-base regulation 1. COr-generated by cellular metabolism + increasedH*. CA CO, + HrO <--> H2CO3€€

H* + HCOr-

2. Elimination of CO, at the alveoli reducesblood [H.] by shifting the equilibrium of this reaction to the left. 3. Retention of CO, increasesblood [H-] by shifting the equilibrium of this reaction to the right. 4. Respiratory acidosis: Hypoventilation leads to increasesin Pa.or.As a result, [Hn] increases,and blood pH decreases.

r80

Physiology 5' Respiratory alkalosis: hnrerventilation decreasesPa.or. As a result, [H*] decreases, and blood pH increases.

ClinicalCorrelate

6' Adjustments to the respiratory-inducedpH changesare made by the kidney (renal compensarion).This generallytakes2_3 days.

Respiratory Acidosis: - t pco,

7' Respiratorycompensationfor nonrespiratoryacid-baseimbalances requiresonly minutes to hours.

Causes:

SLEEP APNEA A' sleep apneais a problem of respiratorycontrol in which loss of pharyngealmuscletone during sleepclosesoffthe upper airway.Thisairway obstruction can be severeenough to impair ventilation to the point that the patient becomeshypoxemic, and in some cases,hypercapr nic' stimulation of the respiratorycontrol systemsby the abnormal blood gasesawakensthe patient often during the night. The result is that the patient rarely experiencesdeep sleepor rapid eyemovement (REM) sleep. B' Sleepdeprivation causesfatigue during the day,and the patient has a tendencyto fall asleep at inappropriate times, making them prone to accidents.

. Sedatives, anesthesia . ALS, multiple sclerosis, polio, Cuillian-Barre . Ainruay obstruction . Adultrespiratory distress syndrome . Chronic obstructive pulmonary (C0pD) disease

c. Left untreated,sleepapneacan lead to many physicalproblems: 1' Pulmonary hypertensionas a result of hypoxia (hypoxic vasoconstriction) 2. Hyperemia 3. Increasedcardiacload 4. Cardiac arrhythmias 5. Prematuredeath D. Factors that contribute to sleepapnea 1. Obesity 2. Largetongue and tonsils 3. Small jaw 4. Deficient skeletalmuscle tone E. Tieatment of sleep apnea centers around ways to prevent or relieve the upper airway obstruction. 1. Dental appliancesthat force the mandible forward 2. Weight loss 3' continuous positive-pressurerespirators(GPAP)applied over the nosewhile sleepingor BiPAP,which is similar but appliespositive airway pressure only during the innj. .!.t. of respiration 4' Surgicalproceduresto remove the uvula or excesstissuesfrom the soft pallet and pharynx

t8l

Respiratory System

EXERCISE A. Oxygen consumption lVor) rises as does CO, production (Vcor). However,Vco, typically rises more than Vo, because more carbohydrate than fat is used for energy. The respiratory exchangeratio (R) rises from 0.8 to about 1.0 with exercise. B. Vo, increaseslinearly with the exercisework rate until Vo, becomes constant (Vor,"u*).An increasein work rate above this level can occur only becauseof anaerobic glycolysis. C. Ventilation increaseswith exercise.At first, it increasesproportionately with Vor. The mechanism responsiblefor this is unknown. As the exercisebecomesmore vigorous, ventilation can increasestill further, possibly becauseincreasesin lactic acid liberate more CO, which further increasesventilation. D. Pulmonary blood flow increases with exercise(becausecardiac output increases),leading to a more uniform distribution of blood flow in the lung. This decreasesventilation-perfusion inequality. However,in a person with normal lung physiology,this inequality is so small that it would have little effect. E. During moderate exercise,there is little changein arterial Por, Pcor, and pH. During strenuous exercise,the increasein ventilation exceedsCO, production,leading to a decreasein Pco, and an increasein Por. pH decreasesduring strenuousexercisebecauseof lactic acidosis.

HIGHATTITUDE A. Becausethe barometric pressureis diminished at high altitudes,the inspired Po, and alveolar Po, are decreased.This leads to a decreasein arterial Po, (hnroxemia). B. The hypoxemia is detectedat peripheral chemoreceptors,leading to reflex hyperventilation, causing a respiratory alkalosis. This alkalosis (along with the hypoxemia) contributes to acute mountain sickness,the symptoms of which include fatigue, headache,vertigo, nausea and vomiting, and insomnia. Acetazolamide, a carbonic anhydrase inhibitor, can reduce thesesymptomsby correctingthe alkalosis. C. The hypoxemia also stimulates the production of erythropoietin from the kidney, which increasesthe production of red blood cells.This increasein red blood cell concentration (polycythemia) increasesthe oxygen-carrying capacity of the blood. D. A right-shift of the oxygen dissociation curve occurs as a result of an increasedconcentration of 2,3-diphosphoglycerate. This resultsin better O, unloading in the tissues. E. The decreasedalveolar Po, results in pulmonary vasoconstriction. Pulmonary vasoconstriction is an advantageousresponseto diminished ventilation of a portion of the lung in order to shunt blood to areasthat are better ventilated. The generalizedpulmonary vasoconstriction that occurs with high altitude can, however,lead to increasedwork of the right heart, right heart hypertrophy, and pulmonary edema.

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Physiology

PATTERNS OFBREATHING-TERMI NOTOGY A. Eupnea-normal

quiet breathing

B. Thchypns4-insleased respiratory rate C. Hyperpnea-increased rate and depth of respiration D. Dyspnea-sensation of breathlessness, labored breathing 1. Orthopnea-dyspnea while recumbent but not upright E. Apnea-cessation of respiration F. Cheyne-Stokes respiration-an abnormal pattern with increasing and decreasing tidal volume and periodic apnea.It is causedby CNS disordersand poor circulation to the brain. G. Kussmaul breathing-regular, rapid breathing with a large tidal volume. It is usually caused bv metabolic acidosis.

t83

Respiratory Pathology pollutants, Thelungisa majordestination foranything thatcanfloatintheair,including spores, bacteria, viruses, andsmoke. Asa result, it isa primary siteforinflammation, infection, and neoplasia. Lungcancer isnowtheleading cause of cancer deathin bothmenandwomen; approximately 900/o of cases arecaused bycigarette smoking. Inadditon, common allergic anddestructive inflammatory conditions, suchasa$hma, bronchitis, andemphysema, areseriously exacerbated bysmoking. This pulmonary pathologies chapter discusses thedifferent withinfectious associated andneoplastic diseases aswellasthecommon environmental agents knownto cause and/orexacerbate pulmonary disorders.

CONGENITAL ANOMATIES A. Pulmonary cysts. There are two types of pulmonary rysts causedby premature separation of the embryonic foregut. 1. Bronchogenic cysts are centrally located, adjacent to bronchi or bronchioles, and occur with or without connections to airways. They are lined by ciliated, mucus-secreting bronchial columnar epithelium and may be single or multiple. Their size varies from microscopic to greaterthan 5 cm in diameter, and they may be associatedwith other rysts of the liver, kidney, or pancreas. 2. Pulmonary cysts are multiple and peripherally located, lacking communication with main bronchi. Infection is frequent (e.g.,abscess);rupture can causepneumothorax and compression of adjacent lung tissue. Dilatation may rupture vessels,leading to hemopWsis. B. PulmonarFatresia. Bilateral pulmonary atresiais not compatible with life; unilateral atresia is usually accompaniedby other serious malformations. C. Pulmonar''hlpoplasia of the lung.

refers to incomplete development of the entire lung or a single lobe

D. Congenital lobar inflation results from bronchial obstruction due to absenceor hypoplasia of the bronchial cartilage with compensatory overinflation of the remaining lung. E. Pulmonar'' sequestrations. Extrapulmonary lung tissue is usually supplied by systemic blood vesselsrather than by pulmonary arteries. It is usually located behind the lung or below the diaphragm.

Bddgeto Gasfiin{estinal Neonates witheither esophageal atresia or tracheoesophageal fistula arevulnerable to pneumonia. aspiration

t85

Respiratory System

Note

INFECTIONS

Thespectrum of infectious pneumonia agents causing continues to change as andthe antibiotia evolve number of immunocompromised patients rises.

Infections in the lung are more common than infections in any other organ, excluding the skin; viral infections are more frequent than other forms of pulmonary infection. A. Bacterial pneumonia occurs when pulmonary defensemechanisms are weakened (e.g., decreasedcough, gag, or nasal clearance;mucociliary damage; macrophage phagocytic defects;pulmonary edema; pooling of secretions;bronchial injuqr) or when the host is otherwise immunocompromised (e.g.,chronic disease,immunologic deficienry,immunosuppressivetherapy,leukopenia).It can be classifiedin severalways: 1. By etiologic agent (e.g.,staphylococcal,streptococcal) 2. By host response(e.g.,suppurative,fibrinous) 3. By anatomic distribution pneumonia)

(e.g., bronchopneumonia, lobar pneumonia, interstitial

B. Bronchopneumonia causesa patchy consolidation of the lung and usually arises as an extensionof pre-existingbronchitis or bronchiolitis. 1. Incidence. It occurs most commonly in infanry and old age.The most common agents pneumoniae,Staphylococcus, Haemophilusinfluenzae,Pseudomonas, include Streptococcus and coliforms. Fungi may be pathogenicin immunosuppressedhosts.

ln a Nutshell Bronchopneumonia . Patchy consolidation involving oneormore lobes . Acute inflammation (neutrophils) into extending alveoli frombronchioles

2. Clinical features include fever, a cough productive of purulent sputum, rales over involved areas,and pleuritic chest pain if peripheral regions are involved. Chest x-ray showsfocal opacities. 3. Pathology a. Grossly, up to 3-4 cm foci of lung consolidation with purulent inflammation are seen.Consolidation is frequently multilobar, bilateral, and basal becauseof gravitational pooling of the infection. b. Microscopic findings are usually a purulent exudate,dominated by neutrophils filling airwaysand alveoli (Figure II-5-1), unlessthe patient is immunosuppressed. 4. Complications include lung abscess, spreadto the pleural space(empyema),spreadto the pericardial cavity (suppurative pericarditis), bacteremiawith metastatic infection, and respiratory failure.

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Pathology

Figure ll-5-1.Acute bronchopneumonia(microscopic). C. Lobar pneumonia is usually causedby a bacterial infection, most commonly causedby S. pneumoniae,Ieading to widespreadconsolidationin largeportions of a lobe. l. Incidence. Lobar pneumonia occurs most often in midlife. Men are involved 3-4 times more frequently than women. Kebsiella and type II pneumococcus occur in elderly, alcoholic,and diabetic patients. 2. Clinical features. There is an acute onset of fever,chills, malaise,and cough with watery sputum initially, followed by frankly purulent, rusty sputum. Shortness of breath, orthopnea,and cyanosiscan occur if pneumonia is sufficientlysevere.Pleuritic chestpain and pleural friction rub occur with peripheral involvement.Limited breath sounds and ralesoccur early,proceedingto dullnessand percussionwith egophony.Increasedtactile and vocal fremitus occur with more severe consolidation. Chest x-ray shows lobar involvement.

Bridgeto Microbiology Pneumonia in diabetis or alcoholis, IhinkKlebsi elIo. Another classic cluefor pneumonia Klebsiello is "currantjelly"sputum.

3. Pathology. There are generally four stagesof the inflammatory response;antibiotics shorten or stop the natural progression. a. The initial stage (24 hours) features acute congestion and hyperemia, vascular engorgement,and intra-alveolarfluid (edema)with few neutrophils and many bacteria. The lung is grosslyboggy,firm, and engorged. b. Earlyconsolidation (24 days)is called"red hepatization" and featuresconsolidation with a neutrophilic infiltrate and fibrin within alveolarspaces.Overlying pleuritis is common. Grossly,the lung is red (due to extravasationof red cells),firm, and airless with a liver-like consistency. c. Late consolidation (4-8 days) is called"gt"y hepatization." There are large amounts of fibrin with decreasingnumbers of red blood cells and white blood cells (many degenerating).Pleuritis is common, and empyema may occur. There is little or no fluid within the exudate.Grossly,the lung has a grayish-brown dry surface. d. Resolution begins after 8 days.There is enzymaticdigestion of the consolidatedexudate, which consistsof fibrin, RBCs,and WBCs. This produces granular, semiliquid debris that is either resorbed,consumedby macrophages,or expectorated("coughed up"). Complete resolution and return to normal ventilatory function occursover 1-3 weeks.

ln a Nutshell LobarPneumonia . Called "lobar" because it involves theentirelobe . Mo$oftendueto pneumonioe Streptococcus . Characterized mainly byan intra-alveolar that exudate in consolidated results lobes(s) ofthelung . Redhepatization followed gray by hepatization

t87

Respiratory System

4. Complications include lung abscess,empyema, and exudate organization rather than resorption. This causesrespiratory difficulty and bacteremia,with metastasesto heart valves (endocarditis),spleen,brain (meningitis), kidney, joints, and pericardium (pericarditis). D. Viral and mycoplasmal pneumonia (atypical pneumonia). Thesereactions are called a!rp. ical becauseof lack of alveolarexudate.Instead,inflammation is found in the lung interstitium and alveolar septae (interstitial pneumonia). Pneumonia is frequently caused by Mycoplasmapneumoniaein crowdedconditions and by viruses,including influenzaA and B, respiratory syncytialvirus (RSV), and adenovirus.

ln a Nutshell Interstitial Pneumonia . Mostcommonly by caused viruses andMycoplosmo pneumonioe . Inflammation isfoundin thelunginterstitium and alveolar septae; thereisno alveolar exudate. . Involves oneor morelobes

Bridgeto Microbiology Theotherfungal diseases affecting tract therespiratory (e.g., histoplasmosis, coccidioidomycosis, bla$omycosis, aspergillosis) arediscussed in detailinthe Mycology chapter ofthe Microbiology in section Ceneral Principles Bookt 0olumel).

1. Clinical features include fever, malaise, and a dry, hacking cough; these symptoms resemblethoseof a severeupper respiratoryinfection. Constitutional symptomsare common: headache,muscle aches,and leg pains.Elevatedcold agglutinins are found in 50% of patientswith mycoplasmalpneumonia and in 20o/oof patientswith adenovirus.There is lessthan 1olomortality. Symptomsare out of proportion to physicalfindings. 2. Pathology a. Grossly, there is patchy-to-diffuse involvement, bilaterally or unilaterally. Affected areasare red-blue with a congestedinterstitium but without consolidation or pleural involvement.There is no pus. b. Microscopically, there is an inflammatory interstitial pattern with widened and edematous alveolarseptae.A mononuclear infiltration of lymphocytes,histiocytes,and plasma cells is usually found. Acutely,neutrophils can be seen.Alveolar damagecan causeexudation of proteinaceousmaterial, cellular exudate,and hyaline membrane lining the alveolarwalls. 3. Diagnosis. Mycoplasmapneumonia is often diagnosedby sputum cultures,complement fixation tests,and nonspecificcold agglutinins reactingwith red blood cells.Cold agglutinins are immunoglobulin M (IgM) antibodieswith specificiryfor the I antigen on adult RBCs.Fetal RBCscarry the i antigen but not I, so specificityis easilytested.Monoclonal cold agglutininsin elderly patientsare indicative of a lymphoproliferative disorder. E. Pneumorystiscarinii pneumonia (PCP). P. carinii is now believedto be a fungal organism; it infects immunocompromised patients. It is commonly seen in acquired immunodeficiency syndrome (AIDS), in oncology patients,and in undernourished children. 1. Clinical features.Patientspresentwith fever,dyspnea(shortnessof breath),hypoxia (low oxygen saturation), and bilateral interstitial infiltrate on x-ray. Lessoften, patients complain of cough. 2. Pathology. Findings include an intra-alveolarexudatewith pneumocysts,cell debris,and proteinaceousfluid. Usually,there is an interstitial inflammatory reaction of mononuclear cells,fibrin, and RBCs.Occasionally,fibrosis, calcification,and granuloma formation occur. Grossly, the lung is red, airless,and beefr. 3. Diagnosis is basedon demonstration of organismsvia silver stain or fluorescent antibody. Sputum induction has a sensitivityalmost equal to that of bronchial washingsand lung biopsy via a bronchoscope. F. Aspiration pneumonia results from aspiration of oral secretionsor gastric contents.It is seenin alcoholics and other debilitated patients with neurologic or anatomic impairment affectingthe swallowing mechanism.A chemical pneumonitis results,often with secondary bacterialinfection from mouth anaerobes,causingnecrosisand abscessformation. G. Pulmonary abscessrefersto an area of inflammation with a central region of liquefaction necrosis.It occursat any agebut is more common in young adults (men > women). It is rare in infants.

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Pathology

1. Pathogens include aerobic and anaerobicStreptococcus, S. aureus,gram-negativerods, and mouth anaerobes,including Bacteroides, Fusobacterium,and Peptostreptococcus. 2. Routes of infection a. Aspiration of gastric contentsand mouth flora b. Bacterialpneumonia (inhalation) c. Septicemboli from the venous circulation or the right side of the heart d. Neoplasiawith postobstructivepneumonia e. Miscellaneoustrauma, extension of infection from other organs, hematogenous spread,or cryptogenic (no identifiable cause) 3. Clinical features include fever, paroxysmal cough with foul-smelling, purulent or sanguineous sputum, and weight loss. Clubbing can occur within weeksof abscessformation. Ten to fifteen percent of patients have underlying carcinoma. With appropriate resolvewithout sequelae.An air-fluid level is antibiotics,75o/oof pulmonary abscesses often seenon chestx-ray. 4. Pathology a. Grossly,lung gangrene(fetid, green-blackmultilocular cavities)is seen. b. Microscopically, there is suppurativedestruction of lung parenchymawithin the central area of cavitation. 5. Complications include respiratory failure, extensionof infection into the pleural space, and embolization to the brain and meninges. H. Pulmonary tuberculosis (TB) primarily affects the lungs and is caused by acid-fast Atypical mycobacmycobacteria.Almost all casesare causedby Mycobacteriumtuberculosls. teria can causeinfection, especiallyin the immunocompromised host. BecauseM. tubercu/oslsis a strict aerobe,reactivationtends to occur in the apex of the lung and renal cortex. There is an increasedincidencein areaswith poor sanitary conditions, poverty,overcrowding, malnutrition, and limited accessto medical care. The emergenceof AIDS and other immunosuppressedstateshas led to a resurgencein the incidenceof TB. Of concern now is the occurrence of multiple drug-resistant TB.

BridgeToMicrobiology in M.tuberculosis isdiscussed intheMicrobiology detail section t ofCeneral Principles Book (Volume l).

l. Primary pulmonary TB a. Pathology.The lung is the usual location of initial infection, typically the lower part of the upper lobe or the upper part of the lower lobe. Parenchymalor subpleural lesions occur associatedwith enlarged,ipsilateral caseouslymph nodes, which are "draining" the parenchyma.The "Ghon complex" refersto radiographicevidenceof a calcifiedperipheral lesion in conjunction with a calcifiedhilar lymph node. b. Clinical features. Most patients are asymptomatic,and the lesionsbecome fibrotic and calcified over time. It is the macrophagethat leads to phagocytosisof tubercle bacilli, epitheloid giant cell fusion, and granuloma formation with central caseous necrosis.The tuberclebacilli survive in granulomasfor years,only to reactivatewhen the patient's immune systemis depressed(e.g.,elderly or malnourished patients or patientswith HIV). 2. Secondarypulmonary TB. Most casesrepresentreactivation (rather than reinfection) of old TB that had disseminatedat the time of primary TB. Reactivationoccurs often in areasof high oxygentension,such asthe lung apices.Only 5-I0o/oof patientsexposedto TB developreactivation.ReactivationTB usually occursin debilitated elderly patients.

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a. Pathology (1) Grossly, there is a small focus of consolidation,usually lessthan 3 cm, in the lung apex.Hilar ly-ph nodes are also involved, developingfoci of tuberculous activity. Parenchymallesionscan developsmall areasof caseousnecrosisthat may not cavitate. The usual course is fibrous encapsulation,leading to fibrocalcific scarsand pleural adhesions.A thick, collagenouswall may totally enclose caseousdebris. This may never resolveand can remain asa granular lesion. (2) Microscopically, characteristicgranulomas composedof epithelioid cells,with occasionalLanghans'giant cells,are seen.Granulomas are surrounded by fibroblastsand lymphocytesand exhibit a region of central caseation(Figure II-5-2). Tlrberclescoalesce,and large areasof the lung becomescarred. b. Complications include hemoptysis resulting from ulceration of the bronchial mucosa, pleuritis, tuberculouspneumonia,and bronchopleuralfistula with empyema. 3. Late progressive pulmonary TB shows progression of an early tuberculous apical lesion to a fibrocaseousareawith cavitation. Spreadis through erosion into an airway to other regionsof the lung, resulting in multiple lesionsthat may cavitate.Spreadmay also occur via the lymphatic systemor blood, leading to distant dissemination.The pleura is often involved and may lead to exudativepleural effusion,frank tuberculousempyema,or massive obliterative fibrous pleuritis. Bronchi are also involved as a result of seedingand can causemucosalulcers.Pathologyrevealscaseatinggranulomas (Figure II-5-3).

Figurell-5-2.Pulmonarygranuloma(microscopic).

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Pathology

4.li:4t :'' ', ;/,/it'!?ai, i

:

: ta'::l at i ':;::: i: ; ' : : '4,', a a !.!'.4?/'?i: . I i '!1"'. :

ii !r :

ln n.:;1

Figure ll-5-3. Multiple causeating granulomas in pulmonary tuberculosis (microscoPic).

4. Miliary TB is due to spreadvia blood or lymphatics. Diseasemay remain confined to the lung but usually disseminateswidely. For example,erosion into a pulmonary artery leadsto lung lesions;erosion into a pulmonary vein leadsto systemiclesions.Extrapulmonary sites of involvement include the renal cortex,lymph nodes,genital tract, peritoneum, bone marrow, adrenalgland, pericardium, and meninges. a. Pathology (1) Grossly, there are small, distinct, firm, yellow and white areasof consolidation. (2) Microscopically, there are individual or multiple confluent regions, showing granulomaswith areasof central caseation. b. Diagnosis is made by skin test, chest x-ray, sputum smear,and culture. If indicated, lung biopsy,urine, gastric aspirate,and CSF need to be evaluated. 5. Isolated organ TB occurs when organismsare destroyedduring hematogenousor lymphatic spreadexcept in a particular organ, €.8.,lymph nodes (scrofula),vertebrae (Pott disease),meninges(tuberculousmeningitis), adrenals,kidneys,and genitals. I. Legionella infections. Legionellapneumophila (a gram-negativebacillus) is the etiologic agent of theseinfections.It is usually found in soil or water.Tiansmissionis via inhalation into the lungs. Major environmental sourcesinclude water reservoirs and cooling units of air conditioning systemsthat may contain blue-green algae and amoebae,among which Legionellacan survive for prolonged periods.

Correlate Clinical pneumophilo Legionello of infection isa result from inhalation oftheaerosol water, most contaminated foundinair commonly systems. conditioning

1. Clinical features. Community outbreakstraced to an infected water source reveal two patternsof illness. a. Pontiac fever is a mild, nonfatal, systemicfebrile illness. b. Legionnaires diseaseis a severepneumonia with l5-20o/omortality. After approximately 5 days of incubation, patients develop fever, dry cough, malaise,chest and abdominal discomfort, confusion, and, occasionally,diarrhea.Frequently,pulse-temperature dissociation exists (a high temperature with no increasein pulse). Severe

t9l

Respiratory System

caseshaveblood-tinged sputum, dyspnea,high fevers,and impressivesystemicsymptoms. Death may occur due to progressiveventilatory failure or from a shock-likesyndrome with disseminatedintravascularcoagulation(DIC) and renal failure. 2. Pathology. Bronchopneumoniawith fibropurulent exudatecan coalesceand occasionaily mimic lobar pneumonia. Microscopically, there is a mononuclear infiltration with macrophagessurrounding necrotic tissue. Surrounding the mononuclear infiltrate are proliferating pneumocytes,hyaline membranes,and edema. 3. Complications a. Inflammation of small pulmonary arteriesand veins can lead to thrombosis. b. Abscessformation is frequent,but the abscesses are small. c. Organization and scarring secondaryto destructive lesions can lead to ventilatory impairment. d. Fibrinous pleuritis is usually mild with serouseffi,rsion. e. Bacteremiais alwaysa risk. L Diphtheria (due to C. diphtheriae)and whooping cough (due to B. pertussis)both cause toxin-mediated upper respiratory tract infections that can be accompaniedby lower respiratory tract infection. The diphtheria toxin inducesnecrosisof the epithelium of the upper respiratory tract, resulting in the formation of a "diphtheric pseudomembrane."

Note

(COPD) GHRONTC OBSTRUCTTVE PUTMONARY DTSEASE

COPD isa groupof disorders thatincludes:

COPD is a group of disorders characterizedby increased resistanceto airflow during both inspiration and expiration due to airway obstruction. The obstruction can occur at any level from the trachea to terminal bronchioles.This group representsthe most common form of pulmonary diseaseand includesemphysema,chronic bronchitis, asthma,and bronchiectasis.

. Emphysema . Chronic bronchitis . Asthma . Bronchiectasis Note . cr,-Antitrypsin inhibits the destruction of elastin by elastase, a proteolytic enzyme carried by inflammatory cells. Elastase actsonalveolar walls. . a,-Antitrypsin deficiency isa hereditary disorder that results in defective secretion of a,-antitrypsin bytheliver. Inhomozygotes, this eventually results in panacinar emphysema and hepatic cirrhosis.

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A. Emphysemarefersto distention of air spacesdistal to the terminal bronchiole with destruction of alveolarseptae,probably secondaryto ischemia. 1. Incidence. Emphysemais associatedwith cigarette smoking, urban living, and pollution. Cigarettesmoke causesan increasein elastaseavailability (releasedby neutrophils and macrophages)and a decreasein antielastaseactivity (due to oxidant effects).Men are affectedmore frequently than women. 2. Types a. Centrilobular emphysema affects the central and proximal part of a lobule; distal alveoli are not involved. It is more common and usually more severein the upper lobes.Inflammation surroundingbronchi,bronchioles,and alveoliis common. b. Panacinar emphysema causesa uniform enlargementof lobules, including terminal and respiratory bronchioles as well as distal alveoli. It is more common and more severein the lower lobes. Alpha,-antitrnrsin deficiency is thought to lead to an imbalancebetween proteaseand antiproteaseactivity. This imbalance then leads to panacinaremphysemaby young adulthood, especiallyin the lower lungs. c. Paraseptalemphysema involvesthe distal region of the acinus, sparing terminal bronchiolesand respiratorybronchioles.It is most severealong the pleura, septae,and the lobule edge.It commonly occursadjacentto areasof fibrosis,scarring,or atelectasis and is more severein the upper lung. Paraseptalemphysemaforms multiple confluent distendedair spaces. It may be the causeof spontaneouspneumothorax(collapsedlung) in young adults.

Pathology

d. Irregular emphysema describesirregular acinus involvement. It is associatedwith scarring. e. Bullous emphysema refers to large, balloon-like distended air spacesin the lung periphery,which can lead to pneumothorax. f. In interstitial emphysema,an alveolartear allows air into the connectivetissuestroma of the lung, mediastinum,or subcutaneoustissue. 3. Pathology a. Centrilobular emphysema(Figure II-5-4) (1) Grossly, the lungs may not be particularly enlargedor pale unlessdiseaseis well advanced.The upper two thirds are more severelyinvolved. (2) Microscopically, central airspaces(respiratory bronchioles and alveolar ducts) are destroyedwith sparing of peripheral alveoli; inflammation around bronchi and bronchiolesis common. b. Panacinar emphysema (1) Grossly, panacinar emphysema causes hyperinflated lungs with increased crepitance.Involved areasare pale as a result of blood vesseldestruction and compression. (2) Microscopically, there is little inflammatory involvement of septae or alveoli associatedwith their destruction.

Figure ll-5-4.Gentrilobular emphysema (gross).

4 . Clinical features include dyspneawith or without cough,weight loss,barrel-chest due to hyperinflation, pursed-lip breathing, prolonged expiratory time, and cor pulmonale (right-sided heart failure).*Pinkpuffers" are patientswho overventilateto maintain oxygenation despitethe elevatedwork of breathing.x-Raysrevealhyperinflation with flattened diaphragms.

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Respiratory System

5. Pathogenesis.There are two theories. a. Protease-antiproteasetheory, as describedpreviously. b. Loss of bronchial cilia as a result of smoking leads to mucus plugging and alveolar overdistension.Alveolar overdistention,resulting from obstruction, can compromise the septalblood flow,leading to ischemiaand alveolardestruction.Inflammation and mucus plugging may exacerbatethe obstruction. 6. Complications include cor pulmonale as a result of increasedpulmonary vascularresistance,ventilatory failure, polycythemia,and pneumothorax. B. Chronic bronchitis is a common disorder that can lead to obstructive airway disease. Chronic bronchitis is a clinical diagnosis,that is, persistentcough with sputum production for at least3 months for 2 consecutiveyears.Sputum variesfrom uninfected mucus (simple chronic bronchitis)to purulent (mucopurulentchronic bronchitis). 1. Pathogenesis.There are two major factors. a. Chronic irritation from inhaled substances(e.9., nitrogen dioxide, sulfur dioxide) may causeinflammation.

In a Nutshell Chronic Bronchitis . lsa clinical diagnosis of persistent cough with production sputum forat for least 3 months 2 years consecutive . lsassociated with infections, cigarette airpollution, and smoking, genetic factors various . Canpresent withmucus plugging, inflammation, fibrosis, and edema, muscle atrophy smooth . lncreases = Reidindex thickness layer ofgland thickness ofbronchial wall Note ln contrast to delayed hypersensitivity skintestsin TB,where thereaction takes 2-3 daysto form,thelgEisreferred mediated reaction to asimmediate hypersensitivity andproduces a wheal andflarein a few minutes.

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b. Recurrent infections do not initiate bronchitis, but they do perpetuateit and result in acute exacerbations. Common organisms include Haemophilus influenzae, Streptococcus viridans, and S. pneumoniae.Smoking can lead to both irritation and infection. Smoke destroysthe lung's ciliary tree, damagesthe mucosa,and interferes with WBC function. It is believedthat changesin the small airwaysare important in the pathogenesisof bronchitis. Small airway obstruction representsthe earliestmanifestation of COPD. Inflammation and mucus plugging increaseresistanceto air flow in theseusually low-resistanceairways.Continued exposureto irritants and repeated infection eventuallylead to chronic bronchitis. 2. Pathology a. Grossly,lungs are boggy,hyperemic,and hyperinflatedwith copious mucus plugging the airways. b. Microscopically, there is hypertrophy of the submucosaiglands first in the large airways and then in smaller airways.Bronchial epithelium may exhibit squamousmetaplasia or dysplasia.Mucus plugging, inflammation, edema,smooth muscle hypertrophy, and fibrosis are all common. 3. Ctinical features. There is a productive cough with copious sputum production, dyspnea, barrel chest, ryanosis,hypercapnia,hypoxia, and frequent infection. Patients are classicallyknown as"blue bloaters" becausethey are constantlycyanotic. 4. Complications. Respiratory failure usuallyoccursduring a bout with an acuteinfection. Cor pulmonale may occur asa result of pulmonary hypertension(increasedresistanceof pulmonary vasculatureas a result of alveolardestruction and hypoxic vasoconstriction). Dysplasiaof bronchial epithelium may lead to cancer. C. Asthma is characterizedby enhancedairway reactiviry leading to intermittent episodesof reversible paroxysmal airway narrowing. 1. Types a. Extrinsic asthma (allergic, atopic). Attacks are triggered by environmental antigens (e.g.,dust, pollen, food). There is frequently a family history of atopy (e.g.,rhinitis, asthma,and eczema).Bronchospasmis mediatedby a tfpe I immunoglobulin E (IgE) hlpersensitivity responseto a particular antigen.Histamine,leukotrienes([Cn, LID4, and LTE'), prostaglandin D, (PGD2),chemotacticfactors, and platelet activation all

Pathology

lead to airway-constricting inflammation and increasedvascular permeability. Serum IgE levels are elevated,and a positive skin test may be demonstrated to the offending antigen. b. Intrinsic asthma (idiosyncratic). Exacerbations frequently follow a viral infection that causesinflammation and a lowering of the vagal threshhold for irritants. Other causesof increasedairway reactivity include stress,pollution, occupationalexposure, exercise,and cold weather. There is no family history, skin tests are negative,and IgE levelsare normal. c. Aspirin-induced asthma may be seen in adults. There is a classic triad of nasal polnrs, rhinitis, and bronchoconstriction. It may be causedby excessiveleukotriene production from inhibition of the cycloorygenasepathway,and it is not immunologically mediated.This syndromemaybe seenwith almost all NSAIDs and acetylsalirylic acid (aspirin) compounds. 2. Pathology Bronchi and a. Grossly,asthmacauseshyperinflatedlungs with small areasof atelectasis. bronchiolesare occludedby thick, tenaciousmucus plugs. b. Microscopically, mucus plugs contain shed epithelium in a spiral configuration ("Curschmann spirals"). Eosinophils and membrane protein form crystalloid collections (Charcot-Leyden crystals). Basementmembrane thickening, an inflammatory infiltrate with large numbers of eosinophils,edema,and submucosalgland hyryertrophy occur. Hypertrophy of bronchial wall muscle is probably caused by repeatedbronchospasm. 3. Clinical features include cough, dyspnea,and wheezing. x-Ray revealshlperinflation. If airway obstruction is severe,the patient may not be able to ventilate,leading to respiratory failure (increasedPco, and decreasedPor). Between attacks,patients are asymptomatic. Emphysemacan alsooccur becausehyperinflation leadsto local ischemiaasa result of capillury compression.

ln a Nutshell SomeMicroscopic Pathologic Findings in Asthma . Mucus plugs containing Curschmann spirals and Charcot-Leyden crystals . Eosinophilic infiltrate . Edema . Submucosal gland hypertrophy . Bronchial wallmuscle hypertrophy

D. Bronchiectasis is an abnormal, permanent dilatation of airways causedby chronic necrotizing infection and obstruction. 1. Pathogenesis a. Bronchial obstruction (e.g.,tumor, foreign body, COPD, mucus plug) leadsto atelectasisand airway smooth musclerelaxation. b. Infection further weakens the airway wall. Organisms include Staphylococcus, Streptococars,enteric anaerobes,and H. influenzae.Patients are susceptibleto recurrent infection due to impaired defenseagainstpathogenscausedby cough, injury to the mucociliary apparatus,and impaired phagocytosis. c. Examplesof disordersin which chronic infection leadsto bronchiectasisinclude: (1) Cystic fibrosis, which is characterizedby exocrinegland dysfunction,leading to viscoussputum (2) Kartagener syndrome, one of severalimmotile cilia syndromes,is characterized by a triad of sinusitis, bronchiectasis, and situs inversus. Absenceof pulmonary cilia interfereswith bacterialclearance. (3) Anomalous intralobar sequestration,which frequently becomesinfected,leading to airway dilatation

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2. Patholog;y a. Grossly, bronchiectasispredominantly affectsthe lower lobes. Dilated airways may be cylindroid, fusiform, or saccular.The lumen is filled with a purulent exudate,and the mucosa is edematousand ulcerated. b. Microscopic findings vary with the chronicity and activity of disease.There may be an acute or chronic inflammatory exudate within bronchi and bronchioles associated with desquamation of the lining epithelium with extensiveareasof necrotizing ulceration. There may also be areasof "pseudostratification"or squamousmetaplasia.In some cases,necrosisleads to abscessformation. 3. Clinical features include cough, fever,and foul-smelling purulent sputum, which is most copious in the morning due to pooling. Clubbing and frequent pneumonia may also be seen. 4. Complications include lung abscess,pneumonia, empyema, and septic emboli.

RESTRICTIVE LUNG DISEASE This is a group of diseasescharacterizedby decreasedlung compliance, i.e., stiff lungs. The decreasedcompliance results in small lung volumes with augmented air flow rates. Varying pathologic processescan result in restriction, including extrinsic disease(neuromuscular,chest wall, myasthenia) and intrinsic lung disease.Intrinsic lung processesinclude interstitial and infiltrative disease,adult respiratorydistresssyndrome (ARDS),pneumoconiosis,and granulomatous disease. A. ARDS is the final common pathway of acute diffrrse alveolar damage (both physiologic and pancreatitis, histopathologic).It can be causedby a variety of insults,including sepsis/shock, burns, trauma, drug overdose,pneumonia,and toxins. 1. Clinical features include the rapid onset of severe respiratory insufficiency, resulting from alveolarflooding with impaired ventilation (decreasedPor; increasedPcor). ARDS frequently requires intubation for ventilatory support. There is a compensatory hyperdynamic state with hyperventilation and increasedcardiac output (increasedheart rate or stroke volume) to ensure oxygen delivery and avoid anaerobic metabolism. X-ray reveals a diffirse alveolar infiltrate. 2. Pathogenesis a. Alveolar membrane damage allows fluid, protein, and cellular debris to enter the interstitium and alveolar space.There is both endothelial and epithelial injury. This damageis due, in part, to neutrophils and macrophagesgenerating oxygen free radicals and degradativeenzfmes as part of an inflammatory reaction. b. Coagulation. Fibrin is found in many alveolar spacesasa component of hyaline membranes.Fibrin is also located within the pulmonary arteries and capillariesand can causethrombotic occlusion. c. The complement cascadeappearsto attract and sequesterneutrophils (C5a). In addition, the "attack complex" (C6C7C8C9) of complement can directly injure cells. d. Cpokines. Macrophages release interleukin-l (IL-l) and tumor necrosis factor (TNF), which attract neutrophils and stimulate them to releasetoxic metabolites. e. Arachidonic acid metabolites produce chemoattractants such as leukotrienes and products of the cycloorygenasepathway.

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Pathology

3. Pathology a. In early gross pathology, the lung shows heavy, firm, boggy congestion and is atelectatic.Interstitial edemaand alveolaredemacauseseptalwidening. In late gross pathology, chronic inflammation can lead to fibrosis. There can be focal areas of intraalveolarhemorrhageand patchy atelectasis. b. Microscopically, edematous alveolar septaewith proteinaceous fluid within alveolar spacesare found. Frequently, hyaline membranes of fibrin and cellular debris line injured alveoli. Inflammatory cells are present and can eventually lead to fibroblast proliferation and collagenformation. In more chronic cases,alveolarspacesbecome relined with cuboidal, type II pneumocftes.The interstitium is widened. B. Pneumoconiosis refers to the presenceof environmental "dust" in the lung and the lung's responseto this foreign entity. It appliesto any aerosol,whether in the form of fumes or particulate matter. Developmentof diseasedependsupon the amount of exposure,the sizeand shape of the particles, and the solubility and cytotoxicity of the offending material. AII can result in progressivemassivefibrosis with diffi.rsescarring and restrictive lung disease. 1. Coal workers'pneumoconiosis occurs after prolonged periods (>10 years)of exposure to coal dust containing both carbon and silica.

ln a Nubhell ARDS . Manycauses, including shock, trauma, sepsis, and aspiration . Diffuse alveolar damage, protein-rich fluid with leaking intoalveoli. . Hyaline membranes, made offibrinandcellular fragments, formin alveoli. . lmpairs gasexchange and in hypoxia results . Fatal in over500/o of cases

a. Clinical features. Most patients are asymptomatic or have a slight cough productive of blackened sputum. X-ray revealsdiffirse nodularities ("tattooirg").A small number of casesgo on to develop progressivediseasewith dyspnea,chronic cough with blackenedsputum, poorly localized chest pain, and frequent infections. If exposure continues, progressive massive fibrosis with large blackened scars (usually in the upper regions of various lobes) with cor pulmonale can develop,and the pleura can becomeretractedand thickenedif near fibrotic lesions. b. Pathology. Microscopically, "coal dust macules" are formed initially by the aggregation of macrophages,creating intensely pigmented areas.With continued exposure and inflammation, these macules become fibrotic nodules with new collagen and reticulin (i.e.,progressivemassivefibrosis). 2. Anthracosis is causedby the inevitableinhalation of some carbonaceousparticlesby city dwellers, cigarettesmokers,and miners. a. Clinical features. Deposition of carbon dust can be seen as black pigment in lung parenchyma,pleura, and lymph nodes.When isolated,it is not associatedwith symptomatic disease. b. Pathology. Macrophages aggregateinto small, peribronchiole regions in an attempt to phagocytosethe dust. 3. Silicosis. Chronic silicosisoccurs with prolonged exposureto silica dust (mining, glass production, sandblasting, farming, road construction), causingan insidious diseasethat can progressto respiratory failure and death. a. Clinical features. Patients with silicosis are at increasedrisk of developing TB. There is no associatedincreasedcancerrisk. b. Pathology. Collagenousfibrotic nodules form whereverthe silica is deposited,probably due to macrophage releaseof lysosomal enzymes and production of fibroblast growth factor (FGF). Initial involvement tends to be in the upper lobes and perihilar region. Pleural involvement creates dense fibrous plaques and adhesions that may obliteratethe pleural cavities.Similar nodulesappearin the lymph nodesand may calciff, resulting in an "eggshell"pattern on chestx-ray. Nodules can increasein size to such an extent that bronchioles,alveoli,pulmonary arteries,and subpleuraltissuecan all be compressed(i.e.,progressivemassivefibrosis).Uninvolved parenchymatends to be hyperinflated and emphysematous.

Note Silica dustinthelungs is ingested byalveolar macrophages, whichbecome damaged. There isthena release ofthemacrophages' lysosomal enzymes and production in of FCF,resulting fibrotic silicotic nodules.

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4. Asbestosisis a diseasecausedby a family of fibrous silicatescommonly found in shipyards,insulation, and roofing industries. a. Clinical features. Many years after exposure,patients complain of dyspnea,chronic dry cough, recurrent respiratory infections (especially viral), and weight loss. Respiratory failure can occur many years after exposure has ceased.Patients with asbestosexposure are at increased risk of developing bronchogenic cancer and mesothelioma (pleural and peritoneal). Smoking causesa multiplicative increasein the risk of developinglung cancer.Patientswith asbestosis are also at risk of developing renal and gastrointestinalcarcinoma. b. Pathology. Smaller asbestosfibers that reach smaller airways and alveoli are phagocytosed by macrophagesafter being covered with hemosiderin and glycoprotein (ferruginous body). This may incite an inflammatory responsedue to lysosomalrupture or oxygenfree radicals.Fibroblastsare abundant and createstriking interstitial fibrosis with septal wall widening, which is usually worse in the lower lobe and near the periphery. This processmay also involve the visceral pleura. In addition, patients developdensehyalinizedand possiblycalcifiedparietal pleural plaquesof varying size. Uninvolved parenchyma becomes hyperinflated, leading to "honeycombing." Secondarybronchiectasismay complicatethe picture. Extensivescarringmay narrow or obliterate alveoli,lymphatics, or pulmonary vessels,leading to pulmonary hypertension and cor pulmonale. 5. Berylliosis is causedby heavy exposureto airborne beryllium or its salts.Becauseof its high tensilestrength and resistanceto heat and fatigue,beryllium is still used in the electronic, ceramic, aerospace,and nuclear energy industries. Diseasecausedby beryllium probably representsa type IV hypersensitivityreaction, with noncaseatinggranuloma formation and eventualfibrosis.There is an increasedincidenceof bronchogeniccancer in patientswith berylliosis. C. Hypersensitivity pneumonitis (external allergic alveolitis) is an immunologically mediated interstitial lung diseasecausedby exposureto organic dustsand other occupationalantigens. 1. Clinical features. Patients tend to have a heightened responseto the offending agent, involving alveoli rather than the airways.Acute attacks are characterizedby fever, cough, dyspnea,and leukocytosis. Nodular and diffuse infiltrates appear on x-ray. Pulmonary function testsmay revealrestriction. Acute attacksare probably mediated via a type III immune complex reaction. If exposure is chronic, progressiverespiratory failure can occur with interstitial fibrosis and obliterativebronchiolitis. 2. Pathology. Microscopically, macrophages,plasma cells, and lymphocytes within the interstitium can be found. Peribronchiolargranuloma can be seen(chronic diseaseprobably representsa type IV delayedhypersensitivityreaction). 3. Types a. Farmer's lung is causedby thermophilic actinomycetesthat grow on hay. b. Byssinosis is causedby cotton, linen, or hemp exposure,leading to bronchospasm (possiblyhistamine related). D. Goodpasture syndrome is a necrotizing hemorrhagic interstitial pneumonia that can lead to hemoptysis (coughing up blood) and rapidly progressive glomerulonephritis (with crescentformation). The diseaseappearsto involve antibody recognition of a common pulmonary and renal basementmembrane antigen.

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Pathology

1. Clinicat features. Goodpasture syndrome usually occurs in individuals in their twenties and thirties and is more common in men. Death usually occurs as a result of complications of renal failure, but massivehemoptysiscan be responsible. 2. Pathology

In a Nutshell

a. GrosslR heavylungs with areasof red-brown consolidationare seen. b. Microscopically, there is focal necrosisof the alveolarwall, associatedwith intra-alveolar hemorrhage,fibrous thickening of the septa,hypertrophy of lining septal cells, and hemosiderin-containingmacrophages.Immunofluorescencestudiesreveallinear deposits of immunoglobulin along renal and pulmonary basementmembranes. 3. Prognosis hasbeen improved by using immunosuppression to inhibit antibody production and by plasma exchangethat can remove antibody and other immune response mediators. E. Idiopathic pulmonary hemosiderosisis an uncommon condition. 1. Clinical features.It is characterizedby the insidious onset of cough, hemoptysis,weight loss,and diffuse pulmonary infiltrates.It occursin young adults and children.Diseasecan vary from mild (occasionalhemoptysis) to severe(pulmonary fibrosis). Most patients have a chronic remittent course over years that eventually improves. The etiology is unknown.

Goodpasture Syndrome glomerular Antibodies against basement andpulmonary result in a membranes pneumonitis and hemorrhagic glomerulonephritis. reveals lmmunofluorescence linear deposits of lgCalong basement theglomerular you membrane. lf seea patient withbothhemoptysis think andhematuria, syndrome. Coodpasture

2. Pathology. There are focal areasof red to red-brown consolidation with degeneration, shedding, and hyperplasia of alveolar epithelial cells and alveolar capillary dilatation. Varying degreesof fibrosis may be seen.Hemorrhage occurs into alveolarspaces.Septae and free macrophageswithin alveolarspacescontain hemosiderin. F. Pulmonary alveolar proteinosis 1. Ctinical features. The diseaseis insidious in onset with cough productive of gelatinous material. The courseis variable,but patients can progressto pulmonary fibrosis (rarely) with dyspnea,cyanosis,and respiratory insufficiency. 2. Pathology. Pulmonary alveolarproteinosisis characterizedbythe accumulationof dense, homogeneous,granular, strongly PAS-positivematerial within the intra-alveolar space. This material contains abundant phospholipid and protein with lamellar bodies and refractile crystals. 3. Etiology. The causesremain obscureand are probably variable,including overproduction of surfactant-like material and a possiblemacrophagedeficiency that preventsalveolar scavenging. G. Diffuse idiopathic pulmonary fibrosis, or usual interstitial pneumonitis (UIP) is a syndrome of unknown etiology that resultsin chronic interstitial pneumonitis, which can lead to interstitial fibrosis and respiratory failure. 1. Clinical features. Men are affected more than women. The usual age for diagnosisis 30-50 years.Progressionis unpredictable;some individuals develop cor pulmonale and cardiac failure within severalyearsdue to lung disease,whereasothers experiencespontaneousremission.The rare, rapidly progressiveform of this diseaseis sometimesknown as the Hamman Rich syndrome. 2. Pathology. There is alveolar wall damage (possibly as a result of immune complex formation), especiallyto type I pneumocytes,that leadsto interstitial edemaand alveolitis. Hyperplasiaof type II pneumocftes occurs in an attempt to restorethe alveolar lining. Recruitment of fibroblastscan lead to fibrosis of both the interstitium and intra-alveolar exudate.The end stageof this processis the "honeycomb lung."

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H. Desquamative interstitial pneumonitis (DIP) is a rare illness of unknown etiology that may be a precursor of interstitial fibrosis of the usual type. 1. Clinical features. Patients present with cough and dyspnea that can progressto ventilatory failure with ryanosis and clubbing. Radiographically, bilateral lower lobe groundglassinfiltrates are noted. Patients with DIP tend to respond more favorably to steroids than do patients with UIP. 2. Pathology. Mononuclear cells are found within alveoli, presumably desquamatedfrom alveolarwalls. Ninety percent of thesemononuclear cellsare macrophages,many of which contain lipid and PAS-positivevacuolesin addition to phagocytosedlamellar bodies. I. Pulmonary eosinophilia is a diverse group of illnessescharacterizedby eosinophilic pulmonary infiltrates. l. Simple pulmonary eosinophilia (Liiffler syndrome) a. Clinical features. Patients develop dyspnea with evidence of both restriction and obstruction on pulmonary function tests. b. Patholog;y.Tiansient pulmonary infiltrates of varying size and shapewith peripheral eosinophilia are seen.There is alveolar septal thickening as a result of eosinophils and occasionalgiant cellswith focal hyperplasiaof alveolarepithelial cells.This most likely representsa type I immune response. 2. Chronic eosinophilic pneumonia a. Clinical features. Patients develop high fevea night sweats,and dyspnea,all of which respondto steroids.This may representa primary immunologic processor a response to a number of parasitic, fungal, or bacterial infections, hypersensitivity pneumonitis, drug allergy,asthma, or allergic bronchopulmonary aspergillosis. b. PathologT. Peripheral and focal areasof cellular consolidation that represent alveolar and interstitial infiltration by lymphocftes and eosinophils iue seen. l. Sarcoidosis is a multisystem disorder of unknown etiology, characterizedby noncaseating granulomata. The diseaseusually involvesthe lung, followed by skin and eyemanifestations.

In a Nubhell Interstitial LungDiseases . Hypersensitivity pneumonitis . Coodpasture syndrome . ldiopathic pulmonary hemosiderosis . Pulmonary alveolar proteinosis . Diffuse idiopathic pulmonary fibrosis . Desquamative interstitial pneumonitis . Pulmonaryeosinophilia . Sarcoidosis 200

l. Epidemiology. SarcoidosisaffectsBlacks more than Caucasians,women more than men. Sarcoidosisis gener"lly. diseaseof young adults aged20-35 years. 2. Pathology. The granulomatous nature of the lesions suggests an immunologically mediated diseaseof the delayedhypersensitivity type. In fact, although patients have low peripheral T-cell counts (and are usually anergic), the number of T-helper cellswithin the lung is greatly increased,whereasT-suppressorcells are lacking. 3. Clinical features. Becausesarcoidosis is a multisystemic illness, presenting complaints vary markedly. a. Most patients seekmedical attention with the onset of respiratory symptoms, such as dyspnea,cough, chest pain, or hemoprysis. Others have systemic symptoms, such as fever,fatigue, weight loss, anorexia, and night sweats. b. Eighty percent presentwith hilar and mediastinal lymph adenopathywithout parenchymal involvement ("potato nodes") seenreadily on chestx-ray.Within the nodesare noncaseatinggranulomata that often contain Schaumann bodies (collection of calcium and protein) and asteroid bodies (star-shapedinclusions within giant cells). Occasionally, small nodules can be found in the lung parenchyma. c. Fifty percent present with a hypersensitivity reaction with fever, polyarthritis, erythema nodosum, and hilar adenopathy.

Pathology

d. Other involved organsinclude skin (nodules,plaques,macules),eyes(iritis, iridocyclitis), liver, spleen,and bone marrow. All involved organs display similar histopathology. 4. Diagnosis. Becauseof the variable presenting complaints, the diagnosis of sarcoidosisis frequently made clinically. Tissue demonstrating noncaseatinggranulomas confirms the clinical impression (Figure II-5-5). This distinguishessarcoid from TB, which shows caseatinggranulomas (central areasof caseousnecrosis).

* ':: ,'# g$

a'

Figure ll-5-5.Sarcoidosis: noncauseating granulomas (microscopic).

5. Prognosis. Sarcoidosis follows an unpredictable course characterized by alternating periods of remission and activity. Most patients recover with minimal or no residual effects.Twenty percent have permanant loss of pulmonary function or visual acuity. Ten percent develop chronic diseasewith pulmonary fibrosis and cor pulmonale. K. Pulmonary disease with collagen vascular disorders. Many collagen vascular disorders affect the lung and can lead to diffirse interstitial fibrosis. 1. Scleroderma classicallycausesinterstitial fibrosis. 2. Lupus erfthematosus causestransient pulmonary infiltrates and, occasionally, severe pneumonitis. 3. Rheumatoid arthritis may cause chronic pleuritis with or without an effirsion, diffi,rse interstitial pneumonitis with fibrosis, intrapulmonary nodules, rheumatoid nodules with pneumoconiosis( Caplan syndrome),or pulmonary hypertension. 4. Wegener granulomatosis is an acute necrotizing vasculitis with granuloma formation involving the lung in addition to the kidney and upper respiratory tract. It may consolidate and causescarring. 5. Lymphomatoid granulomatosis is a pleomorphic cell infiltration and destruction of lung tissue,which in some casesis a true monoclonal B-cell lymphoma.

20r

Respiratory System

In a Nutshell

VASCUTAR DISORDERS

Cardiogenic Pulmonary

A. Pulmonary congestion and edema result from an accumulation of fluid and protein within the pulmonary interstitium and alveolar spaceas a result of hemodynamic (Starling) derangementsor from increasedcapillary/alveolarpermeability.

Edema . Leftventricular failure . Mitral stenosis Noncardiogenic Pulmonary Edema . Septic shock . Pancreatitis . Burns . Toxin inhalation . 0,toxicity . Narcotic overdose . Pneumonia . Organic solvents

1. Most commonly, pulmonary edema developswhen there is an increasein pulmonary capillary pressure,as with left heart failure. Volume overload of the nephrotic syndrome and decreasedlymphatic drainagealso lead to transudation of fluid acrossthe alveolar membrane.As fluid accumulatesin the interstitium, interendothelialjunctions stretch, leading to increasedpermeability to both fluid and macromolecules.The lymphatic flow must be increasedlO-fold beforethe lung's drainagemechanismis overwhelmed,leading to edema.It is only after even higher capillary pressuresare achievedthat fluid moves from the interstitium into the alveolarspace. 2. Alveolocapillary permeability. Edema results after injury to both capillary endothelial and alveolarepithelial cells.Fluid and protein accumulateinitially in the interstitium and subsequentlyin the alveolar space.Noncardiogenic pulmonary edema can result from septic shock, pancreatitis,burns, toxin inhalation, oxygen toxicity, narcotic overdose, pneumonia, organic solvent hypersensitivity,and other causes.Pathologically,the lungs are heavy, wet, and subcrepitant, mostly involving the bases.Alveolar capillaries are engorged,and the alveolar spacecontains a granular pink precipitate.Alveolar microhemorrhageand hemosiderin-containing macrophages are present(FigureII-5-6). If the processbecomeschronic, macrophageswith hemosiderin are abundant,and alveolarwall fibrosis resultsin firm, brown lungs ("brown induration"). Thesepatientsare particularly susceptibleto bronchopneumonia(FigureII-5-7).

Figure ll-5-6.Ghronic passive congestion with hemosiderin-filled macrophages (microscopic).

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Pathology

Figure ll-5-7.Chronic passive congestion with interstitial fibrosis (microscopic).

B. Pulmonaryhypertension. The pulmonary circulation is characterizedby low pressureand work. Pulmonary hypertenlow resistance,which protect the right ventricle from excessive sion usually occursas a result of elevatedpulmonary vascularresistance. 1. Primarypulmonaryhlpertension has an unclear etiology,although there are numerous theories.It generallyaffectsyoung women 2A40 yearsof age.Sometheoriesinclude: a. Multiple small pulmonary emboli, which becomeorganizedand incorporated within arterial walls b. Neurohormonal-induced vascular hyperreactivity, causing chronic vasoconstriction and pulmonary hypertension c. Immune complex-mediated disease d. Diet or medicinal products, such as appetite suppressants,which may causedirect endothelialdamage causingelevatedpul2. Secondarypulmonary hn>ertension resultsfrom known diseases, monary vascularresistanceand pulmonary pressures. a. Increasedpulmonary blood flow may be due to atrial septaldefect,ventricular septal defect,patent ductus arteriosis,or Eisenmengercomplex. b. Hypoxic vasoconstriction may be seenin COPD and interstitial lung disease. c. Elevatedleft heart pressures,transmitted back to the right sideof heart,may occur in congestiveheart failure, mitral stenosis,and left atrial myxoma. necrotizingvasculid. Destruction of pulmonaryvessels may occur in schistosomiasis, tis, multiple pulmonary emboli, sickle cell anemia,scleroderma,and COPD. 3. Pathology. A variety of vascularlesions with much overlap between primary and secondary hlpertension is seen.

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Respiratory System

In a Nubhell Pulmonary Embolism . Verycommon occurence . Occurs during timesof venous stasis, especially prolonged during bedrest orsittingCHF, andin primary venous disease . Mostoftenoriginates from a deepvenous thrombosis (DUDin thelower extremities or pelvic area . Risk factors include: obesity, pregnancy, cancer, oral contraceptives, hypercoagulabil ity,multiple fractures andpriorDVI . lf youaregiven a que$ion ontheexam where a patient (often bedridden post-surgical) develops sudden shortness of breath, thinkpulmonary embolism. Diagnosis wouldbe confirmed witha V/Q (ventilation/perfusion) scan.

204

a. In primary hypertension, medium-sized muscular arteries develop medial hlpertrophy, intimal thickening and fibrosis with adventitial fibrosis, and internal and external elastic membrane thickening and reduplication. Small arteries and arterioles are most affectedwith medial thickening. A "plexiform lesion" may form, consisting of cellular intraluminal angiomatous tufts. b. Secondarychanges are similar to those in the primary diseasebut may have organized thrombi and diffirse atheroscleroticchangeswithout calcification or ulceration. 4. Clinical course. Patients become symptomatic only after the diseaseis well advanced. They usually presentwith dyspneaand fatigue. Occasionally,syncopeor angina can be the initial manifestation. Respiratory failure or decompensatedcor pulmonale result in death within severalyears of presentation. C. Pulmonary thromboembolism and infarction is an underdiagnosedentity (500,000annually; 10olofatal) resulting in occlusion of a pulmonary artery by an embolic blood clot. Thrombosis on top of a nonocclusiveembolus may lead to complete arterial obstruction. The usual sourcesof emboli are the deep veins of the leg. However, a clot can also develop in the pelvic veins and right heart. 1. Risk factors include bed-bound conditions, obesiry cancer,pregnancy,oral contraceptives, hypercoagulabiliry and prior deep venous thrombosis. a. Large emboli may occludethe main pulmonary artery or its major branchesor lodge in the pulmonary arterybifurcation,leading to a "saddleembolus."Suddendeath can follow from blockageof blood flow out of the right ventricle or from acute right heart failure (acutecor pulmonale). b. Small emboli occlude smaller vessels.Fewerthan 10oloof pulmonary emboli causeinfarction asa result of bronchial artery collateralflow to the lung parenchyma.Under theseconditions, hemorrhage with parenchymal preservation rather than infaraion occurs. If the collateral circulation is compromised, even small emboli can causeinfarction. 2. Pathology. Characteristically,infarctions extend to the lung periph.ry forming a wedgeshaped,pleural-basedinfiltrate. Initially, the infarct is hemorrhagic with ischemicnecrosis ("red infarct") (Figure II-5-8). Fibrinous exudateforms on the apposedpleural surface.RBCslysewithin 48 hours, and eventually fibrous replacementbegins at the margins, leading to scarformation.

Pathology

Figure ll-5-8.Pulmonaryinfarct (gross).

3. Clinical features of a pulmonary embolus depend on its size. a. Small emboli causetransient cough, dyspnea,tachycardia,hyperventilation,and possibly chestpain. Infarction may producefever,worseningchestpain, and hemoptysis in addition to dyspneaand tachypnea. b. Large emboli can produce sudden death with a clinical syndrome similar to an acute myocardialinfarction (chestpain, severedyspnea,shock,fever). D. Fat embolism is characterizedbyprogressiverespiratoryinsufficiency,mental deterioration, and occasionallyrenal insufficiency.Theseemboli usuallydevelop 1-3 daysafter a longbone fracture. 1. Pathogenesisis controversialand probably multifactorial. a. Releaseof fat globules from the marrow may simply occlude vesselsin the lung and brain. Smallerglobulesmay fit through the pulmonary vasculatureand causesystemic emboli. b. Chylomicrons may coalescewith stress,leading to vesselocclusion. c. Disseminatedintravascularcoagulation (DIC) may cause obstructive symptoms, exacerbatedby fat emboli. d. Freefatty acidsmay causemicrovasculartoxic injury, leading to capillary block. 2. Prognosis.Mortaliry is high (10-i5%). E. Amniotic fluid embolism. Releaseof thrombogenic amniotic fluid into the maternal circulation during delivery causeswidespreadthrombosis and occlusion of pulmonary capillaries.DIC may follow. There is a high mortality rate.

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MISCELTANEOUS DISORDERS PUTMONARY A. Lipid pneumonia is causedby aspiration of a variety of oils, and it resultsin patchy or diffuse consolidation. The aspirated oil is emulsified upon reaching the alveolus, and oil droplets are phagocytosedby macrophages.In the early stage,the involved alveoli are partially or totally filled with distended,occasionallymultinucleated macrophagescontaining clear cftoplasmic granules.Progressionof diseaseinvolves fibroblast organization of the inflammatory reaction into granulomataand fibrous tissue.

ln a Nutshell Neonatal Respiratory (Hyaline Distress Syndrome Membrane Disease) . Mostcommon cause of deathin premature neonates . Deficiency of surfactant, mainly of composed lecithin dipalmitoyl . Atapproximately the33rd the weekofpregnancy, lecithin concentration increases. Thesphingomyelin remains $able. concentration A lecithin: sphingomyelin ratiogreater orequalto 2:l lunpinthe indicates mature newborn. . Risk factors forneonatal include respiratory distress prematu rean rity,caesa birth,mother with section diabetes mellitus.

B. Neonatal respiratory distress syndrome (hyaline membrane disease)occurs in premature infants asthe result of a deficiency in pulmonary surfactant becauseof inadequatelecithin synthesisby irnmature tnre II pneumocftes. Grossly, the lungs are normal sizedbut solid, airless,and reddish-purple.Alveoli are small and collapsed(atelectasis),whereasproximal alveolar ducts and bronchi are overdistended(emphysema).Necrotic material becomes incorporated into pink fibrin-rich hyaline membranesthat line alveolarducts and alveoli. C. Pneumonia in the immunocompromised host. Pulmonary infiltrates and signsof infection commonly occur in immunosuppressedpatientsundergoing chemotherapy,after transplantation, or with AIDS. A wide arrayof opportunistic infections can causethesepneumonias, many of which rarely causediseasein normal hosts. 1. Cytomegalovirus (CMV) infections acquired postnatally tend to be asymptomatic but can produce seriousillnessin the immunocompromised host, usually involving the lung and intestinal tract. Lung involvementtakesthe form of an interstitial pneumonitis with intracellular inclusions in the alveolarlining cellsand in endothelial cellsof septalcapillaries,as well as in macrophages.Intra-alveolar edema,proteinaceousexudate,and focal hyaline membranesmay appear,depending on the severity of infection. Cellular inclusions occur in enlarged cells (cytomegalo-) with pleomorphic nuclei containing acidophilic nuclear inclusions. The inclusion may be one half the diameter of the nucleus and is surrounded by a clear halo, separating it from the nuclear membrane. Acidophilic inclusions may alsobe seenin the cytoplasm. 2. Pneumocystiscarinii pneumonia (discussedearlier in this chapter) 3. Other infections are caused by fungal (Cryptococcus,Aspergillus) and bacterial (Pneumococcus, S. aureus)agents. D. Atelectasiscan be causedby either a failure of the lungs to expand at birth or by collapseof previously air-filled lungs by processesincluding air obstruction (followed by resorption of air), compression(by blood, fluid, tumor, or air in the pleural cavify), or contraction (by fibrosis). Microscopically, the alveolar spacesare compressedand contain little or no air. Atelectasisis typically a benign condition unless infection supervenesor so much lung tissueis involved as to compromise respiratory function.

LUNGTUMORS Most lung tumors representmetastaticlesions.Of the primary lung neoplasms,most are bronchogenic carcinomas. A. Benign neoplasms 1. Hamartomas are the most common benign pulmonary neoplasm.They affect men more frequentlythan women (3:1) with a peak incidencein the sixth decade.They are uncommon in patientsunder 30 yearsof age.Hamartomas :re mesenchymalneoplasms,composedof a mixture of tissuesusually found in the lung (cartilage,smooth muscle,collagen)in a disorganizedarray.They can becomeextremelylarge despitetheir benign nature and can remain

206

Pathology

clinically silent becauseof their peripheral location. Calcification resemblittg"popped popcorn" occurstn 5-20o/oof hamartomas. 2. Bronchial adenomasarisefrom bronchial mucous glands. 3. Leiomyomas arise from smooth muscle,usually in an endobronchial location. They are usually a diseaseof young women (averageage37)' 4. Hemangiomas are usually peripheral and often subpleural. 5. Lipomas are usually endobronchial and can occur on either side of the bronchial cartilage. 6. Chondromas are derived exclusivelyfrom formed bronchial cartilage. (e.g., 7. Teratomas are rarely found in the lung and may contain tissuefrom any germ layer teeth,hair). g. Endometriosis may be metastatic,or it may arisefrom pleuripotential pulmonary tissue. B. Bronchial carcinoids make up 5o/oof all primary lung tumors. They are a diseaseof young adults (3545 yearsof age).The frequencyis equal in men and women. Smoking does not appearto be an indepenJentrisk factor.The cellsare derivedfrom a precursorcell,are closely ielated to the Kulchitsky neuroendocrine argentaffin cell, and contain neurosecretory granules.The releaseof neuroendocrinesubstancesleadsto the carcinoid syndrome. l. Clinical features. Eighty percent of bronchial carcinoids are central lesions that are "radiographicallysilent" but can lead to bronchial obstruction, causingcough,fever,chest pain, and localizedwheeze.Hemoptysis is presentin approximately50o/o,reflecting ceniral origin and hypervascularity.Complete obstruction can lead to bronchiectasisand pu..rr.hy-al necrosisdistal to the obstruction. Twenty percentare peripheral lesionsthat ur. ,rr,rully clinically silent; they are detected fortuitously on routine chest x-ray as a slightly lobulated nodule. Calcificationis rare.Only 3.5o/odevelopthe carcinoid syndrome with diarrhea,cutaneousflushing, wheezing,heart disease(valvular fibrosis), abdominal pain, and.telangiectasia.Symptoms are due to releaseof such comPoundsas bradykinin' prostaglandins,serotonin,insulin, gastrin,ACTH, and melanocyte-stimulatinghormone' bevelopment of the carcinoid syndrome usually reflectsmetastaticdiseaseto the liver. 2. pathology. Becausethe appearance,both grossly (presenceof a capsule)and histologically (absenceof mitoses),correlatespoorly with the clinical behavior, all carcinoids should be regardedas potentially malignant. They grow as either polypoid lesions or as a predominantly infiltiative process with submucosal growth and minimal protrusion into the lly, they most commonly form clumps of small, uniformly bronchial lumen. Mi*or.opi. staining cells with round nuclei and infrequent mitoses with a rich vascular stroma. Carcinoidscan alsohavenestsor cordsof cellsseparatedby a delicateweb-like stroma.Some form acini and producemucin, whereasothersappearhighly malignant and resembleoat cell carcinoma.Local invasion is relativelycommon. Distant metastasisoccursin2-5o/o. 3. Tleatment is usually surgical removal of nonmetastaticdisease.If metastatic,5-yearsurvival is only 2}o/o,althoughsome havean indolent and protracted coursespanningmany years. C. Bronchogenic carcinoma is the leadingcauseof cancerdeath among both men and women. The female preponderancehas increased,most probably as a result of increasedsmoking among women in the past few decades.Bronchogeniccarcinomaoccurs most commonly in patients 40-70yearsoi"g.. Adenocarcinoma is the most frequent type of bronchogeniccarcinoma, surpassingsquamouscell carcinoma.Carcinoma of the lung begins as an area of cellular hyperplasi. u"a atypia that causesthickening of the bronchial mucosa.Eventually,

207

Respiratory System

an irregular elevationforms that can elevateor erodethe lining epithelium. Continued progression can follow one of three paths: intraluminal growth, infiltrative peribronchial growth, and intraparenchymal cauliflower-like gto*th that pushes normal tissue away. When bulky' hemorrhageor necrosiscan convertthe usual grey-whitefirm massto yellowa white mottled and softer mass.Spreadto hilar, mediastinal,bronchial, and tracheal lymph nodes is common (50olo).Metastasisvia lymphatics or blood occurs relatively early. Oniv approxim ately25o/oof lung cancersare operablewhen discovered. l. Types a. Adenocarcinoma (35o/o)usually forms peripheral tumors that arisefrom distal airways and alveoli, although occasionally they occur proximally, arising from submucosal glands or epithelium. Ttrmors form well circumscribed, gray-white massesthat rarely cavitate.They may alsodevelopin areasof parenchymal scarring (scarcarcinoma,Figure II-5-9). Microscopi."lly' thereis a spectrumof disease. Well differentiatedtumors have cuboidal or columnar cellswith microvilli that form gland-like structuresand produce mucin. Poorly differentiatedtumors form papillarylesionsor solid massesthat tend not to be mucin producing.Adenocarcinomaoccursequallyin men and women and is less closelyassociated with smoking than squamouscell.

Note Small cellcarcinoma cells secrete thehormones ACTH andADH.Thismaygiverise to a Cushing syndrome or syndrome of inappropriate ADH(SIADH), respectively. Squamous cellcarcinoma may secrete a parathyroid hormone-like substance that maycause hypercalcemia. (See Table ll-5-tonpage 211 formoreonparaneoplastic syndromes.)

b. Squamous cell (25o/o)arisesfrom bronchial epithelium after yearsof mucosal alterations, including metaplasia,dysplasia,and carcinoma in situ. The tumor starts as a small red granular plaque or as a focus of whitish leukoplakiaand progresses to a large intrabronchial mass. Cavitation may occur in the lung distal to the mass. Microscopi.ully' there are intercellular bridges connecting the abnormal neoplastic cellsand abundant keratin formation ("squamouspearls").Squamouscell carcinoma is most closely related to cigarette smoking. It tends to metasiasizelocally and somewhat later than the other lung tumors. It is more common in men and is usually centrally located. c. Small cell carcinoma (25o/o)forms proximal, large, soft, gray-white masses that can narrow bronchi circumferentiallysimply by extraluminal tumor bulk. There is rapid growth and early disseminationso that, if untreated,the median survival is lessthan 3 months. Microscopically, fusiform round or polygonal cellsin clustersexhibit neither glandular nor squamouscharacteristics.Cell, upp.oximately two times the "." size of lymphocyteswith inconspicuousnucleoli and modest amounts of cytoplasm (the classic"oat cell carcinoma" presentation).The cytoplasm holds derrse'granules and contains various peptides, suggestingthat small ceil carcinoma is part of the group of cancersderived from neuroendocrineApuD cells. d. Large cell carcinoma ( l5o/o) forms peripheral, anaplasticlesions that can become quite large and active.Microscopically, cells are large with abundant cytoplasm and distinct cytoplasmic membranes,prominent nucleoli, and large nuclei. There is no squamous or glandular differentiation, although large cell cancer may represent a poorly differentiatedform of adenocarcinomaor squamouscell carcinoma. -e[s may contain mucin. Some form multinucleated giant cells.Others have clear cytoplasm, whereasothers form spindles. e. Bronchioalveolar carcinoma (5o/o)is a subsetof adenocarcinomathat arises from terminal bronchioles or alveolar walls. These tumors form peripheral nodules with mucinous grey translucence. Fifty percent secrete mucin. Microscopically, tall, columnar-cuboidal cells grow along the walls of pre-existing alveoli and can project into alveolarspacesin papillary formations. However,most are well differentiated and preservealveolararchitecture.

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Pathology

2. Major risk factors a. Cigarette smoking. The incidence of lung canceris related to the number of cigarettes smoked per day,the duration of cigaretteuse,the depth of inhalation, and the type of cigarette used. Histologic changes in the bronchial epithelium caused by smoking include: (1) Lossof bronchial cilia (2) Basalepithelial hyperplasia (3) Nuclear hlryerchromatism b. Occupational exposure, including uranium mining, metal work, painting, and exposure to radiation, may increasethe risk of cancer. c. Air pollution. Reducing agents (sulfur dioxide and carbonaceousparticulate matter) appear to be carcinogenic,whereasoxidants are not. d. Genetics. There maybe a familial predisposition to lung cancer,particularlywith deletions or mutations of p53 or the retinoblastomagene.

Figure ll-5-9.Adenocarcinoma of lung associated with scar (microscopic).

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Respiratory System

3. Clinical features. There are two modes: early and late, depending upon cell type and site of origin. Stagingof diseaseis by the sizeof the tumor, number of affectednodes,and distant metastasis(TNM system).In the early stageof disease,intrabronchial lesionscause mild cough or a changein the characterof a chronic cough. Partial obstruction may produce focal emphysema.Total occlusionleadsto postobstructiveatelectasisor pneumonia with fever,chills,sputum production,localizedwheeze,hemoptysis,or abscess formation. In the late mode, there is a wide spectrum of presentations.

Note venacava(SVC) Superior syndrome maybea presentation of bronchogenic carcinoma. Inthissyndrome, ob$ruction oftheSVCby tumorresults in dilatation of headandneckveins, facial swelling, andcyanosis.

a. Nonspecific systemic symptoms include weight loss, anorexia, fatigue, weakness, and nausea. b. Intrathoracic spread can lead to Horner syndrome with secondarycervical sympathetic nerve involvement, superior vena cava syndrome, dysphagia with secondary esophagealobstruction, hoarseness with secondaryrecurrent laryngealnerve involvement, diaphragmatic paralysiswith secondaryphrenic nerve damage,and Pancoast tumor (causingulnar nerve pain and Horner syndrome). c. Extrathoracic extension may involve prescalenelymph nodes, brain, liver, adrenal, and, most commonly, bone metastases. d. The systemicsyndromes,or paraneoplastic syndromes, may occur before the lesion is visible on x-ray. (1) Endocrine/metabolicsyndromesare listedin ThbleII-5-1. (2) Neuromuscular syndromes include cerebral encephalopathyand cortical cerebellar degeneration(small cell), peripheral neuropathy with pain, paresthesias, myasthenia(Eaton-Lambertsyndrome),and proximal muscleneuromyopathy. (3) Hematologic/vascularsyndromes include anemia unrelatedto therapy or bone marrow infiltration, coagulopathy (Trousseausyndrome), migratory thrombophlebitis,DIC, noninfectious endocarditis,and arterial embolization. (4) Dermatologic signs are dermatomyositis,hyperpigmentation, and acanthosis nigricans. (5) Skeletal and connective tissue syndromes include hypertrophic pulmonary osteoarthropathy (periosteal new bone formation, clubbing, and arthritis), which is sometimescausedby squamouscell carcinoma.Vasomotor instability with blanching of hands and feet may alsobe seen.

2t0

Pathology

Thble II-s-f . Paraneoplastic syndromes. Hormone Secretedby Tirmor

Pathophysiologic Consequences

ACTH MSH PTH

Cushing syndrome (rare) Increasedskin pigmentation Hypercalcemia,often due to squamouscell carcinoma Hlponatremia Gynecomastia(large cell) Lactation in men or women Diarrhea, hypokalemia, achlorhydria (squamouscell) Hypocalcemia

ADH HCG Prolactin VIP Calcitonin

Definitions: ACTH - adrenocorticotropic hormone; MSH : melanocyte-stimulating hormone; PTH = parathyroid hormone; ADH = antidiuretic hormone; HCG : human chorionic gonadotropin; VIP = vasoactiveintestinal polypeptide.

4. Treatment. Surgical resection offers the only definitive means of therapy by which nonsmall cell lung cancer can be cured. Unfortunately, fewer than 30oloare "curable" upon presentation,so that the 5-year survival has not improved over the last four decades. Adjuvant therapy (chemotherapy and/or radiation) remains controversial. For most patients with non-small cell cancer,palliation of symptoms becomesmost important. A trial of chemotherapy in "healthy" patientsthat is continued only if a responseoccurscan be attempted. Radiation is highly effective palliation for superior vena cava (SVC) syndrome, hemopfysis,pain, and dyspnearesulting from airway obstruction. Lasertherapy can also improve airway obstruction.

MEDIASTINAT MASSES Mediastinal massesoften present as an unexpectedfinding on routine chest x-ray. Symptoms are due to either compressionor invasion of neighboring structures.Vascularlesionsmay present as"masses"in all parts of the mediastinum and include congenitalvascularrings; double superior venaecavae;aortic malformations,aneurysms,and dilatations;aneurysmor dilatation of major aortic branches;and dilated pulmonary arteries.Other massesinclude diaphragmatic herniations and pulmonary lobar sequestrations.The mediastinum can be divided into three compartments,eachwith characteristiclesions: A. The anterior mediastinum rangesfrom the root of the neck, extending down to include the region betweenthe sternum (anteriorly) and pericardialsurface(posteriorly). 1. Thymoma is the most common anterior mediastinal mass. There are four cell types: epithelial,lymphocytic, spindle, and mixed. Benign thymomas have a thick fibrous capsule and do not invade.Malignant thymomas lack a capsuleand do invade.

ClinicalCorrelate Sputum cytology, transbronchial biopsies, and openbiopsies areallusedto diagnose lungcancer. Pathologists to arealsoasked margins evaluate resection aftersurgery the andto detect presence of lymphnode metastases. Evaluation of liver andbonemarrow biopsies arerequired inthesetting of meta$atic disease forthe purpose of staging.

Bridgeto Cardiovascular Theanatomy ofthe mediastinum in isreviewed theCardiovascular Anatomy chapter.

2. Teratomasare tumors derived from pluripotential precursor cells. a. Mature teratomas (dermoid cysts) generally show ectodermal differentiation, although elementsfrom other germ layersmay be present.They are generallybenign, although approxim ately lo/oundergo malignant transformatio n. b. Immature teratomas havea fetal or embryonic appearancemicroscopically;primitive neuroepithelial cells are frequently encountered.Immature teratomas may behave aggressively; tumor behavior correlateswith histologic grade.

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System Respiratory

3. Lymphorna. The most common lymphoma is nodular sclerosingHodgkin disease. Tiachealcompressionoccursin 2096. 4. Glsts of pericardial,bronchogenic,or tlymic origin are alsorarely seen. Bri{e to Hene/L,ymgt Lvmphoma isdiscussed in detailin the Hematologiq Lymphoreticular Pathology chapter ofthisbook.

5. Introthoracic goiter is an unusualfinding. B. The middle mediastinum includesthe pericardium and its contents,lower trachea,carina and mfi bronchi, and lymph nodes. 1 Ct/sts a- Pericardial cysts are usually located in the cardiophrenicangle.They occasionally communicatewith the pericardialspaceand are composedof one mesotheliallaye6 coveringa thin fibrous wall. b. Bronchogeniccystsarelined with ciliated columnarepithelium with mucousglands and cartilagein the wall. c. Enteric c1stsarelined by squamousepitheliumand smoothmusclewithout cartilage. 2. Lymphoma, both Hodgkin and non-Hodgkin types, may involve middle mediastinal nodes, 3. Primarymediastinal carcinoma may arise from cyst epithelium. 4. Granulomatous lesions. Histoplasmosis, sarcoidosis, and TB all may involve middle mediastinalnodes,usually becausethey drain primary lesionsin the lungs. C. The posterior mediastinum includes the posterior pericardium to the anterior vertebral column and posterior ribs, including the paravertebralgutters. 1. Neurogenic tumors are almost alwaysbenign in adults, although 10o/ohave an intraspinal component. Thesetumors are describedmore fully in the Neuropathologysection. a. Schwannomas (neurilemomas) are benign nerve sheath tumors of Schwann cells. b. Neurofibromas are benign nerve sheath tumors of fibroblasts. c. Ganglioneuromas are benign nerve cell tumors of sympathetic ganglion cells. They occur primarily in the second and third decades. d. Ganglioneuroblastomas are malignant tumors of sympathetic neurons; they are common in children and infants. e. Neuroblastoma is also common in children and infants and is highly malignant.

2r2

Pathology

DISEASES OFTHEPTEURA A. Effusions are abnormal accumulations of fluid within the pleural space; they are a common manifestation of both systemic and intrathoracic disease.The normal pleural space contains no more than 15 mL of serousfluid that lubricates the pleural surface.The factors that determine whether pleural fluid accumulates include oncotic pressure in the pleural microcirculation and surrounding tissue,permeability of the pleural microcirculation, pressure in the pleural microcirculation and surrounding tissue,intrathoracic negativepressure, and lymphatic drainage.Pleural effusions can be divided into transudates (low lactate dehydrogenase,lowprotein) and exudates(high lactatedehydrogenase; high protein). 1. Noninflammatory pleural eftrsions (transudates) a. HydrothorilL Noninflammatory serous fluid collects in the pleural cavity as a result of CHF (increasedpressure),renal failure (fluid overload,increasedpressure),cirrhosis (fluid overload, decreasedoncotic pressure), or nephrotic syndrome (fluid overload, decreasedoncotic pressure).The fluid is clear and straw colored, with a specific gravity of less than 1.012 (normal value). It does not loculate unless there are preexisting pleural adhesions. Meigs syndrome is the association of ovarian cancer, ascites,and pleural effusion; it is thought to be causedby lymphatic stasis.

Bridge tg -Cardio-v1Rula1 Nowmaybea goodtimeto review theStarling equation in theCardiovascular Physiology chapter inthisbook. Transudates result fromt P.,J rr",ot a combination of thetwo.

b. Hemothorax follows hemorrhage into the pleural space,often the result of a rupturing aortic aneurysmof iatrogeniccauses,such asbiopsies. 2. Inflammatory pleural effrrsions (exudates) a. Serofibrinous pleuritis is caused by inflammatory diseases within the lung such as TB, pneumonia,lung infarcts,lung abscess,and bronchiectasis.Systemicdisease,such as rheumatoid arthritis, systemiclupus erythematosus,uremia, and diffirse infections, can also causeserous or serofibrinous pleuritis. The fluid consistsof relatively clear, straw-colored fluid with small strands of yellow fibrin and few WBCs. Specific gravit'' is greater than 1.020.Minimal inflammation is present,and the fluid can be absorbed with either resolution or organization of the fibrinous component. b. Suppurative pleuritis (empyema) is a purulent exudate with bacterial or fungal seeding of the pleural space,usually by contiguous spread from the lung. Occasionally, infection can come from blood or lymphatics. It is characterizedby yellow-green pus with massesof polyps and other leukocytes.Empyema infrequently resolvesbut usually organizeswith the formation of tough fibrous adhesionsthat can obliterate the pleural spaceor form a pleural "peel," preventing pulmonary expansion.Calcification is typical of tuberculous empyema. c. Hemorrhagrc pleuritis is uncommon, but it is found in patients with bleeding tendencies,rickettsial disease,and pleural neoplastic disease. B. Pneumothorax is an accumulation of air or gas in the pleural cavit'', leading to collapse of the underlying lung as a result of increasedsurrounding pressure(pleural pressureis usually negative).Pneumothorax is frequently causedby spontaneousrupture of an alveolusor bleb or by a communication between an abscessand either the pleural spaceor interstitium. It is most common in patients with emphysema, asthma, srd TB. Tlaumatic pneumothorax results from puncture of the chest wall with communication between the pleural space and external environment. When air can enter the pleural spacebut not exit during expiration, pressurebuilds, leading to a tension pneumothorax with tracheal deviation, respiratory compromise, and hemodynamic instability.

InlN,11$,etf Transudate Exudate . Specific grmty lesstran 1.012

. Speciftganty grmtettnn 1.020

' l,loninflammatorylnflammatory edema fluid

ederna fluidwifr

rsultingfrom

rnsorhr increased

changcin

permeabilrty

trydro*atic or

.i

osrnotcpr6$re influid intravascuhrto/ J $ucose . J protein influid

t inflamnntory cellsinfluid

21'

Respiratory System

C. Tumors 1. Metastatic involvement of the pleura is most common, usually from the breast or lung. 2. Malignant mesothelioma is a rare tumor that arisesfrom parietal or visceral pleura. It is associatedwith asbestose4posureafter a prolonged latent period of 2545 years.In contrast to bronchogeniccarcinoma,in which smoking and asbestosexposureact synergistically, smoking does not increasethe risk of malignant mesothelioma.The malignant mesothelioma is a diffuse lesion that spreadsover the lung surface,causing a pleural effirsion and invasion of thoracic structures.The lung is encasedby a thick tayerof gray-pink tumor, composed of mesenchy-d stromal cells or even papillary, epithelial-like cells. Patientscomplain of chestpain and dyspnea.prognosisis poor.

IARYNGEAI DISEASES A. Inflammation. taryngitis is usually part of an inflammatory processof the lung and lower respiratory tract. It may also be involved with dififr.rseinfections, such as TB, ryphilir, diphtheria' and local diseaseof the mouth and throat. Although trivial in the adult, laryngeal inflammation can lead to upper airwayobstruction in children. B. Tumors 1. Benign neoplasms a. Pollps usually occur on the true vocal cords as smooth, round nodules that may be pedunculatedor sessile.Polyps are composedof loose connectivetissueand covered by squamous epithelium that can ulcerate when traumatized by the opposite vocal cord. They are associatedwith heavy smoking and vocal cord overuse. b. Papilloma is a true neoplasm,usually a soft, friable nodule on the true vocal cords. Papillomasfrequently ulcerateand bleed with manipulation. They are composedof multiple finger-like projections composed of fibrous tissue coveredwith squamous epithelium. Papillomasrarely undergo malignant transformation. 2. Malignant tumors are uncommon except for those arising from the surfaceepithelium. Most occur on the vocal cords, although they can occur anywhere.Ninety-five fercent are squamous cell carcinomas, which can cause hoarseness,difficulty swallowing, pain, hemoptysis,and, eventually,respiratory compromise.Ulceration can lead to suplrinfection. Complications arise due to direct extension,metastases, and infection. Risk factors include cigarettesmoking, alcohol,and frequent cord irritation. C. Congenital anomalies. Laryngeal stenosis and atresia require rapid diagnosis and tracheostomyat birth. They may be accompaniedby cardiacor renal difects.

214

Pathology

AIRSINUSES DISEASES OFIIIE NASAT CAVITIES ANDACCESSORY A Rhinitis is an inflammation of nasal cavitiescausedby viruses,bacteria,and allergens. Mucinousdischargeandcawrhal exudationarecommon.Thenasalmucosais thickened,edematous,and hyperernic.Nasalcavitiesare narrowed.Turbinatesare enlarged.Inflanmatory hypertrophicswellingof the mucosagivesris€ to nasalpolyps.Micoscopically, polypsshow edemaand infiltration with eosinophilsandplasmacells. B. Sinusitis is inflammation of the nasalaccessorysinuses;it is closelyrelatedto rhinitis. It is usually precededby acute inflammation of the nasal cavities,leading to infection and inflammation of the sinuses.

Note Nasl polyps,a$hma,and arepathognomic sinusitis manifestations of aspirin allergy'

C, Ttrnors. Various types of mesenchymalneoplasmscan occur, although most are poorly differentiatedsouamouscell carcinomas.

215

Respiratory Pharmacology "breathe There area number of classes of drugs thathelppeople easie/' by$imulating dilatation of passages thebronchial or reducing bronchopulmonary inflammation. Thischapter reviews the different classes of drugsthathavebeeneffective in thetreatment of respiratory disorders andtheir pharmacologic properties, specific mechanisms of action, andpertinent sideeffeG.

ADRENERGIC AGONISTS Adrenergic drugs causevasoconstriction by stimulating cr-adrenergicreceptors,cardiac stimulation by stimulating B,-adrenergic receptors,and bronchodilatation by stimulating Br-adrenergic receptors.Adrenergic drugs include the direct stimulants of c-adrenergic and p-adrenergic receptors,such as epinephrine; the indirect and direct stimulants, such as ephedrine; and the selectivep-adrenergic stimulants, such as isoproterenol. This last group of p-adrenergic receptor stimulants may be further subdivided into agents that have a preferential action on bronchial muscles (p, stimulants) and agentsthat preferentially effect the heart (B, stimulants). Various pr-selectivedrugs have been developed primarily for their value in treating bronchial asthma.Through their specificity for pr-adrenergic receptors,they relax smooth musclesof the bronchi but have much lessstimulatory action on the heart than does isoproterenol. A. Epinephrine 1. Pharmacologic properties

Bridgeto Neruous System Foranextensive review of the receptors oftheautonomic nervous system aswellas theiragonists andantagonists, seethePhysiology and Pharmacology chapters inthe Nervous System section.

Note B,arefoundonallsmooth particularly muscles, blood vessels; theirstimulation results invasodilation, a dropin bloodpressure with possible reflex tachycardia.

a. Epinephrine stimulatesboth u- and p-adrenergicreceptors.

Mnemonic

b. o-adrenergic receptorsmediate a potent vasopressoraction on the vasculatureof skin, mucosa,and kidneys.

. 9,4 2 lungs .9,Jlheart

c. A positive cardiacchronotropic and inotropic action is B, mediated. d. Bronchial smooth muscle is relaxedby activation of pr-adrenergic receptorsthat stimulate cAMP production. e. A decreasein mast cell secretions(p, mediated) may also help to alleviate asthma. f. Vital capacity is increasedsubsequentto relief of bronchial mucosal congestion. 2. Pharmacokinetics a. Epinephrine is rapidly absorbedafter intramuscular or subcutaneousinjection. It is not effective if taken orally but can be administered by inhalation of nebulized solution. b. Metabolism occurs by either hepatic oxidative deamination by monoamine oxidase (MAO) or methylation by catechol-O-methyltransferase (COMT). c. The primary excretion product is urinary vanillylmandelic acid.

Bridgeto Pathology Pheochromorytomas are uncommon tumors ofthe producing adrenal medulla catecholamines. Their presentation isidentical to sideeffects andtoxicity of epinephrine, andtheir diagnosis involves the measurement of elevated urinary VMA.

217

Respiratory System

3. Indications for use. Epinephrine is usefrrl for acute asthmatic attacks to provide rapid relief of respiratory distress,for hypersensitivity reactions to drugs and other allergens, for the prolongation of infiltration anestheticaction, and for its topical hemostatic effect. 4. Side effects and toxicity a. Excessivestimulation of adrenergic receptors causes anxiery tremoS palpitations, tachycardia,headache,diaphoresis,and pallor. b. Contraindications include hypertension, hlperthyroidism, ischemic heart disease, and cerebrovascularinsufficienry (not recommended over age 60 unless asthma is intractable).

ln a Nubhell Epinephrine stimulates crand adrenoreceptors and isused B foracute reactions, allergic especially anaphylactic shock. It isalsousedforacute asthma attacks andrespiratory distress. There areoften unwanted sideeffects associated withepinephrine's p, stimulation (e.g., tremor, palpitations, tachycard ia).

Note preparations Anumber ofOTC andherbal medicines contain ephedrine andanalogs and maybeabused fortheir psychostimula nt-likeeffect.

B. Ephedrine 1. Pharmacologic properties a. Ephedrine stimulates both o- and B-adrenergicreceptors;it also increasesthe release of norepinephrine (an indirect action). b. An increasein pulse pressureis causedby vasoconstrictionand cardiacstimulation. c. It is a CNS stimulant. 2. Pharmacokinetics a. Ephedrine is rapidly absorbedafter oral administration. b. Ephedrine is similar to epinephrine but has a longer duration of action, more pronounced central actions, and a much lower potenry. 3. Indications for use include chronic casesof asthma that require continued medication (used only occasionally now that Br-selectiveagentsare available) and as a mydriatic (in aqueoussolution). 4. Side effects and toxicity a. CNS stimulation may occur, manifesting as nervousness,excitabiliry or insomnia. b. Increasedperipheral vascularresistancemay result from its use. C. Isoproterenol 1. Pharmacologic properties a. Isoproterenolstimulatesp-adrenergicreceptors(9r and 0r) and hasvery little effecton o-adrenergicreceptors. b. Almost all smooth muscleis relaxed,especiallybronchialsmooth muscle,by stimulating the production of cAMP (p, mediated). c. Peripheral vascular resistanceis lowered in skeletal, renal, and mesenteric vascular beds. 2. Pharmacokinetics a. It is rapidly absorbed after inhalation. b. Metabolism occurs in the liver and elsewhereby COMT. 3. Indications for use. As a bronchodilator, isoproterenol relieves respiratory distress in severeasthmatic attacks.It is rarely used now that more selectiveagentsexist. It may prove useful in heart block.

2t8

Pharmacology

4. Side effects and toxicity. Acute toxicity is less than that seen with epinephrine. Thchycardia, headache,flushing, nausea, dizziness,and diaphoresis are common side effects.Anginal pain or cardiac arrhythmias may occur. Tolerance may occur with frequent administration.

ADREN ERGIC AGON |STS Fr-SELECTTVE

Note Headache andflushing are directsymptoms ofthe vasodilatory actionof p, agonists.

Br-Selectiveadrenergic agonists offer the advantageof minimal cardiac side effects. They also have greater bioavailability secondaryto less enzqatic degradation. Structural modifications make many of these drugs less susceptibleto COMT and MAO. They are most often used as inhalants, thus minimizing systemic side effects. A. Metaproterenol 1. Pharmacologic properties a. Relaxes smooth muscle of bronchi, uterus, and skeletal muscle vasculature and decreasesairway resistance. b. Causesmuch lesscardiacstimulant action than isoproterenol(ro F, stimulation). 2. Pharmacokinetics a. Metaproterenol is structurally similar to isoproterenol except for the positions of the hydroryl groups on the phenol ring; it is resistant to COMT methylation. b. It can be taken orally or inhaled and has a duration of action up to 4 hours. 3. Indications for use. It is effective as a bronchodilator in the treatment of bronchial asthma and reversiblebronchospasm.

ClinicalCorrelate agonists are B,-selective currently themainstay inthe treatment ofacute asthma. Theyhavetheadvantage of minimal cardiac sideeffects andgreater bioavailability.

4. Side effects and toxicity a. Sympathomimetic stimulation may cause tachycardia, hypertension, nervousness, tremor, palpitations,nausea,and vomiting. b. Must be usedwith caution in patients with severehypertension, severecoronary artery disease,congestiveheart failure, and hyperthyroidism. c. Tolerance is less likely to develop to inhaled metaproterenol than to inhaled isoproterenol. B. Terbutaline 1. Pharmacologic properties a. It is resistantto COMT methylation. b. A synthetic sympathomimetic, it is a relatively selective pr-receptor agonist when given orally. c. It causescardiovascular effects similar to isoproterenol when administered subcutaneously. 2. Indications for use. As a bronchodilator in asthma,terbutaline is the only F, agonist used parenterally for the treatment of status asthmaticus. 3. Side effects and toxicity a. Oral preparation causestremor. Dizziness,neryousness,fatigue, tinnitus, and palpitations are rare. b. With subcutaneous administration, adverse reactions resemble those seen with epinephrine.

Note Salmeterol isa newer, longerp, agoni$ acting usedfor prophylaxis. asthma

2t9

Respiratory System

C. Albuterol 1. Pharmacologic properties are similar to terbutaline. a. Albuterol is a relativelyselectiveBr-adrenergicreceptoragonist. b. It is availableas oral and aerosolpreparations. c. Its peak effectis in 30-40 minutes with a 3- to 4-hour duration of action after inhalation. 2. Indications for use.Albuterol is an effectivebronchodilator in reversibleobstructiveairway disease.

ln a Nutshell Allcr Epinephrine Ephedrine + a n d B receptors

B

3. Side effects and toxicity a. Nervousness,tremor, headache,insomnia, weakness,dizziness,tachycardia,and palpitations may occur.

lsopropterenol + receptors only

b. Albuterol should be used with caution in patientswith coronary artery insufficiency, hypertension,hyperthyroidism,and diabetesmellitus, and in patientsreceivingMAO inhibitors or tricyclic antidepressants.

Metaproterenol Terbutaline - F,, seleCtrve Albuterol

c. It has lessB, stimulation than isoproterenol,metaproterenol,and terbutaline.

(THEOPHYLUNE, METHYUXANTHINES AMtNOpHytHNE,CAFFEINE, THEOBROMTNE) Severalmechanismshavebeen proposedto explain methylxanthine-inducedbronchodilatation: /) accumulation of cAMP due to inhibition of cyclicnucleotidephosphodiesterases,2) increases in intracellular calcium, and 3) blockade of adenosine receptors (adenosinecausesbronchoconstrictionand increasesmast-celldegranulationof histamine). A. Theophylline 1. Pharmacologic properties. Theophylline relaxesbronchial smooth muscle, producing an increasedvital capacity; is a potent CNS stimulant; improves diaphragmatic contractility; has a positivecardiacinotropic action; and increaseswater and electrolyteexcretion. 2. Pharmacokinetics a. Theophylline can be administeredorally, rectallSor parenterally.It is distributed into all body compartments and is 600lobound to plasmaproteins. b. Subjectto hepatic metabolism,it has a half-life of 8 hours.

CilinicalCorrelate Theophylline isa second-line agent fortreating asthma. lts significant sideeffects include gastro nervousness, intesti nal irritation, andarrhythmias. Thearrythmias result from blockade ofadenosine (adenosine receptors decreases AVnodal conduction).

220

3. Indications for use. It is effectiveas a bronchodilator in asthmaand COPD, can improve diaphragmaticfunction in COPD, and can reduceprolonged apneain preterm infants. 4. Side effects and toxicity a. Oral administration may causeheadache,nervousness, dizziness,nausea,vomiting, and epigastricpain. b. Intravenous administration may resuit in cardiac arrhythmias, hypotension, cardiac arrest,and seizures. c. In children, CNS stimulation, diuresis,and feversare seen. d. Serum levels should be monitored becausetoxicity is seenat levelsgreaterthan 20 mglL; beneficialeffectsbegin around 7-10 mg/L.

Pharmacology

5. Drug interactions a. Barbiturates, phenytoin, and smoking increasetheophylline metabolism. b. Allopurinol, propranolol, cimetidine, erythromycin, and influenza vaccine decrease theophylline metabolism. B. Aminophylline is a widely used soluble theophylline salt (theophylline ethylenediamine), particularly in the treatment of status asthmatics.

CROMOTYN SODIUM ANDNEDOCROMIT A. Pharmacologic properties 1. It has no direct adrenergic,bronchodilator, antihistaminic, or anti-inflammatory actions. 2. It inhibits the degranulation of mast cells and releaseof histamine and other autacoids after immunologic and nonimmunologic (e.g.,exercise,hlryerventilation) stimulation. B. Pharmacokinetics 1. Cromolyn sodium is administered by inhalation. Oral absorption is very poor. The absorbed drug does not undergo metabolic degradation.Most is excretedunchanged within a few days. 2. Maximal plasmalevelsare reachedwithin minutes with a plasma half-life of I to 1.5hours. A pharmacologic responseis observedwithin weeks. C. Indications for use 1. Cromolyn sodium is used only to prevent asthmatic attacks (particularly in cold- and exercise-inducedasthma).It is ineffectivefor the treatment of acuteasthmaattacks. 2. Partialor completeprotection is experiencedin children with chronic unstableasthma.A smaller number of adults benefit from prophylactic use of this drug. 3. An inhaled nasalpreparation is used in allergic rhinitis. 4. Effects may not be seen for 4-6 weeks. D. Side effects and toxicity 1. Sideeffectsoccur in lessthan 5oloof patients. 2. Sorethroat, cough, and dry mouth are the most common problems. 3. Urticaria, maculopapulardermatitis, and gastroenteritismay also occur.

CORTICOSTEROIDS Corticosteroids are potent antiasthmatic drugs whose use is limited by the frequenry of adverse systemicreactions. Corticosteroids reduce inflammation and edema and potentiate the bronchodilating effectsof adrenergicagonists.The short-term administration of intravenouscorticosteroids is frequently necessaryin the treatment of status asthmaticus. Once the acute episode is controlled, oral therapy with a short-acting corticosteroid is established,and the dosageis reduced. Prednisone,prednisolone, and methylprednisolone are equally effective oral preparations.Beclomethasonedipropionate is an aerosolthat exertsa more localizedeffect.

221

Respiratory System

A. Prednisone and prednisolone

ClinicalCorrelate Corticosteroids mu$be tapered because theysuppress production endogenous by theadrenal gland, andacute withdrawal canprecipitate an addisonian crisis. Sideeffects of corticosteroids include: . Osteoporosis . Hyperglycemia . Dysphoria/psychosis . Potentialfor immune suppression

Clinical Correlate Lowdosage prevents the desensitization of B,receptors thatwouldoccur withchronic useof p,-agonists ClinicalCorrelate Aerosolized steroids suchas beclomethasone aredelivered directly to thelungs and produce fewersystemic side effects.

ClinicalCorrelate lpratropium bromide isoften usedin COPD because it produces bronchodilatation andreduces secretions.

1. Indications for use a. Theseagentsare useful in severechronic and acutebronchospasm. b. Optimally, oral steroidsare tapered,and the patient can be placed on inhaled preparations once the acuteepisodehas resolved. 2. Side effects and toxicity include suppressionof growth, osteoporosis,aggravation of diabetes,asepticbone necrosis,and adrenocorticalsuppression. B. Beclomethasone dipropionate 1. Pharmacologic properties a. Beclomethasonedipropionate is an esterifiedchlorinated analogof betamethasone. b. The aerosol preparation is inhaled in metered doses. c. A highly potent corticosteroid,it actslocally on respiratory mucosato reduceinflammation. d. It manifests only minor systemic absorption and rapid metabolism, and it has no effect on the hypothalamic-pituitary-adrenal axis. 2. Indications for use. Beclomethasonedipropionate servesas a substitutefor oral preparations in selectedindividuals with severesteroid-dependentasthma. 3. Side effects and toxicity a. Becauseit is inhaled, systemicside effects are greatlydiminished. b. Hoarseness,sore throat, and dry mouth are the most common side effects. c. Oropharyngealand laryngealcandidal infection may occur; to prevent infection, the mouth should be rinsed after eachdose.

ATROPINE ANDIPRATROPIUM BROMIDE A. Mechanism of action. These agentsact by blocking muscarinic receptors, thereby inhibiting acerylcholine-inducedbronchoconstriction ("anticholinergics,'). B. Indications for use 1. In the past, anticholinergicswere first-line drugs for asthma treatment; they have since been supplantedby adrenergicagonists. 2. They are usedin asthmapatientsunresponsiveto adrenergicagentsand methylxanthines. C. Side effects and toxicity l. Anticholinergic side effectsinclude drowsiness,sedation,dry mouth, blurred vision, urinary retention, and constipation. 2. CNS side effectsare not as pronounced with ipratropium becauseit does not crossthe blood-brain barrier.

222

Pharmacology

ANTITEUKOTRIENES This newer classof drugs usedin the treatment of asthmaworks by inhibiting the formation or action of the leukotrienes. A. Zileuton is a selective inhibitor of 5-liporygenase and thus blocks the synthesis of leukotrienes.It has a rapid onset and is used in combination with steroids.Its slow onset of activity forcesits use for prophylaxis.It can causediarrhea and headacheand can increase the risk of infection. B. Zafirlukast blocks the LTD* leukotriene receptors.

Bridgeto General Principles Toreview and thebiosynthesis see effects of theleukotrienes, within theAutacoid chapter thePharmacology section of z theCeneral Principles Book (Volume ll).

Bridgeto Pathology pulmonary 0bstructive ischaracterized by disease overproduction of mucus (chronic bronchitis, asthma, bronchiectasis) or lackof recoil ofthelungparenchyma (emphysema).

22',

SECTION III

RenaVurlnary System

RenallUrinaryEmbryology is andurethra), ducts(ureters andexcretory bladder, of thekidneys, consisting Theurinary system, the from contribution a smaller with derivatives andendodermal frommesodermal mainly formed isvestigial; themesonephros Thepronephros formsequentially. systems Threeseparate ectoderm. intothedefinitive develops disappears; themetanephros butthenmainly transiently, mayfunction provide to themalereproductive important contributions ducts Thepronephri(mesonephric kidney. sinus, ducts, theurogenital fromthemetanephric arederived excretory ducts system. Thepermanent ectoderm. andsurface

ANDURETERS KIDNEYS Renal development is characterizedby three successive,slightly overlapping kidney systems. A. Pronephros. Segmentednephrotomes appear in the cervical intermediate mesoderm of the embryo in the fourth week. These structures grow laterally and canalize to form nephric tubules. Successivetubules grow caudally and unite to form the pronephric duct, which emptiesinto the cloaca.The first tubules formed regressbefore the last ones are formed. By the end of the fourth week,the pronephros disappears. B. Mesonephros.In the fifth week,the mesonephrosappearsas"S-shaped"tubules in the intermediatemesodermof the thoracic and lumbar regionsof the embryo. l. The medial end of eachtubule enlargesto form a Bowman capsuleinto which a tuft of capillaries, or glomerulus, invaginates. 2. The lateral end of each tubule opens into the mesonephric (Wolffian) duct, an intermediate mesodermderivative. 3. Mesonephrictubules function temporarily and degenerateby the beginning of the third month. The mesonephricduct persistsin the male as the ductus epididymis, ductus deferens,and the ejaculatoryduct.

Bridgeto Reproductive derivatives Themesonephric inthe in detail arediscussed Embryology Reproductive of Organ Systems chapter (Volume lV). Book2

C. Metanephros. During the fifth week,the metanephros,or permanent kidney, developsfrom two sources:the ureteric bud, a diverticulum of the mesonephric duct, and the metanephric mass,from intermediatemesodermof the lumbar and sacralregions.

227

Rena/UrinarySystem

Stomach Midgut Cecum

Allantois Cloaca

Pronephros

Urogenital sinus Mesonephros

Metanephrogenic mass

Hindsut ffi3,|tr,' Figure lll-1-1.pronephros, mesonephros,and metanephros. l' The uretericbud penetratesthe metanephricmass,which condensesaround the diverticulum to form the metanephrogenic cap. The bud dilates to form the renal pelvis, which subsequentlysplits into the cranial and caudalmajor calyces.Each majo, .Jp buds into the metanephric tissueto form the minor calyces.One to three million collecting tubules develop from the minor calyces,thus forming the renal pyramids. 2' Penetrationof collectingtubulesinto the metanephricmassinducescellsof the tissuecap to form nephrons, or excretory units. a. The proximal nephron forms Bowman capsule, whereasthe distal nephron connects to a collectingtubule. b. Lengthening of the excretory tubule gives rise to the proximal convoluted tubule, loop of Henle, and the distal convoluted tubule. 3. The kidneys develop in the pelvis but appear to "ascend" into the abdomen as a result of fetal growth of the lumbar and sacralregions.With their ascent,the ureters elongate, and the kidneys become vascularized by lateral splanchnic arteries, which arise from the abdominal aorta.

ADRENAT GTANDS The adrenal glands lie above the kidneys and are of dual origin. The cortex develops from the mesoderm of the coelomic epithelium, and the medulla is derived from neural crest cells,which migrate to the areaand differentiateto form catecholamine-producingcells.

228

Embryology

BIADDER ANDURETHRA A. Urorectal septum dividesthe cloacainto the anorectalcanal and the urogenital sinusby the seventhweek. 1. The upper and largestpart of the urogenital sinusbecomesthe urinary bladder, which is initially continuous with the allantois.As the lumen of the allantoisbecomesobliterated, a fibrous cord, the urachus, connectsthe apex of the bladder to the umbilicus. In the adult, this structure becomesthe median umbilical ligament. 2. The mucosaof the trigone of the bladder is formed by the incorporation of the caudal mesonephric ducts into the dorsal bladder wall. This mesodermal tissue is eventually replacedby endodermal epithelium so that the entire lining of the bladder is of endodermal origin. 3. The smooth muscle of the bladder is derived from splanchnicmesoderm. B. Male urethra is anatomically divided into three portions: prostatic, membranous, and spongy (penile). l.

The prostatic urethra, membranous urethra, and proximal penile urethra developfrom the narrow portion of the urogenital sinus below the urinary bladder.

2. The distal spongy urethra is derived from the ectodermalcellsof the glanspenis. C. Femaleurethra. The upper two thirds developsfrom the mesonephricducts, and the lower portion is derived from the urogenital sinus.

ENITAIABNORMALITIES CONG A. Renal agenesis,failure of one or both kidneysto deveiop,is due to early degenerationof the uretericbud. Agenesisis fairly common in the unilateral form but leadsto deathshortly after birth in the bilateral form. B. Renal cysts are the formation of thin-walled, fluid-filled cystsfrom blind tubules, perhaps arising from improper linkage betweenthe collectingducts and distal convolutedtubules. C. Pelvic and horseshoe kidney. Pelvic kidney is due to a failure of one kidney to ascend. Horseshoekidney is a fusion of both kidneys at their ends and failure of the fusedkidney to ascend. D. Double ureter is due to the early splitting of the uretericbud or the developmentof two separatebuds. E. Extrophy of the bladder is a protrusion of the posterior urinary bladder wall through a weakenedanterior abdominal wall. The defectivewall is causedby deficient mesenchymal invasion of the areaand subsequentpoor closure. F. Patent urachus is a failure of the allantois to be obliterated. It causesurachal fistulas or sinuses.Remnantsof the allantoic stalk may give rise to urachal cysts.In male children with congenital valvular obstruction of the prostatic urethra or in older men with enlarged prostates,a patent urachusmay causedrainageof urine through the umbilicus.

229

RenaVUrinary Histology products Theurinary isthemajorsystem involved in theexcretion of metabolic waste system and a homeostatic balance excess water fromthebody. lt isalsoimportant in maintaining offluidsand Theurinary theurinary bladder, andthe electrolytes. system consists of twokidneys, twoureters, produced is via bladder urethra. Urine bythekidneys andisthentransmittedtheureters to the for Theurethra isthefinalpathway urineto theexterior. Thissystem temporary storage. thatconveys function intheproduction which alsohasanimportant endocrine of reninanderythropoietin, respectively. influence bloodpressure andredbloodcell(RBC) formation,

KIDNEYS A. Overview 1. The kidneys are retroperitoneal organs that remove urea and other waste products from the blood. In addition, they regulatethe chemical composition of plasma and the extracellular fluid of the body. 2. Eachkidney is composedof stroma and parenchyma. a. The stroma consistsof a tough fibrous connectivetissuecapsuleand a delicateinterstitial connective tissue composed of fibroblasts, wandering cells, collagen fibrils, and a hydrated proteogly.un extracellular matrix, which is collectively called the renal interstitium. b. The parenchyma consists of more than one million elaborate uriniferous tubules that representthe functional units of the kidney. 3. The kidney containsa hilum, a cortex, and a medulla. a. The hilum is located medially and servesasthe point of entrance and exit for the renal artery, renal vein, and ureter. (1) The renal pelvis, the expanded upper portion of the ureter, divides into two or three majorcalyces upon entranceinto the kidney.These,in turn, divide into eight minor calyces(FigureIII-2-1).

2rl

RenafUrinary System

Cortex

Me d u l l a

Minorcalyx

Renal pyramid

Majorcalyx H i l um

Renal c o l u mn (of Beftin)

Renal pelvis

Figure lll-2-1.Organizationof the kidney. (2) Branchesof the renal artery,vein, and nerve supply eachpart of the kidney. b. The cortex forms the outer zone of the kidney, aswell asseveralrenal columns, which penetratethe entire depth of the kidney (seeFigureIII-2-1). c. The medulla appearsas a seriesof medullary pyramids. The tips of the pyramids point toward the renal pelvislocatedat the hilus. The apexof eachpyramid directsthe urinary streaminto a minor calyx.TWoor three pyramids may unite to form a papilla. d. A renal lobe is defined as a medullary pyramid surrounded by its associatedcortex. 4. Uriniferous tubules consistof two functionally relatedportions calledthe nephron and the collecting tubule. B. Nephron consistsof a renal corpuscle,proximal convoluted tubule,loop of Henle, and distal convoluted tubule. The renal corpuscleconsistsof a tuft of capiliaries,the glomerulus, surrounded by a double-walledepithelial capsulecalledBowman capsule. 1. Glomerulus is madeup of severalanastomoticcapillaryloops interposedbetweenan afferent and an efferentarteriole.The endothelium of the glomerulusis thin and fenestrated. Plasma filtration (ultrafiltration) occursin the glomerulus. 2. Bowman capsule (Figure ll[-2-2) consistsof an inner viscerallayer and an outer parietal layer. The spacebetween these layers,the urinary space,is continuous with the renal tubule. a. Visceral layer is apposedto the glomerulus and closelyfollows the branchesof the glomerular capillaries.The viscerallayer is composedof a singlelayerof epithelialcells resting on a basal lamina, which is fused with the basal lamina of the capillary endothelium.

2t2

Histology

Afferent arteriole Efferent arteriole Viscerallayer (Podocytes) Area of detail

Parietal layer

Urinary space Fenestrated Basal lamina

Figure lll-2-2. Bowman capsule diagram.

(l)

The cells of the visceral layer, called podocytes, are elaborate and their nuclei bulge into the capsularspace.

(2) Cytoplasmicextensionsof podocytes,called pedicles, rest on the basal lamina. The pediclesof adjacentpodocytesinterdigitate along the basallamina. (3) Betweenadjacentpedicles,a thin slit diaphragm assistsin preventinglarge plasma proteins from escapingfrom the vascularsystem. b. Parietal layer is composedof a simple squamousepithelium that is continuous with the proximal convoluted tubule epithelial lining. 3. Proximal convoluted tubule is the longest and most convoluted segmentof the nephron. a. It is lined by a singlelayer of cuboidal to low columnar cellswith rounded nuclei and eosinophilicgranular cytoplasm.

ClinicalCorrelate processes Insomedisease (i.e.,diabetes mellitus, glomerulonephritis), the glomerulus becomes more permeable to proteins, leading to theappearance of protein intheurine(proteinuria).

b. Cell boundaries interdigitate with those of adjacent cells laterally and basally.

ztt

Rena/Urinary System

Note Nephrons nearthe junction corticomedullary are juxtomedullory called nephrons. These nephrons haveverylongHenle loops; therefore, theyarecritically important in establishing the gradient hypertonic inthe medullary interstitium.

c. The proximal convoluted tubule also possesses an apical brush border that provides the cell with a much greatersurfaceareafor reabsorptionfrom, and secretioninto, the fluid that becomesurine in the kidney tubules.In fact, most of the componentsof the glomerular filtrate are reabsorbedin the proximal tubule. 4. Loop of Henle is a hairpin-like loop of the nephron that extendsinto the medulla and consistsof thick and thin segments. a. The thick proximal portion of Henle's loop, or the descending thick segment, is a direct medullary continuation of the cortical proximal convolutedtubule. b. The descendingand ascendingthin segmentsof the loop of Henle are lined by a single layer of flat, squamous epithelial cells with nuclei that bulge into the lumen. c. The thick distal portion of the loop of Henle, the ascendingthick segment,ascendsto the cortex and is continuous with the distal convolutedtubule. It is lined by cuboidal cellsthat contain numerous invaginationsof cytoplasmand many mitochondria. 5. Distal convoluted tubule is lined by cuboidal cells that contain a granular cytoplasm. a. Cells of the distal convoluted tubule near the afferent arteriole are taller and more slenderthan elsewherein the distal tubule. They constitute the macula densa. (l ) Their nuclei are packed closely,so the region appearsdarker under the light microscope. (2) The macula densais thought to sensesodium concentrationin the tubular fluid. b. The major function of the distal tubule is to reabsorb sodium and chloride from the tubular filtrate.

Bridgeto Physiology In response to vasopressin (ADH)secreted bythe neurohypophysis, ng collecti permeable tubules become to waterand,thus,areimportant inthekidney's roleinwater conservation andurine concentration.

C. Collecting tubules consistof archedand straight segments. l. The arched collecting tubule segments,which arevariably present,arelocatedin the cortical labyrinths and empty into the straight collecting tubule segments,which pass through the medullary rays. 2. Epithelial cellsof the collectingducts range from cuboidal to columnar. 3. Identification of thesetubules is facilitatedby their distinct intercellularborders asa result of the lack of complex interdigitations seenin the proximal and distal tubules. D. Vascular supply beginswith the renal artery, entersthe kidney at the hilum, and immediately divides into interlobar arteries. These arteries supply the pelvis and capsulebefore passing directly betweenthe medullary pyramids to the corticomedullary junction. 1. The interlobar arteriesbend almost 90 degreesto form short, arching, arcuate arteries, which run along the corticomedullary junction. 2. The arcuatearteriessubdivideinto numerousfine interlobulararteries, which ascendperpendicularly to the arcuatearteriesthrough the cortical labyrinths to the surfaceof the kidney. Each interlobular artery passes approximately midway between two adjacent medullary rays.The location of interlobular arteriesrepresentsthe virtual boundariesof renal lobules. 3. The interlobular arteriesthen give off branchesthat becomethe afferent arterioles of the glomeruli. 4. As the afferent arteriole approachesthe glomerulus, some of its smooth muscle cellsare replacedby myoepithelioid cells,which are part of the juxtaglomerular apparatus.

214

Histology

5. The juxtaglomerular apparatusconsistsof juxtaglomerular cells,polkissencells,and the macula densa (Figure lll-2-3). a. The juxtaglomerular cells secretean enzyme called renin, which enters the bloodstream and converts the circulating polypeptide angiotensinogen into angiotensin I. Under the action of convertingenzyme,angiotensinI is convertedto angiotensinII, a potent vasoconstrictorthat stimulatesaldosteronesecretionfrom the adrenal cortex. Aldosterone increasessodium and water reabsorption in the distal portion of the nephron. b. Polkissen cells are located between the afferent and efferent arterioles at the vascular pole of the glomerulus,adjacentto the macula densa.Their function is unknown.

Proximal tubule 0

Efferent arterioles

1' o

G lo me ru l a r epi th e l i u m

Basementmembrane of Bowmancapsule Epitheliumof Bowmancapsule

Poikissencell Juxtaglomerular cells (Secrele rp-v.rln < i6-3s'aof€s Con1.r(aSiOr 4 *.qie (o^l?rF{ +d ,e-qU[^s;' I

Efferent arteriole

Afferent arteriole

gY[" A.qiolcn3in 11 1 g.t0,r.t faSO cay.S{r.) 1

Distal tubule

Renal artery J Interlobar arteries J Arcuate arteries J Interlobular arteries J Afferent arterioles J Clomerular capillaries

J

; Glomerular basement membrane

ln a Nubhell

Macula densa

In a Nutshell JCA(uxtaglomerular apparatus) consists of: . Juxtaglomerular cellsin (some afferent arteriole alsoin efferent arteriole) . Macula densa . Polkissen cells Juxtaglomerular cells secrete renin.

@ ntdos\Qrt*tL sgc t

v^ k w&,c-
Figure lll-2-3.Renal corpuscle and juxtaglomerular apparatus.

6. Efferent glomerular arteriole divides into a secondsystemof capillaries,the peritubular plexus, which forms a densenetwork of blood vesselsaround the tubules of the cortex. 7. Arterial supply of the medulla is provided by the efferentarteriolesof the glomeruli near the medulla. a. The arteriolae rectaeand the correspondingvenaerectaewith their respectivecapillary networks comprisethe vasarecta,which suppliesthe medulla. b. The endothelium of the venaerectaeis fenestratedand playsan important role in maintaining the osmotic gradient required for concentratingurine in the kidney tubules.

2t5

Rena/Urinary System

URETERS The calyces,renal pelves,and ureters constitute the main excretory ducts of the kidneys. The walls of these structures, in particular of the renal pelvis and ureter, consist of three coats: an inner mucosa,a middle muscularis,and an outer adventitia. A. Mucosa of the calycesand ureter is lined by a transitional epithelium,which varies in thicknesswith the distention of the ureter. In the collapsedstate,the cells are cuboidal with larger dome-shapedcellsin the superficiallayer.In the relaxedstate,the lumen of the ureter is thrown into folds that generallydisappearwhen the organ dilatesduring urine transport. B. Muscularis consistsof an inner longitudinal and an outer circular layer of smooth muscle. In the distal ureter,an additional discontinuousouter longitudinal layer is present. C. Adventitia consistsof loose connectivetissuewith many large blood vessels.It blends with the connectivetissueof the surrounding structuresand anchorsthe ureter to the renal pelvis.

URINARY BTADDER The urinarybladder functions asa storageorgan for urine. The structure of the wall of the bladder is similar to but thicker than that of the ureter.

Note plasma Thesurface membranes of bladder epithelial cellsarespecialized to prevent watermovement fromtheinter$itial compartmen| thisprevents dilution oftheconcentrated (hypertonic) urine.

A. Mucosa of the urinary bladder is usually folded, dependingupon the degreeof the bladder distention. 1. The epithelium is transitional and the number of apparent cell layers depends on the fullness of the bladder. a. As the organ becomes distended, the superficial epithelial layer and the mucosa becomeflattened,and the entire epithelium becomesthinner. b. At its fullest distention, the bladder epithelium may be only two or three cells thick. 2. Lamina propria consistsof connectivetissuewith abundant elasticfibers. B. Muscularis consistsof prominent and thick bundles of smooth musclethat are looselyorganized into three layers. C. Adventitia coversthe bladder except on its superior part, where a serosa is present.

URETHRA A. Male urethra servesas an excretory duct for both urine and semen. It is approximately 20 cm in length and has three anatomic divisions. 1. The prostatic portion is lined by transitional epithelium similar to that of the bladder. The prostatic urethra is surrounded by the fibromuscular tissue of the prostate,which normally keepsthe urethral lumen closed. 2. ln the membranous and penile portions, the epithelium is pseudostratified up to the glans.At this point, it becomesstratified squamous and is continuous with the epidermis of the externalpart of the penis. a. The membranousurethra is encircledby a sphincterof skeletalmusclefibers from the deep transverseperineal muscle of the urogenital diaphragm, which also keepsthe urethral lumen closed. b. The wall of the penile urethra containslittle musclebut is surrounded and supported by the cylindrical erectilemassof corpus spongiosumtissue.

216

Histology

B. Fernaleuethra is considerablyshorterthan that of the maleurethra.

,

9,!9jgl !qj!r!*

1. It s€rvesas the terminal urinary passage,conducting urine ftom the bladder to fte vestib'le of the v'lva'

, Theshorterfemaleurethra leadsto a greaterincidence of 2. The epitheliumbeginsat the bladderasa transitionalvarietyandbecomesstratifiedsquaurinarytractinfecttons in mouswit}r sma.llareasof a pseudostatifiedcolumnarepithelium. womentnanmen. 3. The muscularis is rather indefinite but does contain both circular and longitudinal smooth musclefibers. through the 4. A urethralsphincteris formed by skeletalmuscleasthe femaleurethrapasses urogenitaldiaphragm.

2r7

Anatomy RenaVUrinary andurethra. involved intheurinary system include thekidneys, urinary bladder, Theorgans ureters, venous drainage, reviews theirgross including arterial supply, andlymphatic Thischapter anatomy, andinnervation.

KIDNEYS A. The kidneys area pair ofbean-shapedorgansapprodmately12cm long. They extendfrom vertebrallevel Tl2 to L3 when the body is in the erectposition. The right kidney is positioned slightly lower than the left becauseof the massof the liver. 1 Int€rnal sructure. Within the denseconnectivetissueof the renalcapsule,the kidneysubstanceis divided into an outer cortexand an inner medulla(FigureIII-2-1 ftom previous chapter). a. Cortex containsglorneruli, Bowrnancapsules,and proximal and distal convoluted tubules.It forms renal columns,which extendbetweenmedullarypyramids. b. Medulla consistsof 10-18striatedpyramidsand containscollectingducts and loops of Henle.The apexof eachpyramid endsasa papilla wherecollectingductsopen. c. Calyces.The minor calycesreceiveone or more papillae and unite to form major calyces,of which there aretwo to threeper kidney. d. Renalpelvis is the dilat€d upper portion ofthe ureterthat receivest]le major calyces. 2. Arterial supply. The pairedrenal arteries arebranchesof the abdominalaorta. a. Int€rlobar arteries travel in renalcolumnsin the cortical areasb€tweenpyramids. b. Arcuate arteries run parallelto basesof pl,ramids. c. Interlobular arteries arebranchesof arcuat€arteries. d. Afferent arterioles leadto capillarytufts of glomeruli.

Notc are"end Therenalarteries i.e., arteriet" thereis insufficient collateral flowto mainhinperfusion intheose of occlusion.

3. Venousdrainagefollows the samepattern asthe art€ries. a. The right renalvein entersthe infelior v€nacaya. b. The left renal vein receivesthe left gonadalvein, the left suprarenalvein, and the left inferior phrenic vein, and may contiibute a root of the hemiazygosvein beforecrossing ante;ior to the aortato join the inferiot venacava.

Eridge to Histology Referto histology to continue themicroscopic bloodsupply of tirekidner/s.

4. Lymphatic drainage.The kidneysdrain to the lumbar nodes.

2t9

RenafUrinary System

5. Innervation is primarily sympathetic with postganglionic cell bodies located in the renal plexus. a. Preganglionic sympathetic fibers are from thoracic splanchnic nerves. b. Pain afferentsfrom the renal pelvis travel in thoracic splanchnic nerves.

ClinicalCor_eLale

URETERS

Themo$common sites of constriction susceptible ureteral to blockage byrenalcalculi:

A. Ureters are fibromuscular tubes that connect the kidneys to the urinarybladder in the pelvis. They run posterior to the ductus deferensin males and posterior (inferior) to the uterine arteries in females.

. Where therenalpelvis foins theureter

B. Theybegin as continuations of the renal pelvesand run retroperitoneally, crossingthe common iliac arteries as they passover the pelvic brim.

. Where theuretercrosses thepelvicinlet

URINARY BTADDER

. Where theureterenters the walloftheurinary bladder

A. Structure 1. The urinary bladder is covered superiorly by peritoneum and is located infraretroperitoneally. 2. The body is a hollow muscular cavrty. 3. The neck is continuous with the urethra. 4. The trigone is a smooth triangular iuea of mucosa located internally at the base of the bladder. The base of the triangle is superior and bounded by the two openings of the ureters. The apex of the trigone points inferiorly and is the opening for the urethra. B. Blood supply 1. The bladder is supplied by vesicular branches of the internal iliac arteries. 2. The vesicular venous plexus drains to internal iliac veins. C. Lymphatics drain to the external and internal iliac nodes. D. Innervation 1. Parasympathetic innervation is from sacral segments 2, 3, and 4. The preganglionic parasympathetic fibers travel in pelvic splanchnic nerves to reach the detrusor muscle. 2. Sympathetic innervation is through preganglionic fibers, which are derived from Tl l through L2. Most of these fibers synapsein the vesicular plexus.

URETHRA A. Male urethra is a muscular tube approximately20 cm in length. The urethra in men extends from the neck of the bladder through the prostate gland (prostatic urethra), through the urogenital diaphragm of the perineum (membranous urethra), and then to the external opening of the glans (penile or spongyurethra). B. Female urethra is approximately 4 cm in length and extendsfrom the neck of the bladder to the external urethral orifice of the vulva.

240

RenalUrinaryPhysiology andthe isthefiltration of plasma theglomerulus Theprimary action ofthekidney through Basic renalfunctions through theepithelial cellsofthenephron. reabsorption of select substances of solutes, bodyfluidvolumes andtheirconcentrations include theregulation ofthevarious produG pH pressure, of end of metabolism. blood as well as the excretion regulation of body and regulation of body intheexcretion ofwa$eproducts, Thischapter willdiscuss theroleofthekidney of bodyfluid fromthefiltrate, hormonal function, regulation recovery of substances composition, volume, andregulation of bloodpressure.

BODYFLUIDCOMPARTMENTS A. Total body water (TBW). In a lean man, TBW constitutes approximately 600/oof the total body weight. Two thirds of the TBW is intracellular fluid (ICF), and one third is extracellular fluid (ECF). ECF is composed of approximately 75o/ointerstitial fluid and 25o/oplasma. The more adiposetissue,the lower the percentageof body weight that is TBW. 1. The actual amounts of body water vary widely becauseadipose (fat) tissuehas a much lower water content than other cells of the body. 2. Quantitative determination of TBW is achievedby measuringthe volume of distribution of tritiated water ('HrO), deuteratedwater ('HrO), or antipyrine. B. Extracellular fluid (ECF) has a high sodium chloride (NaCl) content and low potassium (K+) and protein contents. It consistsof interstitial fluid, plasma,and transcellularwater or fluid. Total ECF is determined by measuring the volume of distribution of solutes (e.g., inulin, mannitol, rs5gn2-; that move freely acrosscapillary walls but do not permeatecell membranes. 1. Interstitial fluid (ISF) a. Osmolarity of ISF is the sameas ICF fluid, that is, 290 mOsm/kg water. b. Concentrations of potassium ion (K*), protein, and organic phosphate in ICF are high and NaCl is low as comparedto their concentrationsin ISF. 2. Plasma and blood plasma a. Plasmavolume is determined by measuring the volume of distribution of radioactively labeled serum albumin or of Evansblue dye (which binds to albumin).

In a Nutshell H20(IBW) Totalbody

./\ /\ zlzw

rir tcr

/\ /\ t/+Plasma sf+sr (=t/qrgw) (=t/tztsvu)

In a Nutshell Volume Measurements . TBWvia,H,0orantipyrine . ECF viamannitol orinulin . Plasma vialabeled albumin or Evans blue Ineachcase, iniected amountof sub$ance r,^r. _vortrrE=@

b. The osmolarity of plasmais slightly higher than that of ISF becauseof the presenceof plasmaproteins,which constitute approximately60/oof the plasmavolume. c. The percentageof blood volume occupiedby cells,or the hematocrit, is approximately 45o/o.The male hematocrit is typically slightly higher than the female hematocrit.

241

RenafUrinary System

3. Transcellularfluid is a miscellaneouscollection of spacesthat are separatedfrom ECF by alayer of epithelial cells. a. It includes ocular fluid, cerebrospinalfluid, aqueoushumor, synovial fluid, gastrointestinal secretions,and urine in the bladder. b. Composition of thesefluids varies as determinedby epithelial pumps. C. Water and solute distribution between ICF and ECF 1. Water distribution is determined by the content of osmotically active substances,especially ions, sincewater diffrrsesfreely along its concentrationgradient. 2. Solute distribution dependsupon the diffi.rsibility of the substanceacrossthe cell membranes,i.e.,small free ions will move more easilythan ions bound to plasmaproteins that cannot easilycrossthe cell membrane.

FTUIDREGUTATION ANDEDEMA A. Addition or removal of various fluids. The cell membrane is freely permeable to water; therefore, after equilibration, intracellular osmolality alwaysequals interstitial osmolality. 1. Water.When water is absorbedinto the blood, the osmolarity of ECF is reduced,and ECF becomeshypotonic with respectto ICF.Water diffusesinto the cellsdown its osmotic gradient until intracellular osmolarity is reducedto that of ECF. 2. NaCl solutions. NaCl is confined largely to the extracellular compartment becauseof the action of the Na+-K+ pump and the resting membrane potential of cells. Sudden high-salt intake increasesthe osmolarity of the extracellularcompartment without having much immediate effect on cell contents. Increasedextracellular osmolarity causes water to leavecells,reducing intracellular volume, increasingintracellular osmolarity, and resulting in increasedintra- and extracellular osmolarity by transferring water from inside to outside of cells. a. Isotonic NaCl given intravenously remains almost entirely extracellular. It will therefore effect no changeon the osmolarity of ECF and will causeno net movement of water acrossthe cells.Isotonic NaCl, therefore,causesan increasein overall ECF volume by the exactamount that was introduced. b. Hypertonic NaCl acts like a combination of isotonic NaCl and solid NaCl. There is some isotonic expansion of extracellularvolume and some increasein extracellular osmolality with the resultant extraction of ICF. c. Hypotonic NaCl acts like a combination of isotonic NaCl and pure water. There is some isotonic increasein extracellularvolume and proportional increasesin intracellular and extracellularvolumes with associatedreductions in intracellular and extracellular osmolalities. 3. Mannitol stays in the extracelluiar compartment and, therefore, acts like NaCl. Hypertonic solutions of mannitol are used in patientswith cerebral edema as a result of trauma or hemorrhage.A bolus of hypertonic mannitol is used to drive water from the brain into the blood vesselsto mitigate swelling of the brain. 4. Protein solutions given intravenouslystay in the vascularcompartment. High concentrations can induce removal of fluid from interstitial spaceinto plasma. B. Edema is defined as an overexpansionof the interstitial fluid volume. Normally, the volume and pressureof the blood is monitored in part by the juxtaglomerular apparatusof the kidney, and NaCl and water are excreted or retained by the kidney to regulate blood volume.

242

Physiology

This volume ratio depends on the exchangeof fluid acrossthe capillary endothelium of all tissues(in addition to the kidney nephrons). In edema,fluid leavesthe vascularbed and enters the interstitial space,resulting in a reduction in plasma volume and a related fall in blood pressure.This causesthe kidney to retain salt and water,much of which accumulates in the interstitium.

Note Wherever Na*goes, H,Ofollows.

1. Development of edema occurs in two stages: a. Redistribution of fluid from the vascularto the interstitial compartment b. Retention of salt and water by the kidney 2. Distribution of edema is governed by local tissue tension and the force of gravity. a. Local tissuetension is lowest around the eyes(periorbital) and in the ankle (particularly the medial surface) and these are the most common sites for edema.Massive retention of water will causeother tissuesto swell (genitalia,hands,legs,face)and may also causean accumulation in the pericardial,pleural, or peritoneal spaces. b. Interstitial fluid is not confined by epithelia and slowly moves between cells under the influence of gravity. Lying down will therefore cause fluid to move superiorly and standing up will causefluid to move inferiorly. 3. Causesof edema a. The exchangeof fluid acrossthe capillary endothelium is representedby the equation: Fluid movement= K6[(Pg+ &) - (Pt + ruc)] where K6is the permeability constantof the capillary,P. and Pi are capillary and interstitial hydrostatic pressures,respectively,and n. and fii are the protein osmotic (or oncotic) pressuresof capillary and interstitial fluid, respectively.

ln a Nubhell lnterstitium fr,

Pc

( 1) Movement is controlled by the forcespromoting efflux from the capillary (P. and n1),and the forcesfavoring return of fluid to the capillary (P1and n.). (2) Fluid not reabsorbedinto the venous system returns via the lymph system. Therefore,the net volume leavingthe capillary bed, 2 to 3lld, is equal to the rate of lymph flow. b. Capillary blood pressure(P.) is more affectedby increasesin venouspressurethan by changesin arterial pressurebecausethe capillary is somewhatprotectedfrom fluctuations in arterial pressureby arteriolesand precapillarysphincters,which respond to increasesin blood pressureby constriction.This is why patientswith hypertensionbut without heart failure do not commonly exhibit edema. c. Generalizededema is causedby a drop in plasmaoncotic pressure(n.), whereasfactors that influence interstitial oncotic pressure(rci), such as inflammation, tend to causelocalizededema.

rt. P. 'l

Figure lll-4-1.

In a Nubhell Edema isusually by: caused

d. Congestive heart failure. Retention of NaCl and water by the kidney is secondaryto reduced cardiac output and systemicblood pressureproduced by left heart failure. Excesssalt and water expand the vascular volume, preferentially on the venous side becauseit is the most compliant part of the system,increasingthe capillary hydrostatic pressure.Periorbital edema is rarely seenin patients with heart failure becausethey are orthopneic (difficulty breathing when lytt g down) and usually sleep on two or more pillows, draining edema awayfrom the face and eyes.

. 1 P,(more out) seeps . J 7r,(less reabsorbed)

e. Glomerulonephritis. In contrast to congestiveheart failure, where retention of NaCl and water is secondaryto the reduction in blood pressure,glomerulonephritis causes primary salt and water retention as a result of damage to the kidney. A reduced

. Anycombination ofabove

. t permeability . Blockage oflymphatic drainage

24t

Rena/Urinary System

Note CHF+tP. Because theheartisnotable to pumpasefficiently (maintain cardiac output), getsbacked up. everything heartactsasa Theinefficient venous and dam.Thus, pressures hydrostatic capillary increase. Inaddition, perfusion inadequate kidney leads to saltandwater (t renin+ 1 retention -+ 1 angiotensin aldosterone), which theproblem by exacerbates P,. further increasing Note Glomerulonephritis + 1 P. for1 P, Herethemechanism isviatheinability ofthe kidney to excrete damaged to t waterandsalt,leading t vascular volume + capillary pressure. hydrostatic Note Nephrotic Syndrome . Edema . Proteinuria . Hypoalbuminemia . Hyperlipidemia . Thelossof protein (albumin) leads thevascular is to .! n,.Thus, space unable to holdonto itswater.

glomerular filtration rate (GFR) is partially responsiblefor NaCl and water retention. The salt and water retained expand the vascular space, resulting in the following effects: (1) Increasedvenous return from the expandedvolume causesincreasedend diastolic volume (EDV). The increasedEDV stretchesthe ventricular musclein diastole, causing increasedforce of contraction in systole.The resultant increased cardiac output causes increased blood pressure (i.e., hypertension), which inhibits renal renin release. (2) Increasedblood volume predominantly accumulateson the venous side of the circulation, where distensibility is greatest (high compliance). The resultant increasedpressureraisesthe pressurein the capillaries,increasingtheir P.,leading to transudation of fluid into the interstitium, and causing edema. The increasedvenous pressurestimulates the releaseof atrial natriuretic factors from the atria of the heart. The atrial natriuretic factors act on the collecting duct to inhibit sodium reabsorptionand promote diuresis. f. Liver diseaseresults in the reduction of plasma volume causing either an accumulation of fluid in the peritoneal cavity (ascites)or generalizededema.The reduction of plasma volume frequently leadsto the retention of volume by the kidney via filtration or enhancedreabsorption,thereby exacerbatingthe edema. (1) Cirrhosis of the liver is often a product of chronic alcohol abuse,in which the liver developsfibrosis or mechanicalvenous obstruction, raising pressurein the liver acini and causingascites(transudate). (2) Other liver disease.Liver damage may reduce production of plasma protein such as albumin. The resulting hypoalbuminemia lowers plasma oncotic pressure (rc.), allowing fluid to leak out of the capillaries,leading to generalized edema. g. Nephrotic syndrome is the loss in the urine of >3.5 g protein/day,which is the maximum rate at which the liver can synthesizeplasmaprotein in the adult. Plasmaprotein falls, lowering plasma oncotic pressure (ru.) and causing generalizededema. Significant edemadevelopsonly after substantialchangein plasma oncotic pressure. The reduced plasma oncotic pressure(n.) allows fluid to leak into the interstitium, lowering plasmavolume, and resulting in secondarysalt and water retention. h. Burns and inflammation. Burns act directly on capillary walls by increasingtheir permeability.Edemais localizedto the areaof the damagebecauseof locally increasedtissue oncotic pressureni. Tissuedamageinitiates the inflammatory response,resulting in the releaseof histamine.

NephriticSyndrome . Hematuria

(1) Histamine increasescapillary wall permeability,allowing plasmaprotein to leak into the interstitial space,and raising tissueoncotic pressure(n1).

. Hypertension . Oliguria

(2) Histamine causesvasodilatation,increasingthe blood flow and capillary hydrostaticpressure(P.).

. fuotemia . Edema Notethattheedema of (nephriti$ glomerulonephritis is plasma withexpanded associated volume the 1T P,), whereas nephrotic edema isassociated with (J r. ) with hypoalbuminemia secondary hypovolemia(JP. ).

244

i. tymphatic obstructive edema (1) Filariasisis causedby a filarial worm, Wuchereriabancrofti,which invadesand blocks ly-ph channels,causingdramatic accumulationsof local edemaknown as elephantiasis. (2) Malignancy often leadsto tumors metastasizingto ly-ph nodes,blocking lymph flow and causinglocal edema.Surgeryto removetumors (e.g.,radical mastectomy) may include removal of lymph nodes, resulting in reduced ly-ph flow and local edema.

Physiology

4. Body fluid disturbances in either ECF or ICF result in the retention of excessbody fluid, ultimately involving the kidney. a. ECF abnormalities. Edema (increasedECF volume) occurswith cardiovascular,kidney, or liver disturbances.It producesa distortion of tissue structure with increased diffusion from capillariesto cells. b. ICF abnormalities may result from abnormally elevatedpermeabilitiesof cell membranes or from decreasedactivity of Na+ pumps, leading to cellular swelling. They produce changesin cell solute concentrations,disturbed enzyme reactions,and distorted cell shape. c. Short-term weight changes usually reflect changesin body fluids rather than true changesin muscle or fat mass.

Note Burns permeability t capillary + t leakage protein ofplasma into interstitium + J n, andt n,. ClinicalCorrelate Weight loss/gain in patients withrenal disease isthebest wayto monitor fluiddiuresis/retention.

Thble III-4-1. Causesof edema. Diseaseor Condition

Physiologic Effects

Congestiveheart failure Glomerulonephritis (primary sodium ion [Na+] retention) Cirrhosis of the liver (ascites)

Increasedcapillary hydrostatic pressure(P.)

Liver disease(hypoalbuminemia) Nephrotic syndrome

Decreased plasmaoncotic pressure(rc.)

Burns Inflammation

Increasedcapillary permeability followed by increasedinterstitial oncotic pressure(ni)

Filariasis Malignancy

Lymphatic obstruction (blockageof lymph flow)

KIDNEY A. The nephron (Figure III-4-2) is the functionai unit of the kidney (approximately1.5million per kidney). It consistsof a vascularfilter (the glomerulus) and Bowman capsule,leading to a long tubule composedof a singlelayer of specializedepithelial cells. 1. Typesofnephrons a. Cortical nephrons, located just under the capsulein the outer region of the cortex, haveshort loops of Henle. b. Juxtamedullarynephrons arelocateddeepin the cortex at the corticomedullaryjunction and account for l5o/oof all nephrons.Their long loops of Henle dip deeply into the medullary zoneand papillary portions of the kidney. 2. Nephron components include the glomerulus, proximal convoluted tubule, straight proximal tubule, thin descendinglimb of Henle, thin ascendinglimb of Henle, thick ascendinglimb of Henle,specializedmacula densa,and distal convolutedtubule. Multiple distal tubules fuse and empty into each collecting duct. The juxtamedullary nephrons, as well as the cortical nephrons, have a capillary bed associatedwith their convoluted portions.

ln a Nutshell Thenephron consists of: . Clomerulus Bowman capsule Proximal convoluted tubule Loopof Henle Distal convoluted tubule Collecting duct

245

Rena/Urinary Systean

Bowman capsule

Afferent arteriole

Glomerulus Distal tubule

Collecting duct Efferent arteriole

II

pcr^fnf\

t-.cdulla-

+ Minor Calyx

Figure lll-4-2. Nephron diagram.

B. Urine formation begins with the formation of an ultrafiltrate of plasma from the glomerular capillaries located in Bowman's capsule.The ultrafiltrate moves down the tubule, is subjected to reabsorption and secretion,and finally enters the pelvis of the kidney as urine. 1. Reabsorption involves the transport of solute (or water) from the tubular lumen to the peritubular capillary. 2. Secretion involves the transport of solute from the peritubular capillaries into the tubular lumen.

246

Physiology

ANDGLOMERULAR FITTRATION GTOMERUTUS The ultrafiltrate moves from the glomerular capillary lumen to Bowman's space,which leads directly to the proximal convoluted tubule at the urinary pole of the renal corpuscle. A. Ultrastructure of glomerular capillary

Note

1. The endothelium has numerous pores or fenestrations that are small enough to restrict the passageof cells.The large endothelial nuclei bulge into the capillary lumen. 2. The basement membrane consistsof a nonporous gel with fibrous elementsthat permit the free passageof small molecules through the aqueous phase while trapping colloids and proteins. It may act as the filtration barrier of the nephron.

lfthere isdamage tothis plasma protein endothelium, willleakthrough + proteinuria.

3. Podocytes are specializedepithelial cells that lay down and maintain the basementmembrane and scavengeproteins that slip by the filtration barrier. a. They contact glomerular capillaries via pedicels, which are interdigitating foot processesthat rest on the outer layer of the basementmembrane. b. Spacesbetween the pedicels are slit pores, or filtration pores, which may restrict filtration of protein while permitting water and solutesto pass. B. Glomerular filtration. Approximately 25o/oof the resting cardiac output passesthrough the kidney. The glomerular filtrate consists of a protein-free filtrate of plasma and represents approximately 20o/oof renal plasma flow (Tablelll-4-2). Thble lll-4-2.

Glomerular filtration.

Resting cardiac output Renal blood flow Renal plasma flow Glomerular filtration

5000mVmin 1200ml/min 650ml/min 125ml/min

(72ooud) (1728ud) (e36ud) (l8oud)

1. Forces of glomerular filtration. Starling forces regulatethe distribution of fluid between any capillary and its adjacent interstitial fluid. They also apply at the glomerular filtration barrier. The net filtration pressureis: (P.-Pi) -(n.-rri),

Note TotalCFR= suffiof filtration rates in allofthefunctional nephrons. lt serves asan index renal of overall function.

where P. is the glomerular capillary hydrostatic pressure(approximately 45 mm Hg); P, is the Bowman capsule hydrostatic pressure (approximately 10 mm Hg); n. is the protein osmotic pressureof plasma (approxim ately28 mm Hg, but increasingalong the capillary) ; and n1is the protein osmotic pressureof tubular fluid (negligible amount). Net filtration pressureis therefore(45 - 10) - (28 - 0) = 7 mm Hg. The glomerular capillariesare short with a large radius so there is only a small drop in blood pressureas fluid flows through. As the protein-free filtrate of plasmapassesinto the nephron, the protein osmotic pressure of the plasma left behind increasesrapidly; equilibrium is achievedsomewherealong the capillary. 2. Permeability of glomerular capillaries is determined by the size and number of the pores. a. Everything up to a molecular weight of 5,000 daltons passesfreely through fenestrations; permeability falls as molecular size increases.Solutes with a molecular weight greater than 70,000 daltons will not passthrough the pores.

247

Rena/Urinary System

b. This selectivity is similar to that of muscle capillaries,but the number of pores is about a 100-fold greater, hence permeability is much higher. Some small molecules are bound to plasmaprotein and do not crossthe glomerular filtration barrier (e.g.,fatty of plasmaCa2*). acids,thyroid hormone, sexhormones, approximately 50o/o 3. Renal handling of freely filtered substances

Note product of Ureaisawaste (thus metabolism nitrogen protein lts degradation). is: structure 0

ll H,N-C-NH,

a. Urea is freely filtered at the glomerulus; approximately half of this filtered load is passivelyreabsorbedin the proximal tubule. The rest of the nephron is relatively impermeable to urea except for the deepestpart of the collecting duct, whose urea permeability is increasedwhen antidiuretic hormone (ADH) is present.The amount of urea excretedrangesfrom approximately 670/oof the filtered load in a person who is drinking a large volume of water, down to approximately 25o/oin a dehydratedperson. b. Creatinine is the hydrated and excretedform of creatine, a product of the hydrolysis of creatine phosphate. Creatinine is produced at a relatively constant rate by muscle. Freely filtered at the glomerulus, it is not reabsorbed, and a very small amount is secretedinto the nephron. Creatinine excretion, therefore, exceedscreatinine filtration by l0-20o/o.Creatinine clearancehowever,estimatesglomerular filtration rate (GFR) fairly accuratelybecausethe error due to secretionis balancedby an overestimation of plasma creatinine inherent in the measurement methodology. GFR can be approximated from creatinine clearanceas follows:

Note ucreatinine x v

Experimentally, CFRis most measured viathe commonly of inulinwhere, clearance uinulin xV -Tinrlin = CFR

ClinicalCorrelate Indiabetes mellitus, the plasma glucose concentration Theresult is exceeds T,". glycosuria. Theclassic signs of mellitus arepolyuria, diabetes polyphagia, glycosuria, and polydipsia.

GFR =

Pcreatinine

whereV= urine flow rate, U = urine, and p = plasma. c. Glucose is freely filtered in the glomerulus and is actively reabsorbed in the proximal tubule by a mechanismthat hasa reabsorptiontransport maximum (T11),(i.e.,the transport of glucoseincreaseswith concentration up to a point and then remains constant with further increasesin concentration).The plasmaconcentration of glucoseis approximately I mg/ml. The amount filtered (or the filtered load) is the GFR (120 mVmin) x I mg/ml, which equals 120 mg/min. Sincethe T- for glucoseis 370 mg/min, glucoseis not normally found in urine. Glucosewill appearin urine in diabetes mellitus, where the increasedplasma glucoseproducesan increasein the filtered load of glucose,exceeding the T- for reabsorption (Figure III-4-3). In renal glycosuria, there is a geneticdefectin the reabsorptivepump, resulting in the excretionof glucose.

."rs$ Glucose reabsorption (mg/min)

370 Plasmaglucoseconcentration(mg/dl)

Figurelll-4-3.Glucosereabsorptionfrom proximaltubule with increasingplasmaconcentrationof glucose.

248

Physiology

d. Amino acids are freely filtered in the glomerulus and are actively reabsorbed in the proximal tubule by T--dependent mechanisms.As with glucose,the filtered load of amino acids is well below their T*, and measurablequantities of amino acids do not appear in the urine unless there is a genetic defect in one or more of the transport mechanisms. 4. Filtration of calcium and phosphate. Calcium (Ca2*) and inorganic phosphate (P1)exist in plasma near their maximum solubility, that is, C*+ x Pi - constant (the solubility constant). Anything that affects plasma Ca2+ concentration will therefore have an opposing effect on plasma Pi. a. C,a2+.The plasmaconcentrationof Ca2+is 8-10 mg/dl, with half of the total bound to negatively charged serum albumin. Most of the filtered Ca2+is actively reabsorbed from all parts of the nephron exceptthe thin limbs; the remainder is excreted(approximately 100 mg/day). Plasma Ca2+ is regulated by the balance between intestinal absorption, renal excretion, and exchange with bone. Approximately 3G-80o/oof ingested Ca2+ is absorbed from the intestine, but some is also secreted into the intestinal tract. b. Phosphate is freely filtered at the glomerulus; its filtered load is close to its T^. Significant quantities of Pi are excreted,and the kidney regulatesthe plasma concentration of P1. c. Regulationbyparathyroidhormone serum Ca2+concentration.

(PTH). PTH is secretedin responseto decreased

Note Remember thatCa"and phosphate areinversely related. Whenphosphate iselevated, Ca*islow andviceversa.

ClinicalCorrelate -+ t Hyperparathyroidism PTH + hypercalcemia. include: Symptoms

(1) PTH promotes osteoclasticactiviry mobilizingC^z* from bone, increasingplasma Ca2+.

. Hypercalciuria -r renal stones

(2) It increasesthe activity of renal vitamin D, lcr-hydroxylase, an enzfme required for synthesisof 1,25(OH)2vitD, (calcitriol), which increasesintestinal absorption of Ca2+.

. O$eitis qBtica fibrosa (disorder ofbone metabolism secondary to T bonemetabolism)

(3) PTH increasesC*+ reabsorption from the nephron and reducesthe T- for Pi, increasing P1excretion. 5. Regulation of sodium. The averageAmerican daily Na+ intake is about 150 mmol, most of which is excretedby the kidney, with a variable amount lost in sweat.Of the 25 moles of Na+ fi"ltered each day, between 97 and 100o/ois reabsorbed by various parts of the nephron. Na+ excretion is also regulated by blood pressureindependently of plasma Na+ concentration. There are several mechanisms, including GFR, the renin-angiotensinaldosteronesystem,and various others, such as sympathetic nerves,atrial natriuretic hormone, and physiologic distribution of renal blood flow.

. Cl+ anorexia, loss, weight constipation, nausea, vomiting . Neuro manifestations + emotional lability, changes inmentation

a. In the proximal tubule, 70o/oof Na+ is actively reabsorbed;Cl- and water follow passively.

ln.q.-i{;$fpll

b. In the ascending limb of loop of Henle, 20o/oof Na+ is reabsorbed (Na+-K+-zClcotransport); the ascendinglimb is relatively impermeable to water.

Summary of Na* Reabsorption . PCT-> 7Wo

c. In the distal tubule, 5o/oof Na+ is reabsorbed (Na+-Cl- cotransport); the tubule is relatively impermeable to water.

. Ascending loop+ 200/o

d.In the collecting duct, 3 to 5o/oof Na+ is reabsorbed by electrogenic Na+ channel pumps that are aldosterone regulated; the duct is variably permeable to water with regulation by ADH, i.e., an increasein ADH will lead to an increasein H2O permeability and reabsorption.

. DCI+ 5olo . Collecting duct+ 3-50/o P.Sr PCf

i s pcrrw'ca-L\e

{ o rrla.{ L tc UCQli"tlt'tLu'\C wnd€.t }t-*.^f-tl

-r f+ D tsl

249

Rena/Urinary Sy$em

Clinical Correlate Hypoaldosteronism . t Na.loss + hypovolemia, J cardiac output, J renal blood flow . t K*retention -+ hyperkalemia, cardiac arrhythmias . t H*retention + acidosis Bridgeto Pharmacology Diuretis arediscussed in inthePharmacology detail section. Note ADHrelease isprimarily driven bychanges inosmolarity, although hugefluctuations in volume ADH canstimulate secretion aswell.

€linicalCorrelate (Dl) Indiabetes insipidus either doesnot anindividual havethecapability to synthesize ADH(central Dl)or theADHreceptors onthe collecting ductareresistant (nephrogenic Dl).ln either case, a functional deficit of ADHleads to theinability to reabsorb H,0,leading to massive diuresis andurine output.

250

e. GFR. Largeblood pressurevariations causechangesin glomerular capillary pressure despiteautoregulation,and the filtered load of Na+ can changealong with GFR and excretionif Na+ reabsorptionis unchanged. f. The renin-angiotensin-aldosterone system is a volume-dependent system. High blood pressuredecreasesrenin secretion,decreasingangiotensin II, reducing aldosterone,leadingto decreasedNa+ reabsorptionin the collectingduct and increasedNa+ excretion. 6. Diuretics generallyincreaseurine volume. In most cases,they inhibit Na+ reabsorption, thereby increasing Na+ excretion. IncreasedNa+ excretion lowers plasma osmolaliry which lowers ADH and increaseswater excretion.Different agentsact on different parts of the nephron (seeFigure III-6-1 in the RenaliUrinary Pharmacologychapter). 7. Water. The volume of water filtered is the GFR (lS0 l/day), and the volume of urine produced is approximately 1.5 Uday.Therefore,over 99o/oof the filtered water is passively reabsorbedby the nephron. a. The rate of reabsorptiondependsupon the plasmaconcentrationof ADH. Stimuli for the releaseof ADH include: (1) An increasein plasma osmolality, detectedby osmoreceptorsin the hypothalamus. (2) A drop in blood volume detectedby baroreceptorsin the carotid sinus, aortic arch, and atria. b. ADH actson the collecting duct, increasingpermeability to water. c. An osmolality gradient in the renal medulla ranges from an isotonic 300 mOsm/l near the cortical boundry up to 1200 mOsmil deep in the medulla (Figure III-4-4). This gradient is the result of action by the countercurrent multiplier, a complex mechanismused to concentratethe urine prior to excretion. (1) The ascendinglimb of the loop of Henle activelypumps NaCl into the cortical interstitium. However,becauseit is not permeableto water,the osmolality of the tubular fluid falls to approximately 100 mOsm/I. (2) If ADH concentrationis high, the cortical collecting duct becomespermeableto water,and water diffusesout until the contentsreach300 mOsm/l (isotonic with the cortical interstitial fluid). (3) The collecting duct passesback through the increasinglyhypertonic medulla, and water flows down its osmotic gradient through the epithelium. The resulting urine will have an osmolality of 1200 mOsm/l and a volume as low as 0.3 ml/min (approximately500 ml/day). d. The volume of urine excreteddependsupon fluid intake. In the absenceof ADH (due to diabetesinsipidus or water diuresis),urine flow may be 30 llday with an osmolality of only 50 mOsm/l. If an individual drinks largevolumes of fluid, plasmaosmoiality falls,and ADH releaseis inhibited, resulting in a largevolume of hypotonic urine. In the absenceof ADH, the collecting duct becomesimpermeableto water, resulting in an accumulation of water in the tubule despitethe osmotic gradient betweenthe tubular fluid and its adjacentinterstitium.

Physiology

;lJft5PqftT

.^^^ iTf.*j"id+ffi|

:.'wilK Loopot I I Interstitial Henle lluid

I lcollecting lnterstitialduct lluid

Figure lll-4-4. The countercurrent mechanism for concentrating the urine. per liter.(Reprintedwith permission Numericalvaluesare in milliosmoles from GuytonAC:Textbookof MedicalPhysiology, 8th ed. Philadelphia, PA, W.B.SaundersCompany,1991,p 310.)

8. Potassium. The daily intake of K+ is approximately 70 mmol. Becausethe plasma concentration of K+ is significantly lessthan that of Na+, very little K+ is filtered. a. Passivereabsorption of 70o/oof frltered K+ occurs in the proximal tubule, active reabsorption of 20o/oof filtered K+ occurs in the ascendingthick loop, and active reabsorption of l0o/oof fi.lteredK+ is accomplishedby the collecting duct intercalated cell. b. A variable amount of K+ is passivelysecretedby principal cellsof the collecting duct. c. The amount of K+ excretedby the nephron dependson passiveK+ secretion,the rate of which varies with intracellular K+ concentration and the electrochemicalgradient of K+ between the tubular cells and lumen. The major factors that increasethe rate of K+ secretion and excretion are increasedingestion of K+, alkalosis,and increased aldosterone(aldosteronecausesan increasein Na+ reabsorptionand an increasein K+ secretion). d. Diuretics can increaseor decreaseK+ excretion, depending on their site of action. Most diuretics increaseK* excretionand hypokalemiais a significant side effect.

251

RenafUrinary System

ACID.BASE REGUTATION A. Bufferiog. Ao excessof acid will result in most of the hydrogen ions (H+) binding to other compounds to counteract their acidic properties, a processknown as buffering.A small amount remains as free H+ in solution; its concentration (pH) is a valuable clinical indicator. The body buffers carbonic acid, a volatile acid, differently from other acids,called fixed acids. 1. Fixed acids are buffered by approximately half of the H+ reacting with extracellular bicarbonate (HCO:-): HzCOr <+ H+ + HCO3- e+ HzO + COz The other half of the H* enters cells in exchangefor Nan and K*, where it reacts with protein, organic phosphate,and bone. 2. The volatile acid H2CO3 cannot react with HCO3- becauseit is intrinsic to the HCO3buffer system.All of the H+ therefore enters cells,with approximately one-third reacting with hemoglobin in RBCs and approximately two-thirds reacting with protein, organic phosphate,and bone. B. Hydrogen ion. A very small amount of H+ is filtered becausethe plasma H+ is only 10-7'4 moVl (pH 7.a). H+ is actively secretedby the nephron; most is secretedin the proximal tubule, with approximately 10olosecretedin the collecting duct. Most of the H+ secreted reactswith and titrates HCO:- in the tubular fluid as follows: H+ + HCO3- e+ H2O + COz Approximately 9o/oreactswith ammonia: H++NH3eNHe* Approximately 7o/oreactswith other urinary buffers, mainly phosphates: H++HPOnz-+>H,PO,C. Acid-base balance 1. For each H+ secretedinto the tubular lumen, one HCO3- is returned to the interstitial fluid and then to the blood. When H+ reactswith and titrates HCO3- in the tubular fluid, the HCO3- returned to the interstitial fluid represents"reabsorbed"HCO3-. When H* reactswith ammonia or phosphates,the HCO:- returned to the interstitial fluid representsnew HCO3-, thereby replenishingthe HCO3- Iost in the titration of fixed acids.

Note ln acid-base di$urbances, the keyisto lookat H. andHCO,-. . lf H.andHCO,change in thesamedirection, then respiratory . lf H.andHCO,change in opposite directions, then metabolic

252

2. The rate at which the kidney secretesH+ determinesthe value of plasma HCO:- so that an increasein the rate of H+ secretiongenerallyincreasesplasma HCO3-. The following factorsincreasethe rate of H+ secretion: a. Respiratoryacidosis(high P.or) stimulatesH+ secretionand, therefore,increasesplasma HCO:-. This is referredto as renal compensation for respiratory acidosis. b. Aldosterone-increased Na+ reabsorption in the collecting duct causesH+ secretion, which maintains electrical balance. c. Na+ reabsorption is electricallybalancedby either passiveK+ secretionor active H+ secretion.If intracellular K+ is in short supply,H+ secretionis stimulated. D. Acid-base imbalance. The kidney and the lung share responsibiliry for maintaining acidbasebalancein the body. The lung handlesHzCOr (volatile acid) by controllinS P.o, levels, and the kidney dealswith other acids and replacesHCO3- used by the buffering system. There are four generaltypes of pH disturbance,and combinations are possible.

Physiology

l. Respiratoryacidosis. The main effect is an increasein P.or, resulting in an increasein H+. The kidney compensatesby increasingrenal secretion of H+ and increasingrenal absorption and synthesisof HCO:-. Respiratory acidosismay be produced by any cause of hypoventilation, including acute respiratory failure, cardiac arrest, pneumonia, and opiate overdose. 2. Respiratory alkalosis. The problem is a decreasein body P.or; HCOr- falls becauseH+ leavesthe cells and reactswith it. The kidney compensatesby decreasingH+ secretion and decreasingHCO.- reabsorption. Any causeof hyperventilation may produce this condition, including pulmonary embolism, sepsis,and high altitude. 3. Metabolic acidosis. The primary defect is excessproduction or inadequate excretion of H+. The excessH+ is buffered in part by reacting with HCO3-, which therefore decreases. The lungs compensateby increasingexpulsion of COr. Metabolic acidosismay be produced by a variery of disorders, including diarrhea, keioacidosis,renal failure, and toxic ingestions. 4. Metabolic alkalosis. The problem is excessbase or too much excretion of H*, causing a rise in plasma HCO3-. The lungs compensateby retail"g 99r. Conditions associated with metabolic alkd6sis include dehydration and vomiting. The expectedkidney compensations1J H* secretionand J HCO3- reabsorption) will not occur if the metabolic alkalosisis accompaniedby severevolume depletion, becausevolume depletion results in increasedH* secretion(in part due to aldosterone).

CIRCULATION RENAT A. Renal vasculature. The glomerular and peritubular capillary beds are arranged in series,so the efferent arteriole is a true portal vessel.The efferent arterioles of the juxtamedullary nephrons branch into two different capillary networks, the peritubular capillaries in the cortex and the vasa recta in the medulla. The peritubular capillaries and the vasarecta flow in parallel. B. Blood distribution. Approximately 10o/oof the renal blood flow perfusesthe renal capsule, perirenal fat, and upper part of the ureter, and never gets into the nephrogenous zone. The oth.t 90oloflows through the afferent arterioles, glomerular capillaries, and efferent arterioles, and then divides. Five percent enters the vasa recta, perfusing the medulla; the rest remains in peritubular capillaries,perfusing the cortex. C. Regulation of renal blood flow l. Systemicblood pressure. As systemicblood pressureincreases,renal blood flow would be expectedto increaseproportionately, according to the Ohm s law for vascular flow: (PA_Pv) t'low = Rvascular

ln a Nubhell . Respiratory f Pco, acidosis: Hypoventilation Cause: t Renal, Compensation: of HCO,reabsorption . Respiratory JP.o, alkalosis: Hyperventilation Cause: Renal, t Compensation: of HCO,excretion . Metabolic acidosis: J HC0,of Cause:Accumulation (e.g., diabetic acids tissue ketoacidosis, hypoxia) Respiratory, Compensation: hyperventilation . Metabolic t alkalosis: HC0,of baseor lngestion Cause: (lossof H.),loop vomiting diuretia andthiazide

Respiratory, Compensation: (notalways hypoventilation nf er'-o comPlete) lF fvsir{ olrglttt \*:*6c t atdog;+crr'* a q+6,g333-tie -++ ln a Nubhell

n nul,looano* is where P6 is the arterial blood pressure,Py is the venousblood Pressure'and R r"r..r1u, to 140 60 from pressures arterial mean of the range over the vascular resistance.However, mm Hg, the renal blood flow changesonly slightly becauseof autoregulation of renal blood flow. The regulatory mechanism involves progressiveconstriction of the afferent arterioles asblood pressureincreases,in turn regulating GFR aswell. Any increasein GFR is significant, becauseit increasesthe Na+ filtered and, thus, the amount excreted.Two mechanismsexplain autoregulation, which also works in reverse,maintaining blood flow as pressurefalls over the operant range.

Autoregulation or decreasing Byincreasing the resi$ance, vascular renal itselfa con$ant kidney assures bloodflowovera widerange of bloodpressures.

25'

Rena/Urinary System

a. Myogenic response is found in other organs, notably the brain and heart. "singleunit" smooth muscle surrounds most arterioles and responds to increasesin arteriolar blood pressureby contracting, thus raising resistanceto flow. The increasedpressure stretchesthe muscle, causing the opening of stretch-activated Ca2+channels so that calcium enters the smooth muscle cell where it binds to calmodulin, activates myosin light-chain kinase,and stimulates smooth muscle contraction, constricting the arteriole. b. Tubuloglomerular feedback is a feedbackloop that requires the macula densa to monitor eventsdownstream and to alter the filtration rate accordirgly.The macula densais at the junction of the thick ascendinglimb of the loop of Henle and the distal tubule, where the condition of the tubular fluid can be monitored and a signal can be sent to the afferent and efferent arterioles.This mechanismis not well understood, however,as no sensorysignal has been demonstrated.

Note . OnewaythatB-blockers reduce hypertension isby blocking reninrelease. . ACEinhibitors (which block production) angiotensin || relieve hypertension by inhibiting efferent arteriole constriction.

Bridgeto Heme/tytnph

2. Sympathetic nervous system. The autonomic innervation of the kidney is solely sympathetic. Sympathetic fibers innervate both afferent and efferent arterioles. The effect of sympathetic stimulation on vasomotor tone is, therefore, the product of two distinct processes:

a.Alpha(") d"JffIi";*tar

smoothmusclecellsstimulatetheir contraction,

which causes greater constriction of the afferent arteriole because it has thicker smooth muscle than the efferent arteriole. b. Beta (B) .6;p;Xl?^"?-i"har myoepithelial cells (juxtaglomerular apparatus) of the afferent arterioles releaserenin when stimulated, and the intrarenal angiotensin II generation causesconstriction mainly of the efferent arteriole. The net effect is that glomerular capillary pressure (and GFR) is maintained while renal blood flow is reduced. All components of the biochemical sequence that leads from renin to angiotensin II are found in the kidney, but some of these components are at higher concentration elsewhere. 3. Angiotensin II. Angiotensin causesgreater constriction of the efferent arteriole than of the afferent arteriole. The production of angiotensin from angiotensinogenis under the control of renin. Renin releasefrom the JG cells is promoted by three types of stimuli:

Recall thatthekidney also produces thehormone a. Stimulation of renal sympatheticnerves(p1 receptors) erythropoieti n.Eryth ropoieti n b. A reduction in perfusion pressureof the kidney (direct effect on juxtaglomerular cells) isproduced bytheendothelial c. A reduction in Na+ delivery to the macula densa (tubuloglomerular feedback) cellsof theperitubular capillaries in response to 4. Prostaglandins. Catecholamines and angiotensin bind to distinct receptors, but their I'r jrvhnst(icandsiirrulates the vasoconstrictor activities are both mediated through the phosphatidyl biphosphate sysdr r.? tonermanowrtof roduce tem, using inositol triphosphate as a secondmessenger. As inositol triphosphateis made, rr'1;rr sqfihroeyt&$rvthropoietin is diacylglycerol is also produced, which eventually acts as a precursor for the 'nr.'""t drsolsfudifihb ' prostaglandins. Hematologi(Lymphoreticula r a. The main renal prostaglandins are prostaglandin E2 (PGE2) and prostaryclin (PGlz), Histology andPharmacology both vasodilators.They modulate the direct vasoconstrictor effectsof norepinephrine chapters. (predominantly afferent) and the indirect effects of angiotensin II (predominantly efferent). b. Severalnonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of the prostaglandins; the hypoperfusion of conditions like congestiveheart failure (CHF) may actually lead to renal ischemia and oliguria (reduced urine flow) or even acute renal failure.

2t4

Physiology

5. Pregnancy. Renalblood flow and GFR increasesubstantially (up to 40o/o)in pregnanry as a result of the effectsof gestationalhormones. D. Measurement of blood flow l. Clearanceof a substanceis defined as the volume of plasmathat is completelyclearedof the substanceper unit time. For example,if the clearanceof a substanceis given as 3 ml/min, then 3 ml of plasma would be clearedcompletely of the substancewithin one minute. The units of clearanceare alwaysvolume (plasma)/time. a. Para-aminohippuric acid (PAH) is a substancethat, at a lessthan saturating concentration, is completely secretedinto the proximal tubule and excreted into the urine. The volume of plasma clearedof PAH (Cpnu) is therefore approximately equal to the volume of plasma flowing through the nephrogenous zone,or the effectiverenal plasma flow (ERPF).ERPF can then be calculatedfrom measuring the concentration of PAH in the urine.

ERPF:$}}L:cprn where Uro" is the concentration of PAH in the urine, Vis the urine flow, and Pronis the concentrationof PAH in plasma. 2. Becauseapproximatelyonly 90o/oof renal plasma flows through the nephrogenouszone (the remainder flows through the vasarecta,kidney capsule,perirenal fat, and the upper part of the ureter), the actual renal plasma flow (RPF) could be calculatedas ERPF/0.9. Practically speakingthough, ERPF and RPF are essentiallyequivalent terms. 3. Renal blood flow (RBF) is calculated from RPF as: RPF RBF=

l-H.-"tr*it

255

RenalUrinary Pathology Thekidney isa complex bya variety organ oftenaffected andcongenital ofacquired disorders. glomerulonephritis Common disorders include andneoplasms suchasWilms'tumor andrenal cell plays carcinoma. Because thekidney sucha central rolein homeostasis, damage to theorgan can havefar-reaching Forexample, isinvolved effects. thekidney in bloodpressure since regulation production through therenin-angiotensin system andintheregulation of redbloodcell(RBC) itssynthesis through of erythropoietin, renaldisease cancause bothhypertension andanemia. Thekidney isalsofrequently affected bysystemic disease, disorders, suchasautoimmune amyloidosis, septicemia, anddiabetes. Infact,renal failure isoneofthemostcommon causes of deathin systemic lupuserythematosus anddiabetes. processes Thischapter willfocusonthedisease associated withthekidney aswellasdisorders of therestoftheurinary system.

CONGENITAT ANOMATIES OFTHEKIDNEY A. Agenesis.Bilateralagenesis is incompatiblewith life. Unilateralagenesismayhaveadequate renalfunction but may developprogressiveglomerularsclerosis. B. Hypoplasia is the failure of the kidnep to dev€lopto normal weight;it is usuallyunilateral. Thereare a decreased number of calycesand lobules. C. Horseshoekidney is a fusion of the kidneys,usuallyat the lower pole.It is found in I in 750 autopsies.Patientshavenormal renalfunction but maybe predisposedto renal calculi. D. Abnormal locations. The most common abnormal location is the pelvic kidney. There is normal function; howev€r,tortuosity of uretersmay predisposeto pyelonephritis.

CYSTIC DISEASE A. Childhood polycystic disease 1. Incidence.This is a rar€ autosomalrecessive disease, 2. Clinical features.Patientspresentin infancy with progressiverenal failure; if the infant survives,he maydevelophepaticfibrosisand portal hypertension. 3. Pathology a. Grossly,there are bilaterally enlargedkidneyswitlt smooth surfaces.The cut section with multiple small cpts in the cortex and medulla showsa spongeJikeappearance, (FigureIII-5-1).

257

Rena/Urinary System

b. Microscopically, there is a rylindrical dilatation of tubules. c. Most casesalso have multiple hepatic rysts.

Figure lll-5-1. Infantile polycystic kidneys (gross).

B. Adult polycystic disease l. Incidence. This diseaseaffects I in 500 people, showing autosomal dominant inheritance.It has a negativefamily history in 25o/oof cases,implying a new mutation.

Note Foradultpolycy$ic disease, thinkliverq6tsandberry aneurysms inaddition to renalqrsts.

2. Clinical features. Patients usually have normal renal function until middle age,at which time they present with renal insufficienry, hematuria, flank pain, and hypertension. Extrarenal manifestations include liver cysts, berry aneurysms in the circle of Willis, mitral valve disease,and colonic diverticula. Most patients develop hypertension, and 50-75o/odevelopend-stagerenal failure by their seventhdecade.Diagnosisis best made by ultrasound; three rysts in each kidney of an adult with a family history confirms the diagnosis. 3. Pathology a. Grossly, there is marked bilateral enlargementwith large rysts bulging through the surface.Cysts (3-4 cm diameter) are filled with serous,turbid, or hemorrhagic fluid (FigureIII-5-2). b. Microscopically, functioning nephrons are present between the cysts. Cysts involve lessthan l0o/oof nephrons,but they gradually expand and compressthe rest of the kidney, interfering with its function. This is the reason why kidney function can remain normal for many years.

258

Pathology

Figure lll-S-2.Polycystic right kidney in an adult (gross).

C. Other cystic diseases l. Simple cystsare a common postmortem finding with little clinical significance.They may be singleor multiple, 1-5 cm, and filled with clear fluid. If discoveredin life, they must be differentiated from malignanry. 2. Cystic renal dysplasia is the persistenceof undifferentiatedstructuresin the kidney (i.e., undifferentiatedmesenchymeor cartilageor immature ductules).It may be unilateral or bilateral,and it is a sporadic disorder (not familial). 3. Medullary sponge kidney refers to multiple rystic dilatations of collecting ducts in the medulla.Most patientsare asymptomaticbut havean increasedrisk for kidney stonesand their complications.Diagnosisis made by intravenouspyelogram (IVp). 4. Acquired cystic disease.Multiple cortical and medullary rysts may result from prolonged renal dialysis.Cystscontain clearfluid and rangefrom 0.5-2.0 cm in diameter.Thesemay bleed spontaneously,developinto renal cell carcinoma,and sometimesregressfollowing transplantation.

HYPERTENSION Hypertension is defined as an elevatedblood pressuregreaterthan 140/90.Primary (essential) hypertensionhas an unknown etiology and represents90o/oof cases.Secondaryhypertension makesup the remaining l0o/oof casesand may be secondaryto renal, vascular,endocrine, or neurogenicdisorders. A. Essential hypertension 1. Etiologies a. Environmental factors. High dietary sodium in predisposedpatients exacerbatesthe problem. Obesiry stress,and oral contraceptivesmay contribute to the development of hypertension.

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b. Physiologic theories

Note ThatMayRaise Factors BloodPressure . t Clucocorticoids, l,l . ? Norepinephrine, growth epinephrine, hormone . t Aldosterone

(l) A defect in sod.iumexcretion would raise blood pressureby a loss of autoregulatory function (i.e.,loss of ability to respond to elevatedblood Pressureby excreting excesssodium and water). (2) An increase in peripheral resistance could come from increased sympathetic tone. 2. pathology. There is frequently a hyaline deposition in arteriolar walls, narrowing the lumen. Hig6 blood pr.srrt. may causeatrophy and scarring of the glomeruli and tubules. B. Secondary hypertension 1. Etiologies a. Renal disease.Chronic renal disease,acute glomerulonephritis, and renin-producing tumors all lead to high blood pressure. b. Vascular disease.Coarctation of the aorta and renal artery stenosisboth reduce renal blood flow,leading to increasedrenin production and hypertension. 2. Pathogenesisof renal hypertension a. Increased renin secretion (l) Renin, which is released from the juxtaglomerular apparatus, converts angiotensinogen to angiotensin I, which is converted to angiotensin II in the lung. Angiotensin II causesarteriolar constriction and stimulates aldosterone se.rltion-by the adrenal cortex. Aldosterone causes sodium retention, which Ieadsto an increasedintravascular volume. (2) Malignant hlpertension, unilateral renal artery stenosis,renin-producing tumors, vasculitis,and chronic renal tailure all lead to increasedrenin production. b. Decreased renal antihypertensive substances. Prostaglandins and kinins typically lower blood pressure;however,they cannot be synthesizednormally in renal failure. c. Renal artery stenosis is a potentially curable form of hypertension. It stimulates renin secretionbecauseof reduced blood flow past the juxtaglomerular aPParatus. ( l) Pathology. It is most commonly causedby atherosclerosis(in patients >50 years) or fibromuscular dysplasia(in patients <20 years).The kidney exhibits ischemic atrophy with interstitial atrophy and a chronic inflammatory infiltrate. (2) Diagnosis is made by arteriography. Not all anatomic lesions have functional significance. C. Malignant hypertension is a syndrome of severehypertension (blood pressure is usually >Z0O1L40-* Hg, but there is no absolutelimit) and acute end-organ damage.It usually occurs in patients with long-standing, poorly controlled hlpertension. The S-yearmortality rate is 60-700/o.

260

Pathology

1. Clinical features a. There may be manifestations of increased intracranial pressure, including papilledema (with retinal hemorrhages and exudates),headache,vomiting, and scotomas. Symptomsmay progressto lossof consciousness and seizuresand may alsocausesubarachnoid or intracerebralbleeds. b. Cardiac failure. Left ventricular dysfunction may occur early. c. Malignant nephrosclerosis may lead to proteinuria, hematuria, and sometimesacute renal failure. Patientswith renal failure have a higher mortality rate. 2. Pathology a. Grossly, the kidneys have petechial hemorrhages on the surface. b. Microscopically, fibrinoid necrosis of arterioles appearsas an eosinophilic granular deposition within vesselwalls (Figure III-5-3). If inflammatory cells are present,the processis called necrotizing arteriolitis. Hyperplasticarteriolitis of interlobular arteries appearsas laminated, concentrically arranged smooth muscle cells and collagen. There may also be necrosisof glomeruli. c. Ocular manifestations include retinal hemorrhages,exudates,and papilledema. d. Cardiac manifestations include heart failure, hypertrophy, and dilatation. e. The central nervous system (CNS) may suffer petechial hemorrhages,microinfarcts, and subarachnoidor intracerebralbleeds.

Figure lll-5-3. Malignant hypertension with fibrinoid necrosis (microscopic).

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Rena/UrinarySystem

DISEASES GTOMERUTAR A. Overview 1. Glomerular response to damagecan take severalforms. a. Cellular proliferation may include mesangial,epithelial, and endothelial cells. b. Thickening of the basement membrane of the glomerular capillaries most often results from subepithelial deposition of fibrin and immune complexes,followed by secretion of more basementmembrane material by endothelial and epithelial cells. c. Leukocytic infiltration. Neutrophils and monocftes may be attracted by antigen-anti body (Ag-Ab) complexes. d. Sclerosisand hyalinization are due to an accumulation of eosinophilic material, composed of plasma proteins and mesangialmatrix. This may lead to irreversible injury. 2. Pathogenesis

Note Goodpasture basement Anti-glomerular membrane andanti-alveolar basement membrane. isalsodiscussed Coodpasture Pathology in theRespiratory chapter.

a. Anti-glomerular basement membrane antibodies. Nephritis results from antibodies against fixed antigens in the glomerular basement membrane, which produce linear staining by immunofluorescent microscopy. Autoimmune glomerulonephritis accountsfor lessthan 5oloof all glomerulonephritidesand is the basic mechanismof Goodpasture syndrome, which also includes antibodies against the basement membrane in pulmonary alveoli. b. Antibodies against other antigens. Glomerulonephritis may result from antibodies against other fixed antigens or antibodies in glomeruli. These produce a granular ("lumpy-bumpy'') pattern on immunofluorescence. c. Circulating immune complexes.Ag-Ab complexesbecome trapped within glomeruli, causing glomerular injury. Antigens may be exogenous (e.g., serum sickness)or endogenous(e.g., systemiclupus erythematosuswith DNA-anti-DNA complexes). The immunofluorescent pattern is granular. d. Mediators of ittj""y. After Ag-Ab interaction, injury may result from a variety of mechanisms,including activation of the complement system,macrophages,and the coagulationsystem,and attraction of neutrophils and monocytes. B. Clinical syndromes in glomerular disease 1. Nephritic syndrome. Patients with acute nephritis present with proteinuria, hematuri4 red blood cell (RBC) casts, and varying degreesof renal insufficiency and hlryertension. Many glomerular diseasesmay result in a nephritic picture, including SLE,and, classically, acute post-streptococcalglomerulonephritis. 2. Nephrotic syndrome is a clinical tetrad of generalizededema, severeproteinuria (>3.5 g/day), hypoalbuminemia (<3 g/dl), and hlryerlipidemia. It results from a loss of the chargebarrier of the glomerular basementmembrane (GBM) with an increasedpermeability to albumin. This leads to massive proteinuria and edema. Hyperlipidemia may result from increasedlipoprotein synthesisinduced by hypoalbuminemia.The most common causeof nephrotic syndrome in children is lipoid nephrosis (minimal change disease);in adults,the most common causeis membranous glomerulonephritis. 3. Rapidlyprogressive glomerulonephritis (RPGN). Also called"crescentic GN," RPGN is a syndrome of rapidly deteriorating renal function that accompaniesglomerular injury. Clinically, patients presentwith a nephritic urine sediment and renal failure. Histologically, accumulation of "crescents"or proliferation of parietal epithelial cells and migration of macrophagesin Bowman spaceare seen.RPGN may occur spontaneously(idiopathic), be

262

Pathology

associatedwith multisystem disease(such as vasculitis or Goodpasture), or follow poststreptococcaVpostinfectiousglomerulonephritis. Tieatment is controversial,and prognosis is poor. C. Glomerulonephritis (Refer to Thble III-5- | on page 269) 1. Acute poststreptococcal glomerulonephritis a. Clinical features. This diseaseaffectschildren more frequently than adults and usually occurs 1-2 weeks after streptococcalinfection of the throat or skin (only certain strains of p-hemolytic group A streptococcitypically produce nephritis). There is a nephritic picture with hematuria,oliguria, and hlpertension. Laboratory studiesshow elevated antistreptolysin O (ASLO) titers and low serum complement.

Flashback to System Cardiovascular Poststreptococcal rheumatic inthe feverisdiscussed Pathology Cardiovascular chapter.

b. Pathogenesis. The mechanism is immune-related; the disease is probably due to immune complex desposition. c. Prognosis (1) Children. Ninety-five percent recover, although microscopic hematuria and proteinuria may persistfor months. A few go on to chronic renal damage(RPGN or chronic glomerulonephritis). (Z) Adults. There is a 30-407o incidence of chronic renal diseaseafter the acute attack. d. Pathology (1) Microscopically, there is diffuse cellular proliferation and leukocytic infiltration, producing hypercellular glomeruli. (2) Electron microscope examination shows subepithelial humps of amorphous Ag-Ab complexes. (3) Immunofluorescence showsgranular depositsthroughout the glomerulus. 2. Lipoid nephrosis (minimal change disease) a. Clinical features. This is the most common causeof nephrotic syndrome in children. Its peak incidence is 2-3 years of age, and it may be associatedwith food allergy, certain medications,or hematologicmalignancies. b. Pathogenesis.The mechanism is unknown, but the diseaseis thought to result from a lymphokine producedby T cells.Electron microscopyshowsfusion of epithelialfoot processes(podocytes);this may representloss of the glomerular polyanionic filtet which leadsto proteinuria. c. Prognosis. Renal function does not usually deteriorate.This syndrome is usually steroid responsive,especiallyin children. Complete recovery is expected. d. Pathology (1) Light microscopy findings are normal; thus, the name"minimal changedisease." (2) Electron microscopy shows a diffuse loss of epithelial podocyte food processes but no electron-densedepositsin GBMs. (3) Immunofluorescence is negative. ( ) Histochemical studies show a loss of negatively charged glycoproteins in the GBM.

26t

ncrd/t dnarySyshm

3. Membranous glomerulonephritis a. Clinical features. This is the most common causeof nephrotic syndrome in adults, but it is rare in children. There is usually an insidious onset of proteinuria; hematuria and mild hypertension may occur. There may be a genetic predisposition. Most cases are idiopathic, but some are associatedwith infection, drugs, tumors, and systemic disease. b. Pathogenesis.Subepithelial immune depositsin the GBMs damagethe capillarywalls. c. Prognosis. There is a variable natural history. Five to twenty percent of patients have spontaneousremission, but the incidence of end-stagerenal diseaseis 600loat 6 years. Renal vein thrombosis may occur. Tieatment is very controversial and not clearly effective.It is not steroid responsive. d. Pathology (1) Grossly, the kidneys are swollen and pale. (2) Microscopicallp there is a diffirse thickening of the capillary walls. (3) Electron microscopy shows subepithelial deposits along basementmembranes. (4) Immunofluorescence shows a granular pattern of immunoglobulin and complement. 4. Membranoproliferative

glomerulonephritis

(MPGN)

a. Clinical features. Tn'o-thirds of patients have the nephrotic syndrome; the rest have non-nephrotic range proteinuria or a mixed nephritic/nephrotic picture. MPGN accountsfor 5-10o/oof casesof idiopathic nephrotic syndrome in adults and children. MPGN may be secondary to many systemic disorders, including complement deficiency,chronic infections, and chronic lymphocytic leukemia. b. Pathogenesis (1) Tlpe I shows immune-complex deposition in the subendothelium and mesangium. (2) Type II shows C3 nephritic factor (an antibody against complement component C3) with IgG autoantibody in serum that can activate the alternate complement pathway. Dense deposits are seen along the glomerular and tubular basement membranes on renal biopsy. c. Prognosis is poor, and treatment is controversial. The diseaseis slowly progressive.Half of all patients die of chronic renal diseasewithin 10 years of the diagnosis.There is a high incidence of recurrence of this diseasein patients with transplants. Patients with MPGN secondaryto other diseasesmay respond to treatment of the primary illness. d. Pathology (1) Microscopically, there is mesangial proliferation and basement membrane thickening. Tlam-tracking or splitting of the basement membrane may be seen in silver staining, while periodic acid-Schiff (PAS) stains show generalizedthickening. (2) Electron microscopy in tfpe I diseaseshows subendothelial deposits of C3 and IgG; in tlpe II disease(also called densedeposit disease),homogeneousdeposits within GBM, usually only C3, are seen.

2U

Pathology

5. Focalsegrnentalglomerulosclerosis a. Clinical features.It accountsfor 10%-15%of casesof nephrotic syndromein children and adults. As comparedto lipoid nephrosis,thesepatients-moreoften have hematuria,hlpert€nsion, impaired GFR,and nonselectiveprot€inuria.

l{oie

varib. Pathogenesis.The mechanismis probablyimmunologic (possiblyan aggressive ant ofiipoid nephrosis)or a secondaryreactionofresiiualnephrosis toiephron loss. Intravenousdrug abuseis implicated'in somepatients.

. "Focal"refersto invlivement ot ontysome ,i"rarri,. ' "Diffuse"meansall glomeruli areinvolved'

children,respondto steroids.More than c. hognosis is poor; somepatients,especia.lly 50% of patientsdevelopend-stagerenal diseasewithin l0 yearsof diagnosis.Thereis a high rate of recurrencein transplants.

' "Segmenhl" meansonly parlsof theglomerulus are involved.

d. Pathology

. "Global" meansthe entire glomerulus is involved'

(1) Microscopically, segmentalsclerosisand hyalinization of glomeruli are seen. The syndromeinitially affectsa few glomeruli along the nedullary border,and only part of the tuft exhibitssclerosis. (2) El€ctron microscopy showsnonscl€roticregionsthat exhibit loss of foot proasin lipoid nephrosis;scleroticsegmentsshowincreasedmesangialmatrix cesses deposits. and mesangia.l (3) trnmunofluorescenceshowsIgM and C3 depositsin the scleroticsegments. 6. Anti-GBM antibody disease a. Clinical features. This diseasecausesrapidly progressive glornerulonephritis (RPGN).When accompaniedby pulmonary involvement,it is known asGoodpasture syndmmc. The mechanisminvolvesantibodiesdirectedagainsta collagencompob. Pathogenesis. membranes. nentof basement

NOte involves Plasmapheresis to remove filteringo{ plasma AyAb complexes'

steroids,and cftotodc drugs. Endc. Prognosis.Treatmentincludes plasmapheresis, is begunbeforethe serum failure may be avoided if aggressive treatment stagerenal creatinineis over 7-8. d. Pathology ( I ) The microscopicpattern is that of RPGNwith proliferation, crescents,and fibrinoid necrosis. (2) Elecrronmicroscopyshowsno deposits,but thereis GBM disruption. (3) Irnmunofluorescenceshowsa linear pattern of immunoglobulin in the GBM. 7. Idiopathic rapidly progressiveglornerulonqrhritis a. Clinical features. Patientspresentwith nephritis but have a rapid progressionto severerenalfailure, to any severe b. Pathogenesis.The medranismis immunologic;crescentsarea r€sPonse glomerularinjury. c. Prognosis is extremelypoor if untreated,although there are possiblebenefitswith Many patientsdevelopend-stagerenal disease. steroidsand plasmapheresis. d. Pathology (1) Grossly,bilaterallyenlargedpaiekidneysareseen. (2) Light microscopy showshlaercellular glomeruli vrith crescentformation and fibrin deoosition.

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RenafUrinary System

(3) Electron microscopy findings are variable; patients may or may not have electron-densedeposits. (4) Immunofluorescence may show granular or linear depositsof immunoglobulin and complement. 8. Focal proliferative glomerulonephritis a. Clinical features.This may occur as a primary focal glomeruionephritis or as a mild manifestationof a multisystemdisorder such as SLE,Goodpasture,subacutebacterial endocarditis(SBE),or Wegenergranulomatosis.The syndrome may be subclinicalor presentwith hematuria or proteinuria, and occasionally,the nephrotic syndrome. b. Pathogenesis.The mechanismis immunologic. c. Prognosis is variable. d. Pathology showsproliferation limited to particular segmentsof certain glomeruli. 9. IgA nephropathy (Berger disease) a. Clinical features.This disorder producesmild proteinuria. Hematuria may be recurrent. It occasionallycausesthe nephrotic syndrome. It usually affects children and young adults and may follow a respiratory infection. It is the most common causeof glomerulonephritis. b. Pathogenesis.The mechanismis unknown. There is a possibleentrapment of circulating immune complexeswith activation of the alternatecomplementpathway.There is also a possiblegeneticpredisposition. c. Prognosis is slowly progressive,that is, half progressto chronic renal failure within 20 years. d. Pathology (1) Light microscopy is variable;it may be normal. There may be segmentalproliferation, mesangialproliferation, or crescentformation. (2) Electron microscopy shows mesangial deposits. (3) Immunofluorescence showsmesangiulIgA deposition without complement. 10. Chronic glomerulonephritis a. Clinical features. This is the final stageof many forms of glomerular disease,so the rate of developmentis variable.Patientsmay presentwith anemia,anorexia,malaise, nausea)vomiting, proteinuria, hypertension,and azotemia. b. Pathogenesis.The mechanism depends on the underlying etiology. It may follow RPGN, membranous glomerulonephritis, MPGN, IgA nephropathy,focal segmental glomerulosclerosis,and others. It is rare after poststreptococcalglomerulonephritis. Twenty-fivepercent of patientswith chronic glomerulonephritis have no documented history of acuteglomerulonephritis. c. Prognosis is poor. Patientsusually progressto end-stagerenal disease. d. Pathology (1) Grossly, shrunken kidneys are seen. (2) Light microscopy showshyalinization of glomeruli, interstitial fibrosis, atrophy of tubules, and a lymphocytic infiltrate.

256

Pathology

D. Hereditary nephritis (Alport syndrome) is a hereditary abnormality of collagen, resulting in renal disease,deafness,and ocular abnormalities (e.g.,dislocatedlens,corneal dystrophy, cataracts). 1. Incidence. It is primarily an X-linked disorder;women are carrierswith mild forms and men developthe frrll-blown syndrome. 2. Clinical features.Patientshavehematuria and proteinuria, which slowly progressto renal failure. 3. Pathology rangesfrom mild focal proliferative glomerulonephritis to RPGN. There are no immune complexes.On electron microscopy,the GBM is thickened and split. These findings are characteristicbut not diagnostic.A loss of tubules and interstitial fibrosis is also seen.The GBMs in Alport syndromelack the Goodpastureantigen and do not bind anti-GBM antibodies. E. Glomerular injury in systemic disease 1. Systematiclupus erythematosus 2. Amyloidosis 3. Diabetesmellitus 4. Goodpasturesyndrome 5. Wegenergranulomatosis 6. Bacterial endocarditis may lead to immune complex nephritis. It produces focal, segmental necrotizing glomerulonephritis, MPGN, or rapidly progressiveglomerulonephritis with crescentformation. It is associatedwith low serum complement levels and usually reverseswith treatment of the infection. 7. Henoch-Schiinlein purpura a. Clinical features.Henoch-Schonleinpurpura is a systemicvasculitis,resulting in purpuric plaques on the extremities and buttocks, arthralgias, hematuria, abdominal pain, vomiting, and gastrointestinalbleeding. b. Incidence. It is more common in children than adults and may follow respiratory infection. c. Pathology is the same as IgA nephropathy. 8. Multiple myeloma is a hematologic malignanry characterized by overproduction of monoclonal immunoglobulins and often excessmonoclonal light chains.The kidney in multiple myeloma can show a variety of pathologic lesions,including tubular plugging by casts of myeloma protein (myeloma kidney), amyloid, hypercalcemic nephropathy, and light-chaindepositiondisease.

(ATN) NECROSTS ACUTE TUBULAR ATN is acute renal failure associatedwith reversibleinjury to the tubular epithelium. It is the most common causeof acuterenal failure (FigureIII-5-4).

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RenaflUrinary System

Figure lll-5-4.Acute tubular necrosis.

A. Tlpes 1. Ischemic ATN is due to decreasedblood flow causedby severerenal vasoconstriction, hypotension,or shock.It is the most common causeof ATN. 2. Nephrotoxic ATN is caused by heavy metals (e.g., mercury, lead, gold), drugs (e.g., polymyxin, methicillin, sulfonamides),organic solvents(e.g.,carbon tetrachloride,chloroform, methyl alcohol), ethyleneglycol,phenol, pesticides,or myoglobin. B. Pathogenesis.Ischemia or toxins causetubular damageand may lead to: 1. Vasoconstriction of preglomerular arterioles,leadingto a decreasedGFR 2. Tubular obstruction by castsformed from tubular debris. (Urinary obstruction causes increasedintraluminal pressureand decreasedGFR.) 3. Backleakageof fluid from the tubules into the interstitium, causingincreasedinterstitial pressureand tubular collapse 4. Decreasedglomerular capillary permeability C. Pathology 1. Ischemic ATN a. Focal regions of tubular necrosisare interspersedbetweenlarge unaffectedregions. b. Ttrbulorrhexis refers to rupture of basementmembranes. c. Obstruction of tubular lumina by hyaline and granular castsinterferes with tubular function and urine flow. 2. Nephrotoxic ATN a. Necrosis is most prominent in the proximal tubule. b. Ttrbular basement membranes are uninvolved. 3. Epithelial regeneration is a healing process.It is characterizedby flat epithelial cells, mitotic figures,and hyperchromaticnuclei.

268

Thble III-5- f . Glomerulonephritides. TyP.

Clinical Presentation

Mechanism

Prognosis

Light Microscopy

Electron Microscopy

Immunofluoresc€nce

Poststreptococcal glomerulonephritis

Nephritis; elevatedASLO; low complement;children > adults

Immunologic

Most completelyrecover; occasionallyprogressesto RPGN

Polymorphonuclearneutrophil leukocyteinfiltration; proliferation

Subepithelialhumps

Granular pattern; GBM and mesangiumcontain IgG and C3

Lipoid nephrosis (minimal change)

Nephrotic syndrome;children > adults

Unknown

Renalfunction usuallypreserved;may respondto steroids

Normal

No deposits;Iossof epithelial foot processes

Negative

Membranous glomerulonephritis

Nephrotic syndrome; adults > children

Immunologic

Lessthan 50oloprogress; may respondto steroids

Capillary wall thick-ening

Subepithelialspikes;lossof epithelialfoot processes

Granular pattern of IgG and C3

Membranoproliferative glomerulonephritis

Variable:mildproteinuria, mixed nephritic/nephrotic, or frank nephrotic syndrome

Type I: immune complex and both classic and alternate complement pathways Type II: immune complex and alternate complement pathway

Poor responseto steroids

Basementmembranethick and split; mesangialproliferation

Type I: subendothelial deposits TypeII: densedepositdisease

TypeI: IgG and C3, Clq, and C4 TypeII: C3 (IgG,Clq, and C4 usuallyabsent) "C3 nephritic factor"

Focal segmental glomerulosclerosis

Nephrotic syndrome

Immunologic; aggressive variant of lipoid nephrosis; IV drug abuse; HIV nephropathy

Poor,rare steroid response

Focal and segmental sclerosis and hyalinization

Epithelial damage;lossof foot processes

IgM and C3 focal deposits

Goodpasture's syndrome

RPGN + pulmonary hemorrhage

Anti-GBM

Often poor, but some respons€to steroids, plasmapheresis, and cytotoxic drugs

Crescents; mesangial proliferation in earlycases

GBM disruption;no deposits

LinearIgG and C3

IdiopathicRPGN

RPGN; may follow flu-like syndrome

Immunologic

Extremelypoor

Crescents

Variable,+ deposits;all haveGBM ruptures

Granular or linear

Focal proliferative glomerulonephritis

Primary focal glomerulonephritis or part of multisystemdisease;may be subclinicalor presentwith hematuria,proteinuria, nephrotic syndrome

Immunologic

Variable

Proliferation limited to certain segments of particular glomeruli

Variable; may show m€sangial deposits

Variable; may show mesangial deposits

IgA nephropathy (Berger'sdisese)

Variable:recurrent hematuria, mild proteinuria, nephrotic syndrome; children and young adults

Unknown

Usually slowly progressive

Variable:normal or segmental/mesangialproliferation or crescentic

Mesangialdeposits

MesangialIgA deposition

Chronic glomerulonephritis

Chronic renal failure; may follow a variety of acute glomerulopathies

Variable

Poor

Hyalinized glomeruli

Negative

antibodies

Negativeor granular

N'

Or r0

'E' qf ri

-o o oc

Rena/Urinary System

D. Clinical features. AIN has four phases: l. In the initial phase (36 hours), the precipating event (e.g.,shock,toxins) occurs. 2. During the oliguric phase (10 days), there is decreasedurine output (50-400 ml per duy). Uremia, fluid overload, and hyperkalemia may occur. 3. During the diuretic phase, there is a gradual increasein urine volume (up to 3 Uday). Hypokalemia, electrolyte imbalances,and infection may occur. 4. In the recovery phase (third week), there is an improved concentrating abiliry normalization of blood urea nitrogen (BUN) and creatinine,and restorationof tubular function as new epithelial cells grow in. E. Prognosis is excellentif the patient survivesthe diseaseresponsiblefor the ATN.

TUBUtOINTERSTITIAT DISEASE Note Tubulointerstitial disease usually affects females more thanmales because the female urethra isshorter.

A. Pyelonephritis is an infection of the renal pelvis, tubules, and interstitium, i.e., everything but the glomerulus. 1. Etiology. Etiologic agentsare usually Gram-negativebacilli (e.g.,Escherichiacoli, Proteus, Kebsiella,Enterobacter),or S.faecalis.In general,etiologic agentsare organismsderived from the patient'sfecal flora. 2. Pathogenesis a. Ascending infection is the most common route. The sequenceof eventsis as follows: ( 1) First, there is colonization of the distal urethra and vaginal introitus by bacteria. (2) Bacteria enter the bladder, facilitated by urethral instrumentation, short urethras, or urethral trauma during intercourse. (3) There is an inability to clear urine from the bladder.Urinary stasisis causedby bladder obstruction or inability to frrlly empty the bladder as seenduring pregnancy, bladder diverticula, or benign prostatic hypertrophy. (4) Proliferation of bacteria in the urine leads to cystitis, infection of the urinary bladder, causing frequency, urgency, dysuria, and suprapubic pain. Systemic signs (e.g.,fever) are uncommon. Acute rystitis will produce a suppurativeexudate and ulcer formation; chronic cystitis produces a mononuclear exudate, fibrosis,and loss of elasticityof the bladder wall. (5) Vesicoureteral reflux (VUR) allows bacteria to ascend to the kidneys; during micturition, urine is forced up one or both ureters. (6) Intrarenal reflux permits spreadof bacteriato the renal parenchyma. b. Hematogenous infection is much lesscommon as a source of pyelonephritis.With urinary obstruction, the kidney is predisposedto infection during states of bacteremia.The undamagedkidney is normally resistantto hematogenousinfection. 3. Acute pyelonephritis a. Pathogenesis.Predisposing factors are urinary obstruction, vesicoureteralreflux, pregnancy,urethral instrumentation, diabetesmellitus, and other renal pathology. b. Incidence. Women predominate among patients under age40. In later years,there is an increasingincidencein men due to benign prostatic hypertrophy.

270

Pathology

c. Clinical features include fever, malaise, dysuria, frequency, urgency, and costovertebral angle tenderness. Urine shows many WBCs and WBC casts.Urine culture tfpically showsgreater than one million organismsper milliliter. It may be difficult to distinguish rystitis from pyelonephritis, but the presenceof fever, costovertebral angle tenderness,and WBC castsin the urine are helpful in the differential d. Pathology ( 1) Grossly, scatteredyellow microabscesseson the renal surfaceare seen;the lower and upper poles are most commonly involved ("polar abscesses").

ClinicalCorrelate Symptoms offever, costovertebral angle tenderness, andWBC casts distingu ishpyeloneph ritis fromcystitis.

(2) Microscopically, there are foci of interstitial suppurative necrosis and tubular necrosis.Healing is characterizedby a mononuclear cell infiltrate and fibrosis; scarring leadsto deformation of the calfx and pelvis. Blunting of the calycesmay be seenon intravenouspyelogram. e. Complications (1) Necrotizingpapillitis occurs in diabetesand in patients with urinary obstruction. It is characteruedby yellow coagulativenecrotic regionsof the apicalpyramids. (2) \onephrosis (i.e., the filling of the renal pelvis, calyces,and ureter with pus) occurswith completeurinary obstruction. (3) Perinephricabscess refersto the extension of pus through the renal capsulewith abscessformation in perinephric tissue.

Note Anytimethereisfluidstasis, bacteria canmultiply.

4. Chronic pyelonephritis is characterized by interstitial parenchymal scarring, which involves and deforms the calycesand pelvis. a. Pathogenesis (1) Reflux nephropathy is the most common type. It resultsfrom VgR and subsequent infection. (2) Chronic obstructive nephropathy results from infection superimposed on urinary obstruction. b. Clinical features. There may be an insidious or acute onset. Patients present with renal failure and hlpertension. Pyelogramsare diagnostic. Proteinuria is a poor prognostic sign. c. Pathology (1) Gross pathologic examination is the most important. There are irregular scarring and deformed calyceswith overlying corticomedullary scarring. (2) Microscopic examination shows chronic inflammation with tubular atrophy and interstitial fibrosis.Thesefindings are rather nonspecific. 5 . Toxic nephritis a. Acute allergic interstitial nephritis is a hlpersensitivity reaction to infection or drugs (e.g.'NSAIDs, syntheticpenicillins, sulfonamides,furosemide,rifampin), resulting in interstitial edema with a mononuclear infiltrate. Clinic"lly, it presents 2 weeks after exposureto the etiologic agent with hematuria, pyuria, eosinophilia, and azotemia. b. Analgesic nephritis is interstitial nephritis and renal papillary necrosis, induced by large dosesof analgesiccombinations (usuallyphenacetinand aspirin).

27r

RenaflUrinary System

6. Other forms of tubulointerstitial nephritis a. Goutynephropathy is the deposition of urate crystalsin tubules, inducing tophus formation and a chronic inflammatory reaction. Urate crystals appear as birefringent, needle-shapedcrystalson light microscopy. b. Acute urate nephropathy is due to precipitation of crystals in the collecting ducts, causingobstruction. It may be seenin lymphoma and leukemia,especiallyafter therapy,when there is a high rate of nucleic acid turnover. c. Hypercalcemia results in calcium deposition in the kidney and stone formation. d. Multiple myeloma. Some Bence-Jonesproteins are directly toxic to tubular epithelium and also lead to cast formation and urinary obstruction. For unknown reasons, lambda chains are more toxic than kappa chains.

DISEASE VASCUTAR ANDISCHEMIC A. Renal infarcts 1. Pathogenesis.Ischemia may be causedby embolization of mural thrombi or valvular vegetations of the left heart, aortic dissection, or paradoxical embolization from aortic aneurysm. 2. Pathology. There are sharply demarcatedpale regions,usually wedge-shaped,that undergo necrosiswith subsequentscarring. 3. Clinical features. Infarcts may be asymptomatic, or they may causepain, hematuria, and hypertension. B. Diffrrse cortical necrosis 1. Pathogenesis.Disseminatedintravascularcoagulation(DIC) or vasoconstrictioncan lead to ischemia of the entire cortex. 2. Pathology. Ischemic necrosisof the renal cortex may develop. 3. Clinical features are acute anuria and uremia. C. Renal vein thrombosis 1. Pathogenesis.Thrombosis of one or both renal veins may occur.This condition is associated with the nephrotic syndrome, particularly membranous glomerulonephritis, although a causalrelationship is not established.Renal cell carcinoma may also provoke vein thrombosis as a result of direct invasion by tumor. 2. Ctinical features. Thrombosis may present with hematuria, flank pain, and renal failure. 3. Pathology a. Grossly, the kidney is enlarged,and the vein contains a thrombus. b. Microscopically, hemorrhagic infarction of renal tissue is the predominant picture. D. Sickle cell anemia. Blood in the vasa recta tends to sickle in responseto the hlpertonic, hypoxic milieu of the renal medulla. This produces patchy papillary necrosis and occasional cortical scarring.

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UROTITHIASIS A. Incidence. Urolithiasis occurs in up to 60/oof the population; men are affected more often than women. B. Pathogenesis.There is a familial predisposition,which dependson the type of stone. l. Calcium-containing stones (75-80o/o).Most patients have hypercalciuria without hypercalcemia;20o/ohave hlperuricosuria. 2. Magnesium-ammonium phosphate ("struvite") stones (15olo)occur after infection by urea-splitting bacteria (such as Proteus),which transform urea into ammonia. The urine becomesalkaline, resulting in precipitation of magnesium-ammonium phosphatesalts. Thesesaltsform large stones(e.g.,staghorncalculi).

Bddgeto youseeProfeus, When think g urea-spl ittin stoneformi ng, andalkaline urine.

3. Uric acid stones (5olo)are seenin gout, leukemia, and in patients with acidic urine. 4. Cystine stones (1o/o)are associatedwith an inborn error of metabolism (e.g.,cystinuria, an autosomalrecessiveamino acid transport disorder). They are very rare. C. Pathology. Most stones are unilateral and are formed in the calyx, pelvis, and bladder (FigureIII-5-5).

D. Clinical features. Calcium stonesare radiopaque; they are the only ones that can be seenon x-ray. Renal colic may occur if small stonespassinto the ureters,where they may also cause hematuria and urinary obstruction and predisposeto infection.

Figure lll-5-5. Nephrolithiasis (gross).

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RenafUrinary System

ANDHYDRONEPHROSIS OBSTRUCTIVE UROPATHY A. Etiologies include urolithiasis, benign prostatic hypertrophy, pregnancy, neurogenic bladder, tumor, inflammation, and congenital anomalies (e.g., posterior urethral valves, strictures). B. Pathogenesis.Hydronephrosis is the persistenceof glomerular filtration despite urinary obstruction, causingdilation of calycesand pelvis and reabsorption of the filtrate into the vascularsystem.A high pressurein the collecting systemcausesatrophy and ischemia. C. Pathology. There is dilatation of the pelvis and calyceswith blunting of renal pyramids, leading to progressiveparenchymalatrophy (Figure III-5-6). D. Clinical features 1. Unilateral hydronephrosis may remain asymptomaticas the kidney atrophies. 2. Bilateral, incomplete hydronephrosis causesthe patient to lose concentrating ability, causingurinary frequency,polyuria, nocturia, and hypertension. 3. Bilateral, complete hydronephrosis causesanuria, uremia, and death if untreated.

Figure lll-5-6.Hydronephrosis, gross.

TUMORS OFTHEKIDNEY A. Benign tumors 1. Cortical adenomas are a common finding at autopsy.They form 0.5-3.0-cm yellow, encapsulatedcortical nodules.Histologically,they may be identical to renal cell carcinoma and are traditionally distinguishedby size,although small tumors may be invasive.It used to be taught that cortical tumors (3 cm diameter were adenomas.Now CAI scans are finding smallertumors that arebeing removedand demonstratinginvasion on pathological examination.

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Pathology

2. Angiomyolipomas are hamartomas,composedof fat, smooth muscle,and blood vessels. They are particularly common in patientswith tuberous sclerosis. 3. Renal fibroma (hamartoma) is an incidental finding at autopsy.They are small grey nodules within the pyramids. 4. Other benign tumors include hemangiomas, rare renin-producing juxaglomerular cell tumors, and oncocFtomascomposedof eosinophilic cellspackedwith mitochondria. B. Malignant tumors l. Renal cell carcinomas are adenocarcinomas, arising from the proximal convoluted tubule. a. Incidence. They form 90o/oof all renal cancersin adults. Men and women have about equal incidence.They are most common from age50-70. b. Pathogenesis.There is a moderate associationwith smoking and a familial predisposition. This diseaseoccursin two-thirds of patientswith von Hippel-Lindau disease. c. Pathology. Histology may be identical to adenoma,but tumors are prone to metastasesif larger than 3 cm. (1) Grossly, tumors are 3-15 cm yellow lesions found most commonly in the upper pole; they are usually solitary.Commonly, there are areasof necrosisand hemorrhage.The tumor often invadesthe renal vein and extendsinto the vena cavaand even the heart.

Figure lll-5-7. Renal cell carcinoma, gross.

(2) Microscopically, most tumors are composedof clear cellsthat arepolygonal and have abundant clear cytoplasm.There are many patterns (i.e.,papillary,tubular, solid, granular), and cellsmay be fusiform, resemblinga fibrosarcoma. d. Clinical features (1) There is a "classic"triad of hematuria, palpable mass,and costovertebralpain that occursin only |0o/oof cases;hematuria is most important.

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(2) Renal cell carcinomas may remain asymptomatic until they are very advanced. They also may causeparaneoplastic syndromes from ectopic hormone production: polycythemia (erythropoietin production), hypertension (renin production), Cushing syndrome (corticosteroid synthesis),hlpercalcemia (PTH-like hormone), and feminization or masculinization (gonadotropin release). (3) They also may causeamyloidosis,a leukemoid reaction,or eosinophilia. e. Metastases. There is a high incidence of metastasis on initial presentation. Sites include lungs, bones, lymph nodes, liver, adrenals,brain, and the opposite kidney. Metastasesare mainly hematogenousand lymphatic. If a solitary metastatic lesion is present,resectionof the primary tumor and the metastaticlesion may produce a cure. f. Prognosis. Five-year survival depends on stage,but it is especiallypoor (25-50o/o)if the tumor extends into the renal vein. 2. Wilms tumor (nephroblastoma) is a tumor derived from mesonephric mesoderm and composedof epithelium, bone, cartilage,and muscle. a. Incidence. This is a rather common childhood malignancywith peak incidenceat age2. b. Clinical features. Patients present with an abdominal mass as well as hypertension, nausea,hematuria, or intestinal obstruction. Wilms tumor may be associatedwith other congenital anomalies(i.e., aniridia, microcephaly,spina bifida, or hemihlpertrophy of the body). c. Pathology (1) Grossly, most tumors are unilateral but may be bilateral if familial. They make very large, demarcated masses.Cut section reveals grayish, fleshy areas with regions of hemorrhage and cartilage.Ttrmors may rupture through the renal capsule. (2) Microscopically, embryonic glomerular and tubular structures surrounded by mesenchymalspindle cellsmay be seen.Stroma may contain smooth and striated muscle,bone, cartilage,fat, necrotic tissue,and fibrous tissue. (3) Tumor cells contain microdeletions in chromosomes.The genehas been localized to chromosome1lp. d. Metastases.Areasinclude lymph nodes,lungs,liver,and adrenals. e. Prognosis. There is a 90olosurvival rate when patients are treated with surgery, chemotherapy,and radiotherapy. 3. Carcinomas of renal pelvis a. Incidence. Thesenrake up 5-10o/oof primary renal tumors. b. Clinical features. They usually present early with hematuria, and they may cause hydronephrosis and flank pain. c. Pathology. Thesetumors have a papillary configuration similar to transitional cell car cinoma of the bladder with varying degreesof anaplasia.They infiltrate the wall of the pelvis, calyces,and renal vein. d. Prognosis is poor if the tumor has infiltrated.

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Prdrology

URETERS A. Congenital anomalies 1. Double ureters form when ureters join at some point before the junction to the bladder ("Y"-shaped) or enter the bladder separately.This anomaly is associatedwith double rend pelvesor an abnormally large kidney. 2. Aberrant rend vessel. Usually, an aberrant artery arises from a renal artery of the aorta and supplies the lower pole. It may causeureteropelvic obstruction. B. Ureteritis is an inflammation of the ureter, usually as a result of urinary tract infections. 1. Pathology. Erphema and granularity are grossly obvious. 2. Tlpes a. Ulcerative gangrenous ureteritis may be causedby abdominal irradiation. b. Ureteritis follicularis describes subepithelial collections of lymphocytes. c. Ureteritis cystica describessmall mucosal cysts.It results from chronic urinary tract infections. C. Ureteral obstruction results in hydroureter and hydronephrosis. 1. Internal obstruction a. Renal calculi are the most common cause. Th.y usually impact at the ureteropelvic junction, at the entrance to the bladder, and where they cross iliac vessels.Calculi causerenal colic with severepain. b. Strictures may be congenitd or acquired (e.g.,postsurgical,inflammatory). c. Hematomas may result from bleeding in the kidney or proximal ureter. d. Tirmors form intraluminal massesand thickening of the ureteral wall. 2. External obstruction a. Inflammation leads to scar formation. b. Pelvic tunors may compress or invade the ureteral wall. c. Sclerosing retroperitonitis is a fibrosis of retroperitoneal structures, possibly caused by * autoimmune mechanism. Occasionally,it may be drug induced (e.9.,by methysergide,an ergot derivative used in treatment of migraines). d. Pregnancydoes not causeobstruction, but it does causedilation of the ureters by * unknown mechanism. D. Tbmors. Primary tumors are rare. Benign tumors rarely cause obstruction; mdignant tumors are usually associatedwith bladder carcinomas.

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System RenafUrinary

BTADDER A. Congenital anomalies 1. Diverticula are pouch-like evaginationsof the bladder wall. They occur in older men and women. They may lead to urinary stasisand infection. a. Congenital diverticula are due to abnormal development of musculature and are usually single. b. Acquired diverticula result from obstruction of the urethra or bladder neck. 2. Exstrophyof bladder is due to the absenceof the anterior musculature of the bladder and abdominal wall as a result of the failure of down-growth of mesoderm over the anterior bladder. It is usually the site of severechronic infections, ild it leadsto an increasedincidenceof adenocarcinoma. 3. Patent urachus is a fistula that connectsthe bladder with the umbilicus. 4. Urachal cysts are due to the persistenceof the central urachus. Carcinomas may develop in these cysts. B. Cystitis 1. Etiology. Organisms responsibleare usually the patient's fecal flora (e.g.,Escherichiacoli, Less common Proteus,Kebsiella, Enterobacter,Streptococcus faecalis, or Staphylococcus). organisms include Candida albicans, Mycobacterium tuberculosis, Cryptococcus, Trichomonas,viruses, Chlanrydia, and Mycoplasma. 2. Ctinical features. Cystitis causes frequency, urgency, dysuria, and suprapubic pain. Systemicsigns (e.g., fever, malaise,chills) are uncommon with lower urinary tract infections. 3. Pathology a. In acute cystitis, hlperemia developsfirst, followed by a suppurative exudate,leading to a friable, granular mucosa and ulcer formation. (1) Hemorrhagic cystitis is rystitis with marked mucosal hemorrhage. There is often a viral etiology, or it may occur secondary to radiation or chemotherapy (e.g.,ryclophosphamide). (2) Suppurative cystitis describesa marked inflammatory infiltrate with pus. (3) Ulcerative cystitis leadsto marked mucosal ulceration' (a) Membranous cystitis describessolidification of the suppurative exudateto form a pseudomembraneof fibrin and cellular debris. (5) Gangrenous cystitis results in necrosis of the mucosa and, occasionally,underlying tissueswhen ischemiaoccurs. b. Chronic cystitis featuresa mononuclear exudate,fibrosis, and loss of elasticity of the bladder wall. 4. Other types of cystitis a. Cystitis emphysematosaforms submucosalgasbubbles. It occurs mostly in diabetics. b. Encrusted cystitis describesthe precipitation of urinary salts (especiallyphosphates) on the bladder wall. It occurs in an alkaline urine, often produced by urea-splitting organisms such asProteus.

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Pathology

c. Malakoplakia grossly forms soft, broad, yellow plaques in the bladder mucosa, composedof foamy macrophagesand multinucleated giant cellswith concretions. d. Cystitis cystica describescystic mucosal inclusions of transitional epithelium, caused by chronic inflammation similar to those seenin ureteritis rystica. e. Ulcerative interstitial cystitis may arise in chronic cystitis with inflammation and fibrosis throughout the bladder wall. It occursmostly in women. C. Bladder obstruction 1. Etiology a. In men, prostatic enlargementas a result of benign hyperplasiaor carcinoma is the most common cause. b. In women, cystoceleof the bladder is the most common cause. c. Other etiologies include: (1) Congenitalor postinflammatory urethral strictures (2) Fibrosisof the bladder (usually after an episodeof cystitis) (3) Primary or secondarytumors causingcompressionor obstruction (4) Neurogenicbladder (5) Foreignbody or calculus 2. Pathology.Thickening and hlpertrophy of the smooth muscle of the bladder wall leads to trabeculation.This may causethe developmentof diverticula. D. Miscellaneous lesions 1. Fistulas. The most common fistula is a vesicovaginalfistula, which often results from irradiation or malign ancy. 2. Calculi are usually asymptomatic, though they may causeinflammation of the bladder wall. They may form in the bladder or more proximally in the genitourinary tract. E. Ttrmors. Ninety percent of primary bladder neoplasmsare derived from transitional bladder epithelium called urothelium. 1. Papillomas are uncommon and may presentwith hematuria.They form a delicatepapillary projection into the bladder,composedof a central fibrovascularcore coveredby normal urothelium. 2. Carcinomas a. Etiology. Risk factors include: (1) Exposureto industrial chemicalcompounds (the risk may be increased50 times with prolonged exposure) (2) Infection with Schistosomahaematobium (3) Cigarettesmoking b. Types. Transitional cell carcinoma of the urothelium forms 90o/oof cases.Other forms, including squamouscell carcinomasand adenocarcinomas,are rare.

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c. Incidence. Urothelial cell cancercauses3o/oof all.cancerdeathsin the United Statesin both men and women. The peakincidenceis between40 and 60 yearsof age.Therehasbeenan increasingincidencein the last 30 years,probably asa result of cigarettesmoking. d. Clinical features.Bladdercancerusuallypresentswith painlesshematuria.It may also causedysuria,urgency,frequenry,hydronephrosis,and pyelonephritis. e. Pathology dependson the type of cancer;cancersare stagedand classifiedbasedon the degreeof invasion into the tissuelayers. f. Prognosis. Bladder cancerhas a high incidenceof recurrence.The prognosisdepends on grade and stage;overall S-yearsurvival is 30olo. 3. Sarcomasare large polypoid massesthat protrude into the vesicallumen. They are usually leiomyosarcomas.In children, rhabdomyosarcomasmay arise in the prostate and push into the bladder.

URETHRA A. Urethritis presentswith itching, pain, and urinary frequenry.It may be gonococcalor nongonococcal. Organisms responsible for nongonococcal urethritis include Chlamydia, Mycoplasma,and enteric bacteria.Reiter syndrome is the triad of urethritis, arthritis, and conjunctivitis. B. Tumors l. Caruncles are red, small, painful benign massesin the externalurethral meatusof affected women. They are composedof vascularizedfibrous stroma packed with leukocftes. They rarely recur if fully excised. 2. Carcinomas are rare. They occur more frequently in the elderly,arising at the external meatus.They are wart-like, papillary growths, composed of malignant squamouscells, which may protrude into the lumen. They are often causedby papillomavirusesand are increasingin incidence among younger age groups as sexuallytransmitted diseasesin immunocompromisedhosts(i.e.,patientswith AIDS).

280

RenalUrinaryPharmacology (Na*)and promoting primarily Diuretia increase thevolume flowof urine, theexcretion of sodium (Cl) or bicarbonate (HCO,-), either thatis,thoseionsthatconstitute chloride themajorelectrolyte proportional components oftheextracellular fluid.Wat-er iseliminated in anamount to theions excreted, reducing fluid.Clinically, the thevolume of extracellular diuretismaybeusedto decrease fluidin intravascular volume in hypertensive andto mobilize extracellular states excessive edematous Theyfindtheirgreatest usein congestive heartfailure(CHF), cirrhosis with states. ascites, different of diuretia, their andthenephrotic syndrome. Thischapter willdiscuss the types mechanism of action, andtheirclinical uses.

DIURETICS OSMOTIC Osmotic diuretics include mannitol, urea,glycerin,and isosorbide. A. Mechanism of action. Osmotic diuretics are freely filtered at the glomerulus and are subject to little or no renal reabsorption. These agents increase the amount of osmotically active solute in plasma, resulting in expansion of plasma volume. Becausethe agentsare freely filterable, they pass readily into the tubular lumen accompanied by water. The concentration of osmotically active solute in the urine rises and producesa coincident rise in urine volume (FigureIII-6-1). B. Pharmacologic properties 1. Route of administration a. Mannitol is given only intravenously. b. Urea is given intravenously or orally, but it has a bitter taste. c. Glycerin and isosorbide are given orally.

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Note diuretisaremost Osmotic efficient atthelevelofthe proximal tubule, buttheir mechanism of action involves theentire tubule.

Proximaltubule: Osmoticdiuretics acetazolamide

Collectingduct: Spironolactone, amiloride, triamterene

Ascending loopof Henle:Furosemide ethacrynic acid, bumetanide Figure lll-6-1.The sites of action of diuretics.

2. Metabolism a. Mannitol and urea are metabolicallyinert and are excretedunchangedin urine. b. Glycerin is quickly metabolizedto glucose. C. Indications for use 1. Mannitol is used for the prevention and early treatment of acute renal failure causedby trauma or surgery. It may also be used to temporarily decreasecerebrospinalfluid pressure. 2. Mannitol, glycerin,and isosorbidetransiently decreaseintraocular pressureand are used in the treatment of acutenarrow (closed)angle glaucoma. 3. Urea and mannitol have similar osmotic properties,but urea is used much lessfrequently. 4. Clinical use of glycerin and isosorbideis limited to ophthalmologic procedures. D. Side effects and toxicity 1. Headache,nausea,and vomiting are commonly seenwith all osmotic diuretics. 2. Initial plasmavolume expansioncan causedecompensationin patientswith CHF. 3. Pseudohlponatremiais seenwith mannitol. 4. Urea may causethrombosis. 5. Glycerin may causehyperglycemia and glycosuria.

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Pharmacology

AND ACETAZOTAMIDE INHIBITOR: ANHYDRASE CARBONIC DORZOTAMIDE the reaction: A' Mechanism of action' carbonic anhydrasecatal4rzes CO2 + H2O -+ H+ + HCO3Hydrogen ions are normally secreted in the nephron in exchange for filtered Na+. Acetazolamideblocks carbonic anhydraseand inhibits the exchangeof H+ for Na+ in the proximal convoluted tubule, thus interfering with reabsorptionof Na+ and HCO3-. B. Pharmacologic properties l. Acetazolamidehas weak diuretic action, and actson the proximal tubule. 2. IncreasedNa+, K+, and HCO3- are excretedin urine. C. Indications for use 1 Acetazolamideis used primarily in the treatment of glaucoma. It decreasesocular pressure by reducing aqueoushumor formation. 2. Alkalinization of the urine for diuresisof weak acids (e.g.aspirin intoxication). 3. It may be usedasan adjuvant in the treatment of epilepsy,although useis limited because tolerancedevelops. 4. It may alsobe used for prophylaxisand treatment of acutemountain sickness. 5. Metabolic alkalisisfrom thiazides. D. Side effects and toxicity

Note in Diuretia thatresult loadinthe sodium increased tubule/early latedistal an ductcause collecting antiport in Na*/K* increase resulting in potassium activity, H* losses aswellasincreased hence the secretion, andmetabolic hypokalemia with associated alkalisis andloopdiuretia. thiazide

and transient myopia. 1. CNS effectsinclude drowsiness,paresthesias, 2. Metabolic acidosisoccursdue to decreasedHCO3- reabsorption. 3. Other possibleside effectsinclude hypokalemia, rare hypersensitivity (e.g., rash, fever, bone marrow suppression),and renal calculusformation.

DIURETICS THIAZIDE Thiazide diuretics include chlorothiazide, hydrochlorothiazide, benzthiazide, indapamide and metolazone. A. Mechanism of action. Thiazidesare sulfonamide derivativesthat promote diuresisby inhibiting reabsorption of NaCl, primarily in the early distal tubule. IncreasedNa+ load to the distal tubule also promotes increased K+ secretion into urine (Na+/K+ exchange).Thiazides inhibit an electroneutralNa+/Cl- cotransporteron the membraneof early distal cells. B. Pharmacologic properties 1. Thiazidescauseincreasedrenal excretion of Na+, Cl-, K+, and Mg2+, and promote Ca2+ reabsorption. 2. Thiazides are actively secreted,unchanged,in the proximal tubules. 3. Variablecarbonicanhydraseinhibition occurs,but this is not the primary mode of action. C. Indications for use 1. Thiazidesare a mainstay of treatment for mild hypertension.

28t

Renal/Urinary System

2. They are used alone or in combination with other agentsfor diuresis of edema (especially in CHF). 3. Thiazidesreducehypercalciuriain patientswith calcium-containingrenal calculi. 4. Thesedrugs can alsobe used in the treatment of diabetesinsipidus. D. Side effects and toxicity include hypokalemia (especiallydangerous in patients on digitalis preparations),hyperuricemia, hypercalcemia,hyperglycemia(in diabetics),rashes,photosensitivity reactions,fever,hyperlipidemia (except indapamide), and sexualdysfunction.

IOOPDIURETICS Loop diuretics include ethacrynic acid, furosemide, bumetanide, and torsemide. A. Mechanism of action. Theseagentsinhibit reabsorption of electrolytes(Na*, K+, Cl-) in the thick ascending limb of the loop of Henle by blocking the Na+/K+/2Cl- cotransporter. B. Pharmacologic properties 1. These are the most effective diuretics. The ascendinglimb of the loop of Henle has the highest level of NaCl reabsorption by a single mechanism for which an inhibitor exists; therefore, a block at this site results in markedly increasedelectrolyte and water excretion and preventsmedullary concentrationgradient. 2. Increasedexcretion of Na+, Kt, Ca2*,and Mg2+ is seen. 3. Loop diuretics are administeredorally or intravenously. 4. They have a rapid onset of action (30 minutes after oral administration; 5 minutes after intravenousadministration). C. Indications for use 1. Edematous states. CHF with pulmonary edema, liver failure, and renal failure all cause edematreatableby loop diuretics.Thesedrugs are used intravenouslyfor the treatment of acutepulmonary edema. 2. Hlpertension. These drugs are generally too potent for mild hypertension. 3. Hypercalcemia D. Side effects and toxicity

ClinicalCorrelate Loopandthiazide diuretics canbeusedtogether to promote a brisk diuresis. However, this combination alsoproduces signif icant hypokalemia.

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1. The most common side effectsinclude hypotension (secondaryto volume depletion), hypokalemia, metabolic alkalosis,hyperuricemia, ototoxicity (characterizedby transient or permanent deaftress,especiallywith intervenous ethacrynic acid), allergic interstitial nephritis, hyperglycemia(lesserdegreethan with thiazides),and gastrointestinaldisturbances(especiallywith ethacrynicacid). 2. Drug interactions a. Oral hypoglycemics. Loop diuretics causea decreasedhypoglycemic effect. b. Lithium. Chronic administration of loop and thiazide diuretics decreasesrenal lithium clearance. c. Aminoglycosides. Increasedototoxicity and nephrotoxicity (an additive effect) are seen.

Pharmacology

POTASSIUM.SPARI NGDIURETICS

ln a Nutshell

Potassium-sparingdiuretics include spironolactone, triamterene, and amiloride.

. Freely Osmotic filtered, diurdics(mannitoD notreabsorbed . Expand plasma volume Acetazolamide . Inhibits carbonic anhydrase . Interferes with Na*andHCOrreabsorption . Used primarily in glaucoma . lnhibit Thiazides (hydrodordiazftle) reabsorption of NaClin early distal tubule . Used to treatmild hypertension . Block Loopdiuretics (furosemide) Na*/K*/2Clreabsorption in thickascending limb . Used primarily in treatment of edematous $ates . lnhibit PohsiumNa* sparing diuretia reabsorption and (spironolactone) K'secretion in collecting tubule. Spironolactone alsodirectly blocks aldosterone

A. Mechanism of action 1. Theseagentsact on the collectingtubule to inhibit the reabsorptionof Na+ and the secretion of K+. 2. Spironolactone directly blocks aldosteroneaction by competitively binding to its receptor (a structural analog). 3. Tiiamterene and amiloride directly inhibit the reabsorption of Na+, which indirectly inhibits the secretionof K+. They are not aldosteroneantagonists. B. Pharmacologic properties l. Spironolactoneis absorbed orally and metabolized in the liver. Spironolactone'seffect requiresthe presenceof endogenousaldosterone. 2. Amiloride and triamterene work independently of aldosteronelevels. C. Indications for use 1. Combination therapy. These drugs are used in combination with potassium-losing diuretics (usually thiazides)to maintain proper K+ balance. 2. Edematous states. These drugs are especiallyusefi.rlin the presenceof high aldosterone levels(e.g.,hepatic cirrhosis,nephrotic syndrome,cardiacfailure). 3. Diagnosis and treatment of primary hlperaldosteronism (spironolactone) 4. Tieatment of polycystic ovary diseaseand female hirsutism (spironolactone) D. Side effects and toxicity 1. Spironolactone. Hyperkalemia, gynecomastia,nausea,and dyspepsiaare side effects. 2. Tiriamterene. Side effectsinclude hyperkalemia,nausea,vomiting, leg cramps, and megaloblastic anemia in patients with alcoholic cirrhosis (due to inhibition of dihydrofolate reductasein patients with reducedstoresand intake of folic acid). 3. Amiloride. Side effects are hlperkalemia, nausea,vomiting, diarrhea, and headache.

VASoPRESST N (ADH)ANTAGON rSTS A. Demeclocycline antagonizesADH action, an effect that is used for the therapy of the syndrome of inappropriateADH secretion(SIADH). B. DecreasedADH is a side efifectof both lithium use (nephrogenicdiabetesinsipidus) and alcohol ingestion.

Note Certain drup cancause SIADH, including carbamazepine, thiazides, ic certain tricycl phenothiazi antidepressanb, net chlorpropamide, andcisplatin.

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rv sEcTroN

phoreticu lar logic/tym Hemato System

Hematol lar ogiclLymphoreticu Histology Note Blood in origin, it iscomposed isconsidered a modified typeof connective tissue. Mesodermal of (erythrocytes, platelets), proteins (fibrinogen cellsandcellfragments leukocytes, fibrous + fibrin (plasma). ground during clotting), andanextracellular amorphous substance offluidandproteins Bloodcarries awayfromcellsto the oxygen andnutrients to allcellsofthebodyandwaste materials kidney aswellashumoral andlungs. lt alsocontains cellular oftheimmune system factors. elements Thischapter willreview thedifferent bywhichtheyareformed. elements of bloodandtheprocesses

FORMED ELEMENTS OFTHEBLOOD The formed elementsof the blood include erythrocytes,leukocytes,and platelets. A. Erythrocytes, or red blood cells (RBCs), are important in transporting oxygen from the lungs to tissuesand in returning carbon dioxide to the lungs. Oxygen and carbon dioxide carried in the RBC combine with hemoglobin to form oxyhemoglobin and carbaminohemoglobin, respectively. l. Mature erythrocytesare denucleated,biconcavediskswith a diameter of 7-8 pm. a. The biconcave shape results in a 20--30o/oincrease in surface area compared to a sphere. b. Erythrocytes have a very large surface area:volume ratio that allows for efficient gas transfer. 2. Erythrocfte membranes are remarkably pliable, enabling the cells to squeezethrough the narrowestcapillaries.In sickle cell anemia,this plasticity is lost, and the subsequentclogging of capillariesleadsto sickle crisis. 3. The normal concentrationof erythrocftes in blood is 3.5-5.5 million/mm3 in women and 4.3-5.9 millionimm3 in men. Higher counts in men are attributed to the erythrogenic effect of androgens. 4. The packed volume of blood cells per total volume of blood is known as the hematocrit. Normal hematocrit values are 36460/ofor women and 41-53o/ofor men. 5. When aging RBCsdevelopsubtle changes,macrophagesin the bone marrow spleen,and liver engulf and digestthem. The iron and heme of hemoglobin are rerycled.The iron is carried by transferrin in the blood to certain tissues,where it combineswith apoferritin to form ferritin. The heme is catabolizedinto biliverdin, which is convertedto bilirubin. The latter is secretedwith bile salts.

probably You've noticed that thereisnoseparate Hemeilymph Embryology chapter. Thekeyinformation forStepI relates to sitesof hematopoeisis throughout development, Thisisdiscussed previous inthe Cardiovascular Embryology chapter. In a Nutshell Erythrocytes . Biconcave 7-Bum in disks diameter . Nonucleus . Nomembrane-bound (including organelles mitochondria) . Rely on completely anaerobic metabolism (glycolysi$ - 120days . Lifespan.

Bridgeto Biochemistry istheresult Sickle cellanemia pair of a single base substitution leading to the substitution valine for of glutamic acidatthe6th position of oftheB subunit hemoglobin.

B. Leukocytes, or white blood cells (WBCs), are primarily involved with the cellular and humoral defense of the organism against foreign materials. Leukocytes are classified as

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Hematologic/lymphoreticular System

ClinicalCorrelate C6PD deficiency results in hemolysis secondary to J NADPH andtheinability to maintain theRBC membrane integrity. lt isinduced bysulfa drugs, favabeans, and oxidants.

Note Neutrophils with>5lobes are called hypersegmented. They typically represent oldcells. In somepathological states, immature neutrophils can appear with5 or morelobes. ClinicalCorrelate Eosinophilia (anincrease in theabsolute number of eosinophils) isassociated with parasitic infection, allergy, asthma, andsomeneoplasms.

Note . Basophils maysupplement thefunctioning of mastcells in typeI (immediate hypersensitivity) immune resp0nse. . Remember thatmastcells donotcirculate in bloodtheyarefoundin connective tissuetusually inassociation withbloodvessels.

290

granulocytes (neutrophils' eosinophils,basophils) and agranulocrtes (lymphocytes, monocftes). 1' Granulocrtes are named accordingto the staining properties of their specificgranules. a. Neutrophils are 10-16 pm in diameter. (l) They have 3-5 nuclear lobes and contain azurophilic granules (lysosomes), which contain hydrolytic enrymesfor bacterial deitruction, in their cytoplasm. specific granulescontain bactericidalenzymes(e.g.,rysozyme). (2) Neutrophils are phagocytesthat are drawn (chemotaxis) to bacterial chemoattractants. They are the primary cells involved in the acute inflammatorv responseand represent54_620/o of leukocytes. b. Eosinophils (1) They have a bilobed nucleusand possessacidophilic granulationsin their cytoplasm.Thesegranulescontain hydrolytic enzymesand peroxidase, which are dischargedinto phagocyticvacuoles. (2) Eosinophils are more numerous in the blood during parasitic infections and allergicdiseases; they normally representonly !-3o/ooi l.,rkoryr.r. c. Basophils ( 1) They possesslarge spheroid granules,which are basophilic and metachromatic, due to their content of proteoglycansand to heparin, a glycosuminoglycan. Their granulesalso contain histamine. (2) Basophilsdegranulatein certain immune reactions, releasingheparin and histamine into their surroundings. They also releaseadditional vasoactive amines and slow-reactingsubstanceof anaphylaxis(SRS-A) consistingof leukotrienes LTC4'LTD4,and LTE*.They representlessthan lo/o ofleukocytes. 2. Agranulocytes are named accordingto their lack of specificgranules. a' Lymphocytes are generallysmall cellsmeasuring7-10 pm in diameter and constitute 25-33o/oof leukocytes.They contain circular dark-stained nuclei and scantyclear blue cytoplasm. Circulating lymphocytes enter the blood from the lymphatic tissues.Two principal types of immunocompetent lymphocytescan be identified using immunologic and biochemicaltechniques:T lymphocytesand B lymphocFtes. (1) T cells differentiate in the thymus and then circulate in the peripheral blood, where they are the principal effectors of cell-med.iated immunity. They also function as helper and suppressor cells by modulating the immune response through their effect on B cells,plasma cells,macrophage-s, and other T cells. (2) B cells differentiatein bone marrow and possiblyin the gut-associatedlymphatic tissues-(GAIT). They are the principal mediators Lf h,r-oral immunity through their production of antibodies. bnce activatedby contact with an antigen, they differentiate into plasma cells, which synthesizeantibodies that are secretedinto the blood, intercellular fluid, and lymph. B lymphocytes also give rise to memory cells, which differentiateinto plasma cells'oniy after the ,ecJrd exposureto the antigen. They are responsiblefor the secondary, or amnestic resPonsethat occurswhen the body is exposedto an antigen for a secondtime. b' Monocytes vary in diameter from 15-18 pm and are the largest of the periphera1 blood cells.They constitute 3-7o/oof leukocytes.

Histology

(1) Monocytespossessan eccentricU-shapedor kidney-shaped nucleus. The cytoplasm has a ground-glassappearanceand fine azurophilic granules. (2) Their nuclei stain lighter than lymphocyte nuclei because of their loosely arrangedchromatin. (3) Monocytes are the precursors for members of the mononuclear phagocyte system, including tissue macrophages (histiocytes), osteoclasts, alveolar macrophages,and Kupffer cells of the liver. C. Platelets (thromboplastids) are 2-3 pm in diameter. 1. They are anuclear,membrane-bound cellular fragments derived by cytoplasmic fragmentation of giant cells,called megakaryocytes, in the bone marrow.

In a Nutshell T cells+ cell-mediated immunity: . Differentiate in thymus . Helper T cell(CDa) . Cytotoxic T cell(CDB) . Suppressor T cell

3. There are normally 150,000-400,000plateletsper mm3 of blood.

B cells-+ humoral immunity: . Differentiate in bone marrow

4. Ultrastructurally, plateletscontain two portions: a peripheral,light-staining hyalomere that sendsout fine cytoplasmic processes,and a central, dark-staining granulomere that contains mitochondria, vacuoles,glycogengranules,and granules.

. Onceactivated byantigen + plasma cells(make + memory antibodies) cells

5. Plateletssealminute breaksin blood vesselsand maintain endothelial integrity by adhering to the damagedvesselin a processknown asplatelet aggregation. Plateletsare able to form a plug at the rupture site of a vesselbecausetheir membranepermits them to agglutinateand adhereto surfaces.

. Memory cells+ plasma cells aftersecond exposure to antigen

6. Plateletsaggregateto set up the cascadeof enrymatic reactions that convert fibrinogen into the fibrin fibers that make up the clot.

Bridgeto Physiology

2. They have a short life span of approximately 10 days.

PLASMA Plasmais the extracellularcomponent of blood. It is an aqueoussolution containing proteins, inorganic salts,and organic compounds. A. Albumin is the major plasma protein that maintains the osmotic pressureof blood. Other plasma proteins include the globulins (alpha, beta, gamma) and fibrinogen, which is necessary for the formation of fibrin in the final step of blood coagulation. B. Plasmais in equilibrium with tissueinterstitial fluid through capillary walls; therefore,the composition of plasmamay be used to judge the mean composition of the extracellularfluids. Large blood proteins remain in the intravascularcompartment and do not equilibrate with the interstitial fluid. C. Serum is a clearyellow fluid that is separatedfrom the coagulumduring the processof blood clot formation. It has the samecomposition as plasma,but lacks the clotting factors (especially fibrinogen).

TheStepsof Hemostasis . Primary aggregation plug) (formation of platelet . Secondary aggregation (platelets release crand6 granules thatpropagate the plug.ADPisa potent inducer) . Blood (clotting coagulation cascade) . Clotretraction . Clotremoval (viaplasmin) isdiscussed in Thisprocess intheHematologic/ detail phoreticu larPhysiology Lym chapter.

291

Hematologic/tymphoreticular System

ln a Nutshell Lymph capillaries

J Thinlymph vessels ,/\ Thoracic RLymphatic duct duct

JJ Junction of Junction of L internal Rinternal jugular and jugular and L subclavian Rsubclavian

Note = -20/oplasma Lymph fluidtheamount extruded through thecapillaries isgreater than theamount theveins reabsorb. Therefore, thefluid (no remains intheinterstitium RBCs, lymphocyte$. Lymph flowsthrough lymphnodesimmune system surveillance forantigens.

Note Theprocess oferythropoiesis ischaracterized by3 trends: a progressive J incellsize, a progressive lossof organelles, andaprogressivetin cytoplasmic concentration of hemoglobin.

TYMPHATIC VESSETS Lymphatic vesselsconsist of a fine network of thin-walled vesselsthat drain into progressively larger and progressivelythicker-walled collecting trunks. These ultimately drain, via the thoracic duct and right lymphatic duct, into the left and right subclavian veins at their anglesof junction with the internal jugular veins,respectively.The lymphatics serveas a one-way (i.e., toward the heart) drainagesystemfor the return of tissuefluid and other diffirsible substances, including plasma proteins, which constantly escapefrom the blood through capillaries.They are alsoimportant in servingasa conduit for channelinglymphocytesand antibodiesproduced in lymph nodes into the blood circulation. A. Lymphatic capillaries consist of vesselslined with endothelial cells, which begin as blindended tubules or sacculesin most tissuesof the body. Endothelium is attenuatedand usually lacksa continuous basallamina. B. Lymphatic vesselsof large diameter resembleveins in their structure but lack a clear-cut separation between layers.Valves are more numerous in lymphatic vessels.Smooth muscle cells in the media layer engagein rhythmic contraction, pumping ly-ph toward the venous system.Smooth muscleis well-developedin large lymphatic ducts. C. Circulation of lymph is slower than that of blood, but it is nonethelessan essentialprocess. It hasbeen estimatedthat in a single day,50o/oor more of the total circulating protein leaves the blood circulation at the capillary level and is recapturedby the lymphatics. D. Distribution of lymphatics is ubiquitous with some notable exceptions,including epithelium, cartilage,bone, central nervous system,and thymus.

HEMATOPOIETIC TISSUE Hematopoietic tissue is composed of reticular fibers and cells,blood vessels,and sinusoids (thin-walled blood channels).Myeloid, or blood cell-forming tissue,is found in the bone marrow and provides the stem cells that develop into erythrocytes, granulocytes, agranulocFtes, and platelets.Redmarrow is characterizedbyactivehematopoiesis;yellow bone marrow is inactive and containsmostly fat cells.In the human adult, hematopoiesistakesplacein the marrow of the flat bones of the skull, ribs and sternum, the vertebral column, the pelvis, and the proximal ends of somelong bones. A. Erythropoiesis is the processof RBC formation. Bone marrow stem cells (colony-forming units, CFUS) differentiate into proerythroblasts under the influence of the glycoprotein erythropoietin, which is produced by the kidney. l. Proerythroblast is a largebasophilic cell containing a large sphericaleuchromaticnucleus with prominent nucleoli. 2. Basophilic erythroblast is a strongly basophilic celi with a nucleus that comprisesapproximately 75o/oof its mass.Numerous cytoplasmic polyribosomes,condensedchromatin, no visible nucleoli, and continued hemoglobin synthesisare characteristicsof this cell. 3. Polychromatophilic erythroblast is the last cell in this line that undergoesmitotic divisions.Its nucleuscomprisesapproximately50o/oof its massand containscondensedchromatin, which appearsin a "checkerboard"pattern. The polychromasiaof the cytoplasmis due to the increasedquantity of acidophilic hemoglobin combined with the basophiliaof the cytoplasmicpolyribosomes. 4. Normoblast (orthochromatophilic erythroblast) is a cell with a small heterochromatic nucleusthat comprisesapproximately25o/oof its mass.It contains acidophilic cytoplasm

292

Histology

becauseof the large amount of hemoglobin and degeneratingorganelles.The pyknotic nucleus,which is no longer capableof division, is extruded from the cell. 5. ReticulocFte (polychromatophilic erythrocyte) is an immature acidophilic denucleated RBC, which still contains some ribosomes involved in the synthesisof a small quantity of hemoglobin. Approximately |o/o ofthe circulating RBCsare reticulocytes. 6. Erythrocyte is the mature acidophilic and denucleatedRBC. Erythrocytes remain in the circulation approximately 120 days and are then recycledby the spleen,liver, and bone marrow. B. Granulopoiesis is the processof granulocyteformation. Bone marrow stem cellsdifferentiate into all three tfpes of granulocytes(Figure IV-1-1). l. Myeloblast is a cell that has a largesphericalnucleuscontaining delicateeuchromatin and severalnucleoli. It has a basophilic cytoplasm and no granules.Myeloblastsdivide and differentiate to form smaller promyelocftes.

Clinical Correlate of blood Thenumber isa sensitive reticulocytes activity indexof bonemarrow with butmustbeinterpreted The respect to thehematocrit. countwillbe reticuloryte dueto in anemias decreased (e.g., marrow underproduction butwillbe irondeficiency), secondary in anemias elevated (e.g., to RBC destruction hemolytic anemias).

2. Promyelocyte is a cell that contains a large spherical indented nucleus with coarse' condensedchromatin. The cytoplasm is basophilic and contains peripheral azurophilic granules. 3. Myelocyte is the last cell in this seriescapableof division. The nucleusbecomesincreasingly heterochromaticwith subsequentdivisions. Specificgranulesarise from the Golgi apparatus,resulting in neutrophilic, eosinophilic,and basophilic myelocytes. 4. Metamyelocyte is a cell whose indented nucleus exhibits lobe formation that is characteristic of the neutrophil, eosinophil, or basophil. The cytoplasm contains azurophilic granulesand increasingnumbers of specificgranules.This cell doesnot divide. 5. Granulocytes are the definitive cells that enter the blood. Neutrophilic granulocytes exhibit an intermediatestagecalledthe band neutrophil. This is the first cell of this series to appearin the PeriPheralblood. a. It has a nucleusshapedlike a curved rod or band.

Clinical Correlate percentage of Anelevated is an bandneutrophils ofa indicator important suchas systemic stress, to infection. Thisisreferred or described asbandemia asa "left-shift."

b. Bands normally constitute 0.5-2o/oof peripheral WBCs; they subsequentlymature into definitive neutrophils.

29'

Hematologic/Lymphoreticular System

Early basophilic

My eloblas t

Promyelocyte

Late basophi l i c myelocyte

E osi nophi l i c myelocyte

Early neutrophilic myelocyte

N eutrophi l i c metamyelocyte

E osi nophi l i c metamyelocyte

Neutrophil with band-shaped nucl eus

B asophil

E osi nophil

N eutrop hil

Figure lv-l-1. Granulopoiesis.

Note Themainfeature of lymphopoiesis isa progressive decrease in cellsize. Monopoiesis ischaracterized bya reduction in cellsizeand progressive indentation of thenucleus.

C. Agranulopoiesis is the processof lymphocyte and monocyte formation. 1. tymphocytes developfrom bone marrow stem cells(lymphoblasts). a. B cells developin bone marrow and seedthe secondarylymphoid organs(e.g.,tonsils, lymph nodes,spleen). b. Stem cells for T cells come from bone marrow develop in the thymus and, subsequently,seedthe secondarylymphoid organs. 2. Promonocytes differentiatefrom bone marrow stem cells (monoblasts)and multiply to give rise to monocftes. a. Monocytesspendonly a short period of time in the marrow beforebeing releasedinto the bloodstream. b. Monocytesare transportedin the blood but are also found in connectivetissues,body cavities,and organs. c. Outsidethe blood vesselwall, they are transformed into macrophagesof the mononuclear phagocytesystem. D. Thrombopoiesis, or the formation of platelets,occursin the red bone marrow. 1. Megakaryoblastis a large basophiliccell that containsa U-shapedor ovoid nucleuswith prominent nucleoli. It is the last cell that undergoesmitosis.

294

Histology

2. Megakaryocytes are the largest of bone marrow cells,with diameters of 50 pm or greater. They undergo 4-5 nuclear divisions without concomitant cftoplasmic division. As a result, the megakaryocyteis a cell with polylobulated, polyploid nucleus and abundant granules in its cytoplasm. a. As megakaryocfte maturation proceeds,"curtains" of platelet demarcation vesicles form in the cytoplasm. Thesevesiclescoalesce,become tubular, and eventually form platelet demarcation membranes. b. Thesemembranesfuse to give rise to the membranesof the platelets. c. A single megakaryocytecan shed (i.e.,produce) up to 3,500platelets.

295

Hemato IogiclWmphoreticular Anatomy Thisverybriefchapter highlights theanatomy ofthespleen andthelymphatia thatdrainthe posterior wall.Lymphatic iscovered intheanatomy abdominal drainage of individual organs oftheirrespective organsystems sections

SPTEEN A. The spleen lies in the left hypochondriac region, where it is protectedby the rib cage.It is coveredby peritoneum. B. The gastrolienal ligament connectsthe hilus of the spleento the stomach,and the lienorenal ligament attachesthe hilus to the region of the left kidney. The splenic vesselspass through the lienorenal ligament.

TYMPHATICS Drainagefor eachparticular structure is discussedin relation to the structure in other sections of the notes. A. Lymphatics of posterior abdominal wall 1. Lumbar nodes drain the posterior wall, kidneys, ureters,gonads in both sexes,and the uterus and oviduct in women. Thesenodes alsodrain the hindgut, pelvis,and lower limb structuresby way of inferior mesentericand common iliac nodes.Efferentsfrom the lumbar nodes form the lumbar trunks, which drain to the cisternachyli. 2. Cisterna chyli is the dilated initial portion of the thoracic duct, which lies near vertebrae Ll and Lz.It may be rudimentary or altogetherabsent.The cisternachyli receiveslymph from the lumbar trunks and the intestinal trunk. 3. Thoracic duct receivesall the lymph from below the diaphragm from the left upper limb, left side of the head and neck,and left-sidedthoracic structures,exceptfor the lower lobe of the left lung. It begins at the cisternachyli and passesto the thorax through the aortic orifice of the diaphragm.The thoracic duct terminatesat the junction of the left internal jugular and left subclavian veins. The right lymphatic duct receiveslymphatic drainage from the right upper limb, the right side of head and neck, the right side of the thorax, and the lower lobe of the left lung. It terminates at the junction of the right internal jugular and right subclavianveins.

297

phoreticular Hematol ogiclLym Physiology Hemostasis istheprevention of bloodflow.Thehemostatic of bloodlossandthemaintenance include vascular spasm, formation mechanisms involved whena bloodvessel isruptured orsevered plug,bloodcoagulation, intotheclotto close andgrowth offibrous tissue thehole of a platelet permanently. inthelmmunology Thefunctioning ofthelymphoreticular system isreviewed section Bookt (Volume l). of Ceneral Principles Bridge To Histology

VASCUTAR SPASM When a vesselis severed,the loss of pressureresulting from the decreasingblood flow causesa reflex contraction of both circular and axial smooth muscle.This resultsin constriction of the vesselto limit blood loss,plus retraction of the vesselinto the surrounding tissue,protectingthe severedend from exposureto foreign materials. A. The more the vesselis traumatized,the more vascularspasmoccurs;thus, a sharply cut vessel often bleedsmore than a vesselruptured by crushing. B. In capillaries,flow is controlled by a precapillary sphincter that closesif the capillary pressure drops below a critical level. C. Vascularspasmis influenced by neural and humoral factors. 1. Injury stimulatesthe sympatheticnervous systemto produce vasoconstrictionover and abovethat resulting from myogenicreflexes. 2. lnjury leadsto a local releaseof vasoactiveagents,which leadsto further constriction. 3. Blood loss into a tissue (hematoma formation) can causethe local tissue pressureto increase,thereby slowing further blood loss.

PTATETET PIUGFORMATION Plateletsare cellular fragments derived from megakaryocytesin the bone marrow. Under normal conditions, they play an important role in the maintenanceof the endothelial lining of blood vesselsby rapidly repairing small breaks.Upon injury to a vessel,they quickly form a temporary platelet plug in the vesselwall to stem the flow of blood until a more permanent repair can be made.Plateletplug formation occurs in severalsteps: A. Adhesion.A breakin the vesselwall exposescollagenfibersin the endothelialbasementmembrane and underlying connectivetissue.The positively chargedamino acid residues(lysine and hydroxylysine)in the fibers attract nearby platelets,which adhere strongly to the cut surfaces.Plateletadhesionrequiresvon Willebrand factor (vWF), a plasmaprotein that circulatesin a complexwith factor VIII and binds to the plateletmembraneglycoproteinGPlb.

RedCellShape Theredbloodcell,the biconcave disk, hasa unique property. functional lt can change volume considerably without itssurface changing area. Thecellshape, commonly referred to asthe biconcave disk,hasthe geometric formoftheOvalof Cassini. Thisshape canevolve fromtheLemniscate of (actually Bernoulli a torus) where surfaces thebiconcave all actually on the inside touch thewayto theshape of a its changing sphere without the surface Thispermits area. redcellto wellwithosmotic pressure above its to 500/o normal without volume (lysis). the bursting Because surface areadoesnotchange appreciably thereisnostress leading onthecellmembrane to a rupture.

299

Hematologic/tymphoreticular System

B. Aggregation. The increasedturbulence in the areaof injury, along with secretionsreleased by the initially adhering platelets,leadsto the attraction of more platelets,which aggregate with those attachedto the injury site. 1. ADP is releasedfrom plateletsand promotes aggregation. 2. ThromboxaneA, (TxAr) is synthesizedbythe plateletsand promotesplateletaggregation. 3. Prostacyclin(PGIr) is synthesizedby blood vesselendothelial cells and inhibits platelet aggregation. C. Platelet swelling and release reaction. As soon as they adhere to the cut surface,platelets undergo a dramatic changein their morphology, which includes swelling and the assumption of an irregular shape,with numerous spiny processesprotruding from their surfaces. Thesechangesseemto make them sticky so that they adheremore readily to the injury site and to eachother. The result of this large accumulationof plateletsis to form a plateletplug over the injury site.As the plateletsundergo thesechangesthey releaseseveralproducts. 1. Adenosine diphosphate (ADP), a powerful inducer of platelet aggregation,which strengthensthe platelet plug by the addition of more activatedplatelets. 2. Calcium, an essentialfactor to increasethe degreeof aggregationand to strengthenthe plateletplug. 3 Vasoactiveamines, including serotonin, epinephrine, and kinins, all of which promote local vasoconstriction. 4. Thromboplastin, which initiates a seriesof reactionsresulting in the formation of a permanentclot. 5. Platelet factor 3 (PF3), which is involved in plasmacoagulation. D. Summary. The looseplateletplug is usually strong enough to stop the lossof blood. A more permanent sealis formed when the processof blood coagulation further altersthe platelets to bind them tightly together with fibrin and to anchor them firmly to the vesselwalls. The final stepin the processis clot retraction, which is due to a contraction of contractile (actin) proteins within the platelets.If the damageto a vesselis small, the platelet plug alone can stop the blood loss completely.With a larger hole, blood coagulation is also essential.The plateletplugging processis extremelyimportant in closingthe minute ruptures in small vesselsthat occur hundreds of times daily.A deficienry of plateletscan lead to many small hemorrhagic areasunder the skin.

PTASMA COAGUTATION The third mechanismin hemostasisis blood clot formation, which beginswithin 15-20 secondsin a severeirj.try and within 1-2 minutesin a minor one.Coagulationmaybe divided into threestages: A. Initiation by formation of prothrombin activator. Tiauma to the tissuesor to the blood vesselsor contact of the blood with collagenleadsto the formation of prothrombin activator. Either of two basicpathways,both involving a seriesof plasmaproteins known asclotting factors, may be involved: the intrinsic pathway, in which coagulation begins in the blood, and the extrinsic pathway, which begins with trauma to tissuesoutside the blood vessel. B. The coagulation cascadeshowing both intrinsic and extrinsic pathwaysis outlined in Figure IV-3 -1 . C. Extrinsic mechanism of clotting. When a liquid extract of any tissue is added to plasma, rapid clotting occurs.

500

Physiology

1. Damagedcclls releasetwo initiators of clotting, tissue thromboplastin (factor III) and tissuephospholipids. 2. Tisue thromboplastin,alongwith calcium,forms a complexwith factorVII, which, in the presenceof tissuephospholipids,actson factor X to form activatedfactor )C 3. Activatedfactor X, alongwith tisue phospholipidsand factorY form the complexprothrombin aAivator. D. Intrinsic mechanismof clotting This mechanismbeginswith trauma to the blood itself, usuallywhen it comesin contactwith the damagedvessel.The following eventsthen occur: l. PlateletsreleasePF3 (platel€tphospholipids)and calcium.Factor XII (Hagemanfactor) is activatedon contactwith the collagenat the sit€of injury. 2. Activatedfuctor xII actson factor xr to activat€it. 3. Activatedfactor XI actson factor IX (Christmasfactor) to activateit. 4. Activatedfactor Ix, actingtogetherwith factorvlII andwith plateletphospholipids,acti* vatesfactorx.

GiniOl GOffelah Clinically, theintrinsic system canbeassessed bymeasurinS ne pamar mromDopras[n time(PTD;theextrinsic systern is monitored usingthe prothrombin time(pD.

5. ActivatedfactorX combineswith factorV andplatel* phospholipidsto form the complex prothrombin activator.This stepis the samein both intrinsic andextrinsicmechanisms.

Intrinsic Pathway

Extrinsic Pathway

I

Contact of blood with collagen I

+ xilv Xlla

n

Traumato tissues

I

Xla

.(,._to e, tXa llla (plustissuephospholipids) v|1n G,, v t ll a l V l l a ,-cA\ xPFs+ Xa /6a\

V*

Va

Prothrombim

Thrombin(lla)

riorinogefi Fibrinmonomer(la) Figure lV-3-1.Goagulation cascade.

501

System Hematologic/Lymphoreticular

Note Vll, ll (prothrombin), Factors protein protein and lX,X, C, S areallvitamin K dependent.

E. Activation of prothrombin to thrombin. Prothrombin is a plasmaprotein producedby the liver. 1. Prothrombin activator,produced by either the intrinsic or extrinsic pathway,plus Ca2+, convertsprothrombin to thrombin by partial proteolysisof prothrombin. Vitamin K is necessaryfor adequateprothrombin production. 2. Thrombin is a proteolytic enzyme that splits a limited number of proteins at bonds involving arginine and glycine.Thrombin is ableto catalyzeits own activation.It alsoacts on the plateletplug to increaseaggregationand can activatefactor XIII and potentiatethe binding of factorsV and VIII to phospholipid-Ca2+. F. Conversion of fibrinogen to fibrin. Fibrinogen is a large protein (MW approx. 340,000) circulatingin the plasmaat concentrationsof 100-700mg/100ml. Thrombin splitstwo low molecularweight peptides(fibrinopeptidesA and B) from eachfibrinogen moleculeto form a fibrin monomer that has the capacityto automaticallypolymerize with other monomers into long fibrin threads.In the early stagesof this process,the monomers attachto eachother by loosehydrogenand hydrophobic bonds, forming only weak chains.However,factor XIII (fibrin stabilizingfactor) which is also activatedby thrombin, acts on the fibrin monomers Lo catalyzethe formation of covalentbonds beftveenthe monomers and between adjacent fibrin chainsto produce a strong three-dimensionalfiber network. This mesh surrounds the plateletsplug tcl form a permanent clot at the injury site.

Bridge To Pharmacology andstreptokinase Urokinase sources of areexogenous plasminogen activation. Tissue plasminogen (tPA)is activator produced, but endogenously canalsobeadministered asa of acute druginthesetting myocardial infarction.

G. Clot retraction and dissolution. The completed blood clot is a network of tangled fibrin threads,blood cells,and platelets. 1. Shortly after the clot hasformed, it beginsto shrink or retract.Most of the fluid oozesout of the clot in the form of serum, which contains no fibrinogen or other clotting factors. During clot retraction, the edgesof small wounds are pulled together.The retraction is the result of contraction of platelet actinomyosin, which is present in concentrations comparableto those found in muscle. 2. The final step in hemostasisis the dissolution of the clot. This occurs gradually as new fibroblastsarrive at the injury site and begin the processof repair. Fibrinolysis requires activation of the plasmaprotein plasminogen, which occurswhen the clot itself induces the releaseof plasminogen activator. Plasminogen activator converts plasminogen to plasmin, which in turn proteolyzesfibrinogen and fibrin. H. Prevention of coagulation in normal vessels.Under normal conditions,blood flow is iaminar (nonturbulent) and flows over the negativelychargedendothelial cell layer.Sincethe plasma proteins, including clotting factors, are negatively charged themselves,they are repelledfrom contact with the vesselwall. In addition, a number of anticoagulants circulate in normal plasma.Theseinclude: l. Fibrin, which adsorbsmost of the thrombin that is formed, keepingit from spreading. 2. Antithrombin III, an a-globulin that binds to and inactivatesthrombin. 3. Heparin, a polysaccharideproduced by many cell types,promotes antithrombin inhibition of thrombin. 4. Protein C and protein S are vitamin K-dependent plasmaproteins that serveasendogenous anticoagulants.Protein C is activatedby thrombin bound to the endothelial cell membrane protein thrombomodulin.In the presenceof protein S,activatedprotein C promotesanticoagulationby inactivating factorsV and MII. Activatedprotein C alsopromotesfibrinolysis by inactivatingt-PA inhibitor, therebypromoting t-PA fibrinolytic activity.

,02

Hematol ogiclLymphoreticu lar Pathology Disorders oftheheme/lymph system canresult fromunderproduction or overproduction ofthe formed elements oftheblood, hematologic malignancies, orautoimmune disorders. Thischapter will discuss thedifferent presentations, types of disorders, theirclinical andtheirdistinguishing features. Disorders involving thespleen andthymus willalsobereviewed.

ANEMIAS Anemias are a group of disorders characterizedby a decreasein the number of circulating erythrocytes.This decreaseis reflectedin the laboratory valuesof hemoglobin and hematocrit (the percentageof blood volume composedof RBCs). A. Signs and symptoms 1. Anemia causespalpitations, systoliccardiac murmurs, high-output heart failure, pallor, orthostatic hypotension (in casesof decreasedblood volume), fatigue,dizziness,syncope, and angina (due to impaired oxygentransport). 2. Anemia can alsobe causedby an underlying disease.Examplesare infection, bleeding as a result of leukemia,or tissueinfarction due to sicklecell crisis. B. Classification 1. RBC morphology. RBCs may be normal in size (normocytic), large (macrocytic), or small (microcytic). RBC size is measuredin terms of the mean corpuscular volume (MCV). Hgb content may be normal (normochromic) or decreased(hypochromic). 2. Pathogenesis.Anemia may result from blood loss,increaseddestruction of RBCs (hemo lysis), or decreasedproduction of RBCs.The reticulocyte count measuresthe percent of circulating RBCsthat are newly synthesizedreticulocytes.

Note Usethereticulocyte countto production: evaluate RBC = t reticuloryte count t production

a. Patientssuffering from a hypoproliferativeanemiahavelow reticulocytecounts. b. Patientswith blood loss or hemolysis should have a compensatoryincreasein the reticulocytecount, assumingthe marrow is normal. C. Anemia secondary to loss or destruction of RBCs 1. Blood loss

When chronic blood loss leads toirondeficiency, the reticulocyte countwillbelow because ironisnecessary to make reticulocytes.

a. Clinical features. There are variable presentations,depending on rate and severity of blood loss.Chronic blood loss is generallybetter tolerated,as the bone marrow is ableto regeneratelost RBCs by increasingerythropoiesis.Acute blood loss is dangerous;hypo volemiamay leadto shockand deathunlessintravascularfluid deficitsarerapidly restored.

505

Hematologic/tymphoreticular System

Clinical Correlate isnota good Hematocrit indicator of anemia inthe setting of acutebloodlosswon'tfalluntil thehematocrit fluidhashad theextravascular with timeto re-equilibrate intravascular bloodto restore volume.

Note Theeffects ofcompensatory mechanisms depend on whether RBCdestruction is Forexample, acute or chronic. gallstones arise bilepigment in hereditary spherocytosis episode butnotin anacute of hemolysis dueto C6PD deficiency.

{+bad( b Biodtemisty Nowisa goodtimeto review monophosphate thehexose lt isdiscussed inthe shunt. chapter in the Carbohydrates Biochemi$ry section of Principles Bookt Ceneral (Volume l).

b. Pathology. The peripheral blood smear initially shows normocytic normochromic RBCs.As the marrow begins to produce more RBCs,the reticulocfte count increases; these cells are macrocytic and polychromatophilic. Mobilization of platelets and leukocytesmay lead to thrombocytosis and leukocytosis. 2. Hemolytic anemias are a group of disorders characterizedby premature RBC destruction, hemoglobin (Hb) breakdown, and a compensatory increase in erythropoiesis. Hemolysis can be intravascular with elevated serum and urinary Hb, jaundice, urinary hemosiderin, and decreasedcirculating haptoglobin. Extravascular hemolysis generally occurs within organsof the reticuloendothelial system.Somehemolytic anemiasoccur on the basisof a defectinherent to the RBC (intracorpuscularmechanism);others are due to factorsextrinsic to the RBC, such asantibodies(extracorpuscularmechanism).The compensatory accelerationin erythropoiesis may lead to intramedullary erythroid hyperplasia, extramedullary erythropoiesis, skeletal deformities, bile pigment gallstones,and the presenceof nucleated RBCs in the peripheral blood. a. Hereditary spherocytosis (1) Clinical features. There is an autosomal dominant, intrinsic defect in erythrocyte membrane spectrin molecules,leading to a lesspliable, spherical RBC vulnerableto destruction in the spleen.The diseasemay presentwith anemia,jaundice, splenomegaly,cholelithiasis,or all four. (2) Pathology. The peripheral blood smear shows spherical RBCs lacking central pallor and reticulocytosis. The red blood cells also exhibit characteristic increased osmotic fr "Stlit''. (3) Treatment. Splenectomyis the treatment of choice.The postsplenectomyblood smearcontainsmore spherocytesand Howell-Iolly bodies. b. G6PD deficiency (1) Clinical features. The diseaseis due to an X-linked deficiency of the first enzyme in the hexosemonophosphate shunt. RBCs defend themselvesagainst oxidative injuryvia glutathione,which is maintained in a reducedform byNADPH. G6PD is necessaryto generateNADPH. In the absenceof G6PD, oxidative stresson the maybe induced by drugs (e.g.,sulfa, erythrocyteleadsto hemolysis;such stresses quinine, nitrofurantoin), infections (particularly viral), or certain foods (fava beans). (2) Pathology. The peripheral smear shows reticulocytosis and Heinzbodies, which are clumps of Hb degradation products seen after staining RBCs with new methylene blue. c. Sickle cell disease (1) Clinical features. A hereditary hemoglobinopathy is present in 2o/o of the African-American population of the U.S. (approximately 8o/ocarry the trait). HbS has a substitution of valine for glutamic acid at position 6 of the beta chain of Hb. The HbS molecules aggregateand polymerize when deorygenated; this leads to a change in RBC shape called "sickling," with resultant microvascular occlusion and hemolyrir.Although initially reversible,the sickling processeventually leads to irreversible RBC membrane changes.The tendency of RBCs to sickle dependson the concentration of HbS: heterozygoteswho have approximately 600loHbA and 40o/oHbS ("sickle trait") sickle only in extreme conditions; homozygotesfor HgbS ("sickle cell anemia") sickleunder lessextreme conditions. Factorsthat predisposeto sickling include hypoxia, dehydration, and low pH.

504

Pathology

(2) Diagnosis. A "sickle prep" is a blood sampletreatedwith a reducing agent such asmetabisulfite.Sickledcellsmay be seen.The definitive diagnosisis made by Hb electrophoresis. (3) Pathology. There is congestivesplenomegalyin young children. Erythrosrasisin the spleenmay lead to splenicthrombosis and infarction; the resultant scarring may lead to shrinkage of the spleenwith loss of function (autosplenectomy), usuallyby agefive. Microvascularocclusionmay lead to anoxiaand infarction in other tissues,including the liver, brain, kidney, and bones.Vaso-occlusionin the penis may lead to painful prolonged erection (priapism). In the lower extremities,vaso-occlusionmay lead to leg ulcers.Hemoglobinemiamay lead to pigment gallstoneformation.

Note Microvascular occlusion inthe lungwiththeresultant infarction andchest x-rayis verydifficult to distinguish frompneumonia.

(4) Course. This is a chronic diseasepunctuatedby acuteexacerbations. Vaso-occlusive crises ("painfrrl crises")are episodesof hypoxic infarction in bones,lungs, liver, spleen,and other tissuesthat may be triggeredby infection, dehydration,acidosis, or may occur sPontaneously. Aplastic crisesareepisodesof inadequatebone marrow activity that may be triggered by infection or folate deficiency.Parvovirus is a common etiologic agent.Sequestrationcrises occur in children or adults who havenot yet undergoneautosplenectomy, resulting in massivesequestrationand splenomegalywith resultanthypo-volemia that may lead to shock.In addition to crises, the functional asplenia leaves the patients vulnerable to Salmonella osteomyelitis and to infections with encapsulated organisms, such as Pneumococcrzs. Most patientsdie prior to age30. d. Thalassemias.The thalassemiasare an inherited group of disorderscharacterizedby absentor decreasedsynthesisof either the alpha or the beta chain of Hb. (i) Alpha-thalassemia (cr-thal) is due to decreasedor absentsynthesisof the alpha chains of Hb. It is of variable clinical severitysincethe normal person has four alpha genes.In the absenceof alpha chains,T+maydevelopin the fetus or may 0, developin children and adults.Generally,the nonalpha-chainaggregates are less toxic than those of the alpha chains;therefore,the hemolysisand anemiatend to be milder in a- than in p-thalassemia.The patients may have a silent carrier state (deletion of one alpha gene), a-thal trait (deletion of two alpha genes), HbH disease (deletion of three alpha geneswith resultant HbH), or hydrops fetalis (deletion of all four alpha genes),leadingto Hb Bart'sin the neonatewith resultant anoxia and intrauterine death. (2) Beta-thalassemia(F-thal major and B-thal minor) is due to decreasedor absent synthesisof the beta chain, usually asa result of defectivemRNA processing.It is most common in the Mediterranean countries,Africa, and SoutheastAsia. The result of the defect is a hypochromic cell with a relative excessof alpha chains. These alpha chains aggregateand become insoluble, leading to intra- and extramedullary hemolysis. Severeanemia stimulates erythropoietin secretion, leading to enhancederythropoiesisin bone, liver, and spleen.Frequenttransfusion may lead to iron overload.Patientswho are homozygous are said to have B-thalassemiamajor and heterozygotesare said to have B-ihalassemiaminor or B-thalassemiatrait.

In a Nutshell cr-Thalassemia isdueto gene deletion. isdue Bthalassemia to defects processing. in mRNA s -Thalassemia #of Genes Deleted 1 2

Type Silent carrier g,thaltrait

3

HbH disease inadults

4

Hydrops fetalis

(3) Pathology. In B-thal minor, the peripheral blood smear showsvarying degrees of anisocytosis(variation in size),hypochromia, microcytosis,target cells,and stippled or fragmentedRBCs.There is mild reticulocytosis.In more severecases, occasionalnucleatedred ceilsin the periphery are seen.In mild B-thal trait, the RBC count is often elevated.In cr-thal, the peripheral blood smear is variable, dependingon the specificsyndrome,but may show hypochromia, microcytosis,

505

Hematologic/tymphoreticular System

Note Animportant differential feature between the thalassemia traits andiron deficiency isthatthaltraits result in anelevated number of microrytes, whereas iron deficiency results in a decreased number of microcytes. Serum iron,total iron-binding capacity OlBC), andferritin confirm the diagnosis.

target cells, and stippled inclusion bodies (in HbH disease).Splenectomized patients may have Heinz bodies. (4) Course. Alpha-thal may range from asymptomatic (o-thal trait) to lethaliry in utero (hydrops fetalis).Patientswith HbH diseasegenerallyhave a mild anemia requiring transfusion only at times of acceleratedhemolysis or impaired erythropoiesis.Beta-thal major is a severediseasewith growth retardation,skeletal deformities, and hepatosplenomegaly. Multiple transfusions may lead to iron overload with resultant systemiceffects.Most patients die by the third decade. Beta-thal minor is clinically milder and may be discoveredincidentally as a hypochromic, microcytic anemia. e. Autoimmune hemolytic anemia

Todistinguish between u{hal andB-thal traits, anHb electrophoresis should be performed. Alphathal traithas normal HbA, andHbF. Betathaltraithaselevated HbA, andHbF.

(1) Clinical features. Extracorpuscularhemolysis is due to anti-RBC antibodies, which may be primary or secondaryto malignancy,infection, or drug use.The direct Coombs test measuresthe presenceof antibody on RBCs; the indirect Coombs test measuresthe presenceof anti-RBC antibody in the serum. These anemiasare often classifiedon the basis of properties of the antibody. Warm antibody, which functions at body temperature,is generallyIgG and causesmost hemolytic anemiasdue to drugs, as well as malignancy and SLE.Cold antibody functions below body temperature,is usually lgM, and includes hemolytic anemias associatedwith mononucleosis and Mycoplasmainfection, as well as idiopathic hemolytic anemia and hemolytic anemia associatedwith lymphoma.

Note

(2) Pathology. The peripheral smear may show spherocytesdue to injury of antibody-coatedRBCsby the reticuloendothelialsystem.

Thereticuloendothelial system recognizes damaged RBCs and phagocytoses thedamaged or antibody portions coated of themembrane.

In a Nutshell Anemias Caused by Lossor Destruction of RedBlood Cells . Bloodloss . Hereditary spherocytosis . CCPD deficiency . Sickle celldisease . Thalassemias . Autoimmune hemolytic anemia . Trauma to RBCs . Paroxysmal nocturnal hemoglobinuria

506

f. Trauma to RBCs (1) Clinical features.Varied situations,including prostheticvalvesand microvascu* lar fibrin deposition,may injure RBCs. (2) Pathology.The peripheralblood smearmay show RBC fragments(schistocytes), burr cells,helmet cells,and triangle cells. g. Parorysmal nocturnal hemoglobinuria is an acquired deficiency of a membrane glycoprotein that leads to chronic intravascularhemolysis,fypically without dramatic hemoglobinuria (despitethe name). Patientsmay eventuallydevelopother stem cell disorders(e.g.,aplasticanemia,acuteleukemia),but most frequently die of infection or venousthrombosis.

D. Anemias secondary to decreasederythropoiesis 1. Megaloblastic anemias a. Characteristics. A group of anemias characterizedby macro-ovalocytesand large, hypersegmented neutrophils (having greater than five lobes per nucleus) in the peripheral blood. Important causesare vitamh 8,, and folate deficiency. b. Pathogenesis.Vitamin B,, and folate deficienciesresult in impaired DNA synthesis without affecting RNA or protein synthesis;hence, they selectivelyimpair nuclear development.This resultsin destruction of immature RBCswithin the bone marrow (ineffectiveerythropoiesis),as well as extramedullaryhemolysis. c. Classification ( 1) Vitamh B,, deficiency hasprofound neurologicaswell ashematologicsequelae. It may result from multiple causes,including dietary deficiency,malabsorption,

Pathology

competitivetapeworm uptake,bacterialovergrowth,pregnancy,hyperthyroidism, and cancer.A deficienry of intrinsic factor leads to vitamin 8,, deficiency and pernicious anemia. (2) Folate deficiency produces megaloblasticanemia without neurologic changes. Folatedeficiencymay result from deficient intake (poor diet, alcoholism,malabsorption), increasedneed (pregnancy,malignancy,increasedhematopoiesis), or impaired use (antimetabolitedrugs). d. Pathology (1) In pernicious anemia, the peripheral smearshowsmacro-ovalocytesand hypersegmentedpolymorphonuclear leukocytes.The bone marrow is hypercellular with megaloblasticcells showing nuclearlcytoplasmicdissynchrony.The gastrointestinal tract showsatrophic gastritis,absentparietal ceils,and intestinalization of the gastric mucosa.The CNS shows myelin degenerationof dorsal and lateraltracts (i.e.,subacutecombineddegeneration).Perniciousanemiamay be due to antibodiesagainstintrinsic factor or intrinsic f-actorreceptors.

Note Thebody's 8,,stores vitamin aresolarge thatit usually years takes a to develop vitamin B,,deficienry after absorption Folate stops. deficiency develops much morequickly, ontheorderof months, in states ofvigorous production. RBC

(2) Folate deficiency showsa variablepicture, dependingon the underlying disease. Megaloblasticchangesappearin the peripheral blood and marrow without CNS disease. 2. Iron deficiency anemia a. Clinical features.Iron deficiencyis among the most common nutritional deficiencies worldwide.There are many causes, including poor diet, malabsorption,and pregnanmost By far, the common cause of iron deficiency anemia is blood loss, usually ry. from the gastrointestinal,genitourinary, or female genital tract. The finding of iron deficiencyanemia in an elderly patient should alert the clinician to the possibility of an occult sourceof blood loss,often a malignancy. b. Pathology. The peripheral smear shows hypochromic, microcytic changes.The Plummer-Vinson syndrome is a triad of microcytic anemia, atrophic glossitis,and esophagealwebs. 3. Aplastic anemia a. Clinical features. This is a stem cell defect, leading to pancytopenia (i.e., anemia, neutropenia,thrombocytopenia).Therearemultiple etiologies:idiopathic,drugs (i.e., alkylating agents,chloramphenicol), radiation, infections, and congenital anomalies (i.e.,Fanconianemia).

Note Thediagnosis of iron deficiency made iscommonly bydemonstrating lowserum iron,highTIBC, andlow serum ferritin. isno There stainable ironinthebone marrow Theanemia of chronic disease, alsoa microcytic anemia, exhibits lowserumiron,normal-to-low TIBC, andhighferritin.

b. Pathology. The peripheral smear shows markedly decreasednumbers of circulating RBCs,WBCs, and platelets.RBCsare normochromic and normocytic. The bone marrow is hypocellular with a few foci of lymphocytesand plasma cells.Other changes depend on the specific etiology or therapy; multiple transfusions,for example,may leadto hemosiderosis. c. Course.Prognosisis poor. Bone marrow transplant may be curative. 4. Bone marrow failure may result from many etiologies, including space-occupying metastaticmalignanry or granulomas(myelophthisis),liverdisease,chronic renal failure, endocrine disorders,and other infections or inflammations. Myeloid metaplasia with myelofibrosis is a chronic myeloproliferativedisorderin which the myeloid stem cellsare neoplastic,but are produced in reiativelysmall numbersbecausefibrosis of the bone marrow has causedpancytopenia.

Note Incontrast to CML,patients withmyeloid with metaplasia myelof ibrosishavenormal-toelevated leukocyte alkaline phosphatase.

t07

Hematologic/tymphoreticular System

5. Chronic renal diseasecan result in anemia due to an underproduction of erythropoietin by the kidney.

Table IV-4-f .Anemias.

In a Nutshell Anemias secondary to decreased erythropoiesis: . Megaloblastic anemias (8,,,folatedeficiencies)

Type

Peripheral Smear

Hereditary spherocytosis

. SphericalRBCslack central pallor ' Reticulocytosis . RBCswith Heinz bodies . Reticulocytosis

G6PD deficiency Sickle cell disease

. lrondeficiency anemia . Aplastic anemia

cr-Thalassemia

. Bonemarrow failure . Chronic renaldisease

Bone Marrow

. Sickled cells (especially with sickleprep) . Reticulocytosis . Variable but hypochromic RBCs . Microsftosis . Target cells . Stippled inclusion bodies (HbH) . Heinz bodies (if splenectomized)

p-Thalassemia

. . ' .

Megaloblastic

. Macro-ovalocytes . Hypersegmentedneutrophils

Fe deficiency Aplastic

. Hypochromia, microcftosis . J RBC, wBC, platelets RBCsnormochromic, normocytic

Anisocytosis Hypochromia, microcytosis Thrget cells Stippled/fragmentsand RBCs ' Hypercellular ' Nuclear/cytoplasmic dissynchrony . No stainableFe . Hypocellular

POTYCYTHEMIA Polycythemia is an increasein concentration of circulating erythrocytes. This increasemay be primary or secondary absolute or relative. A. Relativepolycythernia occurs due to loss or sequestrationof intravascularvolume without loss of RBCs.Volume loss may be due to decreasedfluid intake, vomiting, diarrhea,burns, or adrenal insufficiency.

Note Progression to myelofibrosis is progression common; to acute myelogenous leukemia islesscommon, butmoreso whenpatients aretreated with radioactive phosphorous (,,P).

508

B. Polycythemia vera 1. Clinical features. Polycythemia vera is a myeloproliferative syndrome characterizedby a marked increasein erythrocfte mass.It is most common in malesage40-60. The etiology is unknown but is probably due to a neoplastic hematopoietic stem cell. There are symptoms of increasedblood volume, vascularstasis/thrombosis,or bleeding tendenry. Patientsmay later develop anemia or acute leukemia due to "bone marrow burn out." Folate deficienry may develop due to the hyperproliferative state.

Pathology

2. Pathology. The peripheral smear shows a markedly increasednumber of RBCs,WBCs, and platelets. Erythropoietin levels are low. The bone marrow shows erythroid hyperplasia with excessnormoblasts.The marrow cavity may expand to cancellousbone and shafts.Later in the disease,fibrosis, aplasia,or leukemic infiltration may be seen.Other problems include vesselsdistendedwith viscousblood, congestivehepatosplenomegaly, and diffr,rsehemorrhages. 3. Management is generallywith therapeuticphlebotomy. C. Secondary polycythemia 1. Clinical features. An increasedRBC mass as a result of increased erythropoietin levels is seen.There are multiple etiologies,including high altitude with low Or, cigarettesmoking with high carbon monoxide levels,respiratory disease,cardiacdisease(e.g.,right-toleft shunts,cardiacfailure), hemoglobinopathies,renal disease(e.g.,cysts,hydronephrosis), and malignancies(e.g.,renal cell carcinoma,hepatoma,leiomyoma, adrenal adenoma, cerebellarhemangioblastoma). 2. Pathology.An isolatederythrocythemia without an increasein WBCs or plateletsis noted.

THROMBOCYTOPENIA Thrombocytopenia is a decreasein the platelet count (normal platelet count = 150,000400,000/mm3). A. Clinical features. There may be bleeding from small vessels,often skin, gastrointestinaltract, and genitourinary tract. The most common sign is the developmentof petechiae (minute pin-sizedhemorrhagesin the skin) and purpura (largered, nonblanchinglesions).Petechiae developbefore purpura, which are more often seenwith combined deficienciesof platelets and plasmaclotting factors. B. Classification 1. Decreasedproduction due to drugs, radiation, myelopthisis,aplasticanemia,or platelet maturation defect (due to vitamin B,, or folate deficienry) 2. Abnormal sequestrationof plateletsin the spleenin congestivesplenomegaly 3. Dilutional (e.g.,massiveblood transfusion) 4. Increaseddestruction,e.g.,DIC, TTR ITR drugs, or malignanry C. Idiopathic thrombocytopenic purpura (ITP) 1. Clinical features. ITP is characterizedby an increasedperipheral platelet destruction in the spleen,often immune mediated. The course may be acute and self-limited (most common form in children), often following a viral infection, or it may be chronic (most common form in adults). ITP may be primary or secondaryto another disorder such as SLE,HIV infection, or hemolytic anemia.The diseasemay presentwith a long history of easybruisabiliry mucous membranebleeding,gastrointestinalor genitourinary bleeding, and petechiae.CNS bleeding may occur. 2. Pathology. The peripheral smear shows a few, large young platelets;other cell lines are normal. The bone marrow shows increasedmegakaryocFtes,some of which may be immature. The skin showspetechiaeand, in severecases,diffrrsehemorrhages.

509

System Hematologic/tymphoreticular

D. Thrombotic thrombocytopenic purpura (TTP) 1. Clinical features. This is a rare diseasecharacterizedby thrombocytopenic purpura, fever, renal failure, neurological changes,and microangiopathic,hemolytic anemia.It appears most frequently in young women. The etiology is unknown; hypotheses include an immunologic reaction to endothelial cells,a primary platelet defect,or a prostaryclin deficiency. Platelet aggregation leads to the development of microthrombi throughout the vasculature,which causesmicroangiopathic, hemolytic anemia. 2. Pathology. The peripheral smearshowsfew platelets,fragmented RBC (schistocytes),and helmet cells.

PLATETET FUNCTION DEFECTS A. Clinical features. Thesedisorders are characterizedby prolongation of the bleeding time in the presenceof a normal platelet count. B. Classification. Qualitative platelet defectsmay be congenital or acquired. They may be classified as follows:

ToPhysiology Flashback Thestepsintheformation of plugarediscussed theplatelet in detail intheHematologi{ Lymphoreticular Physiology chapter.

1. Defectsof adhesion (e.g.,von Willebrand disease,Bernard-Soulierdisease) 2. Defects of primaryaggregation (e.g.,thrombasthenia) 3. Defects of secondary aggregation and release (e.g.,aspirin, storagepool disease) C. von Willebrand disease 1. Clinical features. There is an autosomal dominant defect in von Willebrand factor. This factor is necessaryfor adhesion of platelets to collagen.This results in impaired platelet adhesion, although the plateletsthemselvesare intrinsically normal. It is characterizedby spontaneoushemorrhage from mucous membranes,wounds, and excessivemenstrual bleeding. 2. Pathology. Patients with von Willebrand diseasehave a range of clinical syndromes but are usually diagnosedwhen they bleed after surgery or dental extraction. Von Willebrand factor (v'vYF)is also the carrier molecule for factor VIII, so patients with v\MF deficienry have low factor VIII levels and activiry.As a result, they have a prolonged partial thromboplastion time (PTT) in addition to an elevatedbleedingtime.

DISORDERS PLATETETS OFEXCESS These disorders are defined by the elevation of the platelet count above the normal range. A. Classification 1. Thrombocytosis is a reactive disorder resulting from bleeding, hemolysis,inflammation, malignanry, iron deficienry, stress,or postsplenectomy.

Note platelets Excess donot necessarily cause thrombosis because in myeloproliferative disorders theymaynot function normally.

5t0

2. Essential thrombocythemia is a primary myeloproliferative disorder. Thrombocythemia is also a prominent feature of chronic myelogenousleukemia (CML). B. Pathology 1. In reactive thrombocytosis the peripheral smear shows an elevated platelet count and may demonstrateother signsof an underlying disorder,such as anemia,leukocytosis,or Howell-Jollybodies. 2. Thrombocythemia may lead to dififrrsethrombosis. The peripheral smear often shows very large, abnormal platelets, or hypogranular platelets. In CML, there is an elevated number of immature white blood cells (WBCs) aswell as numerous platelets.

Pathology

FACTOR CLOTTING DISORDERS Clotting factor disordersare characterizedbydeficitsof secondaryhemostasis,due to alteration of the plasma protein factors of the clotting system. A. Clinical features. Bleeding in disorders of secondaryhemostasistends to be from small arteries or into deep structures such as joint spacesor the retroperitoneum. Tiauma may precedethe bleedingbut hemorrhageis often delayed. B. Laboratory values. The most common blood tests to assayfor the presenceof an intact clotting system are the prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time (TT). 1. PT measuresfactors(fibrinogen)I,II,VVII,

and X.

2. PTT measuresXII, prekallikrein, high-molecular weight, kininogen, and factors I, II, V VIII,IX, X, and XI. 3. TT measuresfactor I (fibrinogen). C. Hereditary deficiencies 1. Factor VIII:C deficiency (hemophilia A) is an X-linked recessivedisorder with an incidenceof 1/10,000.It resultsfrom defectivefactor VIII:C or impaired conversionof precursor to factor VIII:C. Severecasesbleed in infancy at circumcision or may have multiple hemarthroses.Moderate caseshave occasional hemarthroses.Mild casesmay be missed until the patients bleed following a dental or surgical procedure.Bleeding may require treatment with cryoprecipitateor lyophilized factor VIII. 2. Factor IX deficiency (Christmas disease,hemophilia B) occurs approximately one-sixth as often as factor VIII deficiency. It is due to inactive or inadequate Factor IX and is also an X-linked recessive. The signsand symptoms are the sameas hemophilia A. Sinceboth hemophilia A and B have a prolonged PTT, thesediseasesmust be distinguishedby specific factor assays. 3. Other inherited clotting factor deficiencies are quite rare and are usually autosomal recessivedisorders.Factor XII deficiencFcausesa very long PTT, but no bleeding disorder. Factor XI deficiency is seen mostly in Ashkenazic fews (German and Eastern Europeandescent);factor XIII deficienry is diagnosedby rapid clot lysis in 5N urea. D. Acquired disorders 1. Vitamin K deficiency. Vitamin K is a fat-soluble vitamin produced by bacterial metabolism of ingestednutrients within the large intestine. It is essentialin the posttranslational modification of factors II, VlI, IX, and X, as well as proteins C and S. Vitamin K deficiency may result from fat malabsorption, diarrhea, dietary deficienry (i.e., usually patients on parenteral feedings who are not receiving vitamin K supplements), antibiotics (which may kill gut flora), and some anticoagulantdrugs (e.g.,warfarin). 2. Liver disease.FactorsII, V VII, IX, X, XI, and XII are synthesizedin the liver; liver disease can result in failure to synthesizetheseclotting factors,with a resultant bleeding diathesis. 3. Disseminated intravascular coagulation (DIC) a. Clinical features. This is an acquired consumption deficiency of clotting factors and platelets, often resulting in fatal thrombosis and hemorrhage. Coagulation system activation leadsto microthrombus formation with consumption of platelets,fibrin, and clotting factors in the vasculature;this leadsto activation of the fibrinolytic system. Hence,morbidity from DIC may be relatedto either thrombosis (tissuehypoxia and infarction) or hemorrhage (coagulation factor consumption and fibrinolysis).

Clinical Correlate Proteins CandSareinvolved in normal People clotlysis. withdeficiencies ofthese proteins maydevelop frequent deepvenous thrombosis. Inaddition, factorV resistant to proteinC hasbeenrecognized asan inherited cause of deep venous thrombosis.

5tl

Hematologic/lymphoreticular System

BridgeTo Pharmacology withvitamin lnterference K-dependent factors isthe basis of oralanticoagulation. Theoralanticoagulant Warfarin isdiscussed in detail inthePharmacology chapter. ClinicalCorrelate A lowfactor Vllllevelmaybe usedto distinguish DICfrom thecoagulopathy of liver failure, hassimilar which fora normalfeatures except to-elevated factor Vllllevel. Notethatfactor Vlllin synthesized inthe endothelium of vessels; the otherclotting factors are synthesized intheliver, Bridge to Pharmacology Chloramphenicol a causes dose-related marrow suppression in allpatients, andaplastic anemia Inrare individuals. Neutropenia dueto alkylating agents ispartof a pancytopenia. Bridge to Pharmacology Cranulorytemacrophage gfactor(CMcolony-$imulatin CSF) andgranulocyte $imulating factor(CSF) arenow usedclinically totreatsome particularly neutropenias, those induced bychemotherapy. Patients recover fromtheir nadirs afewdaysearlier andare spared significant morbidity andmortality. Thefactors arediscussed in thePharmacology chapter.

tl2

There are many etiologies:amniotic fluid embolism, infections (particularly Gramnegativesepsis),malignanry, and major traumas, particularly head injury. The final common pathway is either endothelial injury or the releaseof thromboplastic substancesinto the circulation. The brain is a rich sourceof tissuefactor,which activates factor VII. b. Pathology. There is diffrrsethrombus formation, especiallyin the brain, heart, lung, kidneys, adrenals,spleen, and liver. There may be diffrrse bleeding as well. The lung may show pulmonary edemaand hyaline membraneformation. The CNS showshemorrhagic microinfarcts. The peripheral smear may show signs of microangiopathic hemolytic anemia (schistocytes). c. Diagnosis. DIC is diagnosedin the laboratory by demonstrating low platelets, low fibrinogen, and the presenceof fibrin degradation products. d. Tieatment must be directedto the underlying disease.The courseis variablebut often poor. The use of heparin is controversialbut often helps to slow the consumption of clotting factors. Fresh frozen plasma and platelet concentratemay then be used to replacethe deficits.

NON-NEOPTASTIC WHITE BTOOD CEttDISORDERS A. Leukopenia is a decreasein the circulating WBC count. It may selectivelyinvolve one WBC line, such as lymphocytes (lymphopenia), or more commonly, neutrophils (neutropenia or granulocytopenia). 1. Classification of neutropenias a. Decreasedneutrophil production is seenin megaloblasticanemias,aplasticanemia, some leukemiasand lymphomas, drug suppressionof myeloid stem cell differentiation, or autoimmune attack on stem cells. b. Increaseddestruction of neutrophils is usually due to splenicsequestration,which is often immune-mediated(e.g.,Felty syndrome). c. Drug-induced neutropenia may be seen in patients treated with alkylating agents, chloramphenicol, sulfonamides,chlorpromazine, and phenylbutazone.Mechanisms may include both decreasedproduction and increaseddestruction. The problem is usually reversibleif the drug is stopped. 2. Clinical features usually result from lack of immune defenseprovided by neutrophils. a. Constitutional symptoms include fever, chills, malaise,fatigability, and a high susceptibility to infection, particularly Gram-negativesepticemia. b. Prognosis is often poor with death resultingfrom overwhelminginfection; early diagnosis and antibiotic therapy for infections is required to avoid a fatal outcome. 3. Pathology a. Bone marrow findings depend on the etiology of the neutropenia.The neutropenia may be hypercellular due to increased destruction or megaloblastic anemia, or hypocellular,due to decreasedproduction. RBC and platelet lines may be affected. There may be increasednumbers of lymphocytes and plasma cells that result from relativepreservation. b. Infection. Infected,necrotic ulcersmay occur in the oral caviry skin,vagina,anus,gastrointestinal tract, or, less commonly, in the lungs and urinary tract. Lymphadenopathydraining infected sites may be seen.Uninhibited by neutrophils, bacteriamay form colonies.

Pathology

B. Leukocytosis is an increasein WBC count. 1. Classification. Leukocytosismay occur in a variety of WBC lines. a. Monocytosis may be seen in tuberculosis,endocarditis, malaria, brucellosis,rickettsiosis,and monocytic leukemia. b. Lymphocytosis may be seen in tuberculosis,brucellosis,pertussis,viral hepatitis, cFtomegalovirusinfections,infectious mononucleosis,chronic lymphocytic leukemia (CLL), and some lymphomas. c. Eosinophilic leukocytosis may be seenin neoplasms,allergy,asthma,collagen vascular diseases, and parasiticinfections.Any skin rash may produce eosinophilia. d. Polymorphonuclearleukocytosis (mostcommon) maybe seenin acuteinfection, tissue necrosis,and "stress,"and may be accompaniedby immature forms in the peripheral blood (leukemoid reaction or "left shift"). Chronic myelogenousleukemia (CML) producesextremeleukocytosiswith immature forms and eosinophilsaswell asbasophfia.

Note Leukocyte alkaline phosphatase iselevated in inflammatory Ieukocytosis. It isdepressed in chronic myelogenous leukemia.

2. Pathology. The peripheral blood shows elevation in granulocyte lines. In severeinfections, polymorphonuclear leukocytosismay be accompaniedby morphologic changesin the neutrophil. Dohle bodies are round, pale blue, cytoplasmicinclusions,the product of aggregatedrough endoplasmic reticulum. Toxic granulations are coarse, dark, neutrophilic granules(lysosomeson electron microscopy). C. Nonspecific lymphadenitis 1. Clinical features.Nonspecificlymphadenitismay be causedby drugs,toxins,or infection. It is common in the neck following dental or tonsillar infection, and in the axillae or the inguinal regionsfollowing infectionsof the extremities.Enlargedabdominal lymph nodes (mesenteric adenitis) may cause abdominal pain resembling acute appendicitis. Lymphadeno-pathy may be generalizedin systemicviral or bacterial infections.A syndrome of generalizedlymphadenopathymay be a precursorto AIDS. It is associatedwith hyperglobulinemiaand normal CD4 lymphocyte counts. 2. Pathology a. Acute lymphadenopathy producesswollen,red-graynodeswith prominent lymphoid follicles and large germinal centerswith numerous mitoses.Older patients tend to havelessgerminal centersthan do children. b. Chronic lymphadenopathy (1) Grossfindings are rnost common in axillary and inguinal nodes,which are characteristicallylarge and nontender. (2) Microscopic findings show three basic patterns, though combinations may occur. Follicular hyaerplasia is seen in primary antibody production. It produceslarge germinal centers,containing mostly B lymphoblasts,helper T cells, and histiocFtes.Paracortical hyperplasia is causedby a primary T-cell reaction. It produces reactive changesin the diffuse cortex, encroaching on germinal centers.Paracorticalhyperplasiamay be seenwith use of phenytoin. In sinus histiocytosis, lymphatic sinusoids become prominent and distended with macrophages.It may be seen in nodes draining carcinomas or any chronic inflammation.

Bridgeto lmmunology Follicular isoften hyperplasia seen inbacterial infections or withexposure to new antigens. Paracortical hyperplasia isoften seen in viralinfections orinsecondary immune responses.

5t5

System Hematologic/tymphoreticular

TYMPHOMAS A. Hodgkin disease(Hodgkin lymphoma) l. Overview. Hodgkin diseaseis classicallyconsideredseparatelyfrom other lymphomas (non-Hodgkin lymphomas) becauseits spread is almost alwaysin contiguity (i.e', from one setof lymph nodesto the next). The spleenis involved beforethe liver. It almost never has a leukemic component. It has a high cure rate, and, histologically,it is characterized by the presenceof the Reed-sternberggiant cell (RS cell). The RS cell is large (15-45 tt)' often with two or more nuclei, containing large"owl-eyed"nucleoli surroundedby a clear but halo; cytoplasmis abundant(FigureIV-4-l). The presenceof the RS ceii is necessary disease. of Hodgkin the diagnosis make to not sufficient 2. Incidence. The incidence is 2/100,000.There is a bimodal age distribution (high peak, ages15-35;low peak,after age50) in both men and women. 3. Clinical features. Hodgkin diseasemay presentwith painlesscervical adenopathyor with constitutional(hypermetabolic)symptoms:fevers,chills,night sweats,and weight loss. 4. Pathology.There are four variantsrecognized.In order of bestprognosisto worst: a. Lymphocyte predominance showsa seaof lymphocyteswith few RS cells,a variable number of histiocytes,little fibrosis,and no necrosis. b. Nodular sclerosis is more comlnon in wonren and tends to involve mediastinal, supraclavicular,and lower cervical nodes. There is a mixed infiltrate composed of lymphocytes,histiocytes,a few eosinophils,plasnracells,attclRScells.Birefringentcollagen bands createa nodular pattern. RS cellsare calledlacunar cells. The cytoplasm retractsas a result of fixation and de\dration, giving rise to the appearanceof a nucleussurroundedby a "lacuna"or clearspace. c. Mixed cellularity shows a mixture of neutrophils, lyrnphocytes,eosinophils,plasma cells,and histiocytes.Many classicRS cellsmay be identified. d. Lymphocyte depletion shows rare lymphocytes and many RS cells with variable eosinophils,plasmacells,and histiocytes.Diffuse fibrosis may be seen.

& -#w

F;* '"'* & a€

"4tu

wo

"

Figure lV-4-1.Reed'sternbergcell (microscopic).

tl4

*

Pathology

5. Diagnosis a. Physical examination. All lymph node groups,liver, and spleenmust be evaluated. b. Bipedal lymphangiogram, in which a radio-opaque dye is injected into the lymphatics of the feet to visualizeiliac and para-aortic nodes,may be usefi.rlin stagingsome patients. c. Computerizedaxial tomography (CAT) scan is very useful in visualizing thoracic and upper abdominal nodes. d. Laparoscopy may be used to inspect the liver and spleenand to biopsy the liver. e. Staginglaparotomy may be performed.The abdomenis surgicallyopened,suspicious lymph nodesare removed,splenectomyis performed, and the liver and bone marrow are biopsied. 6. Staging and classification a. StageI is involvement of a single lymph node group or extralymphatic site by direct extensionfrom an involved lymph node (stageIE). b. StageII is involvement of two or more lymph node regions on the sameside of the diaphragm or with direct involvement of contiguousextralymphatic organs (IIE). c. StageIII is involvement of ly-ph node regions on both sides of the diaphragm and may include the spleenor extralymphaticorgan by direct extension(IIIE). d. StageIV is disseminateddiseasein nonlymphatic organs,such as the lung, liver, or bone marrow. e. Classification. "r{'means there are no constitutional symptoms such as fever,chills, or night sweats."B" indicatesconstitutional symptoms (e.g.,stageIIA or IIIB). "E" indicatesdirect extension. 7. Course and prognosis dependson multiple factors,including age (younger do better), the presenceor absenceof constitutionalsymptoms(",{'patients do better),histology(patients with lymphocyte predominance and nodular sclerosisdo better than patients with mixed cellularity or lymphocyte depletion), and stage(the lower the stage,the better). 8. Therapy is usuallya combination of chemotherapyand radiation. One long-term problem encounteredin patients who have undergone therapy for Hodgkin diseaseseemsto be an increasedincidenceof secondarymalignancy,usuallyleukemia,approximately7-10 yearsafter primary treatment. B. Non-Hodgkin lymphomas (NHL) 1. Overview. This is a varied group of lymphoreticular neoplasmsusually characterizedby lymphadenopathy and hepatosplenomegaly. In most casesthe diseaseis first discovered in only one chain of nodes-usually cervical,axillary, inguinal, femoral, iliac, or mediastinal.In approximately30o/oof.cases,initial involvementis extranodal.Unlike Hodgkin disease,NHL do not produce RS cells,they generallydo not spreadin contiguity,and they frequently havea leukemic or blood-borne phase. in chil2. Incidence.The peakincidenceis in the late 50s.NHLs arerareand more aggressive dren and young adults. They may involve lymph nodes or lymphoid tissue in the gut, oropharynx, liver, spleen, and thymus. Presentationsinclude local or generalized lymphadenopathy,abdominal or pharyngeal mass,abdominal pain, or gastrointestinalbleeding. Weight loss is common and is a sign of disseminateddisease.NHLs are common in immunosuppressedpatients,whether iatrogenic,congenital,or aquired as in AIDS.

It5

Hematologic/tymphoreticular System

3. Classification a. NHLs can be divided into two main categoriesof nodular and diffirse and can be classifiedby cell tfpe (lymphocytic, mixed, histiocytic) and degree of differentiation (well-differentiated,poorly differentiated,undifferentiated).Lymphocytic,well-differentiatedhas the best prognosis(untreated). (1) Nodular lymphomas are characterized histologicully by aggregatesof lymphomatous cells arrangedin units resemblinggerminal centers.They are more common in the elderly and have a better prognosis(untreated). (2) Diffuse lymphomas have a sheet of malignant cells destroying lymph node architecture. There is evidencethat some diffirse lymphomas may develop from pre-existingnodular lymphomas.This portends a worse prognosis. b. An alternate classification of NHLS separateslymphomas on the basisof cell of origin: T cell,B cell,histiocyte (macrophages),and unclassifiable.Most ly-phorfttc lymphomas are B-cell neoplasms,exceptfor somelymphoblasticlymphomas and the cutaneouslymphomas (i.e.,mycosisfungoides,Sdzarysyndrome),which are T-cell neoplasms. 4. Types of non-Hodgkin lymphomas (NHL) a. Well-differentiated lymphocytic lymphoma (WDLL) (1) Clinical features. WDLL comprises approximately 5o/oof NHLs and is usually dif;frrse.It usually affects older patients who present with generalized lymphadenopathyand mild hepatosplenomegdy. (2) Pathology. Lymph nodes are replaced by small round lymphocytes with scant cytoplasm,dark nuclei, and rare mitoses.WDLL often seedsthe blood late in the disease,resemblingCLL. The bone marrow is almost alwaysinvolved. (3) Prognosis. Survival is approximately 5-7 years. This diseaseresponds rather poorly to cytotoxic drugs but is often sensitiveto apoptosis inducers, such as fludarabine. b. Poorly differentiated lymphocytic lymphoma (PDIL) (1) Clinical features. PDLL comprises approximately 30o/oof NHLs. It may be nodular or diffrrse.Patientsare usually middle-aged or older. ln 75o/oof cases, they present with lymphadenopathy and infiltration of bone marrow, liver, and spleenat the time of diagnosis. (2) Pathology shows afypical lymphocytes, often larger than in WDLL. Nuclei are irregular, angular, and indented with coarse chromatin. Mitoses are rare. A leukemic phaseis lesscommon than in WDLL. (3) Prognosis is fair; nodular PDLL has a better prognosisthan does diffi,rsePDLL. c. Histiocytic lymphoma

Note Theterm"histiocytic" is actually a misnomer: the tumors arecomposed of monoclonal B cells, notcells of macrophage lineage.

( 1) Ctinical features.This is one of the most common NHLs. It is usuallydiffusebut may be nodular. Diffirse histiocytic lymphoma (DHL) may presentwith nodal involvement (usually on one side of diaphragm), extranodal involvement (gastrointestinal tract, skin, brain, bone), or, rarely,liver and spleeninvolvement. (2) Pathology showslargetumor cellswith vesicularnuclei and prominent nucleoli. The cells may be pleomorphic. A leukemic phase is rare. The bone marrow is involved lessoften than in small cell lymphomas. (3) Prognosis is poor if untreated, but combination chemotherapy may induce remissionand occasionallya cure in lymphomas with a high mitotic rate.

5t6

Pathology

d. Mixed lymphocpic-histiocytic

lymphoma (MLHI)

(1) The diseaseis usually nodular. (2) Pathology shows cells with atypical lymphocytes (as in PDLL) and large cells (histiocytes).Thesecellsare merely cell cyclevariants of the malignant clone. (3) Prognosis is fair and remissionmay be achievedwith combination chemotherapy. e. Lymphoblastic lymphoma (1) Incidence. This is a diffi,rselymphoma that is most common in adolescentsand young adults,but there is a bimodal agedistribution with a secondpeak in the 70s.The male:femaleratio is 2.5:1. (2) Clinical features. MLHL is often associatedwith a mediastinal mass,particularly in boys, suggestinga thymic origin for the neoplastic cells. These cells often expressT-cell markers. (3) Pathology. The cells resemble the tymphoblasts of AtL. They have a uniform size,scantcytoplasm,delicatechromatin, and absentnucleoli. The nuclearmembrane may be loculated or convoluted.There are frequent mitoses. (4) Prognosis is uniformly poor but is improving with recent chemotherapy regimens.T-cell lymphomas usually do worse than B-cell lymphomas. f. Undifferentiated lymphoma: Burkitt (1) Clinical features. This diseaseis endemic in Africa and sporadic in the United States.It usually affectschildren or young adults. Lymphadenopathy is a rare initial presentation. In Africa it often arises in the mandible or maxilla; in the United States,it often arises in the abdomen (gastrointestinaltract, ovaries, retroperitoneum). The etioloW of Burkitt lymphoma is thought to be relatedto Epstein Barrvirus (EBV). EBV may act asa mitogen, initiating a sustainedpolyclonal activation of B cells.This eventually results in a neoplastic proliferation of a singleB-cell clone after a chromosomal translocationoccurs.

Note African Burkitt lymphoma essentially always hasa translocation of B:14,2:8, or 8:22.These translocations bringthec-mycgenenextto enhancers of immunoglobulin heavy or lightchain synthesis.

(2) Pathology. There is a uniform sea of moderately large cells with round nuclei, multiple nucleoli, moderate basophilic cytoplasm with lipid-containing vacuoles,frequent mitoses,and many macrophageswith ingesteddebris,producing the so-called "starry s\y''pattern. A leukemic phaseis rare. (3) Prognosis is fair. Somecuresmay be achievedwith vigorous chemotherapy. g. Undifferentiated non-Burkitt lymphoma (1) Clinical features.This is arare tumor usually affectingadults,and is not associated with EBV. (2) Pathology. The cell type is more variable than in Burkitq it may be multinucleate,havea singlenucleolus,and pale scantcytoplasm.Cell markersshow both Bcell and T-cell neoplasms.They behave aggressivelpas do all diffi,rse,large-cell lymphomas. h. Cutaneous T-cell lymphomas ( 1) Mycosisfungoides. There are three phasesof skin lesions:inflammation, plaque, and tumor. Nodal and visceral dissemination may occur. There are epidermal and dermal infiltrates by neoplastic T cellswith cerebriform nuclei. Nodules and fungating tumors may develop later in the disease.These tumors are usually composedof CD4 type cells.

tl7

Hematologic/lymphoreticular System

(2) sczarysyndrome' This is a rare chronic diseaseassociated erythroderma' exfoliation, and lymphade.rop",rry.;adrrry with progressive,pruritic cells,,,T cellswith cerebri, form nuclei' similar to those seen in fungoides, infiltrate the peripheral lycgsig blood' This may be considereda preterminal phaseof mycosisfungoides. 5' staging of non-Hodgkin lymphomas is simila-rto Hodgkin disease.Staging is lessclinically significant in NHL asprognosis is more affectedby histology, and the disease is often disseminatedat the time oi di"grrorir. 6' Prognosis dependson the extent and.histologyof disease.Treatment is usuallycombined radiation and chemotherapy. Survival is iowly implwing.-Tu-o., with very high offerthebestchance

of curebecause or rn.li.nsitiviry ,"l.ai",irn

ilHtff:fi;*

and

TEUKEMIAS The leukemiasare of malignant neoplasmsof wBC precursors ] Erouq characterizedby abnormal leukocrres in the peripheral b]ood, lr*r, and bone marrow. Most of the ;J.; morbidiry

ffi*:ti[Jfil""ionai

impairment of wB^c,RBC,andplatetets, leading to infectrr,,r,.-

A. Classification

In a Nutsheff Acuteleukemias haveblasts in peripheral bloodand decreased mature cells, while chronic leukemias havean increased number of mature WBCs intheperipheral blood.

1' Acute leukemias are charactetized,,bythe presenceof blasts in the peripheral blood and lack of mature cells'They are usuallyrapidiy fatal if reft ,rntr".t.J (2-4 months). The rwo most common types are acute lymphocytic leukemia (eril und acute myelogenous leukemia (Aur)' Acute monocytic leukemia (AMoL) and acute undifferentiated leukemia (AUt) occur lessfrequently. 2' chronic leukemias are characteri zedbyelevated numbers of more mature reukocytesin the peripheral_blood. They haye a ronger course (if untreated, 3_10+ years). chronic myelogenous leukemia (itvtl) and *;;t^thocytic leukemia (c61 are the rwo most common forms' chronic monocytic leukemia (cMot) is much less common. B' Incidence' There are approximately 7 new cases/100,[[V/year.of all leukemias, 600/o are acute and 40o/oare chronic; of the chronic l.ut -i.r, half are cMf and half cLL. Men have a higher incidence than women (especially cLL). Leukemia is the -or, common cancerdeath in children' The most causeof common leukemiasfor specific age-groupsare listed in ThbleIV-4-2.

Tablerv-4-z.The most commonleukemias for specificagegroups. Age Most common Ieukemia

Under 15 AtL

15-39 AML

40-59 AML and CML

Over60 CLL

Definitions: ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; cML = chronic myelogenous leukemia; cLL = chronic lymphocytic leukemia.

C. Acutelymphocyticleukemia(Att)

518

l' clinical features'ArL accounts for 60-70o/oof at age4; it is rareoverage50.ArL preserrt, childhoodleukemia.Thepeakincidenceis *ith.futigue,f.".; a;;;ondaryto neutropenia andinfection)'bleedingL theform of .pi;,.-;, gi"gi"a pa..rri.,-...hy-ores (secondary to thrombocrtopenia); subarachnoid o. ..r.u.? [.--rn"g. patients -", occur. havelymphadenopathy, may hepatosplenom.gd;o, iorr. pain from infiltration of theseareas.

Pathology

2. Pathology a. Almost all patients presentwith anemia and thrombocytopenia on peripheral smear. The initial WBC count is variable and may be high, normal, or low, dependingon the courseof the disease.Lymphoblasts are prominent and mature WBCs are rare. b. Bone marrow is packed with lymphoblasts-cells with round-oval nuclei, clumped chromatin, l-2 nucleoli, and scantbasophilic cytoplasmwithout granules. c. ALL is the leukemia most likely to involve the nervous system. Neoplastic cells may infiltrate meninges,compressingand destroyingadjacentcerebralstructures. 3. Prognosis a. Death often resultsfrom infection or bleeding.Chemotherapy may induce remission, a state in which leukemic cells are no longer present in bone marrow (although extramedullaryfoci of cancermay persist).Bone marrowtransplantation may rescue as many as 40o/oof children who relapse after chemotherapy. With radiation and intrathecal chemotherapyto prevent CNS involvement,approximatelyhalf the children

Note of preMostALLis composed isthe CDl0(CALLA) B cells. marker. surface diagnostic usually occur, variants T-cell a boysandcausing affecting mass thatmay thymic thetrachea. compress deoxynucleotidyl Terminal in transferase flDT)ispositive bothB-cellandT-cellALLand inAML. isnegative

are cured. b. Prognosisfor adults remains very poor and deciinessteadilywith age,especially10 yearsor more after treatment. D. Acute myelogenous leukemia (AML) l. Clinical features. AML representsapproximately 20o/oof acute leukemia in children and is the most common acuteleukemia in adults.Signsand symptoms resembleALL, except that AML usually presentswith lymphadenopathy or splenomegaly. 2. Pathology. One may seetissueinfiltrates of neoplasticcellscalledchloromas.The primary cell type is variable. a. Myeloblasts have a round-oval nucleus,loose chromatin, two or more nucleoli, and pale blue cytoplasm.They may contain Auer rods (finely granular cytoplasmicbodies),which are abnormal fusedlysosomalstructures' b. Neoplasticcellshave featuresof both myelocytesand monocftes. c. In promyelocytic leukemia, Auer rods are present,and neoplastic cells are filled with gt*.tl.r containing procoagulantmaterial; releaseof this material may lead to DIC. DIC, togetherwith thrombocytopenia due to bone marrow infiltration with leukemic cells,may lead to fatal bleeding. d. Erythroleukemia (De Guglielmo disease)featuresarypical multinucleated RBC precursors.It usually convertsto AML. e. Eosinophilic or basophilic leukemias are rare disorders in which the eosinophil or basophil precursor is the predominant neoplasticcell trpe. 3. prognosis is uniformly poor and patientsusually die within 3 years.Bone marrow transplantation is under investigationand has alreadycured some patients.

519

Hematologic/tymphoreticular System

Thble IV-4-3. The French, American, and British (FAB) classification of myelogenous leukemias. Classification

Description

MO MI

Undifferentiated; no consistentALL markers Myeloblastswithout maturation; cells express HLA, DR, CD34, CDl3, CD15, and CD33 Granulocyte maturation is recognizable Promyelocytic Mixed myeloid and monocytic differentiation Monoblastic or monocytic Erythroid differentiation Megakaryocytic differentiation

M2 M3 M4 M5 M6 M7

E. Chronic myelogenous leukemia (CML) 1. Clinical features. This is primarily a diseaseof middle agebut may occur in children and young adults. Initial symptoms are often fatigue, fever, night sweats,and weight loss. Splenomegaly is common and often massive enough to cause abdominal discomfort. Laboratory studiesmay show marked leukocytosis(50,00G-500,000),low-to-absent leukocyte alkaline phosphatase, elevatedserum vitamin B,, and vitamin B,r-binding proteins, and high uric acid as a result of rapid cell turnover. After a variable remission period, patients may develop blast crisis, which is an acute resistantform of leukemia, leading to death.Approximately two-thirds of patients convert to AML and one-third to B-cell ALL. 2. Pathology

Note ThePhchromosome wasthe firstchromosomal translocation foundto be specific fora disease. lt creates a bcr:abl fusion protein whichphosphorylates tyrosines inappropriately. STl57l isa drugwhich specifically targets thefusion protein (again thefirst)and hasproduced durable remissions.

Note Theclassical CLLcellisthe B CDs cell.CLLcellsdivide veryslowly butdonot undergo apoptosis andso accumulate endlessly.

t20

a. The peripheral smear shows a very high WBC count. Segmented neutrophils, metamyelocftes, and myelocftes are predominant, but promyelocytes and blasts are also present. Eosinophils and basophils are present and often prominent. Lymphocytesare few. There is a moderate anemia with some anisocFtosis.Plateletsare usually increased,often markedly. b. The bone marrow is packed,often 100o/ocellular with hyperplasiaof the granulocytic cell line. c. The spleen may be massively enlarged (up to 5 kg). Leukemic cells may obstruct vessels,leadingto multiple splenicinfarcts. d. Over 95o/oof patients with CML have the Philadelphia chromosome (Pht), the result of translocationfrom the long arm of chromosome22 to chromosome9 in all dividing progeny of pluripotent stem cells.This translocation is pathognomonic and confirms the diagnosis.Prognosisin CML is worse in Phr-negativepatients. 3. Prognosis. Control may be achievedwith hydroxyurea, but blast crisis and death usually ensuewithin 2-3 years.B-cell blast AIL crisis is more treatablethan AML. Bone marrow transplantationhas produced some cures. F. Chronic lymphocftic leukemia (CLL) 1. Clinical features.This is a diseaseof patients usually over 60 yearsof age.It is common in the West and rare in Asians.There is usually an insidious onset,often discoveredincidentally during routine blood testing.The patient may be asymptomaticor presentwith fatigue and weight loss; lymphadenopathy and hepatosplenomegalyare later findings. Patients may develop low levels of gamma globulins with resultant susceptibility to infection. Patients with CLL are also thought to have a higher incidence of visceral

Pathology

malignanry (e.g.,gastrointestinaltract, lung, skin), and develop autoimmune hemolytic anemia more frequently than the normal population. 2. Pathology a. The peripheral smear showsmarked lymphocytosis (50,000-250,000).Normochromic, normocytic anemiais common and autoimmune hemolysismay occur.Plateletsare initiully normal, then decreaseas the bone marrow is replacedby neoplasticcells. b. In the lyrrrph nodes,marked lymphadenopathy may develop late in the disease.Nodes are soft and rubbery. The cut surfaceis homogeneous.On microscopic examination,the infiltrate is indistinguishablefrom diffirse well-differentiatedlymphocytic lymphoma. c. The liver may be enlarged.Infiltrates are usually localized to portal areas. 3. Prognosis. Median survival with treatment is approximately 5 years but varies widely. TWenty-yearsurvivals are reported. Patientsoften die of other diseasesafflicting the elderly. The most important prognostic factor is extent of disease.When the WBC is <50,000 and there is no lymphadenopathy, splenomegaly,anemia, or thrombocytopenia, the patientsdo well. As the WBC count risesand the abovecomplicationsensue,patientsfare worse. G. Hairy cell leukemia l. Clinical features. This is a rare disease.Leukemic cellshave"hair-like" cytoplasmicprojections visible on phase-contrastmicroscopy and sometimes on blood smears.Cells expresssome B-cell antigens.They expresstartrate-resistant acid phosphatase (TRAP). Patientsoften presentwith hepatosplenomegaly. 2. Pathology a. On peripheral smear,pancytopeniais common; leukocytosisis rare. Hairy cells may be seenin peripheral blood. b. Bone marrow and spleenare infiltrated with hairy cells.

Note 2CdA actsto poison adenosine deaminase, allowing accumulation of deoxyadenine, whichisvery toxicto lymphoid cells. The absence ofthisenzyme isone ofthemajorcauses of severe immune combined deficiency

(scrD)

3. Prognosis. This diseasemay now be cured with 2-chloro-deoxyadenosine (2CdA), an apoptosisinducer that is relatedto fludarabine. H. Adult T-cell leukemia/lymphoma 1. Clinical features. This diseaseis endemic in lapan and sporadic in the West. It is caused by the human T-cell leukemia/lymphoma virus (HTLV l), a virus with some similarities to human immunodeficienry virus (HIV). Patients present with lymphadenopathy, hepatosplenomegaly,skin involvement, and hlpercalcemia. The incubation period after exposureto the virus may be decades. 2. Pathology. The primary cell type is the CD4 T cell. 3. Prognosis is poor. However,many infected patients do not progressto disease. I. Myelodysplastic syndromes are proliferative stem cell disorders that are in the gray zone betweenbenign proliferation and frank acuteleukemias. Thesedisordersare characterizedby maturation defectsleading to ineffectivehematopoiesisand typically presentaspancftopenia in elderly patients. One-third of thesepatients later developfrank acutemyelocytic leukemia.

In a Nutshell Leukemia Clues . Children/ -+ ALL lymphoblasts . Myeloblasts -+ AML . Auerrods -+ AML, promyelocytic . DIC -+ Promyelocytic . Elderly -+ CLL . Massive -+ CML splenomegaly . Philadelphia-+ CML chromosome . Tartrate+esistant -+ Hairy cellacid phosphatase (rRAP) . HTLV-I -+ AdultT cell

521

Hematologic/tymphoreticular System

PTASMA CELLDYSCRASIAS A. Hypergammaglobulinemia is an increasedserum level of immunoglobulin. 1. Classification a. Monoclonal immunoglobulin molecules,or M components,belong to a singleclass, subclass,and type. Although complete immunoglobulin molecules circulate in the plasma and interstitium, fragments, such as immunoglobulin light chains, may be found in the urine. Monoclonal gammopathies may be malignant (e.g., multiple myeloma, Waldenstrdm'smacroglobulinemia,heavy-chaindisease)or benign (e.g., monoclonal gammopathy of undetermined significance,MGUS). Approximately 2o/o of MGUS patients progressto frank malignancyeachyear. b. Polyclonal immunoglobulins are usually due to antigenic stimulation. Liver disease also elevatesimmunoglobulins as a result of decreasedcatabolism.Polyclonalhypergammaglobulinemiatypically occurs 1-2 weeksafter an antigen stimulus. It may follow bacterialinfection, or occur with granulomatousdisease,connectivetissuedisorders, and liver failure secondaryto decreasedcatabolism. Pathology is variable and dependson the underlying disorder. 2. Laboratory tests show elevatedserum globulins, an elevatederythrocyte sedimentation rate (ESR),and a positive serum protein electrophoresis.Bence-Jonesproteins (free light chains) may be found in serum or urine. In myeloma, the free light chains are monoclonal. In inflammation, liver disease,or glomerulopathy,the free light chains are polyclonal. 3. Clinical features a. Hyperviscosity of blood may lead to sludging and rouleaux formation with subsequent thrombosis,hemorrhage,renal impairment, CNS disturbances,and right-sided congestiveheart failure. b. Cryoglobulins, immunoglobulins that precipitate in the cold (usually M components), may lead to Raynaudphenomenon,thrombosis,and gangrene. c. M components may interferewith clotting,leading to gastrointestinalor retinal hemorrhage.They most often inhibit factors IX and X. d. The presence of immunoglobulins with antibody activify in the serum may lead to immune-mediated destruction of RBCs,granulocytes,or plateletswith resultant anemia, granulocytopenia,or thrombocytopenia. B. Multiple myeloma l. Clinical features.Multifocal plasmacell neoplasmsin the bone marrow and, occasionally, soft tissues,produce monoclonal immunoglobulins (IgG). Signsand symptoms result from excessabnormal immunoglobulins causinghyperviscosity,and from infiltration of various organsby neoplasticplasma cells.Immune-mediated destruction of blood cells and lack of normally functioning antibodies lead to susceptibility to infection. Proteinuria may contribute to progressiverenal failure. Infiltration of bone with plasma cell neoplasmsmay lead to bone pain and hypercalcemia. Over 99o/oof patients have elevated levelsof serum immunoglobulins or urine Bence-)onesproteins, or both. Serum protein (SPEP)electrophoresisshowsa homogeneouspeak or "spike." 2. Incidence. Peakincidenceis 50-60 yearsold, equally distributed betweenboth men and women.

t22

Pathology

3. Pathology a. Bone. The marrow is infiltrated with plasma cells (usuallyover 30o/o)in various stages of maturation,called"myelomacells."They may resemblelymphoid precursorswith cytoplasmicinclusions (acidophilic aggregatesof immunoglobulin) called Russell bodies.Multiple osteolytic lesions throughout the skeleton,resultingfrom plasmacell secretionof osteoclastactivatingf-actor(OAF), appearas "punched-out" defectson xray. Theselesionsmost commonly involvevertebrae,ribs, skull, pelvis,femur, clavicle, and scapula. b. Kidney. Interstitial plasmacell or chronic inflammatory infiltrate may be seen.Protein castsin distaltubulesresult from glomerulardamageby M proteins. c. Nervous system. Ttrmor infiltrating nerve roots or vertebral compressionfractures may lead to neuropathy or myelopathy. d. Other. Ten percent of patientsdevelopamyloidosis,more often with l, than r chains. Plasmacell infiltrates may be found in lymph nodes,liver, and spleen. 4. Prognosis.Thereis lessthan a 2-yearsurvivalwithout therapy.Deathusuallyresultsfrom infection,bleeding,or renalfailure.Occasionally, thereis a leukemicphasein which plasma cellsinvadetl-reperipheralblood. Chemotherapymay prolong survival.Interferon-cr producesremissionin somepatients.

In a Nutshell Classic Clues forMultiple Myeloma . Monoglonal gammopathy-sin glespike ONSPEP . Proteinuria withBenceprotein in urine Jones . Bonepainand hypercalcemia . "Punched out"or "motheaten" lyticbonelesions onx-ra} " -" '.,: "i :,: :',

5. Solitary myeloma (plasmacl.toma)is a rare, isolatedplasmacell neoplasmin bone or soft tissues(lungs,nasalsinuses,oropharynx).Twenty-fivepercentof patientshaveelevatedM components.If the primary cancer is in bone, plasmacytomais likely to disseminate; extraosseous primaries tend to remain localized.Local diseasemay be surgicallyresectable or curableby radiotherapy.If left untreated,it usuallydisseminates.

Figure lV-4-2.Vertebral column in multiple myeloma (gross).

tzt

Hematologic/tymphoreticular System

Figure lV-4-3.Multiple myeloma with bone resorption (m icroscopic).

C . Waldenstriim macro glob ulinemia

Note A majordifference between myeloma multiple and Waldenstrom macroglobulinemia isthe lackof lyticbonelesions inWaldenstrdm.

l. Clinical features. These are neoplasms of lymphocytoid plasma cells that produce monoclon"l IgM. The diseaseresembleslymphocytic lymphoma. Symptoms are due to hypergammaglobulinemiaand tumorous infiltration. Most patients presentwith constitutional symptoms (i.e., fatigue, weakness,weight loss) but they may present with hepatosplenomegaly, lymphadenopathy,bone pain, and manifestations of hlperviscosity. Ten percent of patients have Bence-|onesproteins in urine. Almost all patients have an M-protein spikeon serumprotein electrophoresis. 2. Incidence. The peak incidenceis at age60-70 yearsin both men and women. 3. Pathology a. Bone marrow shows infiltrates of lymphocytes,plasma cells,lymphocytoid plasma cells, and related variants. There is no bone erosion. Some intensely eosinophilic abnormal plasma cells called "flame cells" are due to immunoglobulin with a large amount of glycosylation. b. Other. Similar infiltrates may be found in lymph nodes,liver, spleen,meninges,and brain. Blindnessand priapism due to hyperviscositymay be seen. 4. Prognosis. There is a 2-5-year survival rate with chemotherapy. D. Monoclonal gammopathy of undetermined significance (MGUS) l. Clinical features.There is an asymptomaticelevationin serum immunoglobulins detected as an M-protein spike on serum electrophoresis. 2. Incidence is approximately |-2o/oof "healthy'' patients and increaseswith age. 3. Pathology. Patientshave a low concentration of M protein, and the bone marrow contains lessthan 5oloplasmacells.

524

Pathology

4. Prognosis. This disorder was initially thought to be benign, but approximately 2o/oof patients a year with MGUS may later develop myeloma, lymphoma, amyloidosis, or Waldenstrom macroglobulinemia. Patientswith this disorder should be followed with periodic evaluationsfor serum and urine immunoglobulins. E. Heavy chain diseaseoccurs (rarely) when a neoplasticclone of plasmacellsor lymphocytes producesa monoclonal ct, y, or M chain.

DISORDERS OFTHESPTEEN A. Splenomegaly including infections(e.g., l. Clinical features.Therearemultiple etiologiesfor splenomegaly, mononucleosis,TB, CMV malaria), congestionwith portal hypertension(e.g.,cirrhosis, portal vein thrombosis,right-sided CHF), inflammation (e.g.,SLEand rheumatoid arthritis), lymphohematogenousdisease(e.g.,myeloma,lymphoma, leukemia),storagedisease (e.g.,Gaucher,Neimann-Pick),and others (e.g.,infarcts,amyloid, tumor). 2. Signs and symptoms. The patient may complain of left upper quadrant discomfort. Sequestrationof blood elementsby an enlargedspleenis known ashnrersplenism and is characterizedbysplenomegaly,reduction of one or more blood cell lines with resultant anemia, leukopenia,or thrombocytopenia, and resolution of the blood disturbanceby splenectomy. 3. Pathology dependson the underlying disease.Congestivesplenomegalymay lead to a large,firm, red spleenwith a thick capsule.

Note leads Absence ofthespleen bodies to HowellJolly (nuclear fragments) in circulating redcells.

B. Splenic infarcts 1. Clinical features. Infarcts initially present with splenomegaly,but then fibrosis and shrinkageoccur. They may be causedby occlusion of the splenic artery or its branches, but are most commonly causedby embolisms from the heart; thrombosis may occur. Occlusion of sinusoidsby sickled cells also producesmultiple microinfarcts, leading to autosplenectomy. 2. Pathology. Infarcts may be single or multiple, small or large.They are usually pale and wedge-shapedwith a broad baseat the periphery.Suppurativenecrosismay develop,followed by scarring. C. Splenic neoplasms 1. Clinical features. Most tumors involving the spleen are lymphohematogenousneoplasms,but others may occur. 2. Primary neoplasms a. Benign. Fibromas,osteomas,chondromas,lymphangiomas,and hemangiomas(often cavernous)are all rare. b. Malignant. Lymphomas are by far the most common; hemangiosarcomasare rare.

€linical Correlate undergoing Recall thatpatienb receive splenectomy should vaccinations them to protect fromencapsulated organisms. forPneumococcus Vaccines are andH.influenzoe available.

from epithelialtumors to the spleenusuallyoccur only 3. Secondaryneoplasms.Metastases with widely metastaticcancer. D. Rupture 1. Clinical features.Rupture is usually due to trauma but may be spontaneousin leukemia, malaria,typhoid fevet and infectious mononucleosis.

,25

Hematologic/tymphoreticular System

2. Pathology. There is usually massiveintraperitoneal hemorrhage.The peritoneal cavity may be seededwith foci of splenictissue. 3. Course. Prompt surgicalintervention is required. E. Congenital anomaliesof the spleen,including accessoryspleensand abnormal lobulations, are common. Small accessoryspleenscan become clinically significant when they enlarge following a therapeuticsplenectomy.

DISORDERS OFTHETHYMUS A. Atrophy of the thymus may be seenin severalcongenitalabnormalitiesand with radiation, chemotherapy,and stress. 1. Pathology

Flashbackto Embryology Remember thatthethird pharyngeal pouch gives riseto gland, thethymus whereas the pouch gives fourth riseto the parathyroids. superior

a. Congenital immune deficiencies as a result of adenosine deaminase deficienry or interleukin-2 (lL-2) receptor deficienry lead to the absenceof lymphoid precursors and failure of the thymus to populate with thymocytes. Severe combined immunodeficiency disorder ( SCID) results. b. Other congenital irnmune deficiencies, such as Nezelof syndrome and DiGeorge syndrome, lead to atrophy or failure to develop a thymus. In DiGeorge syndrome,a defectin the developmentof the third and fourth pharyngealpouchesalsoleadsto the absenceof the parathyroids,causingparathormone deficiencyand tetany shortly after birth. B. Hyperplasia of the thymus with germinal center formation may be seenin some autoimmune diseases,such as myasthenia gravis, where antibodies are made to acetylcholine receptors.Removalof the thymus often curesthe disease. C. Epithelial thymomas are benign in 90o/oof cases. 1. Pathology. Most epithelial thymomas are lobulated and encapsulatedand are composed of a mixture of epithelial cellsand T lymphocytes. 2. Cl"inicalfeatures.The mean ageis 50. They may presentincidentally on chestx-ray with cough, dyspnea,or dysphagia.There is an increasedincidence of thymoma in patients with myastheniagravis. D. Lymphomas may originate in the thymus. The thymus may also be secondarily involved in Hodgkin disease,non-Hodgkin lymphomas,and acutelymphoblasticleukemia.

!26

phoreticu Hemato IogiclLym lar Pharmacology Hemostasis istheprocess thatkeeps bloodin itsfluidstateandwithintheconfines ofthevasculature; plugformation it relies ona delicate balance between theopposing mechanisms of platelet and coagulation ontheonehandandfibrinolysis andclotdissolution ontheother.Hematopoiesis isthe process bywhich thebonemarrow replaces bloodcells. Hematopoiesis involves thedifferentiation of pluripotent (redbloodcells[RBG], platelets, $emcells intodifferent bloodcells types of mature growth monocytes, andgranulocytes). Thisdifferentiation isregulated byspecific factors. Thischapter willreview thedifferent inhibit hemostasis classes of drugs usedto enhance and/or and hematopoiesis.

DRUGS THATAFFECT HEMOSTASIS A. Plateletantagonists 1. Aspirin a. Pharmacologicproperties (l) Aspirin inhibits cyrlooxygenaseand pr€ventsthe synthesisof prostaglandin endoperoxides; thus,it preventsTXA, synthesis. (2) While aspirin ireversibly inhibits plateletfunction, endotheliumcan synthesize more cycloorygenase and producethe anticoagulantPGI, (prostacyclin). (3) The effectof aspirin on plateletenzfmesis permanentfor the life of the platelet (7-10 days). (4) Prolongationof the bleedingtime following a singledosecanlast up to 7 da)'s.

Not€

b. Indications for use

(r) Low-dose isused reinfarction in patients whohave hada aspirin to prevent myocardialinfarctiot' (2) It also now used in a prwentative fashion as prophylaxis againstmyocardial infarction. (3) It is alsousedto prwent occlusionin coronaryartery bypassgrafts. (4) It is givento patientswiti transientischemicattacks(TIAS)to preventstroke.

friJi,.1iilffi,l,n. discussion of nonsteroidal anti-inflammatory agents in theMusculoskeletal Pharmacology ciapterof **' f,l;*lrlt$tt

2. Other antiplatel€t drugs a. Clopidogrel inhibits plateletaggregationby irreversiblymodifting the plat€letADP receptor.It is used for reduction of atherosleroticeventsin those with established atlerosclerosis.

t27

Hematologic/tymphoreticular System

b. Ticlopidine inhibits the expressionof glycoprotein IIb/IIIA receptors on platelet membranes(GPIIb/IIIa havefibrinogen-binding sites).Due to an associationwith life threateningblood dyscrasias, it is reservedfor patientsexperiencingstroke precursors who cannot tolerate aspirin. B. Anticoagulants 1. Heparin a. Pharmacologic properties ( 1) Heparin is a classof large moleculescomposedof anionic mucopolysaccharides in a straight chain. It accelerates antithrombin III (heparin cofactor) binding to thrombin. Antithrombin III inactivatesthrombin; it also inactivatesfactors IXa, Xa, XIa, XIIa, and kallikrein. (2) It is administered intravenously or subcutaneously;hepatic metabolism is by heparinase. (3) Heparin prolongsthe partial thromboplastin time (the most commonly usedtest to monitor anticoagulanteffect),thrombin time, and whole blood clotting time. It is the only drug that produces anticoagulation within minutes. (4) It inhibits clot formation, but it doesnot dissolveexisting clots. b. Indications for use (1) Heparin is usually administeredsubcutaneouslyin low dosesto prevent clot formation in patientsat high risk for thrombosis and pulmonary emboli (e.g.,those at prolonged bed rest). (2) Therapeuticheparin is used to stop ongoing thrombosis (thrombophlebitis). (3) Heparin is used in the acutephaseof myocardialinfarction. (4) It can be used in pregnant women sinceit doesnot crossthe placenta.

Clinical Correlate Theeffects of heparin are reversible withadministration of protamine sulfate.

c. Side effects and toxicity ( 1) Bleedingis the main complication; PTT must be carefullymonitored. Protamine sulfate, which is positively charged,reversesthe anticoagulant effect of heparin. Excessive protamine, however,may have an anticoagulanteffect. (2) Thrombocytopenia is usually transient and mild. (3) Hypersensitivityreactionsmay occur. (4) Osteoporosismay developwith chronic therapy. (5) There is an elevationof liver function tests(LFTs). d. Low molecular weight heparins (LMWHs; ardeparin, dalteparin, enoxaparin) have more antifactor Xa activity, less inactivation of thrombin, and less inhibition of plateletsthan with standardheparin. They have a longer half-life than standardheparin and are used in hip replacements.

,28

Pharmacology

2. Warfarin

h a1ubhell

a. Pharrnacologic properties

Heparin

( 1) Warfarin, a coumarin derivative, int€rferes with the yitamin K-dependent hepatic Post-translational modification of factors II, V , IX, and X, as well as the fibrinolytic factors protein C and protein S. The onset of action is delayed 2-3 daysbecauseof existing yitamin K-dependent factors. (2) warfarin prolongs the prothrombin time (pr), which is used to monitor the pharmacologiceffect, (3) Warfarin is extensively bound to albumin and is metabolized hepaticallv.

(4) It is administered orally. (5) Warfarin crossest}re plac€nta; it should not be used during pregnanry. b. Indications for use are similar to heparin, but warfarin is not indicated for rapid anticoagulation. The PT is monitored becausefactor VII has the shortest half life and the extrinsic pathway is there\ most affected by warfarin. The induction of warfarin therapy requires concomitant heparin therapy becausefibrinolpic factors (protein C and protein S) are depleted first, placing patients at j€opardy for clotting.

Warfarin

. 1 ATIl effed . Indere5 , idr onthrombin ryntresis d vit Kiependert dotinghcb6 'HT** ' Monibred wfl .ciwnlvorse . crren o?tv 'Treatukrty .Treatirxijty

wihflotamine HIHJI' paslna . Rapid anlturag-.2_l daFbeforc (hours) antjcoaSulation ulatbn . Gnbersedin . Cnn't bersedin preSnancy prqnancy

c. Side €ffects and toxicitl' (1) Bleedingcan be treated with concentratesofvitamin K-dependent factors (in severe cas€s)or with vitamin K. (2) Patients with vitamin K deficiency or hepatic insufficiency require lower doses. d. Drug interactions (1) Barbiturates, glutethimide, rifampin, and chronic alcohol ingestion increase the hepatic metabolism via enzyme induction, thereby decreasing the effect of oral anticoagulants. (2) Phenylbutazone and aspirin inhibit platelet aggr€gation and prolong the bleeding time, thus increasing the anticoagulant effect, which can lead to a hemorrhagic diathesis. (3) Clofibrate inceases the metabolism of factors II and X and decreasesplatelet adhesiveness;thus, it may increase th€ anticoagulant effect, which can lead to a hemorrhagic diathesis. (4) Metronidazole, trinethoprirn, disulfiram, cimetidine, phenlbutazone, acute alcohol intoxication, influenza vaccine,and sulfonamides all decreasethe metabolism of warfarin and increaseits anticoagulant effect (can lead to bleeding). 3. Dicurnarol is a coumarin anticoagulant; its mechanism of action is similar to warfarin.

ilote Warfarininteractionswith other drugshashistoriolly beena Boardsfavorite'

4. Anisindione is an indandione derivative; its mechanism of action is similar to that of the coumarin anticoagulants. 5. Hirudin a. Hirudin is a thrombin inhibitor; site of thrombin.

it binds the active site and fibrinogen recognition

b. The drug causeslittle bleeding at therapeutic doses. c. It is administered intravenously ot subcutaneouslv.

,29

Hematologic/tymphoreticular System

Note t-PAselectively activates plasminogen thatisboundto fibrin.Thus, it istheorized to bemoreselective forclotlysis thanstreptokinase and urokinase, whichcause plasm nonselective inogen activation to plasmin, resulting in a morewidespread fibrinolytic state(plasmin lyses fibrinogen, factorV,andfactor Vlll,inaddition tofibrin). ln a Nutshell

C. Thrombolytic agents. Streptokinase, urokinase, and tissue plasminogen activator (t-PA) are capableof activating fibrinolysis and initiating thrombus dissolution. All three agentshave the same mechanism of action; they promote the conversion of plasminogen to plasmin. Streptokinaseand urokinase are used in the treatment of deep vein thrombosis, pulmonary embolism, and the unclogging of cathetersand shunts.AII three agentscan be used in the treatmentof acutemyocardialinfarction.Hemorrhage (especiallysubarachnoid)is the major risk of thrombolytic therapy. 1. Streptokinase a. Pharmacologic properties ( 1) Protein is produced by B-hemolytic Streptococci.It is necessaryto administer an intravenous loading dose to override plasma antibodies that are present from previous streptococcalinfections. (2) There is no enzymaticaction; streptokinaseforms complexeswith plasminogen. The streptokinase-plasminogen complex can then cleavefree plasminogeninto plasmin. (3) Streptokinasehas the longesthalf-life of thrombolytic agents.

Thrombolytic Agents . t Fibrinolysis . Usedintreatment of early myocardial infarction . Mainsideeffect = bleeding

(4) There is no fibrin specificity. b. Side effects and toxicity include bleeding and hypersensitivity-antigenicreactions, such as rashes,fevet and anaphylaxis(rare). 2. Anistreplase (anisoylated plasminogen-streptokinase activator complex [APSAC]) is a complex of streptokinaseand human plasminogenmodified so that it is not readily activated until after it binds. This provides some specificityfor clot fibrinolysis. 3. Alteplase (tissue plasminogen activator [t-PA]) a. Pharmacologic properties ( 1) t-PA is an endogenouslyproducedserineprotease.Therapeuticamountscan be produced by recombinant DNA technology. (2) Unlike streptokinaseand urokinase,t-PA is "fibrin selective";that is, it doesnot activatefree plasminogen.Instead,it activatesonly plasminogenbound to fibrin. No degradationof fibrinogen or other factorsoccurs. (3) It hasa short half-life (lessthan 5 minutes). b. Indications for use. Use is currentlv limited to the treatment of acute mvocardial infarction. c. Side effects and toxicity. Hemorrhage may occur. Despite its fibrin-selectivity, the incidence of bleedingwith t-PA is no lower than with streptokinaseor urokinase. 4. Reteplaseis a derivativeof t-PA. It does not competewith native plasminogenfor binding to fibrin. It is consideredto havelessrisk of hemorrhagethan t-PA. D. Fibrinolytic inhibitor: e Aminocaproic acid (EACA) 1. Pharmacologic properties. Aminocaproic acid is a lysine analog that binds to lysinebinding sites on plasminogen and plasmin to block plasmin'sbinding to fibrin. Thus it is a potent inhibitor of fibrinolysis.

550

Pharmacology

2. Indications for use. It is used to treat systemic hyperfibrinolysis associatedwith surgical complications following heart surgery and portocaval shunt. It may also be used for bleeding associatedwith surgery for carcinoma of lung, prostate, cervix, or stomach, abruptio placentae,and hematologicdisorders,such as aplasticanemia.It can be used to reversethe actionsof streptokinaseor t-PA.

DRUGS THAT AFFECT HEMATOPOIESIS A. Hematopoietic growth factors 1. Epoetin alpha (Erythropoietin; EPO) a. Physiologic properties (1) Erythropoietin is a growth factor produced by the kidney that stimulates RBC production. (2) Production is increasedwith hypoxemiaor anemia. (3) Recombinant erythropoietin is availablefor therapeutic use. It is administered parenterally. b. Indications for use (1) Erythropoietin is used to treat anemia that is secondaryto renal failure and to chemotherapy. (2) Erythropoietin can be usedin the treatment of anemia secondaryto zidovudine (AZT) in patientswith AIDS. (3) Erythropoiesismay be stimulated prior to surgeryto alleviatepotential surgical blood loss.It can alsobe used to facilitate autologousblood donation. c. Side effects and toxicity (increasedviscosity).

include clotting of dialysis tubing and hypertension

2. WBC growth factors are glycoproteinsthat stimulate differentiation of myeloid cell lines. a. Sargramostim is recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is produced by T lymphocytesand other cell types.It stimulates the proliferation of granulocytes,monocftes, macrophages,and megakaryocytes. (1) Indications for use. It is used in the treatment of neutropenia secondaryto a variety of causes(e.g.,chemotherapy,ganciclovir-inducedneutropenia). (2) Side effects and toxicity include induration and thrombophlebitis at the injection site,bone pain, fever,rashes,and myalgias.Dose-limiting conditions include pleuritis, pleural effrrsions,and pericarditis. b. Filgrastim is recombinant granulocyte colony-stimulating factor (G-CSF). G-CSFis producedby monocytes,fibroblasts,and endothelialcells.It stimulatesthe production of neutrophils. (1) Indications for use. It is used for the treatment of chemotherapy-induced neutropeniaand other neutropenias. (2) Side effects are less severethan with GM-CSF; they include bone pain and vasculitis. c. Recombinant forms of interleukin-3 (It-3) and macrophage colony-stimulating factor (M-CSF) are also available.

551

Hematologic/tymphoreticular System

B. Supplementsus€din the treatment of an€mi. 1. Iron a- Iron deficiencyanemiais the most conmon nutritional anemiaworldwide.The anemia is hlpochromic and microcytic. b. Iron levelsmaybe supplementedby the oral administrationof ferrous sulfrte. (1) Foodand antacidsreduceabsorption. (2) Sideeffectsareprimarily gastrointestinal,including nausea,heartbum, abdominal pain, constipation,and diarrhea. (3) Iron overloadmay causehemochromatosis. c. Iron levelsmayalsobe supplemented by the parenteraladministrationofiron dextran, ( 1) Sideeffectsinclude heatlache,fevet lymphadenopathy,and arthralgias. (2) Fatal anaphylacticreactionis rare, but its posible occurrencelimits the use of iron dextran. 2. Folic acid" Folatedeficiencyanemiacan result ftom poor folate absorptionasa result of disordersof the smallintestine,alcoholism,drug interactions,or increasedfolatedemand asa resultof pregnancyandlactation.The anemiais megaloblastic. Oral folic acid is given asa supplement.

9ilitd,!q!'.tlt Megalobla$ic anemiashould neverbetreatedwithfolicacid alonebecause it couldmask pr*ence the of a vitaminB,, deficiency, wtrich,if left Untreated, canresultin neurologic damage.

ttz

3. viteminB,,(crano6slnrrmin) a. Deficiencyof vitamin B,, is usuallydueto inadequateabsorptionsecondaryto failureof parietalcellsto produceintrinsic factor (pemiciousanemia). b. Cyanocobalaminis usedin the treatmentof m€galoblasticanernia. c. Supplementationcan be oral (for nutritional deficiencies),intramuscular,or by deep subcutaneousinjection (the latter two are usedfor perniciousanemiaand ileal disease)'It cannotbe administeredintraYenously'

sEciloNv

Nervous System

Embryology Nervous System in thecontext of its nervous system isbestunderstood Theorganization of themature central closes to whichgradually layer foldsto forma groove, development. Theoutermost of ectoderm lumenpersists fromtheneural tube;the formtheneural tube.Thebrainandspinal corddevelop fortheorganization of boththespinal cordand intheadult. Theblueprint astheventricular system of cellsintosensory anddifferentiation to thesegregation thebrainstemintheadultcanbetraced plates (alar) nervous inthedeveloping system. andmotor(basal)

NEURAL PTATE The neural plate is an ectodermalderivative,which is presentby day 19 in the dorsalmidline of the embryo. A rostrocaudalgroove appearson the midline of the neural plate and invaginates while the lateral borders rise to form the neural folds. Fusion of the neural folds produces the neural tube. Closure of the neural tube initially occurs at the level destined to form the cervical spinal cord. Closure proceedsfrom that point both rostrally and caudally,with complete closureof the anterior and posterior neuroporesduring the fourth week.Incompleteclosureof the posterior neuroporeresultsin spinabifida. Closureof the anterior neuroporeoccursat the lamina terminalis. Failure to closethe anterior neuropore causesanencephaly,failure of the forebrain to develop.

NEURAL TUBE The neural tube developsinto the CNS. Initially, the neural tube is separatedfrom the surface ectodermby the neural crestcells. A. The caudal end of the neural tube developsinto the spinal cord (FigureV-1-1). 1. Basal plates, which are located ventrally (anteriorly), develop into the motor (efferent) part of the spinal cord and brain stem; they contain the motor cells. 2. Nar plates, which are located dorsally (posteriorly), develop into the sensory(afferent) part of the spinal cord and brain stem.

ln a Nubhell . Basal plates: motor . Alarplates: sensory

3. The sulcus limitans is a groove that separatesthe alar and basal plates and extendsfrom the spinal cord into the brain stem.

555

Neruous System

Cavity of neural tube Posteriorgray column

Neural crest.."\

Neural crest cell

{ Whitematter

SulcusI

Graymatter Basalplate

Anteriorgraycolumn

Figure V-l-1.The spinal cord in early development.

B. The rostral end of the neural tube developsinto the brain. Early in development, the brain is divided into three primary vesicles:the rhombencephalon, the mesencephalon, and the prosencephalon. 1. The rhombencephalon, or hindbrain, differentiates to form the: a. Myelencephalon, which developsinto the medulla oblongata b. Metencephalon, which developsinto the pons and cerebellum 2. The mesencephalon is the midbrain. 3. The prosencephalon, or forebrain, differentiates to form the diencephalon and the telencephalon(FigureV- I -2).

Hemispheric

Telencephalon (cerebralhemisphere) Figure V-1-2.The brain of a 6-week-old embryo, with five vesicles.

,t6

Embryology

a. The diencephalon differentiates to form the following structures: ( 1) Thalamus (2) Hypothalamus (3) Posterior lobe of the pituitary (neurohypophysis) (a) Epithalamus (5) Subthalamus b. The telencephalon differentiates to form the following structures: (1) Cerebralcortex (2) Basalganglia (3) White matter

TUBE CEttS NEURAT A. Neural crest cells differentiate into the following: 1. Sensory ganglia of cranial nervesV VII, IX, and X 2. Dorsal root ganglia of the peripheral nervous system (PNS) 3. Schwann cells of the PNS 4. Melanocftes and odontoblasts 5. Enterochromaffin cells (amine precursor uptake and decarborylation cells,APUD) 6. Neurons in parasympathetic and sympathetic ganglia (including adrenal medulla) 7. Leptomeninges (the pia and arachnoid) B. Neuroepithelial cells differentiate into the following: 1. Neuroblasts, which differentiate into neurons 2. Ependymal cells 3. Glioblasts, which differentiate into: a. Astrocftes b. Oligodendrocftes C. Mesenchymal cells are mesodermal derivativesthat differentiate into microglia.

t7

l{eruousSystem

MYETINATION A. Schwann cells are the myelin-forming cells of the PNS. Myelination in the PNS begins during the fourth month of development.

ln a iluBhell Myelination . Schwann cellsinthePNS myelinate asingle axon . Oligodendrocytes inthe CNS myelinate many (50+;axons

558

1. The Schwanncell cytoplasm surrounds all the axons in the PNS and forms the neurilemmal sheath. 2. Certain axons, in addition to their neurilemmal sheath,are myelinated by the Schwann cells. Myelinated irxons have a characteristic shiny white appearance,which causeslarge myelinated tracts to appear white. Myelin is formed when the Schwann cell membrane repeatedlywraps around the axon. Individual Schwann cells myelinate only a portion of a single axon. B. In the CNS, myelination begins during the fourth month of development and continues into the second decade of life. Oligodendrocytes are the myelin-forming cells of the CNS. An individual oligodendrocyte is able to myelinate many axons.

Histology NerveTissue lt provides communication, andconductivity. isspecialized forirritability Thenervous system Nerve tissue is andorgans. functions of bodytissues ofthediverse coordination, andintegration junctions (axons, processes of dendrites), cellbodies andtheirrytoplasmic composed of nerve andtheir (synapses), nerve cellprocesses bundles of peripheral nerve cells between communication (neuroglia). transmit (peripheral Neurons cells and supporting nerves), structures supporting in neurons andparticipate cells support Neuroglial muscles, andglands. impulses to otherneurons, processes. neuronal activity, nutrition, anddefense

NEURONS

tna Nubhell

Neuronsarecomposedof threebasicparts:the cell body (somaor perikaryon) , the dendrites, which receiveinformation ftom other neurons,and a singleaxon, which conductselectrical impulsesawayfrom the cellbody (seeFigureV-2-1).

of: Nervous tissueconsisls

A. The cell body containsa largevesicularnucleuswith a singleprominent nucleolus,mitochondria,andotherorganelles.

. Neuroglia (nerveglue), ptrysioland whichprovide metabolic supportfor neurons

i. The cell body containsabundant rough endoplasmicreticulum (RER),reflecting high rat€sof protein synthesis.At the light microscopiclevel,the RER stainsintenselywith basicdyesand is referredto asNissl substance.

' Neurons (nerve cells)

2, Microtubules and neurofilaments are also prominent; both contribute to the neuronal cytoskeletonand play important rolesin axona.ltransPort. 3. Pigment granulessuch aslipofuscin ("wear and tear" pigment) and melanin (found in somecatecholamineneurons)maybe seenin the cftoplasm.

,r9

Neruous System

Dendrites

Nucleolus

Nisslbody Initalsegment of axon

Node of Ranvier Schwann cell Axon

Figure V-2-1.Neuron structure.

ln a Nutshell

B. Dendrites are neuronal processesthat receiveinformation and transmit it to the cell body. Extensivedendritic branching servesto increasethe receptivearea of the neuron.

Dendrites transmit information C. Auronsare thin, cylindrical processestypically arising from the perikaryon (or from a proxitoward thecellbody and mal dendrite) through a short pyramidal-shaped region called the axon hillock. The cell axons transmit information membrane of the axon is called the axolemma, and the cytoplasm of the axon is called the away fromthenerve cellbody. axoplasm. Axons terminate in specializedendings known assynaptic boutons, which contain synaptic vesiclesfull of neurotransmitter. 1. The axoplasmcontains abundant microtubules and neurofilaments.Both are important in axonal transport. 2. The axon and axon hillock doesnot contain Nissl substance.

540

Histology: NerueTissue

ated or myelinated, depending upon the type of covering provid3. Axons may be ed by their supporting cells. a. Unmyelinated axons in peripheral nerves are surrounded by the cytoplasm of glial cells known as Schwann cells. (1) Theseaxonshave a small diameter and a relativelyslow conduction velocity. (2) A single Schwanncell may ensheathseveralaxons. b. Myelinated axons are larger in diameter and are ensheathedin spiral wrappings of the Schwann cell membrane called myelin. ( I ) One Schwanncell will myelinate only one axon in peripheral nerves.At the junction between two Schwanncells,there is a discontinuity in the myelin. This creates a "collar" of naked axon, called a node of Ranvier, which is exposedto the extracellularspace(FigureV-2- I ). (2) The action potential skips from node to node in a processcalled saltatory conduction. Myelinated axons conduct action potentials rapidly.

Note velocity is Nerve conduction proportional to thediameter oftheaxonandto thedegree of myelination.

(3) Becausemyelin is of membrane origin, it is rich in phospholipids and cholesterol. 4. In the central nervous system(i.e.,brain, spinal cord), glial cellsknown as oligodendrocftes myelinate 50 or more axons per cell, similar to the myelination by Schwann cells.

CTASSIFICATION NEURONAT Neuronal classificationis basedboth on the arrangementof the axons and dendrites and the functional role of the neuron. A. Classification by neuronal processes 1. Unipolar neurons have one axon and no dendrites and probably occur only during development. 2. Pseudounipolar neurons have a single processcloseto the perikaryon, which divides into two branches.One branch extendsto a peripheral ending, and the other extendsto the CNS. Pseudounipolarneurons are found in dorsal root ganglia (DRG) and most cranial ganglia. 3. Bipolar neurons have one axon and one dendrite. Bipolar neurons are found in the cochlearand vestibulargangliaaswell as in the retina and olfactory mucosa. 4. Multipolar neurons have one axon and multiple dendrites. Most neurons in the body are multipolar (e.g.,ventralhorn neuronsin the spinalcord).

ln a Nutshell are neurons Pseudounipolar thattransmit sensory neurons to the information sensory Thecellbodies are CNS. andsensory foundin DRCs ganglia. nerve cranial

B. Classification of neurons by functional role 1. Motor neurons control effector organsand muscle fibers. 2. Sensoryneurons receivesensorystimuli from the internal or external environment and relay them to the CNS.

OFNEURONS ORGANIZATION A. Ganglia are ovoid collectionsof nerve cell bodies in the peripheral nervoussystem.They are encapsulatedby denseconnectivetissuecontinuous with the epineurium and perineurium. Each ganglion cell is envelopedby a layer of small, cuboidal satellite cells, which are analogous to Schwanncells.

541

Neruous System

1. Dorsal root (spinal) ganglia (DRGs) are composedof sensorypseudounipolar neuron cell bodies. 2. Autonomic (sympathetic and parasympathetic) ganglia are composed of multipolar neurons. B. Nuclei are collections of neurons in the central nervous system with a similar function, or that make similar connectionsto other brain regions

SYNAPSES Sypnasesare specializedmembrane junctions designedfor the unidirectional communication betweenneurons or betweenneurons and effector cells.The pre- and postsynaptic membranes are separatedby only 20 nm; this spaceis called the synaptic cleft.

Bridgeto Physiology Neurotransmitters arereleased intothesynaptic cleftviaa process calcium-dependent of exocytosis.

A. Most types of synapsesare either betweenan axon and a dendrite (axodendritic) or between an .xon and a cell body (axosomatic). Synapsesbetween dendrites (dendrodendritic), between axons (axoaxonic), and between soma (somasomatic) also occur. B. Synapticvesiclesare 3G-50p sphericalor ovoid structuresin the axoplasmthat contain neurotransmitter (e.g., acerylcholine;ACh). Neurotransmitters are releasedinto the synaptic cleft at the synapsewhen synaptic vesiclesfuse with the presynaptic membrane. 1. Neurotransmitters may either excite (depolarize) or inhibit (hyperpolarize) the postsynapticmembrane,dependingon the type of receptorto which it binds. 2. Certain neurotransmitters are inactivated in the synaptic cleft by enzymatic degradation (e.g.,ACh is broken down by acerylcholinesterase; AChE), while others are taken up by the presynapticcell (e.g.,norepinephrine) in a processcalledre-uptake. C. The neuromuscular junction, which occurs at the motor end plate, is the synapsebetween neurons and muscle cells.The postsynapticmembrane (i.e., of the muscle cell) is convoluted into numerous folds calledthe subneuralclefts.ACh releasedepolarizesthe sarcolemma via acetylcholinenicotinic receptors.

NERVE FIBERS ANDNERVES A. Nerve fibers are essentiallyaxons,and are usually encasedin a myelin sheath. 1. In the brain and spinal cord, groups of nerve fibers with a common origin, function, and destination are called fiber tracts. 2. ln the peripheral nervous system,nerve fibers are grouped in bundles to form peripheral nerves. B. Organization of peripheral nerves

In a Nutshell Outside + inside: -+ perineurium -+ Epineurium endoneurium

t42

1. The nerve stroma consistsof an externalfibrous coat of denseconnectivetissuecalledthe epineurium. 2. Connectivetissueseptaof the epineurium penetratethe nerve to form the perineurium, which surrounds bundles of nerve fibers. 3. A thin, loose connectivetissuelayer,consistingof reticular fibers and surrounding individual nerve fibers, is called the endoneurium.

Histology: NerveTissue

C. Classification of peripheral nerves 1. Nervesreceiveinformation via synapticinputs to dendritesor the cell body and conduct impulses unidirectionally away from the region via the axon. Afferent fibers conduct impulses toward the CNS; efferent fibers conduct awayfrom the CNS. 2. Typesofnerves a. Sensory nerves contain only afferent fibers. b. Motor neryes contain only efferent fibers. c. Mixed neryes contain both afferent and efferent fibers.

NEUROGTIA Neuroglia play an important role in the normal funaioning of the nervous system.Neuroglia form the myelin sheathsof axons and provide metabolic support to neurons.Neuroglial cellsin the CNS include microglia, astrocytes,oligodendrocytes,and ependymal cells.In the peripheral nervous system, neuroglia cellsconsist of Schwanncellsand satellitecells. A. Astrocytes are the largest of the neuroglial cells. 1. They have centrally located nuclei and numerous long processeswith expandedvascular end-feet,or pedicels,which attach to the walls of blood capillaries. 2. Astrocytesare important in controlling the microenvironment of nerve cellsand participate in the maintenanceof the blood-brain barrier. B. Oligodendrocftes 1. Their nuclei are small and their cytoplasmcontains abundant mitochondria, ribosomes, and microtubules. 2. Oligodendroglia myelinate .rxonsin the CNS. C. Microglia are small, dense,elongated cells with elongated nuclei. Microglia are phagocytic and have similar functions as connectivetissuemacrophages;they are consideredto be part of the mononuclear phagocyte system. 1. They have short processescoveredwith spines. 2. Microglia originate from mesoderm,unlike other neuroglial cells,which originate from neuroectoderm. D. Ependymal cells line the ventricular cavities of the brain and the central canal of the spinal cord. They are columnar cells with elongatednuclei. They are capableof mitosis and can developlong processesthat deeplypenetratethe neural tissue.

ln a Nutshell Types of Neuroglia . Astrorytes provide metabolic andstructural support, maintenance of blood-brain barrier . 0ligodendrocytes myelinate axons intheCNS. . Microglia arephagocytic. . Ependymal cells line ventricles. . Schwann cellsmyelinate axons inthePNS.

E. Schwann cells contain elongated nuclei that lie parallel to the axons of peripheral neurons. Schwann cells myelinate peripheral axons. F. Satellite cells encapsulatenerve cell bodies in peripheral ganglia.

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Histology Sensory Organs Theorgans of special sense include theeyeandtheear.Theyrepresent highly specialized receptors thatdeveloped outside of thecentral nervous system. Theycontain nervecellsandotherelements thatreceive andenhance external stimuli thataretransmitted to thebrain.

EYE A. Structure and function 1. Three compartments of the eye are the anterior chamber,the posterior chamber,and the vitreous cavity. a. The anterior chamber is located between the cornea and the iris and the lens. b. The posterior chamber is located between the iris and the lens. c. The vitreous cavity is located behind the lens and is surrounded by the retina. 2. The eyesare highly specializedphotoreceptor organs situated in the orbits of the skull. B. The wall of the eyeball is composed of three layers:the tough, outer corneoscleralcoat, the middle vascular uvea, and the inner photosensitiveretina (Figure V-3-1). Attached to the middle layer anteriorly is the lens, which separatesthe anterior aqueous humor from the posterior vitreous body.

Note Both theanterior and po$erior chambers contain proteinaqueous humor, a poorfluid.Thevitreous cavity isfilled withthegelatinous vitreous body.

1. The corneoscleral coat is divided into a posterior segment,the sclera,and a smaller transparent segment,the cornea,which lies anteriorly. The cornea is continuous with the scleraat the limbus. a. The sclera,the white part of the eye,is composedof denseconnectivetissuewith collagen bundles, fibroblasts, and elastic fibers.

545

Neruous System

Sclera

Vessel layer

Choroid

Pigmentephithelium Rod and cone segments Externallimitingmembrane Outer plexiformlayer

Retina

Inner nuclearlayer lnner plexiformlayer Ganglioncell layer Nerve fibers Internallimitingmembrane

Figure V-3-1.Layers of the eye.

b. The cornea is composed of five layers: epithelium, Bowman membrane, stroma, Descemetmembrane,and endothelium. (1) The surfaceof the cornea is coveredby stratified squamous,nonkeratinized corneal epithelium that is continuous with the conjunctiva of the eye. (2) This epithelium sits on a specializedlamina propria of collagenfibers known as Bowman membrane. (3) The bulk of the corneais formed by a middle layer of stroma, which is composed of layersof fibroblastsand collagenfibrils embeddedin glycosaminoglycans. (4) Subjacentto the stroma is a very thick basementmembrane called Descemet membrane, which is produced by the posterior corneal epithelium. (5) The posterior cornealepithelium is of the simple squamousvariety and is called the corneal endothelium.

Clinical Correlate lf thecanal of Schlemm becomes toonarrow or ob$ructed, a marked increase pressure in intraocular can glaucoma). occur(e.g.,

c. In the limbus, Descemetmembrane givesway to the trabecular meshwork, which consistsof a spongy network of collagenbundles coatedwith endothelium. (1) The intratrabecular spacesconstitute the canal of Schlemm, which drains fluid from the posterior and anterior chambers of the eyeinto a venoussystem. (2) Obstruction of the flow of aqueoushumor from thesechambersresultsin a rise in intraocular pressure,which may damageneural components. 2. The uvea consistsof the choroid, ciliary body, and the iris, all of which are pigmented. a. The choroid is highly vascularized. ( 1) Abundant melanocytesgive this layer its black color. (2) A thin, amorphous,hyalineBruch membrane separatesthe choriocapillarylayer from the retina. b. The ciliary body is a thickening of the uvea.Its surfaceis coatedby the pigmented ciliated portion of the retina.

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Histology: Sensory Organs

(1) Within the ciliary body is the ciliary muscle, which is composedof smooth muscle fibers and functions in changing the shapeof the lens. (2) The ciliary epithelium aids in the formation of aqueous humor. c. The iris is placed as a diaphragm in front of the crystalline lens.A nonpigmented iris appearsblue. (1) The contraction and relanationof smooth musclescontained in the iris control the sizeof the pupillary aperture and, thus, the amount of light reachingthe lens,vitreous body, and retina. (2) The iris separatesthe anterior and posterior chambers. (3) The iris contains two bands of smooth muscle cells, the sphincter pupillae (under parasympatheticcontrol) and the radial dilator (under sympathetic control). 3. The lens is a biconvex structure characterizedby great elasticity.There are three principal components: the lens capsule,the subcapsularepithelium, and the lens fibers. The body of the lens is composed of prismatic cells joined by numerous gap junctions that form lens fibers. a. Lens capsule. The lens has a thick connective capsulethat is a thick basement membrane of the underlying epithelium. b. Subcapsular epithelium consists of a single layer of cuboidal epithelial cells on the anterior surface of the lens. The epithelial cells divide, providing cells that move inward and become transformed into lens fibers.

ClinicalCorrelate Cataracts areformed bythe accumulation ofpigment in lens fibers, making thelens less transparent. Ultraviolet radiation anddiabetes mellitus cancause cataracts.

c. Lens fibers are elongated and anucleatedcells.The lens is held in position by a radially oriented layer of fibers, the zonule, which inserts on one side to the lens capsule and on the other side to the ciliary body. 4. The vitreous body is a gel containing about 99o/owater that occupies the region behind the lens.Its principal nonaqueouscomponentsare hyaluronic acid and collagenfibrils.

t47

Neruous System

These axons will make up the optic nerve.

ffi. ffi*i., Wrii

--

Wffih,

ffiffi;

W;;

Inner nuclear layer

Ganglion layer

Bipolar cells

Figure V-3-2. Layers of the retina.

5. The retina is the innermost layer of the eye.It is divided into two portions: the posterior portion, which is photosensitive,and the anterior portion, which is not. It constitutesthe inner lining of the ciliary body and the posterior iris (FigureY-3-2).

In a Nutshell Rods contain rhodopsin and arelightsensitive; cones contain iodopsin andare responsible forcolorvision.

a. The pigmented epithelium is composed of columnar cells,which contain melanin. b. Rods and cones are cells with two poles. One pole contains a single photosensitive dendrite, and the other pole establishessynapseswith the cells in the bipolar layer. ( 1) Thesephotosensitivedendritestake the shapeof either a rod or a cone,giving the cellstheir name. (2) The dendrite of the rod is composedof numerous flattenedvesiclesthat contain the pigment rhodopsin, which is bleachedby light. (3) Rods are extremely sensitiveto light and are used as receptorswhen low levelsof light are present. (a) The dendrite of the cone is similar to that of the rod, exceptfor its shape. (5) The cone dendrite containsiodopsin, which is most sensitiveto red light. (6) Two other pigments are also present that have maximal light sensitivity at different wavelengths. c. The external limiting membrane is the thin limiting membrane on which both rod and cone cellslie. d. The outer nuclear layer is formed by the nuclei of rods and cones.

348

Histology: Sensory Organs

e. The outer plexiform layer is composed of synapsesbetween the axons of rods and cones and the dendrites of intermediate neurons. f. The inner nuclear layer contains the nuclei of the intermediate neurons as well as horizontal cells, amacrine cells, and supporting cells. ( 1) Horizontal cells establishcontact between different photoreceptors. (2) Amacrine cells are neurons that establishcontact between ganglion cells. (3) Supporting cells are neuroglial cells that bind the neural cells of the retina. g. The inner plexiform layer is composed of synapsesbetween bipolar cells, amacrine cells,and ganglion cells.

Nole Thefoveaisa depression in theretina thatrepresents the areaof greatest visual acuity.

h. The ganglion cell layer contains the nuclei of ganglion cells. The ganglion cells are typical neurons with basophilic cytoplasm. i. The optic nerve fiber layer consistsof ixons of ganglion cells. (1) The ixons convergeat the optic disk to form the optic nerye. (2) The disk lacks receptors and is therefore known as the blind spot of the retina. j. The internal limiting membrane is a basal lamina that separatesthe retina from the vitreous body.

EAR A. Structure and function 1. The ears are specializedorgans for the functions of hearing and equilibrium. 2. Each ear consistsof three components: the external ear,the middle ear, and the inner ear (FigureV-3-3). a. The external ear capturesthe sound wavesfrom the external environment. b. The middle ear transmits the sound from air through bone to the inner ear. c. The inner ear contains the cochlearportion, which transducessound vibrations from the bone into nerve impulses to the brain. It also contains the vestibular portion, which functions in the maintenance of equilibrium. B. The external ear is composed of elasticcartilage coveredby a layer of skin. Sebaceousglands and a few sweatglands are present in its dermis.

ln a Nubhell . External ear-captures soundwaves . Middle ear-airto bone conduction . lnnerear-transmits to the nerves

1. The enternalauditorymeatus extendsfrom the auride (pinna) to the tympanicmembrane. a. It is a rigid-walled tube supported externally by elastic cartilage and internally by the temporal bone. b. It is lined with skin containing hairs, sebaceousglands, and coiled tubular apocrine ceruminous glands.

549

Neruous System

Semicircular Ampulla Ossicles

Semicircular canal

. , >1.'t

Tympanic Oval membrane window

Scala media (endolymph) Stria vascularis

(endolymph production) Tectorialmembrane Organof Corti Basilarmembrane Spiralganglion Vlll nerve(cochleardivision)

Figure V-3-3.The ear. ( 1) Thesemodified sweatglandstogetherwith sebaceous glandsproduce and secrete a fatly substancecalled cerumen (ear wax). (2) Cerumen servesa protectivefunction. 2. The tympanic membrane of the external ear is an oval structure that receivesairborne vibrations. a. It is coveredby epidermison its outer layerand by simple cuboidal epithelium on its inner surface.A collagenousand elasticconnectivetissuelayer lies betweentheselayers. b. The rympanic membrane transmits sound vibrations to the ossiclesof the middle ear. C. The middle ear lies in the temporal bone,where a chain of three ossicles(malleus,incus,and stapes)connect the tympanic membrane to the oval window. 1. Ciliated simple columnar epithelium lines the middle ear. a. At the junction with the eustachiantube, the epithelium is pseudostratified. b. The epithelium restson a thin lamina propria, which adheresto the underlying periosteum.

550

Organs Sensory Histology:

2. Round and oval windows are found in the medialbony wall of the middle ear. the middl€ and inner ear. a. The round window is a membranethat separates b. The oval window leadsfrom the tympanic cavity to the vestibule of the inner ear. 3. Auditory ossidesamplif the vibrations receivedby the tympanic membraneard transmit th€m to the liqrdd of the inner ear with minimal energyloss.The ossiclesarticulate with one anotler through synovia.ljoints. a. The malleusis insertedin the tfmpanic membrane,andthe staPesis insertedinto the membraneof the oval window. b. The incus is locatedbetweenthe malleusand the stapes. c. T\,r'osmallskeletalmuscles,the tensortympani andthe stapedius,contractto Prevent damageto the delicateinner earwhen the ear is exposedto loud sounds. 4. The middle ear cavity communicateswith the nasopharynxvia the €ustachisn tube' which permits equalpressuresto be aPPliedto both sidesof the tympanic membrane. D. The inner ear (or labyrinth) consistsof two parts:the osseouslabyrinth within the petrous part of the temporalbone;andt}le mernbranouslabyrinth, a seriesof cornmunicatingrnembranoussacsand ductscontainedwithin the osseousportion. 1. Theosseous(bony)labyrinth consistsofbone cavitieslinedby periosteum.Therearethree cavities:the vestibule,semicircularcanals,and codrlea.The osseouslabyrinth contains perilymph,a fluid that is similar in compositionto cerebrospinalfluid andplasma. 2. The rnernbranouslabyrinth is enclosedwithin the osseouslabyrinth and surroundedby perilymph a. It hasthreeparts: (1) The coclrlearducr (scalamedia),which arehousedwithin the cocl ea

Note

(2) The sacruleand utricle, which arelocatedwithin the vestibule

. Themembranous labvrinth a low conhinsendolymph,

(3) Thethreesernicirc,ular ducrs,whic.harelocatedwithin thethreesernicircularcanals b. Regionsof this epitlelium are differentiatedinto recePtororsans: (l) The cochlearduct containstlle organofC,orti. (2) The sacculeand utricle eachcontain maculae. (3) Eachsemicircularcanalhasa crista ampullaris.

);L:flt[-iJ*"-' . lhe bonylabyrinth contains perilymph, esentiallya lowproteinplasma'

c. The membranouslabyrinth is filled with a potassiurn-rich,sodium-poor fluid called endolyrnph,which is similar in compositionto intracellularfluid. 3. The vestibule of the osseouslabyrinth is an irregular avity upon which the oval and round windowsabut. 4. The semicircular canalsconsistof threecanals:superior'posterior,and lateral,which are situatedposterior and superiorto the vestibule. a. The ductsof thesecanalsare filled with endolymphand are arrangedso that eachis perpendicularto the other two. b. A dilated structure, the ampulla, which contains a s€nsory recePtor,the crista ampullaris,is at the baseof eachcanal. arepresentin thecristae. (t) Specialized hair cellsthatrespondto rotationalacceleration

551

J{eruous System

ClinicglCorrelate jerking A sudden, movement of theheadmaycause vertigo or dizziness untilthe "catches endolymph up"and balance isrestored.

(2) During movement, the canals proceed along with the rest of the head, but the endolymph, due to its inertia, lags behind so that the hair cells are subjectedto a drag. (3) When a steadyspeedis reached,the fluid returns to its normal stateand the stimulation stops. c. The semicircular canalsopen into the utricle. 5. The cochlea is a spiral bony canal about 35 mm long that contains the cochlear duct and the auditory receptors. a. When cut transversely,the membranous inner part of the cochleaappearstriangular. ( 1) The lateral wall of the triangle is attachedto the bone. It is coveredwith a special stratified epithelium (striavascularis), which is thought to function in the secretion and maintenanceof the ionic composition of the endolymph. (2) A second side is formed by the vestibular (Reissner) membrane. (3) The third side is formed by the membranous spiral lamina. b. The membranous triangle divides the spaceof the osseouscochleainto an upper part, the scalavestibuli; a middle part, the scala media; and a lower part, the scala tympani. (1) The scalamedia is filled with endoly-ph and is joined by a narrow duct to the saccule. (2) The scala vestibuli and the scala tympani are perilymphatic spaces,which are continuous with each other at the apex of the spiral via the helicotrema. (3) The scalavestibuli begins in the vestibule at the oval window. The scalatympani begins at the helicotrema and ends at the round window, which facesthe middle ear. c. The cochleaspiralsaround a central,cone-shapedmassof spongybone,the modiolus. (1) Nervesand blood vesselsenter and leavevia the modiolus. (2) The spiral ganglion, formed by bipolar neurons in the cochlear division of the eighth cranial nerve, is found within the modiolus. 6. Utricle and saccule a. The utricle is a large oblong sacthat occupiesthe superior and posterior part of the vestibule. b. The sacculeis a small globular sac that lies near the opening of the scalavestibuli of the cochlea. (1) The endolymphatic duct extends from the posterior wall of the saccule. (2) The duct is joined by the utricle saccularis duct and ends in a blind pouch, the endolymphatic sac, on the posterior surfaceof the petrous portion of the temporal bone, where it is in contact with the dura mater. (3) The simple squamouslining of the endolymphatic duct changesto a tall columnar epithelium as it nears the endolymphatic sac. 7. The organ of Corti restson the membranous spiral lamina, which has a layer of organized, collagen fibers called the basilar membrane. a. There is a region of loose connective tissue that is coveredby epithelium called the spiral limbus.

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Organs Sensory Histology:

( I ) This epithelium producesthe glycoprotein-richt€ctorid membrane. (2) The tectorial membranetouchesthe sensoryhair cells. b. Thereis a layerof inner sensoryhair cellsand ttlre rows of outer sensoryhair cells. (1) The two typesof codrlearhair cellscan be delineatedwith the electronmicroscopein a similar mann€r,ascanthe two celltypesin the macula. (2) The inner cellsaregoblet-like.Theyhavemodfied stereociliaat their freesurface andmitochondriaat the base.Theyhaveaferent and eferent neweendings. (3) The outer hair cellsare elongatedand havebasalmitochondria and stereocilia. (4) The hair cellsare innerr"atedby the cochlearnerve. (5) Neither tfpe of cochlearcell hasa true cilium, asdoesthe macula. 8. Maculaeare small differentiatedregionsin the wall of the sacculeand utride. a. The maculaecontain neuroepithelialcells t}lat serveas branchesof the vestibular nerv€. b. The rnaculaeof t}le sacculeand utricle are similar histologica.llybut are positioned perpendicularto eachother'

Bridge tO P_hySiology Thereceotor cellsin the cristaeof thesemicircular onals'aswellasthose inthemaculae of theutricle saccule, are responsible and of for themaintenance and thebody'sbalance equilibrium'

(1) They contain at leasttwo forms of receptorcellsthat are surroundedby supporting cells. (2) All ofthe receptorc€llshavest€reociliaon tleir surface,plus one cilium with its accornpanyingbasalbody,and areoften calledhair cells. (3) A thick gelatinousglycoprotein layer secretedby supporting cells coversthe neuroepithelium. c. Presentin tlis layer are surfacedepositsof crystallinebodies (otoliths' otoconia)' which are composedmainly of calcium carbonate.

555

to Neuroanatomy lntroduction the ofthebrain, understanding a three-dimensional proficiency requires in neuroanatomy Because thatisbothstandardized withnomenclature relationships spatial mustbeableto discuss student bemastered thatshould terms andtheirdefinitions important includes Thischapter andprecise. proceeding rther. fu before

ANDRELATIONS POSITIONS ANATOMIC Throughout thesechapters,referencesare made to various anatomic positions and structures. Knowledgeof theseterms is essentialfor understandingneuroanatomy. A. Anterior is locatedin the front part. B. Posterior is locatedin the back part. C. Ventral is locatedtowardsthe belly or the abdominalside. D. Dorsal is locatedtowards the back side. E. Cranial is locatedtowards the cranium; it usually meanssuperior. F. Rostral is locatedtowardsthe beak (nose).In the spinalcord and lower brain stem,it is used interchangeablywith cranial. G. Caudal is locatedtowardsthe tail; it usually meansinferior' H. Medial is located towards the n-ridline. I. Median is located on the rnidline. L Lateral is located awayfrom the midline. K. Biped and quadruped. In theory, the terms anterior and posterior are usedwhen referring to a biped (e.g.,human), and ventral and dorsal are usedwhen referring to a quadruped. However, anterior and ventral are used interchangeablywith respectto the human spinal cord and lower brain stem,as are posterior and dorsal.The situation is more complex higher up in the brain. Consider a point in the middle of the brain. Anterior and ventral are no longer synonymssinceanterior refersto structuresin front of that point, while ventral refers to structurescloserto the baseof the brain; for example,the frontal lobesare anterior to the superior colliculus,and the inferior colliculus is ventral to the superior colliculus.

555

Nervous System

PTANES OFSECTION A. Frontal (coronal) plane is a vertical plane that divides a structure into front and back parts. B. Sagittal plane is a vertical plane that divides a structure into left and right parts. The midsagittal plane, which divides a structure into equal left and right halves,is the median plane. A parasagittalplane (and there are many) divides a structure into unequal left and right parts. C. Transverse (horizontal) plane is a horizontal plane that divides a structure into upper and lower parts.

HISTOLOGIC ANDANATOMIC TERMINOLOGY A. Individual elements 1. Cellular elements a. Neuron is the whole nerve cell and all of its processes. b. Soma is the cell body of the neuron. c. Perikaryon is the cytoplasm of the soma. 2. Processes a. Axon is a tubular structure that conducts the nerve impulse awayfrom the soma toward another cell. b. Dendrites are processesusually found in the vicinity of the soma and provide most of the receptivesurfaceof the neuron. Most neurons have one axon but many dendrites. c. Nerve fiber is the axon and its associatedcoveringsand supportive tissue. d. Collateral is a branch of an .Lxon. e. Synapseis a communicating junction betweentwo cells.The axon of a neuron is the presynapticcomponent and transmits its information to the postsynapticmembrane, which may be part of a muscle cell or another neuron. Axons can make synapseswith the dendrites,axon, or soma of another neuron. The terminal part of the axon contains vesiclesthat storeone or more neurotransmitters.Neurotransmittersare released into the spacebetweenthe cells(the synapticcleft) and bind to receptorson the postsynaptic membrane, causing either depolarization (usually excitation) or hyperpolarization (usually inhibition). B. Groups of elements l. Cellular elements a. Nucleus is a group of cell bodiesin the centralnervoussystem(CNS) that usuallyhave the samefunction. b. Ganglion is a group of cell bodies in the peripheral nervous system(PNS). 2. Axonal elements a. Nerve is a bundle of nerve fibers in parallel,locatedin the pNS. b. Column usually refers to nerve cell bodies organized longitudinally. It is also used to describeparallel nerve fibers, especiallythe posterior or dorsal funiculi of the spinal cord, which are sometimescalledthe dorsal white columns (the posterior columns).

r56

lntroduction Neuroanatomy:

c. Funiculus is a large group of parallel nerve fibers running along the cranial-caudal axis of the brain stem or spinal cord, which often produces a swelling or bulge of the surface. d. Fasciculusis a group of parallel nerve fibers (e.g.,fasciculuscuneatus). e. Lemniscus is a group of parallel nerve fibers (e.g.,medial lemniscus). f. Tract is a group of parallel nerve fibers that have a similar origin and destination. Thus, the corticospinal tract arises from the cerebral cortex and terminates in the spinal cord, while the spinocerebellartract originates in the spinal cord and terminates in the cerebellum. g. Commissure is a group of nerve fibers that connect analogous structures in the two halvesof the CNS (e.g.,anterior commissure). h. Decussation is a crossingof nerve fibers from one side of the CNS to the other (e.9., pyramidal decussation). C. Neuronal orientation 1. Input/output relations a. Afferent is a fiber or impulse going toward a given structure; that is, input to a structure. b. Efferent is a fiber or impulse going away from a given structure; that is, output from a structure. c. Presynaptic The preqmaptic neuron releasesthe neurotransmitter into the synaptic cleft. d. Postsynaptic.The postsynapticneuron respondsto the action of a neurotransmitter releasedinto the synaPtic cleft. e. Fugal is a suffix usedto indicate that the projection is leavingthat structure (e.g.,corticifugal projectionsfrom the cortex). f. Petal is a suffix usedto indicatethat the projection is entering that structure (e.g.,corticipetal projections go to the cortex). 2. Degeneration/cytoplasmic flow a. Anterograde indicates movement along the axon away from the cell body (e.g., anterogradedegenerationor anterogradetransport). b. Retrograde indicates movement along the axon toward the cell (e.g.,retrograde transport).

t57

Divisions of the Nervous System Thenervous sy$emcanbesubdivided intodistinct structural andfunctional entities. Knowledge of these subdivisions isimportant forunderstanding basic the organization andfunctions ofthe nervous system.

ANATOMIC DIVISIONS A. The central nervous system (CNS) consistsof the brain (brain stem, cerebellum,cerebrum), cranial nervesI (olfactory) and II (optic), and the spinal cord. B. The peripheral nervous system (PNS) consists of all ganglia, cranial nerves III-XII, the spinal nerves,and all of their branches.

FUNCTIONAT DIVISIONS A. The autonomic nervous system (ANS) innervates smooth muscle, cardiac muscle, and glands. 1. The parasympathetic division leavesthe CNS through cranial nerves III, VII, IX, and X and through the sacralregion (S2-S4) of the spinal cord. It is also called the craniosacral system. Stimulation of parasympathetic nerves results in constriction of the pupils, decreasedheart rate, bronchoconstriction, increasedperistalsis,and relaxation of the intestinal sphincters. In general, actions of the parasympathetic nervous system are antagonistic to those of the sympathetic nervous system.

In a Nubhell . Functions ofthe parasympathetic division-"re$ anddigesf' . Functions ofthe sympathetic division"fightorflight"

2. The sympathetic division leavesthe CNS through the thoracic and lumbar segments (TI-LZ or L3) of the spinal cord. It is also called the thoracolumbar system. Stimulation of sympathetic nervesresults in dilatation of the pupils, increasedheart rate and contractiliry bronchodilation, decreasedperistalsis,increasedtone in intestinal sphincters,and increasedproduction and releaseof epinephrine and norepinephrine from the adrenal medulla. B. The somatic nervous system consists of neural structures that innervate muscle derived from embryologic somites, that is, motor neurons that innervate skeletal muscle. Afferent (sensory) information from the musculoskeletalsystemregarding touch, pain, temperature, and proprioception (position sense)are also conveyedto the CNS via the somatic nervous system.The somatic nervous systemis part of the PNS.

559

Meninges, Ventricular Syst€ln, andCerebrospinal Fluid Thebrainandspinal cordfloatwithina protective bathof cerebrospinal fluid(CSF), whichis produced plexus continuously bythechoroid withintheventricles ofthebrain. Additional support (CNS) forthecentral nervous system isderived fromthemeninges, a three-layered structure composed of dense connective tissue. Thechemical integrity ofthebrainisprotected in a different waybytwoseparate systems, theblood-brain barrier andtheblood-CSF barrier.

THEMENINGES The meningesare three connectivetissuemembranessurrounding the brain and spinal cord. The innermost layer is the pia mater, which is attachedto the surfaceof the brain and spinal cord. The middle layer is the arachnoid.Betweenthe arachnoid and the pia mater is the subarachnoid space (SAS), which is filled with CSF.Collectively,the pia mater and arachnoid are referred to as the leptomeninges. A. Pia mater. The pia mater consistsof two layersthat faithfully follow the contours of the surface of the CNS. It surrounds blood vesselsas they enter and exit the CNS. A perivascular space,which may be occupiedby cellsduring infections and inflammatory processes, is thus formed.

In a Nutshell Brain v

Piamater

J Arachnoid

J Dura mater I

B. Arachnoid. The arachnoid is an avascularmembrane.It doesnot follow the contours of the CNS like the pia mater; that is, it passesover sulci.

v

Skull

C. Dura mater. The dura mater consistsof a meningealand a periosteallayer. 1. Dural septa are reflections(folds) of the meningeallayer of the dura mater. a. The sickle-shapedfalx cerebri is the largestof the intracranial septa,lnttg on the midline and separating the two cerebral hemispheres.The smaller falx cerebelli incompletely separatesthe medial surfacesof the cerebellarhemispheres. b. The tentorium cerebelli separatesthe superior surface of the cerebellum from the inferior surfaceof the occipital lobes. c. Together,the tentorium cerebelli and falx cerebri divide the cranial cavity into three chambers.The two lateral chambershouse the cerebralhemispheres,while the posterior chamber (posterior fossa) contains the cerebellumand lower brain stem. d. The diaphragm sellae covers the sella turcica, the cavity in the sphenoid bone that housesthe pituitary gland.

Clinical Correlate Thebrainpasses through a narrow opening inthe tentorium called thetentorial notch. Supratentorial mass lesions cancause herniation oftheunci(medial temporal lobe)through the notch, compressing thebrain stemandassociated structures.

561

Neruous System

2. Venous sinuses of the dura mater are formed in areasin which the meningeal and periosteallayersseparate.The cerebralveins drain into thesesinuses,which drain into the internaljugular veins. betweenthe venoussinusesand the extracranialveins. 3. Emissaryveins fclrm anastomoses

€linicalCorrelate arelifeEpidural hemorrhages because the threatening source ofthebloodisarterial, pressure andsointracranial quickly builds

4. Diploic veins run betweenthe outer and inner tablesof the skull and communicatewith the venous sinusesand extracranialveins via the emissaryveins. 5. Blood supply. The principal sourceof blood is the middle meningealartery (a branch of the maxillary artery),which entersthe skull through the foramen spinosum of the sphenoid bone. Fractureof the temporal or parietal regionsof the skull may laceratethe middle meningealartery (and vein), giving rise to an acuteepidural hemorrhage,a collection of blood betweenthe dura and skull that may causedeath unlesssurgicallyremoved.

THEVENTRICUTAR SYSTEM ClinicalCorrelate of Occlusion oftheaqueduct blocks drainage of CSF Sylvius andleads to increased pressure, intracranial producing hydrocephalus.

A. There are four ventriclesin the brain: two lateral ventricles,a third, and a fourth ventricle. 1. The lateral ventricles are located deep within the cerebralhemispheres,separatedfrom eachother by the septum pellucidum. The lateral ventriclescommunicatewith the third ventriclevia the interventricularforamen (foramenof Monro). 2. The third ventricle is found on the midline within the diencephalonand communicates with the fourth ventricie via the aqueductof Sylvius,which passesthrough the midbrain.

Arachnoid Deepvein of scalp granulations Emissaryvein Diploicvein ----

Skin Galea aponeurotica Pericranium Skull(diploicbone)

Duramater

,l

Arachnoidmater ) Cranial I meni n ges Pia mater I Superiorsagittalsinus Falxcerebri Subarachnoid space lnferiorsagittalsinus

Figure V-6-1.Coronal section of the dural sinuses.

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Neuronatomy: Meninges, ventricular system, andcerebrospinal Fluid

3. The fourth ventricle is located betweenthe dorsal surfacesof the pons and upper medulla and the ventral surfaceof the cerebellum.It communicateswith the SASthrough the two lateral foramina of Luschka and the medial foramen of Magendie. The fourth ventricle is continuous with the central canal of the lower medulla and spinal cord.

In a Nubhell - lateral Luschka - medial Magendie

B. The central canal extendsthroughout the center of the spinal cord, but there is virtually no flow of CSFthrough it in the adult.

(CSF) GEREBROSPTNAT FLUTD Cerebrospinalfluid fills the SASand the ventriclesof the brain. The averageadult has 90-150 ml of total CSRwhile 400-500 ml are produced daily. Only 25 mI of CSFare found in the ventricles themselves.The CSF is renewed constantly. A. CSF formation. About 70o/oof the CSF is secretedby the choroid plexus,which conists of glomerular tufts of capillariescoveredby ependymalcellsthat project into the ventricles(the remaining 30olorepresentsmetabolicwater production). The choroid plexusis locatedin the two lateral ventricles,the third ventricle,and the fourth ventricle.

Arachnoid granulation

Superior sagittalsinus

Lateral ventricle

lnterventricular foramen of Monro

Choroid plexus

Thirdventricle Cerebralaqueduct Foramenof Luschka (lateralaperture) Fourthventricle Foramen of Magendie (medianaperture)

Subarachnoidspace

Figure V-6-2.The ventricular system.

56',

Neruous System

Note granulations are Arachnoid located in thesuperior sagittal border inthesuperior sinus, of thefalxcerebri.

B. Circulation. CSF from the lateral ventricles passesthrough the interventricular foramina of Monro into the third ventricle. From there, CSF flows through the aqueduct of Sylvius into the fourth ventricle; it may reach the SASthrough the foramen of Magendie or through the foramina of Luschka.CSF also flows within the SASup over the convexity of the brain and down around the spinal cord. C. Absorption. Almost all CSF drains into the arachnoid granulations (villi), then through the core of the villi into the venous circulation. D. Composition. Normal CSFis a clear fluid, isotonic with serum (290-295 mOsm/l). The pH of CSFis 7.33 (cf. arterialblood pH 7.40;venousblood pH 7.36). 1. Electrolytes and glucose a. Sodium ion (Na+) concentrationis equal in serum and CSF (138 mEq/l). b. CSFhasa higher concentrationof chloride (Cl-) and magnesium(M#-) than doesserum. c. CSFhasa lower concentrationof potassium(K*), calcium (Ca'*), bicarbonate(HCO3-), and glucosethan does serum. 2. Protein. The concentration of protein (and all immunoglobulins) is much lower in the CSF as comparedto serum. 3. Cellular elements a. Normal CSF contains 0-4 lymphocytes or mononuclear cells per mm3. Polymorphonuclearleukocytesare not found in normal CSF. b. Redblood cells(RBCs)are not normally found in the CSFbut may be presentfollowing traumatic spinal tap or subarachnoidhemorrhage. c. Infectious organisms, cultured from the CSR may be observed upon microscopic examination. d. Tirmor cells may be present in the CSF in caseswith meningeal involvement. E. CSF abnormalities 1. Hydrocephalus is causedby an excessvolume/pressureof CSR producing ventricular dilatation. a. Communicating hydrocephalus is causedby oversecretionof CSF without obstruction. Choroid plexus papilloma should be consideredas a possiblecause. b. Noncommunicating hydrocephalus is causedby obstruction to the CSF flow at the foramen of Monro, the third ventricle, the aqueduct of Sylvius,the fourth ventricle, or the foramina of Magendieor Luschka. 2. Meningitis is an inflammatory response,involving the pia-arachnoidmembranesand the CSF.Changesin the CSF with different forms of meningitis may overlap; the diagnosis is then made by other means (e.g.,culture, epidemiologic data). Three types of abnormal CSFprofiles are commonly describedin meningitis.

Clinical Correlate Normal CSFmaycontain a fewmonorytes or polymorpholymphocytes; nuclear leukorytes arealways abnormal in CSF.

564

a. Decreasedglucose,increasedprotein and elevatedWBCs (mainly polymorphonuclear leukocftes) are typical of bacterial meningitis but may also be observedearly in the courseof viral or tuberculousmeningitides. b. A similar profile (decreasedglucose,increasedprotein), increasedWBC (but predominantly lymphocytes) is typical of fungal, tuberculous,syphilitic, neoplastic,and viral meningitides.Bacterialmeningitis that is partially treated or resolvingmay also produce this profile.

l{euroanatomy: Meninges, ventricular system, andCerebrospinal Fluid

c. Normal glucose,normal or increasedprotein, and elevatedWBCs (mainly lymphoqrtes) may be seen with viral meningitis or encephalitis, parasitic meningitis, parameningealinfections (e.g.,brain abscess), early in the courseof fungal or tuberculous meningitides, or with partially treated or resolving bacterial meningitis.

BTOOD-BRAIN ANDBTOOD-CSF BARRIERS The chemical composition of the brain is maintained within relatively narrow limits despitesizable fluctuations in blood chemistry. The chemical milieu of the brain is maintained by two barrier systems:the blood-brain barrier and the blood-CSFbarrier. A. The blood-brain barrier is formed by capillary endothelium connected by tight junctions. Molecules move acrossthe blood-brain barrier in a variety of ways.Water diffirsesacrossthe blood-brain barrier readily,but glucose,the primary energy sourceof the brain, requires carrier-mediated transport. Active transport systems are capable of pumping weak organic acids, halides, and extracellular K+ out of the brain against their respectiveconcentration gradients. B. The blood-CSF barrier is formed by tight junctions located along the epithelial cells of the choroid plexus.Tiansport mechanismsare similar to that describedfor the blood-brain barrier, although the ability of a substanceto enter the CSFdoesnot guaranteeit will gain access to the brain.

CIRCUMVENTRICUTAR ORGANS Circumventricular organs are specializedregions of the brain located within the ventricular system,where the blood vesselsare lined with fenestratedcapillaries instead of tight junctions. At these sites,proteins and other small molecules dissolvedin the blood are able to affect localized areasof the brain. There are sevencircumventricular organs,but the four most important ones are the pineal gland, the neurohypophysis,the area postrema, and the subfornical organ. A. The pineal gl"t d plays an important role in controlling circadian rhythms. It produces melatonin. B. The neurohypophysis (posterior pituitary) servesas the site of storage and releaseof vasopressin and orytocin, which are involved with water regulation and reproduction. C. The areapostrema servesas a chemoreceptortrigger zone for emesis(vomiting) in response to circulating agents,such as digitalis glycosides,apomorphine, and some of the agentsused in cancer chemotherapy. D. The subfornical organ respondsto blood-borne angiotensin II and initiates water drinking and releaseof vasopressin.

Bridgeto Endosine . Melatonin, produced bythe pineal gland, isessential for normal circadian rhythms. . Melatonin secretion decreases withage; this maybeonereason why older individuals have abnormal sleep cycles.

r65

Anatomy Gross of the Spinal Cord Iheanatomic organization ofthespinal corddiscussed inthischapter serves astheinformation base forsubsequent discussions ol muscle tone, thereflex arganddeficib ausedbydamage toeither the payparticular spinal cordorib asociated spinal nerva. Thestudent should attention totheloction ofthemajor ascending anddescending tracbofthespinal cord. Becuse theorganization ofthe brain stemrepresents anelaboration oftheblueprint used bythespinal cord, $udenb should not proceed tothebrain $emsystem untilthematerial onthespinal cordhasbeen mastered.

l!lenrqni!

OVERVIEW

pAD rhesame surrounds

A. Meningeallining of the spinal cord

bothbrainandspinalcord: piamater,arachnoid, dura mater.

1. The pia mater is attachedto the surfac€of the spinalcord. a. Lateralseptaof the pia €rftendto the dura mater and havea supportiverole. b. The flum terminale is a derivativeofthe pia, which originatesftom the lowerborder of the conusmedullaris.The filum terminaleacquiresa dural coveringat the 52 level and then extendsto the coccfx asthe coccygealligament. 2. Arachnoid.Thezubaradrroidspace(SAS)is fouadbetweenthe arachnoidandthepia mater. 3. Dura mater anchorsthe spinalcord to the vertebrae. B. Extentofthe spinrl cord.Thespinalcordis housedin thevertebralcanal.Itis continuouswith the medrll, at thepyramidaldecussation, andterminatesasthe conusnedullaris (shapedlike a cone)at the interspacebetweenthe fust and secondlumbar vertebraeof the adult. C. Segmentaldivisions of the epinal cord are determinedarbitadly by the 31 pairs of spinal nerves.Beforeenteringthe spinalcord,eadr spinalnervediyidesinto anterior (ventral) and posterior(dorsal)root filaments(FigureV-7-l). 1. There are eight cervic.l pairs of spinal nerves (Cl-{8). The cervical enlargement (C5-T1) givesrise to the rootlets that form the brachial plexus,which innervatesthe arms. 2. Therearetwelvethoracic pairs of spinalnerves(T1-T12). Spinalnervesemanatingfrom thoracic levelsinneryatemost of the trunk. Preganglionicneuronsof the rympathetic nervoussystemarelocatedat both thoracicandlumbarlevelr. 3. Thereare five lumbar pairs of spinal nerves(L1-L5). The lumbar enlargement(L1--S2) givesris€ to rootletsthat form the lumbar and sacralplexuses,which innervatethe legs.

qiniaal Con€late In theadultthespinalcord endsat theLl or L2 vertebrae, solumbar aredoneat L4to Dunctures avoidthecord. h a NUbhell ll Pairsof SpinalNerues ' 8 cervlcal . 12thoraoc ' 5 lumbar . 5 sacral . I coccygeal

4. Therearefive sacralpairs of spinalnerves(Sl-S5). Spinalnervesat the sacrallevelinnervatepart of th€ legsaswell asthe groin area.

t67

Nervous System

5. There is one coccygealpair of spinal nerves.The cocrygealnerves (and 55) are unimportant in humans. 6. The cauda equina (horse's tail) consistsof roots of the lumbar and sacral spinal nerves. Theseroots encircle the filum terminale.

Posterior (dorsal) grayhorn Lateral funiculus

Posterior funiculus

Posterior mediansulcus Posterior intermediate sulcus

Anterior(ventral) grayhorn

Dorsalrootentryzone Intermediate(lateral) gray horn

Dorsal_1 Root t...

filaments VentralI Anterior funiculus

Dorsalroot ganglion Spinal nerve

Anterior median fissure Anterolateral sulcus

FigureV-7-1.The spinal cord.

EXTERNAT STRUCTURE OFTHESPINAT CORD A. The anterior median fissure is a deep furrow on the midline of the anterior surface. B. The posterior median sulcus is a shallow groove on the midline of the posterior surface. C. The anterolateral sulcus is the exit for the ventral root filaments. D. The posterolateral sulcus is the entry zone for the dorsal root filaments.

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Neuroanatomy: GrosAnatomy of theSpinalCord

INTERNAT STRUCTURE OFTHESPINAT CORD (considered in transverse section) A. Graymatter is centrally locatedand shapedlike a butterfly. It containscell bodiesand neuropil.

ln a Nubhell

1. Grossanatomic divisions a. The anterior grayhorn containsalpha and gamma motor neurons.

Anterior horn+ motor

b. The lateral gray horn is most prominent at the thoracic levels where preganglionic sympatheticneurons are located.

Lateral horn+ autonomic

c. The posterior grayhorn is dominated by neurons that respond to sensorystimulation.

Posterior horn+ sensory

2. Cytoarchitectonic divisions (the ten laminae of Rexed) (Figure V-7-2)

Posterior mediansulcus Centralcanal

Anteriormedianfissure Figure V-7-2.Transversesection of the spinal cord, showing the laminae of Rexed. a. Lamina I-VI are located in the posterior gray horn and are concerned primarily with sensory functions. The substantia gelatinosa, which corresponds to lamina II, receivespain, temperature,and touch sensoryinput from dorsal root fibers. b. Lamina VII is located in the intermediate (lateral) gray horn and continues into the anterior gray horn. Lamina VII contains the intermediolateral nucleus and the dorsal nucleus of Clarke (nucleus dorsalis).The cells of the intermediolateral nucleus are the origin of the preganglionic sympathetic efferent fibers, while the cells in the dorsal nucleus of Clarke give rise to the axonsof the uncrossedposterior spinocerebellartract.

Note lf youknowonlyonelamina, it isworthknowing that lamina ll conesponds tothe gelatinosa. sub$antia

c. Lamina IX is located in the anterior gray horn and contains alpha and gamma motor neurons.The alpha motor neurons innervate skeletalmuscle,and the gamma motor neurons innervate the contractile intrafusal muscle fibers of the muscle spindle. Within lamina IX, neurons that innervate flexors are dorsal to those that innervate extensors.Neurons that innervate the proximal musculature are medial to those that innervate the distal musculature.

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Nervous System

3. The central canal of the spinal cord is located on the midline within the gray matter of lamina X; it is lined by ependymal cells. B. White matter is peripherally located and forms a mantle that encirclesthe gray matter. It is composedprimarily of long ascendingand descendingfiber tracts (FigureV-7-3).The names of the tracts are derived from their origin and termination; for example, the corticospinal tract arisesin the cerebral cortex and terminates in the spinal cord. A brief synopsisof the spinal pathwaysfollows. Some of the major pathways (i.e., corticospinal, spinothalamic, and spinocerebellartracts and the posterior columns) are coveredin more detail separately. 1. Anterior white column (funiculus) is located betweenthe anterior median fissureand the anterolateralsulcus. a. Descending tracts (1) Anterior corticospinal tract carries about l0-20o/o of the corticospinal fibers. Found only in upper spinal cord sections,it is an ipsilateral pathway whose fibers crossnear the level of their termination in the cord. The anterior corticospinal tract involves the production of voluntary movements in the upper extremities. (2) Teaospinal tract originatesfrom cells in the superior colliculus.Its fibers crossin the dorsal tegmentaldecussationand then descendto the upper spinal cord levels, where they mediate postural reflexes of the head and upper extremities in responseto visual stimuli. (3) Vestibulospinal tract originates from cells in the lateral vestibular nucleus and projects ipsilaterally to the cord. Neurons that contribute to the vestibulospinal tract facilitate extensorsin order to maintain equilibrium and position.

Fasciculusgracilis

Lissauer tract

Fasciculus cuneatus Posterior spinocerebellar tract

Rubrospinal tract

Anterior spinocerebellar tract Lateral spinothalamic tract

Tectospinal tract

Spinotectal tract Anteriorspinothalamictract Anteriorcorticospinaltract

Figure V-7-3.Transversesection of the spinal cord, showing the ascending and descending pathways.

b. Ascending tracts. Anterior spinothalamic tract crossesnear its origin in the anterior white commissureand ascendsto the ventral posterolateralnucleusof the thalamus.This pathwayconveyspain and temperaturesensation,asdoesthe lateral spinothalamictract, but clinically it is lessimportant.

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Neuroanatomy: Anatomy Gross of theSpinalCord

c. Other tracts. Anterior white commissure. This lies anterior to the central canal and containsfibers that crosshorizontally from one side of the cord to the other. 2. Lateral white column posterolateralsulci.

(funiculus) is located between the anterolateral and

a. Descending tracts ( 1) Lateral corticospinal tract carriesabout 80-90o/oof the corticospinalfibers.This tract originates in the cortex, crossesin the lower medulla (at the pyramidal decussation),and descendsto all spinal cord levels.This pathway involves the production of voluntary movements, especiallyfine movements of the distal musculature. (2) Rubrospinal tract originatesfrom cellsin the red nucleusof the midbrain. These fibers crossat the ventral tegmentaldecussationand descendin the spinal cord. The rubrospinal tract playsa role in voluntary movement, but it is less important than the corticospinaltract. b. Ascending tracts (1) Anterior spinocerebellartract arisesfrom neurons in lamina I, IV, and V in the cord. Most fibers crossand terminate in the contralateralhalf of the cerebellum. The anterior spinocerebellartract carries mainly proprioceptive input (from deep somatic structures,such as muscles,tendons,and joints) from the lower extremitiesand lower trunk. (2) Rostral spinocerebellartract is similar to the anterior spinocerebellartract but carriesinput from the upper extremitiesand upper trunk. (3) Posterior spinocerebellar tract is a predominantly ipsilateral pathway,which terminatesin the cerebellum.The posterior spinocerebellartract carriesmainly proprioceptiveinput from the lower half of the body. T'hecuneocerebellar tract, which arisesin the medulla, is the upper limb equivalentof this tract. (4) Lateral spinothalamic tract arisesfrom neurons in lamina I, IV and V. It crosses near its origin in the anterior white commissureand terminatesin the thalamus. The lateral spinothalamictract carriespain and temperaturesensation. (5) Lissauer tract (posterolateral tract) involves ascendingand descendingfibers from the dorsal roots, which terminate in lamina II (substantiagelatinosa). Thesefibers conveylight touch, pain, and temperaturesensation. (6) Spinotectal tract crossesnear its origin and terminatesin the superior colliculus of the midbrain. Its functional significanceremains unknown. 3. Posterior white column (funiculus) is located betweenthe posterolateraland posterior median sulci. a. Ascending tracts (dorsal columns) ( 1) Fasciculusgracilis is an ipsilateralpathwayfound in all spinal cord segments.It projects to the nucleus gracilis of the medulla. The fasciculusgracilis conducts vibratory sensation,input for tactile discrimination, and proprioceptive information from the sacral,lumbar,and lower six thoracicsegments. (2) Fasciculuscuneatus is an ipsilateralpathwayfound only in the upper spinal cord levels,where it is locatedlateral to the fasciculusgracilis.The fasciculuscuneatus is the upper limb equivalentof the fasciculusgracilis.

ln a Nutshell lmportant SpinalCordTracts Anterior funiculus: . Anterior corticospinal tract Lateral funiculus: . Lateral corticospinal tract . Spinothalamic tract . Spinocerebellartracts Posterior funiculus: . Cracile andcuneate fasciculi (dorsal columns)

t7r

Nervous System

ls the posterior intermediate septumpresent?

cs-T1

ls there an enlargement of the anteriorhorn?

T2_T6

ls the cord smalland round?

ls there an enlargement of the anteriorhorn?

L1, L2

L3-S3

ls the dorsalnucleus of Clarkepresent?

Below 53

c1,c2 FigureV-7-4. Flowdiagram for identification of spinalcordlevels.

4. The fasciculus proprius encirclesthe gray matter of the cord and contains fibers that transmit information betweenvarious spinal cord segments. C. Identifring landmarks of spinal cord levels. Key differences in the size and shape of the spinal cord, aswell as in its grossand microscopic structure,allow the preciseidentification of most levelsof the spinal cord (FigureY-7-4). 1. The posterior intermediatesulcusemergesat the sixth thoracic segmentas the fasciculus cuneatusbeginsto form. Thus, if the posterior intermediateseptum is present,the section must be at T6 or above. 2. An enlargementof the anterior gray horn is a key landmark for the cervical and lumbar enlargements. 3. The small sizeand round shapeof the thoracic cord is usually accompaniedby a distinct lateral horn that is not present at other levels. 4. The nucleusof Clarke is anotherlandmark for the thoracic cord,but it is more easilyidentified at lower thoracic levels. 5. The decussationof the pyramids, which takes a considerabledistanceto complete,presentsa reticulatedappearancealong the lateral edgeof dorsal grayat the uppermost cervical segments.

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Neuroanatomy: GrossAnatomyof theSpinalCord

FUNCTIONAT ANATOMY NERVES OFTHESPINAT A. Efferent pathways 1. General visceral efferents. These autonomic fibers innervate smooth muscle, cardiac muscle,and glands. a. Preganglionic sympathetic cell bodies are found in the C8 through L2 segments.These soma are located in the intermediolateral nucleus,which is located in the lateral horn. b. Preganglionicparasympathetic cell bodies are found in the second,third, and fourth sacralsegments(S2-S4).Thesesoma arelocatedin laminaVll, in a position analogous to the intermediolateral nucleus. 2. General somatic efferents innervate skeletalmuscle and are derived from somites.These efferent fibers arise from the alpha and gamma motor neurons of lamina IX, which is locatedwithin the anterior horn. B. Afferent pathways arise from neurons in the dorsal root ganglia. 1. General visceral afferents carry sensory information from autonomic structures. Technically not part of the autonomic nervous system,they representthe afferent limb of autonomic reflexes. 2. General somatic afferents carry input for exteroceptiveand proprioceptive sensation. a. Exteroceptive input refers to sensation from external structures of the integument, including touch, pain, and temperature. b. Proprioceptive input refers to sensationfrom internal structures, such as joints, tendons, muscle,and fascia.

,7'

SpinalCordRegulation of Skeletal Muscle Activity property Muscle toneisnotaninherent of muscle butratheranimportant measure of theintegrity of thespinal cord,itsassociated afferent andefferent spinal nerves, andtheinfluence of descending pathways fromthebrain. Because spinal reflexes relyuponeachofthese components, theirassessment partofthestandard isanintegral neurologic examination.

ATPHA ANDGAMMA MOTOR NEURONS Alpha and gamma motor neurons constitute the final common pathway by which the nervous system effects changesin skeletal muscle activity. Most of the input to these cells is through interneurons, which receiveafferentsfrom supraspinal (i.e., cerebralcortex, reticular formation, vestibularnuclei,red nucleus),spinal,and peripheral (i.e.,musclespindles,Golgi tendon organs) structures. Otly the alpha motor neurons are stimulated monosynaptically by afferents from muscle spindles,a small group of corticospinal fibers, and possibly other descendingfibers. A. Alphamotorneurons arelargecellsin the anterior horn that innervateextrafusalmusclefibers. 1. A single alpha motor neuron innervatesa group of muscle fibers, which constitutes a motor unit, the basic unit for voluntary, postural, and reflex activity. 2. A collateral from the main axon of the alpha motor neuron may stimulate a Renshawcell (an interneuron in the spinal cord), producing recurrent inhibition of the neuron issuing the collateral, as well as motor neurons supplying synergistic muscles.Disinhibition of motor neurons supplying antagonistic muscles also occurs via interaction with other neurons.

In a Nubhell Motorunit= + alphamotorneuron muscle fibersit innervates

B. Gamma motor neurons supply intrafusal muscle fibers, which are modified skeletalmuscle fibers. Togetherwith their capsule,these fibers form the muscle spindle.

REGUTATION OFMUSCTE ACTIVITY A. Muscle spindles and Golgi tendon org.rns 1. Muscle spindles consist of about 10 modified skeletalmuscle fibers (or intrafusal fibers) within a spindle-shapedconnectivetissuecapsule. a. Both ends of the intrafusal fiber are connectedin parallel with the extrafusal fibers, so thesereceptors monitor the length and rate of changein length of extrafusal fibers. b. Musclesinvolved with fine movements contain a greaterdensity of spindlesthan those used in coarsemovements. c. The muscle spindle is the sensory organ for the stretch reflex.

t75

NeruousSystem

d. Gamma motor neurons of the ventral horn supply motor fibers located at each pole of the muscle spindles. e. Based on the organization of the cell nuclei, intrafusal fibers are classified as either nuclear bag or nuclear chain fypes. Both are innervated by primary afferents(annulospiral endings)and secondaryafferents(flower-sprayendings).

ln a Nutshell Muscle spindles respond tothe in lengh(andrateofchange muscle lengh)ofskeletal fibers; Colgi tendon organs tension. respond tothemuscle

ln a Nutshell Muscle toneisdependent uponbothsensory inputfrom muscle spindles and output fromalphamotor neur0ns.

2. Golgi tendon organs (GTOs) are encapsulatedgroups of nerve endings,which terminate betweencollagenoustendon fibers,usuallyfound near the junction of muscleand tendon. a. BecauseGTOs are connectedin serieswith the extrafusalfibers,they monitor muscle tension. b. When a muscleis stretchedpassively,there is an increasein resistanceup to the point at which the tendon organs polysynaptically facilitate antagonistsand inhibit agonist muscles.This results in a sudden releaseof resistance,called the clasp-knife reaction; it is seenfollowing lesionsof the upper motor neurons. B. Muscle tone. Palpationof a normal restingmuscleor one that is passivelystretchednormally revealssome degreeof tension.Muscle tone, which refersto the tension presentin resting muscles,is largelyunder reflex control. A lesion of either the ventral roots (containing efferents from alpha motor neurons) or dorsal roots (containing afferentsfrom musclespindles) abolishesmuscletone. Muscle tone is not an inherent property of skeletalmuscle. 1. The gamma motor neuronsinfluencethe sensitivityof the musclespindlesand, thus, play a role in muscle tone and reflex activity. Stimulation of gamma motor neurons causes intrafusal musclefibers locatedat the pole of eachmusclespindle to contract,which activatesalpha motor neurons,causingan increasein muscletone. 2. Muscletone and reflex activity alsoare influencedby cerebralstructures(i.e.,cerebralcortex, red nucleus,cerebellum,vestibularnuclei, reticular formation, tectum). 3. Muscle tone is evaluatedclinically by palpation and passivemovements.Certain lesions and diseasescausea decreaseof tone (hypotonia), while others causean increasein tone (hypertonia).

SPINAT REFTEXES

Mnemonic ThepatellarreflextestsL2-L4 is2 function: When thescore quarter, kicka to 4 inthelast fieldgoal.

The spinal cord mediatesa variety of somatic and visceral reflexes.Somatic reflexesalter skeletal muscle activity, while visceral reflexesmodifr smooth muscle, cardiac muscle, and glandular secretions.The simplest reflex is the stretch (myotatic) reflex, which involves two neurons and one synapsein the spinal cord (or brain stem). Most reflexes,however,are more complex and involve one or more interneurons locatedbetweenthe sensoryand motor limbs of the reflex arc. A. The stretch reflex is the contraction of a muscle in responseto stretch of that muscle.The stretch reflex is a basic reflex that occurs in all musclesand is the primary mechanism for regulating muscletone. The knee-jerk reflex is an exampleof the stretchreflex. 1. Thpping the patellar tendon stretchesthe quadriceps muscle and its muscle spindles, which are connected in parallel with the extrafusal fibers. Stretch of the spindles activates sensoryendings (mainly primary la afferents),and afferent impulses are transmitted to the cord. 2. Some impulsesfrom stretch receptorsmonosynapticallystimulate the alpha motor neurons, which supply the quadriceps.This causescontraction of the muscle and a sudden extensionof the leg.

,76

lleuroanatomy: SpinalCordReguhionof SkeletalMuscleActiytty

3. Sorneof the afferentimpulsespolysynapticallyinhibit antagonistmuxles (in this case, : hamstrings). B. The flcxion withdnwd ref,cx is a protectivereflex in which a stimulus (usuallypainftl) causeswithdrawal of the stimulated limb. This reflex may be accompanied\ a crosecd I €xtcnsion rcflcr in which tlre contralaterallimb is €xtendedto help support the body.The : flexion withdrawaland crossedextensionrefloresare demonstratedby a personst€ppingon : a thumb teck with barefeer l. Dependingon how many spinal cord s€gmentsare involved,a reflex may be considered segmental(involving a singleor a few adjacentsegments)or interscgmental(involving : more than a few segrnentsor nonadjacentsegments).

h a ilUbhCIl 2. The frcciculus proprius is a thin layerof white matter surroundingthe gay matter in the :*::** proprius Thefasciculus allonrs spinalcord.Fibersin the fasciculusproprius connectdifferent spinalcord scgments,thus ! diffurent spinal mediating reflores and aiding in the coordination of limb and trunk segmenb b movements. communicate wi0read other.

,77

Functional Anatomy and lesions of theSpinal Cord problems. Spinal cordinjuries cancause devastating Insuchpatients, it isnecessary to determine whichspinal tracts (e.g., orcellgroups havebeendamaged andthesegmental levelofthelesion highcervical, upperlumbar). Thedistinction between upperandlowermotorneuron involvement is important intheirevaluation.

(FASCTCUTUS POSTERIOR COLUMNS GRACTUS AND FASCTCUTUS CUNEATUS) A. Functions. The posterior columns contain mainly ascendingsensory information for joint position (kinesthetic) sense,tactile discrimination, deep touch, and vibratory sensation.Only the fasciculus gracilis is present below T6 of the cord. At more rostral levels(i.e., aboveT6), both the fasciculus gracilis (medially) and fasciculus cuneatus (laterally) can be distinguished.The fasciculusgracilis carries input from the lower extremities and lower trunk; the fasciculuscuneatuscarriesinput from the upper extremitiesand upper trunk (FigureV-9-1). B. Anatomy 1. Fibers in the posterior columns arise from cells in the dorsal root ganglia, enter the cord via dorsal roots, then ascendipsilaterally to the medulla. 2. Fibers in the fasciculusgracilis and fasciculuscuneatusterminate in the ipsilateral nucleus gracilis and nucleus cuneatus of the caudal medulla, respectively. 3. Cells in these medullary nuclei give rise to fibers that crossas internal arcuate fibers and ascendin the medial lemniscus. a. Fibers of the medial lemniscus terminate on cells of the ventral posterolateral (VPt) nucleus of the thalamus. b. From the VPL nucleus, thalamocortical fibers project to the primary somesthetic (somatosensory)areaof the postcentralgyrus,locatedin the most anterior portion of the parietal lobe.

Mnemonic Po$erior columns carry information fromgraceful legs gracilis andcunning hands: carries input fromlower (e.g., extremities legs) and cuneatus carries input from (e.g., upper extremities hands). In a.ilubhell Dorsal rootganglion I

I oorsal I

Y

columns

gracilis Nucleus Nucleus cuneatus (caudal medulla)

I

| (oosasintemal I arcuatefibers) J Mediallemniscus

V VPL

I Y

Somatosensory cortex

t79

Neruous System

Somestheticarea

OW Ventral posterolateral nucleusof thalamus

Nucleusgracilis Nucleuscuneatus

Lower medulla Fasciculusgracilis

Fasciculus cuneatus Dorsal root

Upper spinal cord

Anteriorhorn cell Ventral root

Lower spinal cord

Figure V-9-1.The posterior columns.

In a Nubhell Lesions of posterior columns + ipsilateral lossof: . Proprioception . Vibration . Two-point discrimination

580

C. Lesions of the posterior columns result in the following deficits. 1. There is a loss of joint position sensation, vibratory sensation, and two-point discrimination. 2. There is loss of the ability to identifr the characteristicsof an object (e.g.,size,consistenry, form, shape),using only the senseof touch. This deficit is referred to as astereognosis.

Functional Neuroanatomy: Anatomy andlesionsof theSpinalCord

3. Paresthesias,or abnormal sensations(e.g.,pins and needles),can occur. D. Diseasesaffecting the posterior columns include the following: 1. Thbesdorsalis is one possible manifestation of neurosyphilis,occurring in association with tertiary syphilitic disease.It is causedby bilateral degenerationof the dorsal roots and secondarydegenerationof the posterior columns. There may be impaired vibration and position sense,astereognosis,paroxysmal pains, and ataxia, as well as diminished stretchreflexesor incontinence.Romberg sign, first describedin patientswith tabesdorsalis,is now usedto distinguishbetweenlesionsof the posterior columns and the midline (vermal area) of the cerebellum,both of which may causedisturbancesof posture and stance. a. Romberg sign present. Rombergsign is testedby askingthe patientsto placetheir feet togetherwith their eyesopen.After observingthe ability to maintain the upright posture, patientsare askedto closetheir eyes.If there is a marked deterioration of posture when the eyesclose,this is called Romberg sign, suggestingthat the lesion is in the posterior columns (or dorsal roots). b. Romberg sign absent. Interruption of proprioceptive input from the cord can be compensatedfor by visual input; visual input cannot compensatefor loss of cerebellar input. If the postural instability does not worsen when the eyesare closed,then Romberg sign is absent,which is indicative of cerebellardamage. 2. Subacutecombined degeneration is seenmost commonly in casesof vitamin 8,, deficiency and pernicious anemia.The diseasehas an insidious onset and is characterizedby patchylossesof myelin in the posterior columns and lateral corticospinaltracts.While the associatedmegaloblasticanemia may be reversedby folic acid therapy, central nervous system (CNS) symptoms respond only to vitamin B,r, which must be given early in the courseof the disease. 3. Multiple sclerosis is a demyelinating diseaseof the CNS in which certain myelinated pathways,such as the optic nerve,posterior columns, corticospinaltract, medial longitudinal fasciculus(MLF), and other brain stem tracts, are affected.The illnessis characterized by episodesof focal neurologic deficits that are separatedin place and in time. The diseasecourseis generallyone of exacerbationsand remissions.Patientsmay developthe following symptoms:

In a Nutshell (neu Tabes dorsalis rosyphilis) + degeneration of dorsal rootsandposterior columns.

In a Nutshell Romberg signisa signof damage to theposterior columns rootsof or dorsal thecord.

ln a NuBhell Subacute Combined Degeneration (Vitamin B,, Deficiency) . Lesion of po$erior columns . Lesion of lateral corticospinal tracts

a. Weaknessor paralysisoccursfrom damageto the corticospinaltract. b. Monocular blindnessor scotomaresultsfrom optic nerve damage.

ln a Nutshell

c. Paresthesias occur from damageto the posterior columns.

Multiple Sclerosis

d. Ataxia results from damage to cerebellarconnections in the brain stem, posterior columns, or spinocerebellartracts.

. CNS demyelination

e. Diplopia most often follows damageto the MLF, a brain stem pathwayconnectingthe cranial nerve nuclei that control extraocularmovement with eachother and with the cerebellum,vestibular nuclei, and cervical proprioceptive input. A lesion of the MLF causesinternuclear ophthalmoplegia (INO).

. Focal neurologic deficits separated byplace and time

f. Incontinenceoccurs from damageto spinal cord structures. g. Mental statuschanges(e.g.,inappropriate affect,cognitive deficits) result from cortical involvement.

581

Neruous System

In a Nutshell Tracts Spinothalamic

l V

Dorsal rootganglion

I

V

Dorsal horn

II Anterior

Cross I white commlssure I I

V

VPL

I

v Somatosensory

SPINOTHATAMIC TRACTS A. Functions. The anterior (ventral) and lateral spinothalamic tracts make up the anterolateral system, which is the principal route of conduction for pain and temperature sensation from the extremities and trunk. The spinothalamic tracts also carry input for light touch and sensationfrom certain deep structures (e.g.,joints and muscles),but this has little clinical importance (FigureV-9 -2). B. Anatomy. Pain and temperature (A-6 and C) fibers have cell bodies in the dorsal root ganglia and enter the spinal cord via the dorsal root. Their fibers ascendand descenda couple of segmentsin the dorsolateral tract of Lissauer before synapsingin the posterior horn. The spinothalamic tracts arise from cells in the posterior gray horn. Axons from these cells cross in the anterior white commissure and then ascendin the anterior and lateral spinothalamic tracts. The spinothalamictracts terminate in the VPL nucleus,the posterior nuclear group, and the intralaminar nuclei. Many axons of the spinothalamic tract give offcollaterals to the reticular formation as they ascend.Cells in the VPL nucleus give rise to thalamocortical fibers, which carry somatotopically organizedpain and temperature input to the somesthetic areaof the postcentral gyrus.

cortex

%u

0@ Ventral posterolateral nucleusof thalamus

Spinothalamictract

Dorsalroot

Anterior whitecommissure Spinalcord

FigureV-9-2.The pain and temperaturepathways.

t82

andLesions of theSpinalCord Anatomy Functional Neuroanatomy:

C. Lesions of the spinothalamic tracts 1. Unilateral lesions causea nearly total loss of pain and temperature sensationfrom the contralateralbody half. The analgesiabegins l-2 segmentsbelow the lesion and includes everphing below that level. 2. Bilateral lesions are usually the result of surgical intervention to help relieve severepain that could not be alleviated by more conventional means.This procedure is referred to as a cordotomy and is successfi,rlfor many patients; other patients experienceonly temporary relief, possibly becausepain ascendsthrough alternate pathways in the spinal cord, reticular formation, and thalamus. 3. Lesions of the central cord involving the anterior white commissure produce a dissociated sensoryloss characteized by bilateral loss of pain and temperature sensationin the dermatomesof the involved segmentswith sparing of tactile discrimination and proprioceptive sensation. Syringomyelia, a disease characterized by progressive cavitation around the central canal, usually involves the cervical spinal cord but may involve other cord regions or the medulla. Early in the disease,there is a loss of pain and temperature sensation,most commonly in the hands and forearms as a result of the destruction of spinothalamicfibers crossingin the anterior white commissure.When cavitation is extensive,other sensorymodalities,togetherwith corticospinalfibers and anterior horn motor cells, may be involved. A late manifestation of cavitation is Horner syndrome, which occurs as a result of involvement of descendingsympatheticfibers to the intermediolateral cell column of C8-L2. Horner syndrome consistsof miosis (pupillary constriction), ptosis (drooping eyelids),and anhidrosis (lack of sweating),involving the ipsilateralhalf of the face.

ln a Nutshell Lesions of thesplnothalamic resultin contralateral tracts lossof pain/temperature 1-2 starting sensation below thelesion; segments white lesions intheanterior in bilateral result commissure lossof pain/temperature sensation. In a Nutshell Hornersyndromeipsilateral . Miosis . Anhidrosis . ftosis

PATHWAYS SPINOCEREBETLAR A. Functions. The spinocerebellartracts carry mainly proprioceptiveinput from muscle spindlesand Golgi tendon organsto the cerebellum,where this information is usedto help monitor and modulate movements. B. Anatomy. There are four spinocerebellarpathways,three arise from cells in the gray matter of the cord; the cuneocerebellartract originatesin the medulla. 1. The ventral and dorsal spinocerebellartracts carry input from the lower extremitiesand lower trunk. 2. The rostral spinocerebellartract carriesproprioceptiveinput from the upper extremities and the upper trunk. 3. The cuneocerebellartracts carry input from the upper extremitiesand upper trunk. 4. Most of the fibers in the dorsal spinocerebellarand cuneocerebellartracts are ipsilateral, while the other two tracts caffy mostly crossedfibers. The ventral spinocerebellartract crossesagain and entersthe cerebellumthrough the superior cerebellarpeduncle. C. Lesions and diseasesof the spinocerebellar tracts. Lesions that affect only the spinocerebellar tracts are uncommon, but there are a group of hereditary diseasesin which degeneration of spinocerebellarpathways is a prominent feature. The most common of these is Friedreich ataxia, which is usually inherited as an autosomal recessivetrait. The spinocerebellar tracts,posterior columns, corticospinaltracts, and cerebellumare all involved.Ataxia of gait is the most common initial symptom of this disease.

In a Nutshell Ataxia Friedreich . Degeneration of spinocerebellar tract . Dorsal columns . Lateral tracts corticospinal

585

Neruous System

In a Nutshell

CORTICOSPINAT TRACT

Cerebral cortex

I

I

I uurrt

I

Spinal cord

II

I

LMN

I Skeletal muscle

A. organization of the motor system involved in voluntary movements 1. The motor cellsin the anterior gray horn of the spinal cord and the cranial nerve motor nuclei are the final common pathways for the control of skeletal muscle activity. These cells are referred to as lower motor neurons (LMNs). They have their origin in the CNS and supply skeletalmuscle.The LMN consistsof the cell body and its peripheral axon. 2. The activity of the LMNs is influenced by the cerebralcortex, red nucleus,cerebellum, vestibularnuclei, and reticular formation, among others. a. The term upper motor neurons (UMNs) is used only in referenceto fibers that originate in the cerebralcortex (corticospinaland corticobulbar tracts). b. Corticobulbar fibers of the UMNs have an origin similar to that of corticospinal fibers,but they terminate in the brain stem on cranial nerve motor nuclei, the reticular formation, and sensoryrelay nuclei. B. Functions. The corticospinal tract mediatesvolitional control of movements and is most important for the production of skilled movement of the distal musculature(FigureV-9-3). C. Anatomy 1. Origin a. The primary motor cortex, located in the precentralgyrus of the frontal lobes,gives rise to about 30o/oof the fibers of the corticospinaltract. b. The premotor area,locatedimmediately anterior to the primary motor cortex, gives rise to about 30o/oof the fibers of the corticospinal tract. Primary and secondary somestheticareaslocatedin the parietal lobe giverise to about 40o/oofthe fibers of the corticospinaltract. 2. C,ourse.Fibers in the corticospinal tract passthrough the internal capsule,a large white matter structure, which carries afferents and efferents to and from the cerebral cortex. Corticospinalfibersthen descendin the ventralportion of the midbrain (cruscerebri),pons (basispontis), and medulla (pyramids).

584

of theSpinalCord andLesions Anatomy Functional l{euroanatomy:

gyrus Precentral of frontallobe (uppermotor neurons)

Cerebral hemispheres

Internal capsule Diencephalon

Cranialneruemotornucleus

Uppermedulla

Inferiorolivary nucleus

Lowermotorneuronfiber

Decussationof lateral corticospinaltract Lower medulla

fibersof Descending anterior uncrossed tract corticospinal

Descendingfibers of the crossed lateralcorticospinaltract

ln a Nubhell cortex Cerebral J

Alphamotorneuron (lowermotor neuron)

Anteriorgrey horn

Gervical spinal cord

radiata Corona J

lnterneuron Figure V-9-3.The corticospinal tract.

a. Eighty to ninety percent of corticospinal fibers crossin the lower medulla and continue in the contralateral spinal cord as the lateral corticospinal tract. Fibers terminate mainly on interneurons but also directly on motor neurons in the anterior gray horn. b. The remaining l0-20o/oof fibers do not crossin the lower medulla but continue asthe anterior corticospinal tract, which crossesshortly before termination (probably on interneurons). c. The lateral corticospinal tract descendsthe fi.rll length of the cord, while the anterior corticospinaltract descendsonly as far as the cervicalcord.

limbof Posterior internal capsule J (midbrain) cerebri Crus J (pons) pontis Basis

J (medulla) Pyramids

J tract Corticospinal (spinal cord)

585

Neruous System

D. ksions of the corticospinal tract. If lesionsof the corticospinaltract occur abovethe pyramidal decussation,the deficits are on the contralateralside of the body; lesionsbelow this level produce ipsilateral symptoms.Corticospinal tract lesionsresult in the following signs and symptoms. 1. Hemiparesis(paresisis weakness)or hemiparalysisis most severein arm and leg flexors. Increaseddeep tendon reflexesand muscle hlpertonia may occur.

ln a Nubhell Thelateral corticospinal tract crosses inthepyramidal decussation inthelower medulla. Lesions above the decussation inthelower medulla result in contralateral UMNsigns; below the decussation, theyresultin ipsilateral UMNsigns.

2. There is decorticaterigidity (i.e.,postural flexion of the arm and extensionof the leg) or decerebraterigidity (i.e.,postural extensionof the arm and leg). 3. The test for the Babinski sign is performed by stroking the lateral surfaceof the sole of the foot with a slightly painfrrl stimulus. Normally, there is plantar flexion of the big toe (i.e., it goesdown). With a lesion of the corticospinal tract, the Babinski sign is present,which is characterizedby dorsiflexion (i.e., plantar extension,upgoing toe) and fanning of the other toes. 4. Loss of superficial abdominal reflexesoccurs.Normally, stroking the skin of the abdomen results in reflex contraction toward the stimulus. 5. There is loss of the cremasteric reflex. Normally, stroking the skin on the upper medial thigh in the male producesa visible contraction of the cremastermuscle.

MOTOR NEURONS OFTHEANTERIOR GRAY HORN Motor of the motor motor

In a Nutshell UMNsigns LMNsigns paralysis Flaccid Spa$ic paralysis Hypeneflexia Hyporeflexia Babinski sign Muscle atrophy Fasciculations

neurons of the anterior gray horn constitute the final common pathway for the control skeletal muscle. The alpha motor neurons (which supply extrafusal fibers) and gamma neurons (which supply the intrafusal fibers of the muscle spindles)are the two types of cellsin lamina IX of the ventral horn. Theseare LMNs.

A. LMN lesions may result from destruction of the motor neurons or their axonsas they pass through the ventral roots and spinal nerves.(Lesionsof the cranial nerve motor nuclei or their fibers are also LMN lesions).LMN lesionsresult in the following signsand symptoms: 1. There is flaccid paralysis or paresisof the specificmusclesthat havelost innervation. 2. Absent or diminished deep tendon reflexes and muscle atrophy may occur. 3. Muscle fasciculation, which are twitches or contractionsof groups of muscle fibers,may produce a movement visible on the skin. Fasciculationsshould not be confusedwith fibrillations, which are invisible 1-5 ms potentials detectedwith electromyography. B. Diseasesaffecting LMNs 1. Poliomyelitis resultsfrom a relatively selectivedestruction of anterior horn motor cellsby the poliovirus, which is a small RNA virus of the picornavirus family. The diseasecauses paralysis of muscles,which become hyporeflexic and flaccid. Some patients may recover most function, while others progressto muscle atrophy and permanent disability. 2. Amyotrophic lateral sclerosis (AIS, Lou Gehrig disease)is a relatively pure motor system diseasethat is usually fatal. Degenerationof anterior horn LMN cells and corticospinal UMN cellsis characteristic,while lesionsin sensorysystemsare rare. Motor cells in the brain stem nuclei maybe involved.Symptomsof both UMN and LMN lesionsoccur,but the symptoms of the LMN lesionsusually occur first.

r86

of theSpinalCord andLesions functionalAnatomy l{euroanatomy:

CORD OFTHESPINAL LESIONS OTHER

$ "gN1$!ell

A. Brown-S€quard syndrome refers to a hemisection of the cord dong the transverseplane. Although the Brown-S€quard syndrome is very unusual in clinical neurology, it servesas an excellent review of spinal cord functions. Hemisection of the cord results mainly in the fol-

Syndrome Brown-Sequard

lowing deficits: 1. An ipsilateral UMN lesion occurs below the level of the injury and an ipsilateral LMN lesion occurs to those musclessupplied by the injured segments. 2. Ipsilateral loss of joint position sens€,tactile discrimination, and vibration sensationresults. 3. Contralateral loss of pain and temperature sensation starting in one or two segments below the level of the lesion is seen. B. Occlusion of the anterior spinal arter''. This artery usually arises from the vertebral arteries, and lies in the anterior median sulcus of the spinal cord. It supplies the anterior twothirds of the cord. Occlusion of the anterior spinal artery interrupts blood supply to the anterior gray horn and anterior funiculi, as well as to the lateral corticospinal, lateral spinothalamic, and spinocerebellartracts, which are located within the lateral funiculi.

belowlesion UMNsigns -+ ipsilateral LMNsignsat levelof lesion + ipsilateral below Dorsal column signs lesion+ ipsilateral loss Pain/temperature l-2 segments starting -> belowlesion contralateral

In.g,Nnbhell AnteriorSpinalArtery Syndrome tracts Lateral corticospinal tracts Lateral spinothalamic horns Anterior

t87

System Nervous TheAutonomic includes system, nervous (ANS), orvisceral thevegetative alsocalled nervous system Theautonomic cardiac muscle, innervate smooth peripheral system that nervous and of thecentral thoseportions of theANS, definition intheclassic arenotincluded fibers Whilesensory andglands. muscle, sensory These visceral motorfibers. asvisceral structures manyofthesame supply afferents visceral ANS and the of the activity The coordinated reflexes. autonomic most limb of the afferent fibers are quiet during environment oftheinternal homeostasis notonlymaintains system endocrine emerSency thataccompanies state of readiness theheightened butalsoachieves moments The andunconscious. involuntary thatarepredominantly exerteffects Bothsystems situations. system. the endocrine ANS and both the for center integrative is the chief hypothalamus

OFTHEANS DESIGN BASIC

ln a Nutshell

Tiansmissionof motor impulses from the central nervous system(CNS) to the visceraoccurs in the ANS through a chain of two neurons.(This is in contradistinction to the innervation of skeletalmuscleby a singleaxon from a CNS neuron.) The first neuron, the preganglionicneuron, is located in the brain stem or spinal cord. The lightly myelinatedpreganglionicfiber that arisesfrom this cell passesthrough either a cranial or spinal nerve to reachan autonomic ganglion, where it synapseswith postganglioniccells.The unmyelinatedaxon that arisesfrom the second,or postganglionic,cell innervatesthe visceraleffectors(i.e.,smooth and cardiacmuscle and glands).

. TheANShastwoneurons fromthe inseries extending the sites: CNSto effector preganglionic and postganglionic neurons. . Thesomatic system nervous between hasoneneuron theCNSandskeletal thelowermotor muscle, neur0n.

NEUROTRANSMITTERS The location of the preganglionicneuronsprovidesan anatomicbasisfor dividing the ANS into parasympatheticand sympatheticparts. A. Preganglionicfibers of both the parasympatheticand sympathetic systemsreleaseacetylcholine (ACh). B. Postganglionicparasympatheticfibers also releaseACh, but most postganglionic sympathetic fibers releasenorepinephrine. Exceptionsare the cholinergic postganglionicsympathetic fibers, which supply sweatglands and mediate dilatation of blood vesselsin skeletal muscle.Most visceralstructuresreceiveboth sympatheticand parasympatheticinput. As a generalrule, the sympatheticand parasympatheticsystemshave opposite effects.The function of the parasympatheticsystemis best summarizedby the epithet "rest and digest,"while the sympathetic systemis used for "fight or flight."

589

Neruous System

In a Nutshell

DIVISIONS OFTHEANS

pathetic-cra Parasym niosacra I CNlll,Vll,lX,X;S2-Sa

A. Parasympathetic nervous system. The parasympathetic or craniosacral division arises from the brain stem and sacralportions of the spinal cord. Preganglionicfibers are long, terminate in ganglia close to or within the target organ they innervate, and releaseACh. Postganglionicfibers are short and also releaseACh.

ln a Nutshell cNill -+ ciliary Edinger-Westphal ganglion + . Pupillary sphincter muscle (miosis) . Ciliary muscle (accommodation) In a Nutshell CNVII . Superior salivatory nucleus + sphenopalatine ganglion gland + lacrimal . Superior salivatory nucleus ganglion + submandibular + submandibular and glands sublingual Note CNVllruns through the parotid, butdoes not innervate it.Theparotid is innervated byCNlX. ln a Nutshell cN lx +parotid inferior*otic salivatory ganglion gland nucleus

ln a Nutshell CNX Dorsal motornucleus ofX + thoracic andabdominal (downto thesplenic viscera flexure)

ln a Nutshell S2-S4innervate thebladder, lowercolon, rectum, and genitalia.

590

1. Cranial division a. Edinger-Westphal nucleus. Preganglionic neurons in the Edinger-Westphalnucleus (located in the rostral midbrain) send parasympatheticfibers to the ciliary ganglion via the oculomotor nerye (CN III). From the ciliary muscle, postganglionic parasympathetic fibers passto the following muscles: (1) Pupillary sphincter muscle. Parasympatheticstimulation causespupillary constriction. (2) Ciliary muscle. Parasympathetic stimulation causescontraction of the ciliary muscle, which relaxesthe ligament of the lens, thus allowing the lens to assume a more rounded shape.This is called accommodation of the lens and is important for focusing on nearby objects. b. Superior salivatory nucleus. Preganglionic neurons in the superior salivatory nucleus send parasympatheticfibers in the facial nerye (CNVII) to the following ganglia: (1) Sphenopalatine(pterygopalatine)ganglion.Postganglionicfibers from this ganglion supply the lacrimal gland and mucous membranesof the mouth and nose with secretoryand vasomotor efferents. (2) Submandibularganglion. Postganglionicfibers from this ganglion are secretory efferentsto the submandibular and sublingual salivary glands. c. Inferior salivatory nucleus. Preganglionic neurons in the inferior salivatory nucleus send parasympathetic fibers in the glossopharyngeal nerye (CN IX) to the otic ganglion. Postganglionic fibers from the otic ganglion are secretory efferents to the parotid gland. d. Dorsal motor nucleus of the vagus. Preganglionic parasympathetic fibers in the vagus nerye (CN X) project to terminal ganglia,which supply postganglionic efferents to the visceraof the thorax and abdomen (i.e.,the heart, lungs, trachea,bronchi, larynx, esophagus,stomach, small intestine, large intestine up to the splenic flexure, abdominal blood vessels,liver, pancreas). 2. Sacral division. Preganglionic parasympathetic neurons in the intermediolateral area of the S2-S4segmentsproject through the pelvic nerve to postganglioniccellsin the terminal ganglia of the pelvic viscera (i.e., urinary bladder,reproductive organs),lower colon (i.e., descending,sigmoid), and the rectum. Parasympatheticstimulation causescontraction of the muscular parts of these viscera and relaxation of the internal sphincters, contraction of the bladder, lower colon, and rectum. Parasympatheticfibers are also responsiblefor clitoral and penile erections;ejaculationhowever,is mediatedby sympathetic fibers. a. Innervation of the urinary bladder is primarily parasympathetic,howeversympathetic fibers do innervate blood vesselsin the bladder wall. (1) Preganglionicparasympatheticfibers arising from S2-S4segmentspassthrough the pelvic nerve and synapsein terminal ganglia in the bladder wall.

Neuroanatomy: TheAutonomic Nervous System

(2) Postganglionicfibers,which passto the detrusor muscle (which lines the bladder wall) and internal sphincter,causecontraction of the detrusor muscle,and relaxation of the internal sphincter. (3) Bladder emptying is effectedmainly by the detrusor muscle.Opening of the internal sphincteris in large part a passivemechanicalresponseto increasedpressure. (4) Micturition in adults is under both reflex and voluntary control, while in infants the bladder actssolelyasa reflex organ with contraction of the detrusor and relaxation of the internal sphincter in responseto increasedintravesicular pressure causedby stretch of the bladder wall.

In a Nubhell S2_S4 I I Pelvic I v nerve ganglion Terminal

II

(5) After infanry, the external sphincter is supplied by somatic efferents that arise from motor neurons in the third and fourth sacral segmentsand travel in the pudendal nerve.

V

Detrusor muscle

(6) Contraction of the externalsphincter preventsmicturition. Voluntary suppression of micturition is mediated by pathways that arise in the frontal lobes. Frontal lobe lesionsmay lead to urinary (and rarely fecal) incontinence. b. Neurogenic bladders (l) Hypotonic (flaccid) bladder. This is generally causedby damage to the sacral spinal cord or caudaequina.This is characterizedbyoverflow incontinencewith a decreasedability to inhibit voiding. Hypotonic bladders are flaccid and distended and there is significant urinary retention, which predisposespatients to urinary tract infections. (2) Spastic (contracted) bladder. This is generally due to suprasacral spinal cord damage.This causesurge incontinence with a decreasedability to inhibit the voiding reflex. There may be some urinary retention due to detrusor-sphincter dyssynergia.This is also calledan automatic neurogenicbladder. B. Sympathetic nervous system l. Preganglionic fibers a. Preganglionic fibers arise from cells of the intermediolateral nucleus in segments TI-L2 and exit the spinal cord via the ventral roots. b. Thesefibersjoin the spinal nervesfor a short distanceand then passthrough the white rami communicantes.(They are white becausepreganglionicfibers are myelinated.) They synapsewith postganglionic neurons in either paravertebral or prevertebral ganglia.

Note Whiteramicarrymyelinated preganglionic gray fibers; ramicarry unmyelinated postga nglion icfibers.

(1) The paravertebralganglia form two symmetric chains along the ventrolateral border of the vertebral column from the upper neck to the coccp<. (2) Preganglionicfibers enter the paravertebralchain and terminate in gangliawithin a few segmentsof the level they enter. (3) Some fibers passthrough the paravertebralganglia without synapsingto form the splanchnicnervesand terminate in the prevertebralganglia,which surround the abdominal aorta and its visceralbranches. 2. Postganglionicfibers are unmyelinated and relatively long (compared to those in the parasympathetic system) and reach their respectiveeffector cells through severalpaths.

Note Whiteramiarefoundat Tl-12.Crayramiare foundatalllevels of the sympathetic chain.

591

NervousSystem

a. Somatic efferents. From the paravertebralganglia,fibers that passto the spinal nerves through gray rami communicantes arise and supply the skin and body wall with: (1) Vasomotor fibers + peripheral blood vessels (2) Pilomotor fibers -> arrector pili muscles of the hair follicles (3) Sudomotor fibers + sweatglands b. C,ardiac efferents (1) Other fibers from the paravertebral ganglia accompany large arteries (e.g., carotid, subclavian) and their branches. (2) Additional fibers from the paravertebral ganglia form discrete nerves (e.g., cardiac nerves from the cervical ganglia). (3) Fibers from the prevertebral ganglia accompanyvisceral branchesof the abdominal aorta in the perivascular plexus.

ClinicalConelate Damage to thesuperior ganglion cervical canresultin Horner syndrome.

3 . Cf,rvicalganglia Preganglionic fibers from T1-T4 ascendto form the three ganglia in the cervical portion of the sympathetic chain: the superior, middle, and inferior cervical ganglia. The latter may fuse with the first thoracic ganglion to form the stellateganglion. a. Superior cervical ganglia. This is the largest of the paravertebral ganglia and gives rise to: (1) Fibers that passto the internal and external carotid arteries to form the plexus around these vesselsand their branches. These postganglionic fibers leave the perivascular plexus and join various cranial nerves to supply the pupillary dilator muscle, Mii{ler muscle of the upper eyelid, the lacrimal and salivary glands, the blood vessels,sweatglands, and the arrector pili musclesof the head. (2) Fibers to the upper 3-4 cervical nerves (3) Nerves that passto the cardiac plexus b. Middle cervical ganglia give rise to: (1) Fibers to the fifth and sixth cervical nerves (2) Nerves that passto the cardiac plexus c. Inferior cervical ganglia give rise to: (1) Fibersto spinalnervesC7,C8, and T1 (2) Nerves that passto the cardiac plexus

,92

Neuroanatomy: TheAutonomic Neruous System

4. Splanclnic nervessupplythe visera of the abdomenand pelvis.

In a l{ubhell

a. The thoracic portion of the sympathaic trunl givesrise to the thoracic splanchnic sometimesleast),which carry nerves,Thesearetwo or threenerves(i.e.,greater,lesser, preganglionicsympatheticfibersandpassthrough the diaph."g"r ir;;;; i;t; vertebralganglia(i.e.,celiac,superiormesenteric,aorticorenal). (1) Greatersplanchnicnerve arisesfrom roots T5-T9 and suppliesthe celiacand superiormesentericganglia. (2) kser splanchnicnerve arisesfrom roots Tlo-T11 and suppliesthe superior mesentericandaorticorenalganglia.

SphnclrnicNerueRoot ' Greater sPlandrnic-T5-Tg . Lesersplanchnic-TlGTl I . Lea$sDlanchnic-Tl2 ' Lumbar-Ll-l2

(3) kast splanchnicnerve,if present,arisesfrom the T12 root and suppliesthe aorticorenalplexus. b. The lumbar portion of the sympathetictrunk givesrise to the lumbar splanchnic nerves.Thesenervescarry preganglionicrympatheticfibers from the upper two lumbar segmentsand terminatein prevertebralganglia(inferior mesentericand h)?ogastric). Postganglionicfibers ftom thesegangliasupply rympatheticfibers to the lower abdominaland pelvicviscera. 5. Adrenal medulla" Preganglionicsympathetic fibers arising from thoracic segments T1G-T12(and travelingir the leser and leastsplanchnicnerves)passdirectl/to the adrenalmedulla.This is the only autonomicstructurethat is supplieddirectlyby preganglionic fibers. Derived from neural crest cells,the adrenalmedulla producesthe catecholaminesnorepinephrineand epinephrine,the latter being the predominant product releasedin humans.The adrenalmedullacanbe considereda sympatheticganglionmodified to releaseits product into the bloodstream.Release of epinephrinecausesan elevation of blood sugar,blood pressur€,heart rate and contractilit),,bronchodilation, and pupillary dilatation.

Bridge to physiology medulla acBlike lhe adrenal postganglionic sympathetic neurons. lt receives preganglionic innervation, but releases norepinephrine and eoineohrine intothe bloodstream

nervesof the headand ne& TableV-10-1.P-arasympathetic Nerve

Preganglionic

Ganglion

CN III

Inferior division

Ciliarv

Postganglionic

Effector

Short ciliarv

Ciliaris and sphincter pupillae

nerves

Branchesof V2

CN VII

Greater superficial petrosalnerve

Pterygopalatine

CN VII

Chordatympani

Submandibular Lingual

CN IX

Lesserpetrosal

Otic

Auriculotemporal

Lacrimal gland and glands of nasal cavity and palate

Submandibular and sublingualsalivary glands Parotid gland

595

ThePeripheral Nervous System (PNS) Theperipheral nervous system consists of allneural structures outside thebrainandspinal ramifications, cord.Hence, thePNSiscomposed of 3l pairsofspinal nerves, theirperipheral the ganglia, partoftheCNS). andcranial nerves lll-Xll(olfactory andopticnerves areconsidered The nerves spinal havea segmental organization evident fromthepresence of dermatomes andspecific regions innervated bycollections nerves A thorough knowledge ofadjacent thatforma plexus. of peripheral nerves isnecessary innervation andisindispensable inthe to understand somatic diagnosis andtreatment disorders ortraumatic injuries. of manyneurologic

NERVES SPINAT While the spinal cord has no intrinsic segmentation,the paired spinal nervesdivide the cord externallyinto 31 segments(i.e.,8 cervical,12 thoracic, 5 lumbar, 5 sacral,1 coccygeal).A spinal nerve is formed by the union of a dorsal afferentroot and a ventral efferentroot. The union of theseroots occursjust distal to the dorsalroot ganglion,which containsthe somataof the afferent neurons. The spinal nerves leave the vertebral canal through the intervertebral foramen. Spinal nerves are often called mixed nerves becausethey contain both afferent and efferent fibers.Thesenervesdivide into four branches(rami).

In a Nubhell A dorsal root(sensory) anda ventral root(motor) uniteto forma spinal nerve. Spinal nerves branch intodorsal and (rami). ventral branches

A. The dorsalbranch dividesinto cutaneous(superficial)and muscular (deep)portions, which supply the skin and musclesof the back, respectively.Thesemusclesare the extensorsof the vertebral column. B. The ventral branch contains generalsomatic efferents(GSE) fibers,which innervate skeletal muscles,and generalvisceralefferent(GVE) fibers,which innervate smooth musclesand glands. C. Rami communicantes link the mixed spinal nerveswith the sympathetic ganglia. 1. White rami communicantes contain preganglionic sympathetic (GVE) fibers, leaving the ventral branch of the spinal nerve en route to the postganglionic cells in the paravertebral and prevertebral ganglia. The white rami also contain general visceral afferent (GVA) fibers,passingfrom the periphery to the spinal nerve and dorsal root. 2. Gray rami communicantes contain unmyelinated postganglionic sympathetic (GVE) fibers,which supply blood vessels,sweatglands,and arrector pili muscles.They originate in paravertebralgangliaand passthrough the gray ramus to join the spinal nerves. D. A meningeal branch re-entersthe vertebral canal to supply the meninges,vertebral column, and associatedblood vessels.

595

Neruous System

GANGTIA A. Dorsal root ganglia Eachdorsal root is connectedto a dorsal root ganglion.The cell bodies of nearly all visceral and somatic afferentsare located in the dorsal root ganglia. B. Autonomic ganglia (sympathetic) 1. Paravertebral ganglia. Each spinal nerve is connected to a paravertebral ganglion through the white and gray rami. Theseganglia are located on the ventrolateral surfaceof the vertebral column. They are arranged segmentallyand ganglia on each side are interconnectedby longitudinal fibers to form two sympatheticchains (trunks). 2. Prevertebral ganglia. Certain preganglionic sympathetic (GVE) fibers passthrough the white ramus and paravertebral ganglion without synapsing; they continue and slmapse with cellsin prevertebralganglialocatedin a plexussurrounding the abdominal aorta and its major visceralbranches.

SEGMENTAT SUPPTY

ClinicalConelate (shingles) Herpes zoster isa virusthatofteninfects dorsal rootsandtheirganglia. During phase theactive of infection, peripherally thevirusmigrates in axons, resulting in painand a vesicular eruption inthe distribution of oneor more dermatomes.

A. Somatic segments. During development, the somites differentiate into myotomes, which form muscle,and into sclerotomes,which form the axial skeleton.Paired somitesare supplied by a correspondingpair of spinal nerves.The dorsal rami of the spinal nervesinnervate relativelydistinct segmentsof the neck and back. In contrast,adjacentventral rami in the cervical,lumbar,and sacralregionsjoin to form the cervical,brachial,lumbar, and sacral plexuses.The ventral rami of the thoracic spinal nerves are predominantly distributed segmentally. B. Dermatomes. A dermatome refersto a cutaneousareasuppliedby a dorsal root and its ganglion. The dermatome suppliedby a given dorsal root usually overlapssomewhatwith adjacent segments. 1. In the trunk, dermatomesare arrangedas consecutivebands. 2.In the extremities, the arrangement of dermatomes is more complex, reflecting the embryonic migration of somitesinto the limb buds.

PTEXUSES The union of adjacentventral rami givesrise to the cervical,brachial,lumbar, and sacralplexus. From these plexuses,peripheral nerves,which contain fibers from two to five adjacent ventral rami, arise.Cutaneousareassuppliedby peripheral nervesdiffer from the dermatomessupplied by dorsal root ganglia.For example,the palmar surfaceof the middle finger is part of the C7 dermatome,but it is suppliedby the median nerve,which receivescontributions from the ventral rami of C6-T1. The pattern of muscular innervation is similar.A singlemusclemay receive fibers from severalventral roots, while a single ventral root may supply severalmuscles. A. The cervical plexus is formed by the ventral rami of spinal nervesC1-C4. It suppliescutaneoussensationto the posterior third of the head and the anterior and lateralportions of the neck. Muscles supplied by this plexus include the diaphragm and infrahyoids. The major nerve branchesare the:

Mnemonic

1. Phrenic nerye, which is derived from C3,C4, and C5. It suppliesthe diaphragm.

q, Co,C,helpto keepyou alive(because theyinnervate thediaphragm).

2. Ansa cervicalis, which is formed by the union of branchesfrom CI, C2, and C3. It supplies the geniohyoid,thyrohyoid, sternohyoid,and omohyoid muscles.

596

3. Great auricular nerye (C2 and C3), which suppliesthe skin behind the ear and on the upper pinna.

Neuroanatomy: ThePeripheral Neruous System

B. Brachial plexus.The ventral rami of spinal nervesC5-T1 join to form the brachialplexus. Nervesin this plexussupplythe upper extremity.The ventral rami giverise to tbreetrunls: C5 and C6 join to form the superiortrunk; C7 continuesasthe middle trunk and C8 and Tl join to form the inferior trunk Eachtrunk dividesinto an anterior and posterior division. The anterior divisionsof the superiorand middle trunls join to form the lateralcord. The anterior division of the inferior trunk continuesasthe medial cord.The posteriordivisionsof all threetrunls join to form the posterior cord. The ventral rami, trunks, and divisionsarelocatedin th€ post€riortriangle of the neck,while the cordsare in the axilla. l. Branchesof the ventnl rarni (roots) include tJre: a. Dorsal scapulrr nerve,whidr arisesfrom C5 and suppliesthe rhomboid and levator muscles. scapulae b. Longthoracicnerra,which arisesfrom C5-C7andsuppliesthe serratusanteriormuscl€. 2. Branchesof the trunks (only the upper trunl givesoff branches)include the: a. Suprascapularnerve (C5 and C6), which suppliesthe supraspinatusand infraspinatus muscles. b. Subclaviannerve (C5 and C6),which suppliesthe subclaviusmuscle. 3. Branchesof the lateral (anterior) cord include the: a. Lateral pectorsl nerve (C5-{7), which suppliesthe pectoralismajor muscle. b. Musculocutaneousnerv€ (C5-C7), which suppliesthe bicepsbrachialis,and coracobrachialismuscles.Its branch,the lateral antebrachialcutaneousnerve,suppliesthe skin of the anterolateralforearm' c. Lateralroot ofthe mediannerve,which,in combinationwith the medialroot, supplies all the musclesof the volar surfaceof the forearmexceptthe carpi ulnarisand the flexor digitorum profundis.It alsosuppliesthe first and secondlumbricalsof the hand.

ln a Nubhell Themusculocutrneous nerve(c5-c7) supplies the armflexorsandprovides sensory innervation to the anterolateral Iorearm.

4. Branchesofthe medial cord include the: a. Medial pectoral nerve (C8 and T1), which suppliesthe pectoralismajor and minor muscles, b. Medial brachial cutaneousnerves (Tl), which are joined by an intercostalbranch from T2. They supplythe skin of the medial arm. c. Medial antebradrial cutueous nerve (C8 and T1), which suppliesthe skin of the medial forearm. d. Medial root of the median nerve,which combineswith the lateralroot to supplythe volar forearm and tfle first and secondlumbricals. e. lflnar nerve (ftom C8 and Tt), which suppliesthe flexor carpi ulnaris and the ulnar portion ofthe flexor digitorum profundis in the forearm.In the hand,the ulnar nerve iupplies the adductoi pollicis, the deep head of the flexor pollicis brevis, the hypothenarmuscles,the dorsaland palmar interossei,and the lumbricalsfor digits 4 and 5. The cutaneousbranchesof the ulnar nervesupplythe skin of the ulnar half of the wrist, palm, and digits 4 and 5. 5. Major nervesof the upper limb include' a. The axillary nerve (C5 and C6), which arisesftom tlre posterior cord ( I ) Motor supplyis to the deltoid and teresrninor muscles. (2) Sensorysupplyis to the skin ofthe lateralarm (lateralbrachialcutaneousnerve).

In a Nubhell UlnarNerve(C&-Tl) ' Motor: - ljlnarflexors - Addudor pollicis - Hypothenar muscles - Inrcross€l - Lumbricb 4and5 . Sensory: - lJlnarhalfofwrist - Palm - 4thand5thdigits

t97

Neruous System

b. Radial nerve (C6-C8), which arisesfrom the posterior cord (1) Motor supply is to the triceps, brachioradialis, supinator, abductor pollicis longus, and the extensor musclesof the wrist and fingers. (2) Sensorysupply is to the skin of the posterior arm (posterior brachial cutaneous nerve),posterior forearm (posterior antebrachialcutaneousnerve),and the radial half of the dorsum of the hand down to the distal interphalangealjoint (superficial radial nerve).

In a ilutshell Nerve Motor

c. Median nerye (Cs-Tl), which is formed by the union of the medial and lateral cords Sensory

AxillaryDeltoid, Lateral arm Teres minor Radial Extensors of Skinof arm,forearmposterior arm,forearm, radial halfof donumof hand(not fingertips) MedianForearm flexors, thenar muscles, radial lumbricals

Radial 2/3 volar of palm, surfaces of thumb,2nd, 3rddigits, radialtl2 of 4th

( 1) Motor supply is to the pronator teres,palmaris longus,flexor carpi radialis,flexor digitorum superficialis,radial half of flexor digitorum profundus, pronator quadratus, abductor pollicis brevis, flexor pollicis longus and brevis, opponens pollicis, and the two radial lumbrical muscles. (2) Sensorysupply is to the skin of the radial two-thirds of the palm and volar surfaces of the thumb, index and middle fingers, and the radial half of the ring finger. C. The lumbar plexus is formed by the ventral rami of the upper four lumbar nerves and lies within the psoasmajor muscle.Major branchesinclude the: 1. Iliohypogastric nerve (T12-L1), which suppliesthe skin and musclesof the lower anterior abdominal wall 2. Ilioinguinal nerve (L1), which passesthrough the superficialinguinal ring to supply the skin of the upper medial thigh and scrotum/labium majora 3. Genitofemoral nerve (Ll and L2) a. The genital branch suppliesthe cremastermuscle. b. The femoral branch suppliesa small patch of skin of the femoral triangle. 4. Lateral femoral cutaneous nerve (L2 and L3), which supplies the skin of the anterolateral thigh down to the knee 5. Femoral nerve (L2,L3, L4), which supplies the skin and dorsal musclesof the anterior thigh, including the: a. Flexorsof the hip-iliacus, sartorius,and pectineus b. Extensorsof the knee-quadriceps femoris c. Skin of the anteromedial thigh and medial leg 6. Obturator nerye (L2,L3, L4), which suppliesthe: a. Adductors of the thigh-gracilis, adductor longus,adductor brevis,adductor magnus, and obturator externus b. Skin of the medial thigh D. The sacral plexus is formed by the ventral rami of the fourth and fifth lumbar nerves (lumbosacraltrunk) and the first four sacralnerves.Branchesof the sacralplexus supply the skin and musclesof the buttocks,posterior thigh,leg, and foot. Other branchessupply the pelvic musculature,viscera,and the perineum. Branchesof the sacralplexus include the: 1. Superior gluteal nerve (L4,L5, 51), which suppliesthe gluteusmedius and minimus 2. Inferior gluteal nerye (L5, S1,S2),which suppliesthe gluteusmaximus 3. Nerve to the quadratus femoris (U,L5, Sl), which alsosuppliesthe inferior gemellusmuscle

598

Neuroanatomy: ThePeripheral Neruous System

4. Nerve to the obturator internus (L5, 51, S2),which also suppliesthe superior gemellus muscle 5. Posterior femoral cutaneous nerve (S1, 52, S3), which supplies the skin of the buttocks and posterior thigh 6. Sciatic nerve (L4,L5, S1,52, S3),which is composedof the common peronealand tibial nerves bound together by fascia.It leavesthe pelvis through the greater sciatic foramen and passesdeep to the midportion of the gluteus maximus. It has no branchesin the gluteal region, but in the posterior thigh, muscular branches(tibial component) supply the hamstrings (i.e.,bicepsfemoris, semitendinosus,semimembranosus,hamstring portion of the adductor magnus). It then divides halfiuay down the thigh into the common peronealand tibial nerves,eachpassinginto the leg. a. The common peroneal nerve passeslaterally around the neck of the fibula, piercesthe peroneus longus muscle, and divides into the superficial and deep peroneal nerves. (1) The deep peroneal nerve passesinto the anterior compartment of the leg, supplying the muscles of this compartment (i.e., the tibialis anterior, extensor digitorum longus, extensorhallucis longus,peroneustertius). (2) The superficial peroneal nerve supplies the peroneus longus and brevis muscles (lateral compartment of the leg), the skin of the lower anterior leg, and the dorsum of the foot. b. The tibial nerve coursesthrough the posterior compartment of the leg to innervate the muscles(i.e., gastrocnemius,plantaris, soleus,popliteus, flexor digitorum longus, flexor hallucislongus,tibialis posterior) and skin of the posterior leg and plantar surface of the foot. The medial and lateral plantar nerves supply the musclesand skin of the sole (i.e.,plantar surfaceof the foot).

ln a NuBhel! Innervation oftheLeg . Anterior compartment + deepperoneal nerve . Lateral -t compartment peroneal superficial nerve . Po$erior -) compartment tibialnerve

599

TheBrainStem groups Thebrainstemcontains thatmediate a wide a multitude offiberpathways andnuclear groups range of sensory Nuclear located mostlaterally areconcerned with andmotorfunctions. somatic, visceral, sensations fromtheheadandvisceral cavities. Mostnuclei located orothersensory nearthemidline havesomatic orvisceral motorfunctions andsendprojections to skeletal and smooth muscles inthehead, neck, andvisceral organs. Manymyelinated fibersystems arepresent inthebrainstemto provide connections between allpartsoftheneuraxis.

ORGANIZATION A transversesection of the brain stem is divided into three areas: A. The basilar portion is the most anterior (ventral) part of the brain stem. It contains fibers from the cortex (e.g.,corticospinaltract). B. The tegmentum is located between the basilar and roof areas.The tegmentum forms the largestpart of the brain stem and containsthe reticular formation, central gray matter, cranial nerve nuclei, and ascendingsensorypathways. C. The roof is the most dorsal part of the brain stem.

401

Neruous System

MEDULLA Medulla (medulla oblongata) is derived from the myelencephalon. It is continuous caudally with the spinal cord at the foramen magnum and proceeds rostrally to the lower border of the pons. A. Anterior surface (FigureV-12-1) 1. The pyramids, which are on the ventromedial surface of the medulla, contain the corticospinaltracts. 2. The decussation of the pyramids occurs at the transition of the medulla and the spinal cord. 3. The olives are located lateral to the pyramids in the rostral two-thirds of the medulla. The inferior olivary nuclei reside beneath the olives. 4. The hypoglossal nerve (CN XII) emergesbetween the pyramids and the olives.

I (Olfactorytract) ll (Opticnerve) Mammillarybody Optic tract Cerebral peduncle Midbrain lll, lv

V VI

Pons vvl, vll, vlll

vtl vill

Upper medulla

lx, x, xll

IX

Lower medulla Crossingpointof fibers formingmediallemniscus and corticospinaltracts

Ventral

Figure V-12-1.Anterior view of the brain stem.

402

Neurcanatomy: TheBrainStem

Superior colliculus

Mldbraln lll, lv

Inferior colliculus

Pons v,vl, vll, vlll Uppermedulla

lx, x, xll

Lowermedulla Grossingpointof fibers formingmediallemniscus andcorticospinal tracts

Dorsal

Figure V-12-2.Posterior view of the brain stem.

B. Posterior surface (Figure V-12-2) 1. The gracile fasciculus is located dorsomedially (just like in the spinal cord) and widens to form the gracile tubercle. The gracile nucleus lies beneath its tubercle. 2. The cuneate fasciculus is just lateral to the gracile fasciculus.It widens into the cuneate tubercle, beneath which lies the cuneatenucleus. 3. The posterior median sulcus continues rostrally from the cord to the obex. The obex is the point in the middle of the rostral-caudal extent of the medulla where the central canal of the spinal cord opens into the fourth ventricle.

40r

Neruous System

Anteriortubercleof thalamus

Thalamus

Opticnerve Lateralgeniculate body

In fu n d i b u l u m Hypophysis (pituitarygland)

Superiorcolliculus

Cruscerebri

lnferiorcolliculus

nerve Oculomotor

Trochlearnerve nerve Trigeminal

Middlecerebellar peduncle

Facialand vestibulocochlear nerves Pyramid

Glossopharyngeal nerye Vagusnerve rootlets

ne Hypoglossal lnferiorolive

Postolivary sulcus

Medulla

Spinalaccessory nerve rootlets Posterolateral sulcus

Figure V-12-3.Lateral view of the brain stem.

Fasciculusgracilis

Nucleusgracilis

Fasciculus cuneatus Nucleus cuneatus

Centralcanal

Spinalnucleus of V andtract

Mediallongitudinal fasciculus

Internal

Lateral spinothalamic tracts

arcuatefibers Reticularformation

Spinocerebellar tracts Pyramid

decussation

Figure V-12-4.Transverse section of the lower medulla.

404

Neuroanatomy: TheBrainStem

C. Lateral surface (Figure V-12-3) 1. The preolivarysulcus separatesthe pyramids from the lateral oval bulges forming the inferior olive. The rootlets of the hlpoglossal nerve (CN XII) emergefrom the preolivary sulcus. 2. The olive is seenon the lateral surface. 3. The postolivary sulcus separatesthe olives from the more posterior inferior cerebellar peduncle (restiform body). This peduncle carries fibers from the spinal cord and inferior olivary nuclei to the cerebellum.The accessorynerve (CN XI) emergesfrom this sulcus. D. Internal structure of the caudal (lower) medulla (Figure V-12-4) 1. Nuclei of the caudal medulla a. Spinal nucleus of the trigeminal nerve (CN V) is located in a position analogous to the substantiagelatinosaof the spinal cord. The spinal tract of the trigeminal nerve lies just lateral to this nucleus and extendsfrom the upper cervical cord (C2) to the midpons. This nucleus and tract receivepain and temperature sensationfrom the face. b. Hypoglossal nucleus (CN XII) supplies the somatic motor fibers to the tongue muscles.It is located in the posterior tegmentum near the midline. c. Dorsal motor nucleus of the vagus nerve (CN X) gives rise to preganglionic parasympathetic fibers of the vagus nerve and is located lateral to the hypoglossal nucleus.

In a iluBhell Spinal nucleus ofCNV+ pain/temperature ofthe face (CN Hypoglossal nucleus Xll)+ moves tongue Donalmotornucleus ofCN X+ parasympathetic to mo$viscera

d. Solitary nucleus and tract are lateral to the dorsal root motor nucleus of CN X. 2. Tracts of the caudal medulla a. The ventromedially located pyramids contain the corticospinal (pyramidal) tracts. Eighty-five percent of these fibers decussatein the caudal medulla and then travel down the spinal cord as the lateral corticospinal tract. b. Medial longitudinal fasciculus (MLF) is located medially in the posterior tegmentum and extendsfrom the upper cervical cord to the midbrain. The MLF connectsthe ocular nuclei of CN III, CN IV, and CN VI with each other and with inputs from the vestibular nuclei, cerebellum,and proprioceptive fibers from the neck. The MLF helps to coordinate eye movements. c. Fasciculus gracilis (medial) and fasciculus cuneatus (lateral) are located posteriorly. Axons in thesetracts terminate in the nucleus gracilis or nucleus cuneatus,respectively. Thesenuclei send offaxons that decussatein the caudal medulla (the crossingixons are the internal arcuate fibers) and then ascendin the medial lemniscus. E. Internal structure of the rostral (upper) medulla (Figure V-12-5) 1. Nuclei of the rostral medulla a. Inferior olivary nucleus is a prominent structure that is shaped like a loosely curled snakeand is located in the anterolaterd tegmentum. It is a cerebellarrelay nucleus and receivesinput from the cerebralcortex and the brain stem. It sendsoutput to the cerebellum (olivocerebellar fibers).

ln a l{ubhell Theinferior nucleus olivary to the sends climbing fibers cerebellum.

b. Hypoglossal nucleus, MLF, dorsal motor nucleus of the vagus nerve, and the spinal tract and nucleus of the trigeminal nerve are located in approximately the samepositions as in the lower medulla. c. Solitar'' nucleus and tract (l',[TS)lie lateral to the dorsal motor nucleus of the vagus nerye. It receivestaste afferents from CN VII (anterior two-thirds of tongue), CN IX (posterior one-third of tongue), and CN X (soft palate and oropharynx).

405

Neruous System

Mnemonic . NTS: Sforsensory . Nucleus ambiguus: mfor motor

d. Vestibular nuclei lie lateral to the solitary tract and nucleus and processinformation from CN VIII concerning equilibrium. e. Nucleus ambiguus is located in the anterolateral part of the tegmentum and supplies motor fibers to skeletalmusclesinnervated by CN VII, CN IX, and CN X. 4th ventricle Mediallongitudinal fasciculus

Solitarytractandnucleus Inferiorcerebellar peduncle

Spinaltract and nucleusof V Lateraland anterior spinothalamictracts Reticularformation

Corticospinal tracts (pyramids)

Hypoglossalnucleus

Dorsalmotornucleus ofX Medialvestibular nucleus Inferior vestibular nucleus

Tectospinal tract Nucleus ambiguus Mediallemniscus

Inferiorolivarynucleus

Figure V-l2-5. Transversesection of the upper medulla.

In a Nutshell Atthislevel, themedial lemniscus ismedial. lt will movelaterally asit travels up thebrainstem. lt carries proprioception, touch, and vibration information about thecontralateral body.

2. Tracts of the rostral medulla a. Corticospinal (pyramidal) tract is located anteromedially and lies ipsilateral to cells of origin in the cerebral cortex. b. Medial lemniscus is a large sensorypathway located near the midline posterior to the corticospinal tract. This tract carries input for proprioception (position sensation), vibration sensation,and two-point discrimination from the contralateral extremities and trunk.

PONS Pons is located between the medulla (caudally) and the midbrain (rostrally). A. Anterior surface.The abducensnerve (CN VI) emergesnear the midline at the junction of the medulla and the pons. B. Lateral surface

Bridge to Pathology A Schwannoma ofthe ve$ibulocochlear nerve is known asanacoustic neur0ma.

406

1. Middle cerebellar peduncle (brachium pontis) carries transverse fibers from the contralateral pontine nuclei to the cerebellum. 2. Pontocerebellar angle is formed by adjacent parts of the medulla, pons, and the cerebellum. The facial (CN VII) and vestibulocochlear(CN VIII) nervesemergefrom the pontocerebellar angle. The facial nerve is located medial to the vestibulocochlearnerve. 3. Trigeminal nerve (CN V) emergesfrom the middle of the pons on the surfaceof the middle cerebellarpeduncle.

Neuroanatomy: TheBrainStem

C. Posterior surface 1. Superior cerebellar peduncle (brachium conjunctivum) is lateral to the fourth ventricle and is the main efferent pathway from the cerebellum. Fibers from the superior cerebellar peduncle decussatein the lower midbrain and terminate in the thalamus, red nucleus, and reticular formation. 2. Floor of the fourth ventricle is formed by the posterior surfaceof the pons. D. Internal structure of the caudal pons (Figure V-I2-6). The basilar portion of the caudal pons contains the corticospinal, corticopontine, and corticobulbar tracts, which pass through the pontine nuclei. The tegmentum of the pons contains the reticular formation.

Cerebellum Fourthventricle Dentatenucleus

Fastigialnucleus

Abducens

lnferiorand superior cerebellar peduncles

nucleus Facial

Internalgenu of V l l Spinaltract of V Spinalnucleus ofV

Mediallemniscus

Trapezoidbody Corticospinaltract

CN VI

Superior olivary nucleus

Mediallongitudinal fasciculus

Figure V-l2-6. Transverse section of the lower pons.

1. Nuclei of the caudal pons a. Abducens nucleus is found near the posterior surfaceon the pons just lateral to the MLF. The position of the MLF changeslittle throughout its course. b. Facialnucleus is locatedin the ventrolateraltegmentum.Fibersfrom this nucleustake a circuitous route before leaving the brain stem. First, they passdorsally and medially, then curve around the posterior side of the abducensnucleus (the curve forms the internal genu of the facial nerve), and, finally, passventrolaterally to exit the brain stem at the pontocerebellarangle. c. Superior olivary nucleus lies immediately ventral to the nucleus of CN VII and receivesauditory impulses from both ears. d. Vestibular nuclei are located near the posterior surface of the pons lateral to the abducensnucleus.

In a Nutshell . Abducens nucleus lateral rectus . Facial -; muscles nucleus of facial expression

Note Thesuperior olivary nucleus is involved in soundlocalization.

407

Neruous System

2. Tracts of the caudal pons a. Central tegmental tract is in the middle of the tegmentum. This tract contains ascendingfibers from the lower reticular formation to the thalamus.This is part of the ascending reticular activating system (ARAS). Descending fibers pass in this tract from the cortex and midbrain to the inferior olivary nucleus. b. Spinal tract and nucleus of the trigeminal nerve are located ventral to the vestibular nuclei and the inferior cerebellarpeduncle. c. Medial lemniscus and trapezoid body form a boundary betweenthe tegmentum and basilar part of the pons. The trapezoid body is an auditory relay station, locatedventral to the medial lemniscus. d. Lateral lemniscus arisesat the level of the trapezoid body and is lateral and slightly posterior to the medial lemniscus.The lateral lemniscuscarriesthe bulk of ascending auditory fibers from both earsto the inferior colliculus of the midbrain. E. Internal structure of the rostral pons (FigureV-12-7) 1. Basilar part of the pons a. Corticospinal tract is more diffuse in the pons than in the medulla. b. Pontine nuclei receive input from the ipsilateral cerebral cortex via corticopontine fibers. The pons sendsa large group of efferentsacrossthe midline and through the contralateralmiddle cerebellarpeduncleto the cerebellum.

Superiorcerebellar

Raphenuclei Reticularformation

Mesencephalic tract of Mediallongitudinal fasciculus

Middlecerebellar peduncle

Principal sensory nucleus of V -_ -.-Motor trigeminal . nucleusof V

olivary Superior nucleus CNV

Centraltegmentaltract Pontocerebellar fibers Mediallemniscus

Figure V-12-7. Transverse section of the rostral pons.

2. Dorsal part of the pons a. Superior cerebellar peduncles form the lateral walls of the fourth ventricle. b. Roof of the fourth ventricle is made up of the superior medullaryvelum.

408

Neuroanatomy: TheBrainStem

3. Tegmenturnof the rostral pons a. Principal sensorynucleusand motor nucleus of the trigerninal nerve.arefound.in tlre posterolateraltegmentum.The motor nucleusis irnmediatelymedialto the principalsensorynucleus. b. Mesencephalic nucleusof CNV is dorsalto the motor andprincipalsensorynuclei of CNV. c. Raphe nuclei are part of the pontine reticular formation and lie in the midline. Neuronsin the raphenudei synthesizeserotonin(5-hy&oxytryptamine,5-HT).

Clinital Conelah lhe JawJerkReflor . ln -+ mesencephalic nucleus of CNV . Out-J motornucleus ol CNV In a NUbhell

d. Locus coeruleus is located iust lateral to the central gray, N€urons in t}le locus coeruleusq,nthesizenorepinephrine.

' Raphe- 5-HT

e. Superior cerebellarpedunclesform the lateralwallsof the fourth ventricle.

' Locuscoeruleus (LQ - NE

MIDBRAIN Midbrain (mesencephalon) is locatedbetweenthe pons and diencephalon.The cerebralaqueduct, a narrow chaanelthat connectsthe third and fourth ventrides,passesthrough the midbrain. Its small diametermakesit a common site for obstruction to the flow of cerebrospinal fluid (CSF). A. Anterior surface l. The crus cerebri, the ventral part of the cerebralpeduncle,carry descendingfibers ftom the ipsilateralcerebralcortex (i.e.,corticospinal,corticopontine,corticobulbar). 2. The interpeduncular fossais the spacebetweenthe cerebralpeduncles. 3. Oculomotor n€rvesemergefrom the interpeduncularfossa. B. Posterior surface(tectum) 1. Corpora quadrigemina (quadrigeminalplate) are four rounded swellings(colliculi). a. Inferior colliculi are the caudalpair. b' superior collic.li are the rostral pair' 2. Tiochlear nerve emergesdorsallynearthe midline caudalto the inferior colliculi. C. Internal structure of the midbrain is consideredat two levels:the caudalinferior colliculi level and the rostral superiorcolliculi level.A horizontal crosssectionof the midbrain may be divided into threeregions:the ventral (basal)crus cerebri; the centrallylocatedtegmenturn, which is continuouswith the pontine tegmentum;and tJretectum (quadrigeminal plate),which lies dorsalto the cerebralaqueduct.The cruscerebriand tegmentummakeup the cerebralpeduncle.A large nucleus containing pigmented cells,the substantianigra, separates the cruscerebriand the tegmentum.

ilote Thetrochrear nerveistheonrv cranialnerveto emerge from thedorsalbrainstem.

1. Internal structure of the caudalnidbrain (FigureV- 12-8)

409

Nervous System

Centralgray

Cerebralaqueduct Nucleusof inferiorcolliculus

Locuscoeruleus

Laterallemniscus

Mesencephalic tract of V

Medial longitudinal fasciculus

Trochlearnucleus

Central tegmentaltract

Mediallemniscus

Substantia n i g ra

:.+-€ {S=4":t?

Corticopontine tracts

.t:^-€?

Cruscerebri Corticospinaltract

Decussation of superiorcerebellarpeduncle Figure V-12-8.Transverse section of the caudal midbrain.

a. Nuclei of the caudal midbrain ( I ) Substantia nigra is the largestnucleus of the midbrain. It appearsblack to dark brown in the freshly cut brain becausenigral cells contain melanin pigments in addition to the neurotransmitter dopamine. An important dopamine pathway ascendsfrom the substantianigra to the striatum (caudatenucleus and putamen) and is called the nigrostriatal pathway. This pathway degeneratesin Parkinson disease.

Note Themesoli mbic/mesocortical pathway dopamine isthought to beoveractive in schizophrenia.

(2) Ventral tegmental area is located ventral and medial to the substantianigra. Cellsin this areaalsogive rise to ascendingdopaminergicfibers,which terminate in the nucleus accumbensand the medial prefrontal cortex. This dopaminergic tract is calledthe mesolimbic/mesocorticalpathway. (3) Periaqueductal (central) gray is a collection of nuclei surrounding the cerebral aqueduct and is consideredpart of the reticular formation. Neurons with high concentrations of serotonin, enkephalin, and neuropeptidesare found in the central gray and play an important role in the modulation of pain. (4) Mesencephalic nuclei of the trigeminal nerve are located on either side of the central gray. Groups of neurons in this nucleus receivesensoryinput from the muscle spindlesof the masseter,the hard palate,and the teeth. (5) Inferior colliculus is a rounded swellingin the caudaltectum. This nucleusprocesses auditory information receivedbilaterally from the cochlearnuclei by axon fibers of the lateral lemniscus.Outputs from the inferior colliculusproject to the ipsilateral medial geniculatenucleus of the thalamus through the brachium of the inferior colliculus. (6) Trochlear nucleus lies immediately dorsal to the MLF at the levelof the inferior colliculus.Neurons in the trochlearnucleus innervate the contralateralsuperior oblique muscleto produce intorsion of the contralateraleye.

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Neuroanatomy: TheBrainStem

b. Tiacts of the caudal midbrain (1) The crus cerebri, which is massive,is a collection of corticofugul fibers located anterior to the tegmentum. It is composed of centrally located corticospinal fibers that are surrounded on both sides(anteromedially and posterolaterally)by corticopontine fibers. (2) Medial lemniscus conveyscutaneousand proprioceptiveinformation in a band of fibers located in the ventrolateraltegmentum. (3) Spinothalamic tract conveyspain and temperatureinformation in a collection of fibers located in the posterolateralpart of the tegmentum. (4) MtF is located near the midline, dorsal to the decussationof the superior cerebellar peduncle. This fiber tract interconnects the vestibular nuclei with the cranial nerve nuclei of the extraocularmuscles(i.e., abducens,trochlear,oculomotor nuclei). (5) Deep cerebellar nuclei send fibers out of the cerebellum,which then crossin the decussation of the superior cerebellar peduncles, located in the midbrain tegmentum. These fibers then continue rostrally and terminate either in the red nucleus or in the ventrolateral nucleus of the thalamus. (6) Lateral lemniscus lies near the lateral surface of the brain stem. This pathway carries ascending auditory fibers, which terminate in the inferior colliculus. Somefibers of the lateral lemniscusproceedpastthe inferior colliculusto terminate in the medial geniculateof the thalamus. (7) Central tegmental tract lies lateral to the MLF. It carries ascendingfibers from the reticular formation to the thalamus and descending fibers from the red nucleus to the inferior olive. 2. lnternal structure of the rostral midbrain (Figure V-12-9)

ClinicalCorrelate TheMLFisimportant in conjugate eyemovements. People withmultiple sclerosis oftenhaveMLFlesions, causing internuclear (lNO). ophthalmoplegia

In a Nutshell . Lateral lemniscus-auditory . Medial lemniscustouch/proprioception fromperiphery

Note

a. Nuclei of the rostral midbrain (1) The large, ovoid red nucleus is located in the anterior tegmentum. The red nucleus receivesinputs from the cerebellum and sendsdescendingoutputs to the spinal cord. It is important for motor coordination and facilitatescontraction of flexor muscles.

Thepresence ofthered nucleus indicates thatyouare intherostral midbrain.

(2) Oculomotor nucleus is found near the midline in the anterior part of the central gray and is adjacentto the MLF. Groups of neurons in this nucleusinnervate all of the extraocular musclesexcept the lateral rectus and the superior oblique. (3) The Edinger-Westphal nucleus is adjacent to the oculomotor nucleus. It provides parasympatheticinput to the eye. (4) Superior colliculus is located in the rostral tectum. In humans, it is primarily a visual reflex center responsiblefor orientation and subsequenttracking of visual stimuli. The superior colliculus alsoservesto shift the position of the head and eyesin responseto somatic and auditory stimuli. The superior colliculus receives input from the retina, spinal cord, visual cortex, and the inferior colliculus. It sendsefferents to the spinal cord and brain stem by the tectospinal and tectobulbar tracts. (5) Pretectal region is composed of several nuclei concerned with visual reflexes. This area mediates the pupillary light reflexesand is located just rostral to the superior colliculus.

4tl

Neruous System

(6) Substantia trigt" and periaqueductal gray occupy positions similar to that seen in the caudal midbrain. b. Tiacts of the rostral midbrain (1) The medial lemniscus shifts from its position in the caudal midbrain and is located in the dorsolateral tegmentum of the rostral midbrain. (2) The crus cerebri and MLF occupy positions similar to that seen in the caudal midbrain.

Superiorcolliculus

Periaqueductal gray

Corticopontine tract Corticospinal

Cerebralaqueduct Oculomotornucleus Medial longitudinal fasciculus Central tegmental tract Medial lemniscus

tract Rednucleus Substantianigra

Corticopontine tract

Ventraltegmental decussation

Oculomotor nerves Figure V-l2-9. Transverse section of the rostral midbrain.

412

CranialNerves

intheheadaswellasmany Thecranial nerves innervate virtually allmuscles andsensory receptors smooth muscles andallinteroceptors intheviscera. Withtheexception oftheolfactory andoptic groupsin thebrain withnuclear nerves, mostcranial nerves areconnected, eitherdirectly or indirectly, knowledge attributes ofthecranial nerves and $em.A comprehensive oftheanatomy andfunctional performing Thisknowledge theirassociated nuclei isessential for a neurologic examination. aidsthe physician in locating thatproduce nerve deficits. A summary ofthecranial thesiteof lesions cranial nerves andtheirfunctions isfoundonthelastpageofthischapter inTable V-15-2.

OVERVIEW A. The twelve pairs of cranial nerves are listed in ThbleV-13-1 (seealso FiguresV-13-1 and

v-r3-2).

TableV-f 3-f . The trrelve pairs of cranial nerves. Cranial Nerve

Name

Action

I il III

Olfactory Optic Oculomotor

Sensory Sensory Motor Motor

tV

Tiochlear

V VI

Abducens

VII VIII

Facial Vestibulocochlear

IX

Glossopharyngeal

Sensoryand motor

X

Vagus

XI

Accessory

Sensoryand motor Motor

XII

Hypoglossal

Motor

Tiigeminal

Sensoryand motor Motor Sensoryand motor Sensory

41,

Nervous System

lX and X

VI vtl xll Nucleus ambiguus

Cervicalnerves

FigureV-l3-1.Nucleiand fibersof the motorcranialnerves.

Note Inthebrainstem, motornuclei aremedialto sensory nuclei.

414

B. Organization of cranial nerye nuclei in the brain stem. The sulcuslimitans is present in the medulla, pons, and midbrain of the adult brain. As in the spinal cord, this sulcusseparates the alar (sensory)and basal (motor) plates.In the spinal cord, the alar plate is posterior to the basal plate; in the brain stem, the alar plate is posterolateralto the basalplate. The sulcus limitans, which divides the sensoryand motor cranial nerve nuclei, is usefrrlwhen considering the location of these nuclei. For example, in the midpons, the motor nucleus of the trigeminal nerve lies medial to the principal sensorynucleus of the trigeminal. Motor fibers from the cerebralcortex, which supply the motor nuclei of the cranial nerves,are part of the corticobulbar tract. These fibers travel together with those of the corticospinal tract but separatefrom this tract at different brain stem levels.

Nerues Cranial Neuroanatomy:

Mesencephalic nucleusof V

Sensoryrootof V

Trigeminal-', ganglion z2

Principal sensory nucleus ofV

,'.4

Spinaltrigeminal nucleusof V

Sensoryrootof:

Vestibularnuclei

nuclei Cochlear IX X

solitarius Nucleus (inputfromVll, lX, andX)

FigureV-l3-2. Nuclei and fibers of the sensory cranial nerves (except the olfactory and optic nerves).

C. Functional components of the cranial nerves. While only four functional components are presentin the spinal nerves(i.e., generalsomatic afferent,generalsomatic efferent,general visceralafferent,generalvisceralefferent),the cranial nervescontain sevenfunctional comPOnents. l. General somatic afferent (GSA) fibers carry input concerned with exteroceptive(tactile, pain, temperature) and proprioceptive (position) sensation. 2. Special somatic afferent (SSA) fibers carry input for the specialsensesof vision, hearing, and equilibrium. 3. General visceral afferent (GVA) fibers carry sensoryinput from the viscera. 4. Specialvisceralafferent (SVA) fibers ca:ir.yinput for specialsensesof olfaction and taste. 5. General somatic efferent (GSE) fibers carcymotor output to the skeletalmusclesderived from the myotomes. 6. General visceral efferent (GVE) fibers are the preganglionic autonomic fibers that supply smooth muscle, cardiac muscle, and glands.Only cranial nervesIII, VII, IX, and X carry GVE fibers.Theseare all preganglionicparasympatheticfibers.

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NervousSystem

In a Nutshell (Branchial SVE Motor) Fibers . CNV -+ chewing . CNVll+ facial expression . CNlXandCNX + larynx, pharynx . CNXl-+ liftshoulders, turnhead

7. Special visceral efferent (SVE) fibers carry motor output to the skeletalmusclesderived from the branchial arches. a. The trigeminal nerve carries SVE fibers to the musclesderived from the first branchial arch (i.e., musclesof mastication,anterior belly of the digastric,mylohyoid). These SVE fibers arise from the motor trigeminal nucleus. b. The facial nerve carries SVE fibers to the muscles derived from the second branchial arch (i.e., musclesof facial expression,posterior belly of the digastric, stylohyoid). These SVE fibers arise from the facial nucleus. c. The glossopharyngealand vagus nerves carry SVE fibers to the musclesderived from the third and fourth branchial arches(i.e.,musclesof the larynx and pharynx). These SVE fibers arise from the nucleus ambiguus. d. The spinal accessorynerve innervatesthe trapezius muscle (lift shoulders) and the sternocleidomastoidmuscle (turn head).

orFAcToRY (CNr) NERVE Olfactorybulb Internalgranulecell

Lateralolfactorytract

Olfactory glomerulus Fiber of the olfactory nerve

Anteriorolfactory nucleus

Cribriform Lateralolfactorystria Nasal mucousmembrane

Figure V-l3-3.The olfactory nerve. A. Bipolar olfactory cells are specializedneurons that function as the smell receptors. These cells give off two axons. 1. One axon extends peripherally to the olfactory epithelium of the nasal mucosa. This peripheral axon terminatesby dividing into the thin olfactory hairs. 2. Another axon extends centrally, and this unmyelinated axon passesthrough the cribriform plate of the ethmoid bone. The central .xons are called olfactory fila and collectivelv form the olfactory nerve. B. Olfactorybulb is an ovoid structure that lies betweenthe superior surfaceof the cribriform plate and the inferior surfaceof the frontal lobe. It is formed by an evaginationof the primitive telencephalon. C. Olfactorypathways are fibers of the olfactory nerve that synapsein the olfactory bulb. Cells in the olfactory bulb send axons through the olfactory tract to the primary olfactory cortex (i.e-,pyriform cortex,part of the amygdala).The two olfactory bulbs are connectedby fibers passingthrough the anterior commissure.

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Nerues Cranial Neuroanatomy:

(CNll) oPTrcNERVE The visual systemis discussedin greater detail in the Visual Systemchapter. A. Passageof light 1. Light must passthrough the cornea,lens, aqueoushumor, and vitreous humor before reachingthe retina (Figure V-13-4). It must then passthrough six layersof the retina to reach the photoreceptive layer of rods and cones.The retina, an evaginatedportion of the diencephalon, contains sevenlayers of neural elements. 2. Photoreceptorsare cellsthat contain light-sensitivephotopigments and releaseneurotransmitter onto the dendritic processesof bipolar and horizontal cells.In turn, the bipolar cells project to the ganglion cellsof the retina. B. Optic nerve arises from ganglion cells. Axons from these cells converge at the optic disc, where they pierce the wall of the eyeball and form the optic nerve. The nerve enters the cranial cavity through the optic foramen. C. Optic chiasm. The optic nerve enters the cranial cavity through the optic foramen. Shortly after passingthrough the foramen, roughly 50o/oof the fibers in the optic nerve crossto the other side in the optic chiasm. The fibers that decussatein the optic chiasm are from the medial half of the retina. Fibers that do not decussateare from the lateral half of the retina. Visual stimuli from the right visual field fall upon the left half of the retina, and visual stimuli from the left visual fietd fall upon the right half of the retina. The net result is that the left hemisphere receivesvisual input from the right visual field.

tn a Nubhell cells Axons oftheganglion of the retinaformtheoptic nerve, whichthenpasses theopticforamen through oftheskull.

417

Nervous System

Rods and cones

Outer nuclear layer Outer plexiform layer Innernuclear layer

Innerplexiform layer

Ganglioncell layer

Optic nerve R = ro d c=cofle

M = mi dgetbi pol ar F= fl at bi pol ar B=rodbipolar A=amacrine

H = hori zontal Q=ganglion

Figure V-13-4.The neural components of the retina.

ln a Nutshell Pathway of VisualSystem Retina + opticnerve + optic chiasm + optictract+ LCN -> + opticradiations occipital cortex

D. Optic tract consistsof fibers betweenthe optic chiasm and the lateral geniculatebody. Its fibers originate from the ipsilateraltemporal retina and the contralateralnasalretina. Most fibers in this tract terminate in the ipsilaterallateral geniculatebody while others (i.e.,those concernedwith visual reflexes)terminate in the pretectalareaand superior colliculus. E. Optic radiation consistsof fibers that arisefrom cellsin the lateral geniculatebody and terminate in the primary visual cortex in the occipital lobe.

ocuroMoToR (CNtil) NERVE A. Oculomotor nuclei are located near the midline just anterior to the central gray matter of the upper midbrain. 1. Oculomotor nucleus. This paired nucleusis the most lateral of the third nerve nuclei. It givesrise to GSE fibers, which supply all of the extraocular musclesexceptthe superior oblique (which is innervatedby the trochlearnerve) and the lateral rectus(which is innervated by the abducensnerve).The musclessupplied include the: a. Medial rectus b. Superior rectus c. Inferior rectus

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Nerues Cranial Neuroanatomy:

d. Inferior oblique e. Levator palpebrae(lifts eyelids) 2. Edinger-Westphalnucleus. This paired nucleusliesjust medial to the oculomotor nucleus. It contains preganglionic parasympatheticneurons, which give rise to GVE fibers, which terminate on cellsin the ciliary ganglion. From the ciliary ganglion,postganglionic parasympatheticfibers passto the ciliary muscle and the pupillary sphincter muscle of the iris. a. Parasympatheticfibers to the ciliary muscle mediate accommodation,a thickening of the lens,which facilitatesfocusing on nearby objects.

ln a Nutshell nucleus Edinger-Westphal I

V

ganglion Ciliary

r\, / \ Ciliary Pupillary muscle sphincter (constricts pupil) (accomodation)

b. Parasympatheticfibers to the pupillary sphincter muscle of the iris mediatepupillary constriction(miosis). B. Afferent connections l. Corticobulbar fibers from both cerebralhemispheresaswell astectobulbarfibers from the superior colliculus and pretectalareasupply all oculomotor nuclei. 2. The medial longitudinal fasciculus(MLF) connectsthe cranial nerve nuclei that supply the extraocularmuscles(CN III, ry VI) with eachother,permitting conjugateeyemovements. C. Course of the oculomotor nerve. Axons from cells of the oculomotor nucleuspassanteriorly through the red nucleusand leavethe ventral surfaceof the midbrain near the midline. The third nerve entersthe orbit through the superior orbital fissure. D. Lesions of the oculomotor nerye l. Completelesionof the oculomotor nervecausesparalysisof the:

ln a Nutshell

a. Levator palpebrae superioris, which results in drooping of the affected upper eyelid (ptosis)

CNlll Lesion . ftosis

b. Extraocularmusclessuppliedby the third nerve (i.e.,medial rectus,superior rectus,inferior rectus,inferior oblique), which resultsin deviation of the eyelaterally (as a result of the unopposedlateral rectus) and downward (as a result of the unopposedaction of the superior oblique). The lateral deviation of the eyeis calledexternal strabismus.

. Eyelooksdownandout, causing vision double

c. Sphinctermuscleof the iris, which resultsin pupillary dilation (mydriasis)and lossof pupillary constriction (miosis) in responseto light

. Mydriasis . Loss of accommodation

d. Ciliary muscle,which resultsin failure to focuson nearbyobjects(lossof accommodation) 2. Brainstem lesions may involve the oculomotor nuclei or third nerve fibers as they pass through the red nucleusor cerebralpeduncle.Someof the more common causesinclude vasculardisease,multiple sclerosis,and brain stem glioma. 3. Peripheral lesions a. Fibersin the oculomotor nerve are organizedso that parasympatheticfibers lie external to those that supply the extraocularmuscles.Therefore,compressivelesions(e.g., temporal lobe herniation, aneurysms)tend to involve the parasympatheticfibers first, producing mydriasis and loss of the pupillary light reflex before paralysis of the extraocular muscles.In contrast, vascular disease(e.g., in diabetesmellitus) often affectsthe deeperfibers,causingptosis and paralysisof the extraocularmuscleswhile sparing the pupil.

ClinicalCorrelate of CNlll Cross-Section

r---'r--

parasympathetic

Y al)

--\<-J / \.\---l

somatomotor

ofthenerve Compression fir$ + loseparasympathetic (diabetes mellitus) Vascular -+ losesomatic efferents

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Neruous System

b. Common causesof peripheral third nerve lesions include vascular disease,tumor, aneurysm(most often involving the posterior communicating artery), meningealdisease,and orbital disease.Herniation of the medial temporal.lobe under the free edge of tentorium cerebelliis an important causeof third nerve damageand may occur secondaryto a subdural or epidural hematoma causedby head trauma. Immediate medical or surgicalintervention may be required to savethe patient'slife.

TROCHTEAR (CNtV) NERVE A. Tiochlear nuclei are located near the midline in the anterior part of the central gray matter of the lower midbrain. Thesenuclei are located at the level of the inferior colliculi, while the oculomotor nuclei are locatedat the level of the superior colliculus.They supply GSEfibers to the superioroblique muscle. B. Afferent connections are very similar to those of the oculomotor nuclei. Corticobulbar fibers from both hemispheressupply eachnucleus,tectobulbar fibers, and the MLF.

In a Nutshell CNlVistheonlycranial nerve that: . Exits fromthedorsal brainstem . Innervates contralateral STTUCTUTCS

C. Course of the trochlear nerve. Axons from the trochlear nuclei decussatein the superior (anterior) medullary velum after passing around the posterior part of the central gray. The trochlear nerve exits the brain stem near the posterior midline just below the inferior colliculi. It hasa long intracranialcourse,passingthrough the cavernoussinusbeforeenteringthe orbit through the superior orbital fissure.The trochlear nerve is the only cranial nerve that carries fibers arisingin the contralateralnucleusand attachesto the posteriorpart of the brain stem. D. Lesionsof the trochlear nerve produceweakness(or paralysis)of the superior oblique muscle, which causesdiplopia on looking downward and awayfrom the affectedside. Isolated lesionsof the fourth nerve are uncommon. Tiochlear nerve lesionsmay be causedby vascular diseaseand tumors invading the superior medullary velum. Difficulty in walking down stairs is a classiccomplaint of patients affectedby trochlear nerve lesionsbecausethey cannot look downward.

TRTGEM|NAT (CNV) NERVE The trigeminal nerve is the largestof the cranial nerves.It has four paired nuclei and carries both motor and sensory impulses. Peripherally,there is the large trigeminal (semilunar or gasserian)ganglion. From this ganglion, three divisions of the trigeminal nerve (Vl, V2, and V3) emerge. A. Trigeminal nuclei 1. Motor (masticatory) nucleus is located in the lateral pontine tegmentum just medial to the main sensorynucleusof the trigeminal.

420

Nerves Cranial Neuroanatomy:

Ventral trigeminothalamic tract

To VPM thalamus

1

Principal sensory nucleusof V

Mesencephalic nucleusof V

Trigeminal nerve

Dorsal trigeminothalamic tract Motor trigeminal nucleus

Spinal trigeminal

tract

Spinaltrigeminal nucl eus

FigureV-13-5.The trigeminal nuclei. a. Afferents include corticobulbar fibers from both hemispheresand various brain stem structures,including the mesencephalicnucleusof the trigeminal nerve. b. Efferents.This motor nucleusgivesrise to SVE fibers,which passin the mandibular (nerve) branch to supply the: (l) Musclesof mastication (i.e., masseter,temporalis, medial and lateral pterygoid muscles) (2) Tensortympani (3) Mylohyoid (4) Anterior belly of the digastric muscle (5) Tensorveli palatini

2. Main sensory nucleus is locatedjust lateral to the motor nucleus.This nucleus is a rostral continuation of the spinal nucleusof the trigeminal nerve. a. Afferents. The main sensory nucleus receivesthe central axons from cells in the trigeminal ganglion,which conveytactile and pressuresensationfrom the face. b. Efferents. Axons from cellsin the main sensorynucleus crossand ascendin the ventral (anterior) trigeminothalamic tract to terminate in the VPM. 3 . Spinal trigeminal nucleus is a caudal continuation of the main sensorynucleus,extending from the midpons to the cervicalcord.

Note information Allsensory fromthe face-+ VPM information Allsensory fromtherestofthe body+ VPL

a. Afferents. Certain central axons from cellsin the trigeminal ganglion descendin the spinal tract of the trigeminal nerve and synapseon cells in the spinal nucleus.These axons carcyinput concerningpain and temperaturesensationfrom the face.

421

Neruous System

ln a Nutshell . Mainsensory nucleus of V -+ discriminative touch of face . Spinal trigeminal nucleus + pain/temperature offace . Mesencephalic nucleus ofV + proprioception of face

Note Themesencephalic nucleus of CNV istheonlyexample in whichtheprimary sensory cell bodies reside withintheCNS instead of in ganglia.

ln a Nutshell . Ophthalmic (Vt) branch passes through thesuperior orbital fissure oftheskull . Maxillary (V2) branch passes through theforamen rotundum oftheskull . Mandibular (Vl) branch passes through theforamen ovale oftheskull

b. Efferents. Axons from cells of the spinal trigeminal nucleus cross and ascendin the ventral trigeminothalamic tract to terminate in the VpM. 4. Mesencephalicnucleus is locatedalong the lateralborder of the central gray in the upper pons and midbrain. This is the only nucleus in the CNS that receivesproprioceptive inputs from musclespindles.This function is fulfilled by the dorsal root ganglion cellsfor the trunk and extremities. a. Afferents carry proprioceptiveinput from joints, musclesof mastication,extraocular muscles,teeth, and periodontium. b. Efferents pass to the motor nucleus of the trigeminal and the cranial nerve nuclei supplying the extraocularmuscles.Someof thesefibers synapsemonosynapticallyon the motor neurons,forming the anatomic substratefor myotatic reflexessuch as the jaw jerk. c. Trigeminal (semilunar, gasserian) ganglion contains the cell bodies for all afferenrs of the trigeminal nerve exceptfor proprioceptive inputs that are transmitted to the mesencephalicnucleus.This ganglion is located in the middle cranial fossanear the petrousbone. B. Divisions of the trigeminal nerve 1. Ophthdmic division (Vl) is purely sensory.It receivesinput from the upper eyelid, cornea,conjunctiva,frontal sinus,internal nares,and forehead.This nerve exits the cranial cavity through the superior orbital fissure. The ophthalmic division is often infected with the herpeszostervirus, while involvement of the lower two divisions is rare. 2. Maxillary division (V2) is purely sensory.It receivesinput from the lower eyelid, upper cheek,upper lip and gums,palate,and most of the nose.This nerve exitsthe cranial vault through the foramen rotundum. Of the three divisions of the trigeminal nerve,the maxillary division is the most frequently affectedby tic douloureux (trigeminal neuralgia). The mandibular division is alsocommonly affected,while involvementof the ophthalmic division is rare in this painful disorder. 3. Mandibular division (V3) is both motor and sensory.It exits the cranial cavity through the foramen ovale. a. Motor input is describedabove. b. Sensoryinput comesfrom the externalear,lowerlip,lower gums,teeth,chin, and general somatic sensationfrom the anterior two-thirds of the tongue (tastefor the anterior two-thirds is carried by the chorda tympani branch of the facial nerve). C. Lesions of the trigeminal nerve are manifested clinically by sensory, motor, and reflex deficits.Damageto the trigeminal systemmay occur in the brain stem (its nuclei and fibers extend from the medulla to midbrain) or periphery. Common causesinclude vasculardisease,multiple sclerosis(only involvesthe CNS), tumor, cerebellopontineanglelesions(most often an acousticneuroma), tic douloureux, and herpeszosterophthalmicus. 1. Sensory deficits from lesionsof the trigeminal nerve include loss of tactile, proprioceptive, temperature,and pain sensationfrom the face. 2. Motordeficits result from lower motor neuron lesionsinvolving the musclesof mastication. a. Temporalisand masseterinvolvement causesunilateral atrophy and weaknessof jaw closure. b. Pterygoid involvement causesunilateral weaknessof jaw opening. When the patient opensthe jaw, it deviatestoward the side of the lesion.

422

Neuroanatomy: Nerues Cranial

3. Diminished reflexes a. Corneal reflex. Tactile stimulation of the cornea causesblinking of both ipsilateral (direct reflex) and contralateral (consensualreflex) eyelids.The afiferentsfrom the cornea passin the ophthalmic division of the trigeminal nerve to the main sensory nucleusof the trigeminal. Interneuronsin this nucleussend descendingfibers to both facial motor nuclei. The efferent limb is mediated by fibers in the facial nerves,which supply the orbicularis oculi muscles. (1) With a lesion of the left trigeminal nerve,neither eyewill closeif the left cornea is stimulated (absenceof both the direct and consensualreflexes). (2) With a lesion of the left facial nerve,only the right eyewill closeif the left cornea is stimulated (absenceof the direct reflex). b. Jaw jerk reflex is elicited with the mouth slightly open and relaxed. The examiner placesa finger horizontally acrossthe patient's chin and taps lightly with the reflex hammer. Normally a slight contraction may be seen.However,bilateral lesionsof the fifth nerves(which are not common) causea lossof this reflex.Bilaterallesionsof the corticobulbar fibers supplying the motor nucleusof the trigeminal (as in pseudobulbar palsy) causehlryeractivity of this reflex.

ln a Nutshell Lesions of CNV . Sensory deficits oftheface . Lossof corneal reflex (afferent limb) . Lossof jawjerkreflex (afferent limb) andefferent . Flaccid paralysis ofthe muscles of mastication . Deviation ofthejawto the sideofthelesion . Trigeminal neuralgia

(CNVr) ABDUCENS NERVE A. Abducens nucleus. This paired motor nucleusis located in the lower pons, ventral to the floor of the fourth ventricle near the midline. It supplies GSEfibers to the lateral rectus muscle. B. Afferent connections arevery similar to those of the oculomotor and trochlearnuclei. Input to eachabducensnucleuscomesfrom both cerebralhemispheres(corticobulbar fibers), the tectum, and the MLF. C. Course of the abducens nerve. Axons from the abducensnucleus passventrally through the tegmentum and basalportion of the pons, exiting the pons near its border with the medulla closeto the anterior midline. It ascendsalong the ventral surfaceof the brain stem and bends around the tip of the petrousbone to enter the cavernoussinus.The sixth nerve enters the orbit through the superior orbital fissure.

In a Nutshell Except fortheopticnerve, that every cranial nerve innervates theeye[CNlll,lV, the V 0l), Vllpasses through fissure. The superior orbital goes through the opticnerve opticforamen.

D. Lesions of the abducensnerve produce paralysisof the lateral rectus muscle (lateral rectus palsy),which causesmedial deviation of the affectedeye (as a result of unopposedaction of eyeto relievethe diplopthe medial rectus) and diplopia. The patient may closethe afiflected ia. Lesionsof the abducensnucleus causelateral gazeparalysis,and both eyesare forcefully directed awayfrom the side of the lesion.Both eyesare affectedbecausethe abducensnucleus containsneuronsthat project to the contralateraloculomotor nucleusvia the medial longitudinal fasciculus. 1. Abducens nerve or nucleus lesions may be causedby vasculardisease,multiple sclerosis, and brain stem gliomas. 2. Peripheral lesions a. Increasedintracranial pressureof any cause(e.g.,hydrocephalus)may affect one or both abducensnerves.Sincethe actual lesion may be far awayfrom the nerve,this is calleda falselocalizing sign. b. Direct involvement of the peripheral nerve may result from vascular disease, meningealdisease,tumor,lesions of the tip of petrousbone (e.g.,middle ear infection, mastoiditis) or cavernoussinus,aneurysm,or orbital disease.

ln a Nutshell Lesion of CNVl . Medial with strabismus theeye inability to abduct . Horizontal (double diplopia vision)

42',

Neruous System

(CNVil) FACTAT NERVE The seventhnerve has two motor nuclei and a sensorynucleus.One motor nucleus supplies SVE fibers to the musclesof facial expressionand the stapediusmuscle,while the other sends preganglionicparasympathetic(GVE) fibersto the pterygopalatineand submandibularganglia. The sensorypart of the facial nerve carriestastefrom the anterior two-thirds of the tongue and cutaneoussensationfrom the back of the ear and externalauditorv meatus. A. Facial nerve nuclei

Note Theupperfacereceives bilateral innervation; thelower facereceives contralateral innervation.

1. Main motor nucleus in a transversesection of the facial nucleus is located in the lateral reticular formation of the caudalpons, just abovethe superior olive. a. Afferents. Corticobulbar fibers from the motor cortex of the cerebralhemispheresto the main nucleus of CN VII are crossedfor the lower half of the face.The motor neurons concernedwith the upper facereceivecorticobulbar fibers from both hemispheres. b. Efferents. Motor fibers (lower motor neurons) to the muscles of facial expression include the: (1) Platysma (2) Stapedius (3) Orbicularis oculi (4) Orbicularis oris (5) Occipitalis (6) Auricular (7) Frontalis (8) Zygomaticus (9) Buccinator (10) Stylohyoid ( I 1) Posteriorbelly of the digastric

ln a Nutshell Superior salivatory nucleus ./\ /\ fterygopalatine Submandibular ganglion ganglion

ll

VV

glandsSubmandibular Lacrimal and sublingual salivary glands

2. Superior salivatory nucleus is located posterolateralto the motor nucleus of CN VII. Two groups of axonsleavethis nucleusand travel togetherfor a short distancein the intermediate nerve.One group of fibers entersthe superficialpetrosalnerve and terminatesin the pterygopalatineganglion, while the other group travelsin the chorda tympani nerve to reachthe submandibular ganglion. a. Pterygopalatine ganglion. Postganglionic parasympathetic fibers from this ganglion supply the lacrimal gland overlying the eye as well as the palatine and nasal glands of the mouth and nose. b. Submandibular ganglion. Postganglionic parasympathetic fibers from this ganglion are secretoryefferentsto the submandibular and sublingual salivaryglands. 3. Gustatory nucleus. The rostral portion of the nucleusof the solitary tract receivesall of the SVA fibers for taste, which pass in the seventh,ninth, and tenth cranial nerves. The facial nerve supplies the taste buds on the anterior two-thirds of the tongue, the glossopharyngealnerve carries taste input from the posterior third of the tongue, and the vagus nerve from the epiglottis (thesetaste buds are only present during infancy). The taste afferentsin the facial nerve arise from cells in the geniculateganglion. Peripheral fibers reach the anterior two-thirds of the tongue by passingthrough the intermediate,

424

Neuroanatomy: Cranial Nerues

chorda tympani, and lingula nerves.Central fibers travel in the tractus solitariusto reach the nucleussolitarius. 4. Trigeminal main sensory nucleus. The facial nerve also carries some cutaneoussensation from the back of the ear and the external auditory meatus.Thesefibers travel in the intermediate nerve to the brain stem, where they ascendwith the trigeminothalamic tract. B. Course of the facial nerye. Fibers from the main motor nucleus take a circuitous route in the brain stem before they exit laterally at the border of the pons and medulla. 1. These axons initially project toward the medial border of the abducensnucleus,where they turn sharply and loop around this nucleus.This loop is called the internal genu of the facial nerve.Thesefibers then passventrally and laterally,joining the other fibers of the facial nerve,which take a more direct route through the brain stem. a. The seventh and eighth cranial nerves passthrough the internal auditory meatus to enter the middle ear. b. The motor portion of the facial nerve (but not the chorda tympani, which carries tastesensationfrom the anterior two-thirds of the tongue) then entersthe facial canal and leavesthe skull through the srylomastoid foramen. 2. The facial nerve entersthe parenchymaof the parotid gland, where it divides into its terminal branches. C. Lesions of the facial nerve l. Lower motor neuron lesions,which interrupt fibers in the facial nerve,result in paralysis of the musclesof facial expressionon the side of the lesion. Musclesin the upper and lower faceare affectedequally.Lossof tastein the anterior two-thirds of the tongue suggeststhat the lesion is proximal to the stylomastoidforamen since the chorda tympani joins the facial nerve in the middle ear. 2. Bell palsy is a common neurologicdisorder characterizedbyan acuteseventhnervepalsy, which is painlessand is not accompaniedby any deficit in cutaneoussensation.Most patients make a completerecoverywithin a month. 3. Upper motor neuron lesions that interrupt the corticobulbar fibers to the motor nucleus of the facial nerve result in paralysisof the contralaterallower half of the face only. Lower motor neurons in this nucleusthat supply the upper half of the facereceivecorticobulbar fibers from both hemispheres,while those that supply the lower half of the face receivecorticobulbar fibers from the contralateralhemisphereonly.

(CNVlll) NERVE vEsTrBUrococHrEAR

ln a Nutshell Lesions of CNVll . Flaccid paralysis of muscle (upper offacial expression andlowerface) . Loss reflex of corneal (efferent limb) . Hyperacusis (dueto paralysis) stapedius muscle . Loss fromanterior of taste 213oftongue

ln a Nutshell . UMNlesions result in weakness of contralateral lowerfaceonly. . LMNlesions in result paralysis ipsilateral ofthe face. andlower upper

This nerve consistsof two parts: the vestibular nerve and the cochlearnerve. The specialend organs for the vestibular (cristae ampullaris and maculae) and the cochlear (organ of Corti) portions of the nervelie in the inner ear deepin the temporal bone. They are suspendedin perilymph, a fluid that is similar to CSF.The semicircularcanalsand scalamedia of the cochleaare filled with endolymph, a fluid with a high-protein content. A. Vestibular nerve carriessensoryinput from the cristaeampullaris of the semicircularcanals and the maculaeof the utricle and saccule.The soma of thesesensoryneurons are locatedin the vestibularganglion. 1. Sensoryendorgans a. The semicircular canals are three tubes located in each inner ear and oriented at 90' to each other. The ampulla is the dilated terminal portion of the canal,located near

425

Nervous System

ln a NuBhell . Thesemicircular canals gular detect an acceleration. . Theutricle andsaccule gravity detect andlinear acceleration.

ilote ganglion Thevestibular contains thecellbodies ofthe neurons thatreceive information fromthe ve$ibular sensory haircells, andsendinformation to the vestibular nuclei.

Note Haircellsintheorgan of Corti areinnervated byCNVlll, whose cellbodies reside inthe ganglion. spiral

the junction with the utricle. The sensorycells,with their hairs coveredby a gelatinous mass called the cupula, are in the ampulla. The crest containing the sensory cells is calledthe cristae ampullaris. The semicircularcanalsdetectmovementsassociatedwith angular accelerationand deceleration. b. The utricle and saccule are oriented perpendicular to each other. Both have a region called the maculae, which contains the sensoryepithelium. The hairs of thesesensory cells are coveredby a gelatinoussubstance(otolithic membrane) containing calcium carbonatecrystals(otoconia).The utricle and sacculesensechangesin the position of the head in space. 2. Vestibular ganglion is locatedin the inner ear and containsbipolar neurons.The peripheral axonssupply the sensoryepithelium of the cristaeampullaris and maculae,while the central axons form the vestibular nerve. Almost all these fibers terminate in the vestibular nuclei, but a small group passto the flocculonodular lobe of the cerebellum. B. Cochlear nerve 1. Organ of Corti is the sensoryend organ. Pressurewavestransmitted through the perilymph displacethe basilar membrane,causinga shearingeffect in the hairs of the receptor cells,which are embeddedin the tectorial membrane.This generatesaction potentials in the cochlearnerve. 2. Spiral ganglion containsbipolar sensorycellsthat sendshort peripheral axonsto the hair cells of the organ of Corti and long central axons,which form the cochlearnerve.These terminate in the dorsal and ventral cochlearnuclei. The cochlearnerve carries afferents for the specialsenseof hearing. 3. Cochlear nuclei (i.e.,ventral cochlearnucleus,dorsal cochlearnucleus)are locatedlateral to the inferior cerebellarpeduncle at the junction of the pons and medulla. Both the fibers in the cochlearnerve and the cellsin the cochlearnuclei are tonotopically organized (i.e., different frequenciesare carried and sent to distinct locations).

(CNrX) GToSSoPHARYNGEAT NERVE A. Glossopharyngeal nuclei 1. SVE fibers arise from the rostral nucleus ambiguus and supply the srylopharyngeus muscle. 2. GVA fibers supply the baroreceptorsin the carotid sinus; the fibers terminate on cells in the caudal part of the nucleus solitarius.Changesin blood pressurein the carotid sinus are detectedby thesebaroreceptors.An increasein blood pressureleadsto an increased rate of firing in theseafferents,resulting in a reflex decreasein blood pressureand heart rate.A reduction of blood pressurein the carotid sinusleadsto the oppositeeffects.(The vagusnervecarriesinput from baroreceptorsin the aortic arch,which havea similar function to those in the carotid sinus.) 3. SVA fibers carrying taste sensationfrom the posterior one-third of the tongue travel to the glossopharyngealnerve and terminate in the rostral portion of the nucleussolitarius (gustatorynucleus). 4. GSA fibers supply: a. The skin behind the ear. These fibers enter the spinal tract of the trigeminal (after passingthrough CN IX) and terminate in the spinal trigeminal nucleusof CN V.

426

Neuroanatomy: CranialNerves

b. The posterior one-third of the tongue, eustachiantube, and posterior part of the upper pharynx. These fibers terminate in the caudal part of the spinal trigeminal nucleus. Fibers supplying the posterior tongue and pharynx carry the sensorylimb of the gag reflex. The motor limb of this reflex is carried by fibers from the nucleus ambiguus, which exit via the vagus nerve. A lesion of the glossopharyngealnerve results in an ipsilateral loss of the gag reflex.

ln a Nubhell GagReflex . UpCNlX(unilateral) . DownCNX (bilateral)

B. Course of the glossopharyngeal nerve. The glossopharFngealnerye emergesfrom the rostral medulla at the posterolateralsulcus.It leavesthe cranial cavlty through the jugular foramen.

(CNX) VAGUS NERVE A. Vagus nerve nuclei 1. Main motor nucleus (the vagal part of the nucleus ambiguus). The nucleus ambiguus is located in the anterior portion of the reticular formation and extends throughout the medulla. a. The rostral portion of this nucleus sendsmotor fibers through the glossopharyngeal nerve to supply the stylopharyngeusmuscle. b. The middle portion of the nucleus ambiguus sends motor fibers through the vagus nerve to supply the musclesof the larynx and pharynx. c. The caudal portion of the nucleus ambiguus sendsmotor fibers in the cranial part of the spinal accessorynerve (CN XI) that later join the vagus nerve and supply intrinsic laryngeal muscles. 2. Dorsal motor nucleus is located anterior to the floor of the fourth ventricle and ventral to the sulcus limitans. Cells of this nucleus give rise to preganglionic parasympathetic fibers, which are distributed widely to postganglionic neurons supplying the visceraof the thorax and abdomen. 3. Sensoryfibers a. GVA fibers supply the larFnx, pharynx, trachea,esophagus,baroreceptorsin the aortic arch, and the viscera of the abdomen and thorax. Thesefibers terminate in the caudal part of the nucleus solitarius. b. SVA fibers supply taste buds around the epiglottis. These fibers terminate in the rostral part of the nucleus solitarius.

ln a Nubhell from Baroreceptor information upCN theaorticarchtravels information X;baroreceptor fromthecarotid sinustravels

upcNlx.

c. GSAfibers supply the posterior part of the externalauditory meatusand the skin behind the ear.Thesefibers travel in the vagus and terminate in the spinal trigeminal nucleus. B. Course of the vagus nerve. The vagus nerve emergesas 8-10 rootlets at the postolivary sulcus of the medulla just caudal to the glossopharyngealnerve. These rootlets come together to form a single nerve just before the superior ganglion. The vagus nerve leavesthe cranial cavity through the jugular foramen. C. ksions of thevagus nerve causesignsand symptomsasa result of interruption of motor fibers. 1. Weakness(or paralysis) of the palate (and loss of gagreflex) ipsilaterally may occur, producing nasalspeechand possiblynasalregurgitation of food.

427

Neruous System

In a Nutshell Lesions of CNX . lpsilateral weaknes ofthesoft palate, pharynx, andlarynx, leading to dfficulties with talking andsunllowing; ifthe lesion isbilateral, complete paralysis laryngeal mayoccur, whichcanbefatal. . Lossof gagreflex (efferent limb) . Parasympathetic disturbances ln a Nubhell Lesions of CNXl . Paralpis ofthe $ernocleidoma$oid muscle, resulting indifficulty in turning thehead tothe contralateral side . Paralysis ofthetrapezius muscle, resulting in shoulder droop

2. Weakness(or paralysis) of the ipsilateral vocal cord may occur, resulting from selective involvement of the recurrent laryngeal nerve, a branch of the vagus,which supplies all of the laryngeal musclesexcept the cricothyroid. The cricothyroid is supplied by the superior laryngeal nerve, which is another branch of the vagus. Unilateral vocal cord paralysis leadsto hoarsenessand diminished volume of the voice. 3. Bilateral lesions of the vagus nerve lead to paralysisof the pharynx and larynx. This causes death as a result of asphyxiation.

(CNXr) sPrNArACCESSORY NERVE The spinal accessorynerve consistsof two distinct parts. A. The cranial root fibers originate from the caudal nucleus ambiguus and supply the intrinsic musclesof the larFnx. Thesecranial fibers begin as part of CN XI, join the vagusnerve, and finally reach the intrinsic laryngeal musclesthrough the recurrent laryngeal nerve. B. The spinal root fibers originate from cellsin the spinal accessorynucleus(found in the anterior gray horn in the rostral five cervicalsegments).Theseaxonspassthrough the foramen magnum to enter the cranial cavity and join the fibers of the cranial root to exit the cranial cavity through the jugular foramen.Thesefibers soon separatefrom thoseof the cranial root and supply the sternocleidomastoid muscle and upper trapezius muscle.

(CNXil) HYPOGTOSSAT NERVE Hypoglossalnerve is a motor nerve that innervatesthe intrinsic musclesof the tongue as well as the genioglossus,hyoglossus,and styloglossusmuscles. A. Hlpoglossal nucleus is located near the midline below the floor of the fourth ventricle in the caudalmedulla.This motor nucleussuppliesGSEfibersto the musclesmentioned above. B. Course of the hnroglossal nerve. The hypoglossalnerve emergesfrom the preolivary sulcus of the medulla as a number of rootlets. It exits the cranial cavity through the hypoglossal canal in the occipital bone. C. Lesions of the hlpoglossal nerve

In a Nutshell Lesions of CNXll . lpsilateral paralysis of the tongue . Deviation ofthetongue toward theweakside

428

1. Lower motor neuron lesions produce unilateral tongue weaknesswith fasciculationsand atrophy.The fasciculationsare only pathologic if presentwhen the tongue is at rest in the mouth floor. When askedto protrude the tongue,the intact genioglossusmusclepulls the baseof the tongue forward, causingthe tongue to deviatetowards the side of the lesion. 2. Upper motor neuron lesions, involving corticobulbar fibers that supply the hypoglossal nucleus,produceweaknessor paralysiswithout atrophy or fasciculations.Most of the corticobulbar fibers arise in the contralateralhemisphere,and an upper motor nerve lesion causesweaknessof the contralateraltongue muscles.If, for example,the lesion is in the left internal capsule,there is weaknessof the right tongue muscles,causinga deviation of the tongue towardsthe right side upon protrusion.

l{euroanatomy: Nerves Cranial

Thble V-13-2. Cranial nerye branches and funaions. Nerve

Branches

Functions

CN I (olfactory)

Specialsensory(smell)

CN II (optic)

Specialsensory(vision)

CN III (oculomotor)

Superior division Inferior division

CN IV (trochlear)

Voluntary motor Voluntary motor Parasympathetic Voluntary motor

CN Vl (ophthalmic)

Frontal Lacrimal Nasociliary

Generalsensory

CN V2 (maxillary)

Infraorbital Zygomatic Posterior superior alveolar Greaterand lesserpalatine Nasopalatine Pharyngeal

Generalsensory

CN V3 (mandibular)

Voluntarv motor Muscular branches: to musclesof mastication, tensor tympani, tensor veli palatini Mylohyoid nerve Voluntary motor Inferior alveolar (long) buccal Generalsensory Auriculotemporal

CNVI (abducens) CN VII (facial)

Voluntary motor Motor root Greater (superficial) petrosal nerve Chorda tympani

Voluntary motor Parasympathetic Parasympathetic Specialsense(taste)

CN VIII (auditory, vestibulocochlear)

Specialsense(hearing, equilibrium)

CN IX (glossopharyngeal)

Voluntary motor Generalsensory Specialsense(taste) Tympanic nerve Lesserpetrosalnerve Nervesto carotid sinus and carotid bodv

CN X (vagus)

General sensory, parasympathetic Parasympathetic General visceral afferent

CN XI (spinal accessory)

Parasympathetic Voluntary motor Generalsensory Specialsense(taste) Generalsensory Voluntary motor Generalsensory Voluntary motor Voluntary motor

CN XII (hypoglossal)

Voluntarv motor

Internal laryngeal nerve External laryngeal nerve Recurrent laryngeal nerve

429

Lesions of theBrainStem andCranialNerves boththecorticospinal tractandnearby Inmanypartsofthebrainstem, a lesion mayinvolve cranial (CNS). Involvement nerve fibers astheyexitfromthecentral nervous system of thecorticospinal in hemiparesis tractabove thepyramidal decussation inthelowermedulla results ofthe of cranial nerve fibers contralateral arm,trunk, andlegbutdoesnotaffect theface.lnvolvement paresis produce involvement supplied. Thus, thecontralateral ofthe anipsilateral ofthosemuscles involvement ofthefacial muscles isreferred to arm,trunk, andlegmuscles together withipsilateral hemiplegia theresult of a brainstemlesion. asanalternating andisusually

MEDUttA A. Medial medullary syndrome is most frequently due to occlusion of the vertebral artery the anterior spinal artery,or one of their branches. 1. Corticospinal tract lesions produce contralateralhemiparesisof the arm, trunk, and leg (upper motor neuron lesions). 2. Medial lemniscus lesions produce a contralateral deficit of proprioceptive and tactile sensation.As with corticospinal tract lesions,theselesionsinvolve the body but sparethe face. 3. Lesions of the hnroglossal nerve exiting the medulla or the hypoglossalnucleus produce an ipsilateralparalysisof half the tongue that progressesto muscle atrophy (lower motor neuron lesion). B. Lateral medullary syndrome is usually due to occlusion of the posterior inferior cerebellar artery (a branch of the vertebral). This primarily affectsthe dorsolateral part of the rostral medulla. However,this syndrome may be due to occlusion of the vertebral artery or one of the lateral medullary arteries.Structuresaffectedand the resulting symptoms are describedbelow. 1. Spinothalamic tract lesions produce a pain and temperaturesensationdeficit to the contralateral body half.

ln a Nubhell MedialMedullary Syndrome . Contralateral spastic hemiparesis (corticospinal tract) . Contralateral lossof proprioception, and touch, vibration in body sensation (medial lemniscus) . lpsilateral paralysis of the (hypoglossal nerve tongue or nucleus)

2. Iesions of the vestibular nuclei and pathways produce nystagmus,diplopia, vertigo, nausea,and vomiting. 3. Lesions of the glossopharyngeal and vagus nerves exiting the medulla produce ipsilateral dysphagia(difficulty in swallowing), hoarseness,and diminished or absentgag reflex. 4. Lesions of descending sympathetic fibers produce an ipsilateral Horner syndrome (i.e., miosis,pseudoptosis,anhidrosis).

4rl

Nervous System

L1:-!J!lt:fl Laionsin thelateralmedulla produce painand contralateral

-*' ;li'l;iliJ,li;:il #

r^-^^-^....^

l^--

:- rL^

L^.l.

temDerature lossintheface.

5. Iesions ofthe spinaltract and nudeus of the trigeminal nerneproducean ipsilateralsensory deficit of half the face.Pain or paresthesia(sensationsuchasnumbnes or buming without anystimulus)mayoccuron the ipsilateralhalf of the faceaswell aslossof comeal reflex(sensorylirnb CN V motor limb CN VII).

produces'lh and Y#[f#H.trfJfr: ;ffi'L'fil;l5;:ffS:H1trI PONS A. Iesions of the basalpons 1. C,orticospinaltract lesionsproducea contralateralhemiparesisof the arm and leg. 2. Lesionsofthe abducensnerve exiting the caudalponsproducean intemal strabismusof the ipsilateral eye (ftom paralysisof the lateral rectus). This results in diplopia on attemptedlateralgazeto the affectedside3. Lrsions of the facial nerve eriting the caudalpons produce an ipsilaterallower motor neuron lesionthat involvesthe musclesof facialerqxession,Facialnervelesionsproduce Bell palsSand the facial musclesareparalyzed.

Eddge to PdrologY uc.uson oTrneDarame.tan branches ofthebasilarartery produces a medialpontine syndrome.

B. ksions of the medial pons areusuallydueto occlusionof a paramedianbranchof the basilar artery' 1. Corticospind tract lesionsproducea contralateralhemiparesisof the arm and leg. 2. Corticobulbar tract lesions producea contralateralhemiparesisof the musclesof facial expressionthat is more severein the lower face' 3. Medial lemaiscus lesions produce a contralateraldeficit of tactile and proprioceptive sensationthat involveshalf of the body. 4. Lesionsof the aMucens nucleus producelateral gazeparalysisin which both eyesare forcefully directedto the sidecontralateralto tlte lesion.

.'ffiil#;fl'tr[:fJ:ilffi

:'J,."i.fi f ;Ht',"rrthe-anteriorinreriorcere

1. Spinothalamictract lesions producea deficit of pain and temperaturesensationinvolving the contralateralbody. 2. Iesions of the vestibular nuclei and pathways(caudalpons) producerryntagmus, vertigo,nausea,andvomiting. 3. Lesionsofthe coclrler nucleusor auditorynerve (caudalpons)produceunilateraltinnitus and deafiress.

(i'e" nbers produce anips'aterar Horner svndrome

1!!-d*_!g-lg!!-o!9_ry

" *::ffJff;frf,

Occlusion of anteriorinferior cerebellar arterVOrSUOeriOr Cerebellar arterycanleadto pontinelesions. donolateral

5. ksions of the spinal tract and nucleusof CNV (caudalpons) produceirnpairedipsilar eral facialsensation.

4t2

ffif*f"

6. fusions of the facial nucleusand associated structuresproduceipsilateralfacialparalysis, lossof tasteftom tle anterior two-thirds of the tongue,lossof lacrimation and salivation, and lossof the cornealreflex.

Neuroanatomy: lesionsof theBrainStemandCranialNerves

D. Pontocerebellaranglesyndrome is usuallydue to an acousticneurorna of CN VIIL This is a slow-growingtumor, which originatesftom Schwanncells in the vestibularnerve (less commonly the auditory nerve).As the tumor grows,it exertspressureon the lateralpart of the caudalponswhereCN VIII emerges,that is,the pontocerebellarangle.Other lesionstlnt occur near this site and should be consideredin the differential diagnosisinclude meningiomas,neuromasof CN V CN VII, or CN IX, aneurysmsof the basilarartery and metastases.Structuresaffectedand the resultingsymptomsaredescribedbelow 1. Vestibulocodrlearnerve lesionsproducetinnitus, hearingloss,unsteadiness and los of balance,vertigo,and lossof normal vestibularreflexes. 2. Trigeninal nervelesionsproducefacialpain,ipsilateralsensorydeficit of ha.lfthe fuce,and lossof the comealreflercipsilaterally. 3. Facial nerve lesions produceipsilateral facial weakness(usually late). 4. Iesions of the inferior and middle cerebellarpedunclescausefailure to producewellcoordinatedvoluntary movements(ataxia)predorninandyin the ipsilateralentremities. E. Parinaud syndrorne,a lesionof tlre superior colliculi, usuallyoccursasa result of a pineal tumor. The mostcommonsignis paralysisof upwardgaze,but an impaireddowo*,"rd g"r., pupillary abnormalities(e.g.,slighdy dilated pupils, which may show an impaired light or accommodationreaction),and signsof elevatedintracranial pressureare also seen.Pineal tumors usuallyoccurbeforeage30.Compressionofthe cerebralaqueductcanresultin noncommunicatinghydrocephalus.

h a t{ubhell ParinaudSyndrome ' lmpaired verticalgaze . puoillarvdisturbances ' Elevated intracranial pressure . Ndroceohalus

qrt

Reticular Formation lt islocated inthecentral Thereticular formation isphylogenetically anoldportion ofthebrain. Thereticular formation iscomposed of brainstemandextends fromthemedulla to thalamus. groups groups in of fibers. Discrete of diffuse of different sized cellsenmesheda complex tangle partofthereticular formation. cells, suchasthecranial nervenuclei, arenotconsidered nervous system, Thereticular formation hasconnections withalmost allotherpartsofthecentral thalamus, limbic including thespinal cord,cranial nerve nuclei, cerebellum, hypothalamus, striatum, formation iswell-designed to coordinate and system, andcerebral cortex. Thus, thereticular partsoftheCNS. roleintheregulation integrate theactions of different lt plays animportant of impulses, respiration, cardiovascular muscle andreflex activity, central transmission of sensory responses, behavioral arousal, andsleep.

ORGANIZATION A. Mediolateral differentiation. The medial two-thirds of the reticular formation is the effector portion. It containsboth large and small cellsand is the sourceof almost all long ascending and descendingprojections. The lateral third of the reticular formation contains only small cellsand influencesthe activity of the medial portion. In both regions,there is a great deal of dendritic overlap.Collaterals originating from different afferent systemsoverlap considerably. B. Rostral caudal differentiation. There appearsto be a segmental organization. Dendrites of reticular formation cells are oriented in a transverseplane, as are collaterals that enter the reticular formation. Certain horizontal (transverse)segmentsreceiverelatively discreteinput and may project to only certain portions of the CNS.

CONNECTIONS A. Efferent connections are long ascending and descending projections that arise from the medial two-thirds of the reticular formation. 1. Reticulospinal fibers terminate on cellsin laminae VI-UII and, to a small extent, in lamina IX of the spinal cord. These fibers influence both alpha and gamma motoneurons. Different parts of the reticular formation may inhibit or facilitate the activity of alpha motoneurons. Some reticular neurons project to cells throughout the spinal cord, suggesting that the reticular formation may help coordinate the activities of different spinal cord levels.

ln a Nubhell Reticulospinal fibersregulate theactivlty of o andy motoneurons inthespinal cord.

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2. Longascending fibers passto the nonspecificthalamic nuclei, hypothalamus,limbic system structures,striatum, and cerebralcortex. 3. Reticular formation cells project to other brain stem areas.Reticularformation efferents influence all sensoryand motor cranial nerve nuclei. Some reticular formation cellssend long axons in both a rostral and caudal direction, suggestinga role of the reticular formation in coordinating activitiesat different levelsof the CNS. B. Afferent connections 1. Direct spinoreticularfibers are numerous. 2. Secondarysensoryfibers reachthe reticular formation from the ascendingsensorytracts of the spinal cord (i.e., medial lemniscus,spinothalamictract, spinocerebellartracts), the vestibularand cochlearnuclei, optic reflex centers(e.g.,superior colliculus), and olfactory structures. 3. Other important afiferentsto the reticular formation arisefrom the cerebellum,hypothalamus, globus pallidus, substantianigra, and cerebralcortex.

NUCTEI OFTHERETICUTAR FORMATION By definition, the reticular formation consistsof diffuse cell groups that do not possesssufficient organizationto be classifiedas nuclei. However,there are some important exceptions.

ln a Nutshell Theraphe nuclei contain serotonergic neurons with projections widespread inthe Theyplaya rolein CNS. mood, aggression, andthe induction ofnon-REM sleep. ln a Nutshell Thelocus coeruleus contains norepinephrine neurons and projections sends to most brain areas. Noradrenergic mechanisms areimportant in arousal andintheregulation of REM sleep. ln a Nutshell ThePACcontains opioid receptors andmaybeinvolved intheperception of pain.

4T6

A. The raphe nuclei are a narrow column of cellsin the midline of the brain stem, extending from the medulla to the midbrain. Cells in some of the raphe nuclei (e.g.,the dorsal raphe nucleus) synthesize serotonin (5-hydroxytryptamine, 5-HT) from r-tryptophan. Serotoninergic efferents ascend to several mesencephalic,hypothalamic, and thalamic nuclei. Thesefibers also supply the cerebellum,limbic system,striatum (caudateand putamen), and cerebralcortex. Descending5-HT fibers passto cranial nerve nuclei, medullary and pontine reticular formation, and the spinal cord. It hasbeen proposedthat serotoninergic fibers are responsiblefor the induction of non-REM sleep. B. Locus coeruleus.This pigmented nucleus lies just lateral to the floor of the rostral part of the fourth ventricle. Cells in this nucleus synthesizenorepinephrine and send ascending fibers to the entire cerebral cortex, limbic structures, and thalamic hypothalamic nuclei. Norepinephrine fibers also suppiy the cerebellum,reticular formation, and spinal cord. The locus coeruleusis thought to play an important role in REM (paradoxic) sleepand control of cortical activation. C. Periaqueductal gray (PAG). This is a region of denselypacked neurons surrounding the cerebralaqueductin the midbrain. It has connectionswith parts of the reticular formation, hypothalamus,thalamus, limbic system,and spinal cord. Opioid receptorsare present on many PAG ceilsand suggesta possiblerole of the PAGin pain control. However,the endogenous opiatesalsobind to other cellsin the brain and spinal cord. D. Paramedian pontine reticular formation (PPRF). This arealies closeto the abducensnucleus and mediatesconjugategazeto the ipsilateral side.It has connectionswith the oculomotor, trochlear, and abducensnuclei, as well as with the pretectal area,vestibular nuclei, and cerebellum.

Neuroanatomy: Reticular Formation

FUNCTIONS FORMATION OFTHERETICUTAR A. Control of muscle tone and myotatic reflexes. Electrical stimulation of the reticular formation may either inhibit or facilitatereflexesand muscletone, dependingon which portion of the reticular formation is stimulated. B. Central transmission of sensory impulses are influenced by the reticular formation through reticulospinal fibers and those fibers supplying the sensory cranial nerve nuclei. C. Respiration (rhythmic breathing and respiratory reflexes) is largely under the control of the reticular formation. Stimulation of widespread parts of the reticular formation affects respiration. There may be an "inspiratory center" located in the medulla and an "expiratory center"locatedlateral and rostral to the inspiratory region, extendinginto the pons. D. Cardiovascular functions are in part controlled by the reticular formation. Theseeffectsare complex and involve both the heart and peripheral vasculature.The nucleus of the solitary tract, which receivesafferentsfrom baroreceptorsin the aortic arch and carotid sinus,sends efferentsto cells of the reticular formation concerned with cardiovascularresponse. E. Ascendingreticularactivation system (ARAS).In humans and other mammals,there is a consistentrelationship betweenthe stateof consciousnessand the electroencephalogram(EEG). 1. The earlieststageof quiescentsleepis accompaniedby synchronizedEEG spindle activity, oscillating at a frequency of 7-l4hertz (Hz). At deeper stagesof sleep,EEG activity slowsto a frequenryof 0.54H2. 2. As the organism is aroused into an attentive, alert state,the EEG changesto wavesof greater frequency and lower voltage, which is referred to as EEG desynchronization or arousal.The arousalresponseis mediatedby the ARAS, which is in large part contained in the reticular formation. 3. Brain stem lesionsinvolving the reticular formation may produce coma. Similarly, experimental transection of the midbrain causesanimals to passinto a state of behavioral somnolence and EEG synchronization.

ln a Nubhell Lesions involving theARAS canproduce stupor andcoma.

4. Electrical stimulation of certain parts of the reticular formation or nonspecific thalamic nuclei (intralaminar and midline nuclei) producesbehavioral arousal.However,simulation of certain portions of the reticular formation may causeEEG synchronizationand sleep. 5. The precise pathway of the ARAS has not been elucidated. It appears to involve fibers ascendingfrom the reticular formation to the intralaminar and midline nuclei of the thalamus. From thesenuclei, fibers may travel directly to the cerebralcortex. Ascending nonadrenergicfibers to the cerebralcortex may mediatepart of the arousalresponse. F. Sleep 1. There are two principal phasesof sleep:non-REM and REM. a. There are four stagesof non-REM sleep.As one passesfrom light (stage1) to deep (stage4) sleep,the EEG activity becomesmore synchronized. b. During REM (paradoxic) sleep,the EEG shows faster activity that is irregular (desynchronized) and closelyresemblesthe EEG of a normal alert subject.REM sleepderives its name from the rapid eyemovementsthat are observed.There is a significant reduction in skeletalmuscle tone during REM sleep.Individuals who are awakenedduring REM remember dreaming while those awakenedfrom non-REM sleepdo not. c. During a night of sleep,an individual passesthrough about 4-7 qcles of non-REM followed by REM. The percentageof time spent in REM sleepincreasestowards morning. Rougily 25o/oof total sleeptime is REM.

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Bridgeto Behavioral Sciences Sleep andsleep disorders are alsoreviewed intheBehavioral section Sciences ofCeneral Principles Book z $olumell).

2. Neural basis of sleep stages.Most serotonin-secretingneurons in the raphe nuclei are maximally active during waking and display reduced activity during REM sleep. Monoaminergic cells in the locus coeruleusdemonstratereduced activity during REM sleep too. By contrast, cholinoceptive neurons in the pontine reticular formation fire rapidly and phasically during REM sleep. Cholinergic neurons in the gigantocellular tegmental field of the pontine reticular formation receive inputs from the dorsal raphe and the locus coeruleus.The periodicity of REM and non-REM sleepis controlled by a network of oscillatinggroups of neurons in the reticular formation. 3. Sleepdisorders a. Somnambulism (sleepwalking) tends to occur more often in children than adults. It almost alwaysoccurs during non-REM sleep and may occur together with enuresis (bed wetting) or night terrors, which are more intense than nightmares and occur most often in children.

ClinicalCorrelate Innarcolepsy, there are sudden uncontrollable episodes ofREM sleep. Dextro-amphetamine isuseful inthetherapy of narcolepsy.

b. Enuresis is a common childhood sleep disorder, affecting roughly l0o/o of children betweenthe agesof 4 and 13 and occurring more often in boys than girls. It usually occurs during non-REM sleep. c. Narcolepsy is characterizedby recurrent episodesof an uncontrollable desireto sleep. Typically, there are two to six episodesper day, and the individual is easily arousable. During these sleep attacks, the EEG first shows the REM pattern, which may be followed by non-REM sleep.This is never seen in normal subjects.Roughly 70o/oof patients with narcolepsyalso suffer from cataplery. d. Cataplexy refers to attacks of paralysisof somatic muscles,which occur during wakefulnessand are usually precipitatedby bouts of laughter or crying or by strong emotional stimuli.

458

TheVestibular System Thevestibular sy$emplays animportant roleinvisual maintenance orientation, of equilibrium, and modification of muscle tone.Inthehealthy individual, theactions ofthevestibular system arerarely noticed. Whenthesystems fails, however, thesymptoms areobvious andcanbedisabling. Although thevestibular system modulates movement, it isa purely sensory system whose impact on physiology movement canonlybeappreciated if itsanatomy and arewell-understood.

VESTIBUTAR NUCTEI There are four vestibular nuclei located in the rostral medulla and caudal pons. The vestibular nuclei receive afferents from the vestibular nerve, which innervates receptors located in the semicircularcanals,utricle, and saccule. A. Primaryvestibular fibers terminate in the vestibular nuclei and the flocculonodular lobe of the cerebellum. B. Secondary vestibular fibers, originating in the vestibular nuclei, join the medial longitudinal fasciculus(MLF) and supply the motor nuclei of CN III, CN IV and CN VI. Thesefibers, which originate primarily in the medial and superior vestibular nuclei, are involved in the production of conjugate eyemovements. Thesecompensatoryeyemovements representthe efferent limb of the vestibulo-ocular reflex, which enablesthe eye to remain focused on a stationary target during movement of the head or neck. C. Vestibulospinal tracts project to all levelsof the spinal cord and increasemuscle tone in the extensors. 1. Normal muscle tone is maintained by a fine balance of excitatory (i.e., vestibular nuclei, part of the reticular formation) and inhibitory (i.e., motor cortex, the red nucleus,cerebellum, part of the reticular formation) input.

ln a Nutshell . Primary vestibular fibers project fromthevestibular sensory organs tothe vestibular nuclei andthe flocculonodular lobeofthe cerebellum. . Secondary ve$ibular fibers influence eyemovement centers, extensor muscles, andthecerebellum.

2. Transection of the midbrain between the superior and inferior colliculi produces a condition known as decerebrate rigidity. Tiansection at this level decreasesinhibition of extensorsby the motor cortex and the red nucleus,therebyproducing excessmuscletone in the extensorsor "antigravity" muscles. D. Vestibulocerebellar fibers include primary fibers of the vestibular nerve and secondary fibers from the vestibular nuclei. These fibers enter the cerebellum through the juxtarestiform body, a part of the inferior cerebellarpeduncle.

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VESTIBUTAR DYSFUNCTION Vestibulardysfunction may result from either peripheral or central lesions.Common peripheral causes include labyrinthitis, infection, M6nidre disease,vascular lesions, and trauma. Common centralcausesinclude vascularand demyelinatinglesionsand tumors. Manifestations of vestibular dysfunction include vertigo, nystagmus,and difficulty performing coordinated movements such as walking. A. Vertigo refers to the perception of rotation, which may involve either the subject or the externalspace. 1. Vertigo may result from a lesion of either the peripheral (end-organ, nerve) or central (nuclear, brain stem pathways) vestibular structures. The vertigo is usually severein peripheral diseaseand mild in brain stem disease. 2. Chronic vertigo (i.e.,persistinglonger than 2-3 weeks)strongly suggestsa central lesion, 3. Vertigo may also be due to a variety of drugs, including anticonvulsants,aspirin, alcohol, and certain sedativesand antibiotics. B. Nystagmus refers to rhythmic oscillations of the eyesslowly to one side followed by a rapid reflex movement in the opposite direction. Nystagmus is defined by the direction of the rapid reflexmovement. It is usually horizontal, although rotatory or vertical nystagmusmay also occur.Vertical nystagmusis observedrarely in peripheral disease. 1. Nystagmusmay result from irritation or a lesion of the labyrinth, vestibularnerve or nuclei, or from drugs.Nystagmusalsomay be due to a metabolic diseaseor a lesion of the cerebellum, visual system(usually reflex centersand their connections),or the cerebralcortex. 2. Testsfor nystagmus a. Caloric stimulation (vestibulo-ocularreflex). First the tympanic membraneis examined to ensure that it is intact. Elevating the head 30 degreesabove the horizontal plane placesthe horizontal semicircular canal in the vertical position. When cool water is introduced into the externalauditory canalin this position, nystagmusoccurs even in the normal individual; the fast component is to the side opposite the stimulated ear.If hot water is introduced, the fast component is toward the stimulated side. Similar resultsare produced if the head is tilted backrvards60 degrees.

Mnemonic COWS testfornystagmus: Warm, Cold,Opposite; Same

b. Rotation test. The head is elevated30 degrees,and the individual is spun in a revolving chair.After about a dozen revolutions, the chair is stopped quickly. The endolymph in the semicircularcanal continuesto move in the direction of prior rotation, producing nystagmus(definedby the fast component) in the direction oppositethe previous rotation; vertigo,past-pointing,and postural deviationsare in the samedirection. C. Mdnidre diseaseis characterizedby abrupt, recurrent attacksof vertigo lasting minutes to hours accompaniedby tinnitus or deafnessand usually involving only one ear.Nauseaand vomiting and a sensationof fullnessor pressurein the ear also are common during the acute episode.The attacksoften are severe,and the patient may be unable to stand. The disease usually occurs in middle age and resultsfrom distention of the fluid spacesin the cochlear and vestibularparts of the labyrinth.

MO

Neuroanatomy: TheVestibular System

D. Labyrinthitis also presentsas a sudden onset of vertigo which may be mistaken for M6niire disease.La\rinthitis, however,is more likely to be a secondaryeffect related to otitis media and meningitis. In extreme cases,patients may not be able to walk; those capableof walking may fall toward the affected side. E. Benign positional vertigo. This is thought to result after an otoconia is dislodged from the utricle to strike the cupula of the (usually) posterior canal, causing intense vestibular stimulation. The best treatment is to reposition the patient's head in specific ways to maneuver the loose otoliths out of the posterior canal.

ln a t{ubhell Mdniere disease andlabyrinthitis aretwodiseases inwhich vertigo isa primary symptom.

MI

TheAuditorySystem (usually intheair)intosounds, Theauditory system transduces mechanical energy vibrations the mostimportant ofwhichformsthebasis forlanguage. Thecomplexity of auditory transduction makes thesystem moresusceptible to damage thanmostoftheothersenses. Hearing lossisa sign of a disease, nota diagnosis. A correct diagnosis requires anunderstanding oftheanatomy and physiology oftheauditory system.

PHYSICS OFSOUND

In a Nutshell

Sound consistsof oscillationsor vibrations of a medium, usually air. The auditory systemdecomposescomplex soundsinto simple sine waves.The frequenry of the sinusoidal oscillationsis perceivedaspitch, which humans are ableto detectbetween20 cyclesper second(i.e.,20hertz [Hz]) and 20,000cyclesper second(or 20 kHz).Normal human conversationrangesfrom 10M,000 Hz. The amplitude of thesesine wavescorrespondsto loudness.The auditory threshold is 0 decibels (dB). Soundsin excessof 120 dB produce pain and may damagehair cellsof the inner ear.

Thehuman hearing range is 20-20,000 Hz.Frequency is perceived aspitch; amplitude corresponds to loudness.

TRANSMISSION OFSOUND

ln a Nutshell

A. Soundwaves travel through the external auditory canal and causethe tympanic membrane (eardrum) to vibrate.Movement of the eardrum causesvibrations of the ossiclesin the middle ear (i.e., the malleus,incus, stapes)that are transferred through the oval window and into the inner ear.The pressurewave in the inner ear is transmitted through the perilymph until it reachesthe round window, where the energy is dissipated.The ossiclesincreasethe efficienry of waveconduction from the air to perilymph.

Tympanic membrane

B. The tympanic (acoustic) reflex, which is elicited by loud sounds,protects the delicate structures of the inner ear by attenuating the intensity of transmitted vibrations. The afferent limb of the acoustic reflex is carried in the cochlear nerve, while the efferent limb is mediated by the trigeminal and facial nerves, which supply the tensor tympani and stapedius muscles, respectively.Contraction of these muscles markedly reduces the conduction of vibrations through the ossiclesto the inner ear,especiallyfor low frequencies.

Stapes

J Malleus

J lncus J J Ovalwindow

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Nervous System

ln a Nutshell vibration Ossicle

J Waves inperilymph J Bending of stereocilia

J Haircelldepolarization

ClinicalCorrelate High-Hz sounds are transduced near theoval window; low-Hz sounds are transduced near theround window. High-Hz haircellsare lostwithage,producing high frequency hearing loss.

ORGAN OFCORTI A. Structure. The organ of Corti is the structure within the inner ear that actually transduces physical forces into bioelectrical phenomena. The organ of Corti is located within the cochlear spiral, a tube containing three compartments separatedby two membranes. The upper and lower compartments (scala vestibuli and scala tympani, respectively) contain perilymph while the middle one, the scala media, contains endolymph. Reissner membrane separatesthe scala media and vestibuli, while the basilar membrane separatesthe organ of Corti from the scalatympani. The organ of Corti lies on the basilarmembrane and is bathed by endolymph of the scalamedia. B. Function. Sound transduction takesplace at the hair cells of the organ of Corti, which have apical stereocilia imbedded in the tectorial membrane. Vibration of the basilar membrane, in responseto pressurewavestransmitted through the perilymph, deforms the hairs through a shearing effect, generating action potentials in the cochlear nerve fibers. Hair cells located near the base of the basilar membrane (near the oval window) transduce high frequenry sounds;low frequencysounds are transducednear the helicotremaor apex.Thus, the inner ear is tonotopically organized with the auditory spectrum spread acrossthe basilar membrane in an orderlv fashion.

(CNVril)ANDNUCTEI cocHrEAR NERVE A. Cochlear nerve. The spiral ganglion, located in the bony modiolus, contains soma whose peripheral axons contact the baseof each hair cell of the organ of Corti. The central axons from thesebipolar cellsform the cochlearnerve, which joins the vestibular nerve to form the vestibulocochlearor eighth cranial nerve. B. Codrlear nuclei. The ventral and dorsal cochlear nuclei are located lateral to the inferior cerebellarpeduncle at the junction of the pons and medulla. Central a.xonsfrom cells in the spiral ganglion supply both ipsilateralcochlearnuclei (FigureV-17- 1). Both the fibers in the cochlear nerve and the cells in the cochlear nuclei are tonotopically organized.

44

Neuroanatomy: TheAuditorySystem

ral fissure

Transverse temporal gyrus Auditoryradiation Medialoeniculate nucleus-ofthalamus lnferiorcolliculus

Midbrain

Laterallemniscus Dorsalacousticstria Dorsalcochlearnucleus lntermediateacousticstria Ventralcochlearnucleus Cochlearnerve Medulla

Ventralacousticstria

body Superior olivarynucleusTrapezoid FigureV-l7-l . The auditorypathways.

AUDITORY PATHWAYS SECONDARY A. Ventral acoustic striae originate in the ventral cochlear nucleus. 1. Most fibers of the ventral acoustic striae exit the ventral cochlear nucleus mediallv and form the trapezoid body just ventral to the pontine tegmentum. 2. These fibers terminate in the ipsilateral and contralateral nuclei of the trapezoid body and superior olivary nuclei. The superior olivary nuclei, which are the first relays to receivebinaural input, use differencesin sound amplitude and phase angle to locate the origin of soundsin the environment.

In a Nubhell Thesuperior olivary nuclei receive binaural input andhelpin localization ofsounds.

3. Cells in these nuclei, along with a small percentageof cells in the ventral cochlear nuclei, project to the inferior colliculus via the lateral lemniscus. B. Intermediate acoustic striae are axons of cells in the posterior part of the ventral cochlear nucleusthat traversethe pontine tegmentum and ascendin the contralaterallateral lemniscus.

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NervousSystem

C. Dorsal acoustic striae are axonsof cellsin the dorsalcochlearnucleusthat crossthe pontine tegmentum before ascendingto the inferior colliculusvia the lateral lemniscus. D. The lateral lemniscus carries auditory input from the cochlear nuclei, the nuclei of the trapezoid body, and the superior olivary nuclei to the inferior colliculus in the midbrain. Eachlateral lemniscuscarriesinformation derived from both ears;however,input from the contralateralear predominates.

In a Nutshell

OTHER CENTRAT CONNECTIONS

Primary auditory cortex is gyrus, located intheHeschl alsoknown asthetransverse gyrus. temporal

The inferior colliculus sendsauditory information to the medial geniculate body (MGB) of the thalamus. From the MGB, the auditory radiation projects to the primary auditory cortex located on the posterior portion of the transverse temporal gyrrs (Heschl gfms; Brodmann areas4l and 42). The adjacent auditory associationarea (secondary auditory area) makes connections with other parts of the cortex, including Wernicke area,which plays a crucial role in the comprehensionof language.

M6

TheCerebellum (asisthepons) intheposterior andislocated isderived fromthemetencephalon Thecerebellum pons roofofthe medulla. The the and to the lies dorsal Thecerebellum cavity. fossa ofthecranial peduncles. The cerebellar ofthesuperior surfaces bythemedial isformed fourthventricle rostral whichisoneofthedural cerebelli, bythetentorium iscovered ofthecerebellum surface superior folds. cord,inferior thespinal including of sources, inputfroma variety receives sensory Thecerebellum pontine nuclei, andthevestibular nucleus, cuneate accessory formation, nuclei, reticular olivary prolection to (mainly a largeipsilateral lobe)sends thefrontal cortex Thecerebral nerve andnuclei. via hemisphere cerebellar to thecontralateral inturn,project nuclei, which, thepontine inputs, these peduncle. integrates Thecerebellum pontocerebellar cerebellar fibers ofthemiddle plays important an thalamus, and stem, projections brain red nucleus, to the its efferent andthrough is dysfunction Cerebellar muscle tone. of andregulation of movement roleinthecoordination sideofthebody. ontheipsilateral expressed

ANATOMY EXTERNAL The cerebellum consistsof the medially located vermis and two cerebellar hemispheres. The cerebellarcortex consistsof multiple parallel folds that are referred to asfolia. A. The anterior lobe is the portion of the cerebellumthat is rostral to the primary sulcus (fissure) and is concernedwith coarsemovements of the body and head.It is alsoreferredto as the paleocerebellum. B. The posterior (middle) lobe is locatedbetweenthe anterior and flocculonodular lobes.This is the largestlobe of the cerebellumand is concernedwith the production of coordinated, fine voluntary movements. It is also referred to as the neocerebellum. C. The flocculonodular lobe is that portion of the cerebellumposterior to the posterolateral fissure.The flocculonodular lobe consistsof the medial nodule and paired lateral flocculi and is the phylogeneticallyoldest portion of the cerebellum.It has important connections with the vestibular nuclei. It is also referred to as the archicerebellum or the vestibulocerebellum.

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Vermis

Primaryfissure

Anterior lobe

Horizontal fissure

Pyramis

Posterior lobe

Uvula Tonsil Posterolateralf issure Flocculus Nodulus

Flocculonodular lobe

Figure V-18-1.Lobes and fissures of the cerebellum. D. Three-paired cerebellar peduncles. All afferent and efferent projections of the cerebellum traversethe inferior, middle, or superior cerebellarpeduncles. 1. Inferior cerebellar peduncle (restiform body) a. The posterior (dorsal) spinocerebellar tract arises from cells in Clarke column (nucleus dorsalis) in the thoracic and lumbar segmentsof the cord and conveysmainly proprioceptive information from the leg and lower trunk on the ipsilateral side. b. The rostral spinocerebellar tract arisesfrom cells in the cervical cord and transmits mainly proprioceptive information from the upper extremities.One-third of this tract passesthrough the inferior cerebellarpeduncle, while the remaining two-thirds pass through the superior cerebellarpeduncle. c. The cuneocerebellartract is the equivalent of the posterior spinocerebellartract for the upper extremitiesand neck.It arisesfrom cellsin the accessory(external) cuneate nucleusof the medulla. d. The olivocerebellartract is a crossedtract that originatesfrom cellsin the inferior olivary nuclei and constitutesthe largest group of fibers passingthrough the inferior cerebellarpeduncle.Axons of the olivocerebellartract terminate as climbing fibers. e. Vestibulocerebellar fibers include primary vestibular fibers and secondary fibers from the vestibularnuclei; the latter are more numerous. f. Reticulocerebellar fibers arise from cells in the reticular formation.

In a Nutshell Themiddle cerebellar peduncle contains crossed pontocuebellar fibers. M8

g. Fastiogiobulbar tract. This small tract, the only efferent pathway in the restiform body, projectsfrom the fastigialnucleusof the cerebellumto the vestibularnuclei and reticular formation. 2- The middle cerebellar peduncle (brachium pontis) contains fibers traversingfrom the contralateralpontine nuclei to the cerebellum.This pathway enablesinformation originating in the cerebral cortex to reach the cerebellum, which will, in turn, fine tune the activify of the primary motor cortex.

TheCerebellum Neuroanatomy:

3. The superior cerebellarpeduncle (brachium conjunctivum) is the principal efferentpathway of the cerebellum. Fibers originating from the dentate nuclei exit the cerebellum through the superior cerebellarpeduncle and project to the red nucleus, reticular formation, and thalamus (mainly the ventrolateral and ventroanterior nuclei). In addition, the anterior (ventral) and rostral spinocerebellartracts travels through this peduncle.

ANATOMY INTERNAL The cerebellar cortex forms the surfaceof the cerebellum. The subcortical white matter of the cerebellum is called the arbor vitae (tree of life). Buried deep within the arbor vitae lie four paired cerebellar nuclei. A. The cerebellarcortex hasthree layers,unlike the cerebralcortex,which hassix (FigureV-18-2).

ln a Nubhell cerebellar Thesuperior peduncle contains: . Dentatorubrothalamic tract (dentate + red nucleus nucleus + thalamus; of the themajoroutput cerebellum) . Ventral androstral r tracts spinocerebella

Granularlayer Subcorticalwhite matter Figure V-l 8-2.The cerebellar cortex.

l. The molecular layer is the outer layer and is made up of basket and stellate cells as well as parallel fibers of the granule cells. 2. The Purkinje layer is the middle layer and is composed of a single layer of large, flaskshaped Purkinje cells. The extensivedendritic tree of the Purkinje cell extends into the molecular layer.The single axon exits from its base and projects to one of the deep cerebellar nuclei or vestibularnuclei of the brain stem. 3. The granular layer is the innermost layer of cerebellarcortex and contains Golgi type II neurons,granule cells,and glomeruli. Each glomerulus is surrounded by a glial capsule, which is a specializedregion for complex synaptic connections. The granule cell is the only excitatory neuron within the cerebellarcortex. B. White matter (or arbor vitae) contains all of the afferent and efferent projections of cerebellar cortex.

In a Nubhell CortexLayers Cerebellar . Molecular (outer) . Purkinje (middle) . Cranular (outer)

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C. Paired deep nuclei (from medial to lateral) l. The fastigial nucleus lies in the vermis and is the most medial nucleus. 2. Globose nucleus 3. Emboliform nucleus. Together,the globose and emboliform nuclei constitute the interposed nuclei. 4. The dentate nucleus is the largest and most lateral nucleus. It is involved with coordination of movement of the extremities.

CIRCUITRY OFTHECEREBETLAR CORTEX ln a Nutshell Therearetwotypesof fibers thatproject intothe cerebellum: . Mossy fibers-+ excitatory fibers fromthespinal cord, pons, andvestibular nuclei . Climbing -> fibers excitatory fibersfromthe inferior olivary nucleus

Extrinsic input to the cerebellarcortex can be divided into two groups: climbing fibers that originate from the inferior olivary nuclei and mossy fibers that carry the remainder of the extrinsic input. Mossy fibers exert an excitatory effect on granule cellsand Golgi cells.Granule cells are the key to understandingthe circuitry of the cerebellum.Each granule cell sendsits axon into the molecular layer, where it gives off collaterals at a 90 degreeangle that run parallel to the cortical surface(i.e.,parallel fibers). The granule cell axonsstimulate the distal apical dendritesof the Purkinje cellsas well asbasketand Golgi cells. A. Golgi cells receive excitatory input from mossy fibers and from the parallel fibers of the granule cells.The output of the Golgi cell is to the granule cell,where it exertsan inhibitory effect. The basket cell, with its main input from the excitatory parallel fibers, inhibits the Purkinje cells. B. Purkinje cells, the final common pathway for cortical output of the cerebellum,receiveexcitatory input from climbing and parallel fibers and inhibitory input from the basket cells. Purkinje cellsproject a singleaxon through the granular layer and the underlying arbor vitae to inhibit the deep cerebellarnuclei or the vestibularnuclei in some instances.

CIRCUITRY OFTHEDEEP CEREBELTAR NUCTEI A. Input. The Purkinje projections to the deep cerebellarnuclei and the vestibular nuclei are inhibitory. Input from extracerebellarsources(e.g.,vestibularnuclei, inferior olivary nuclei, vestibularganglion,reticular formation, pontine nuclei) is excitatory. 1. Purkinje cells representthe largestsourceof input to thesenuclei. Projectionsfrom the cerebellarcortex terminate in the deep cerebellarnuclei in an orderly fashion. Medial (vermal) regionsof cortex project to medial nuclei; lateral areasproject to lateral nuclei. a. Fibersfrom the vermis project to the fastigialnuclei. b. Fibers from the paravermal cortex primarily project to the interposed (globoseand emboliform) nuclei. c. Fibers from the cortex of the lateral cerebellarhemisphere project to the dentate nucleus.

In a Nutshell

2. Inferior olivary nuclei send excitatoryprojectionsto the deep nuclei. 3. vestibular nuclei send excitatoryprojections to the deep nuclei.

ThePurkinje cellsofthe cerebellar cortex inhibit the deepnuclei;the deepnuclei project outofthecerebellum.

450

B. output. Efferentsfrom the deep cerebellarnuclei project to the: 1. Red nucleus and thalamus. Projectionsoriginating from the dentate (most important), emboliform, and globosenuclei leavethe cerebellumvia the superior cerebellarpeduncle, crossin the midline in the decussationof the superior cerebellarpeduncles,and terminate

TheCerebellum Neuroanatomy:

in the red nucleusand ventral lateral nucleus (VL) of the thalamus.VL, in turn, projects to the motor cortex. (The motor cortex projects to pontine nuclei. The pontine nuclei project through the middle cerebellarpeduncleto the contralateralcerebellarcortex,thus completingthe circuit.) 2. Reticular formation 3. Vestibular nuclei. Most of the axonsthat project to thesenuclei originate from the fastigial nucleus, vermis, and flocculonodular lobe. Fibers to the vestibular nuclei project through the inferior cerebellarpeduncle.

OFTHECEREBETLUM WITHLESIONS ASSOCIATED SYMPTOMS Cerebellardysfunction may result from damageto the cerebellumitself or to its afferent or efferent connections.Cerebellardysfunction is manifestedby abnormalitiesof the motor systembut not paralysisor paresis.Symptomsassociatedwith cerebellarlesionsare expressedipsilaterally. A. Difficulty maintaitrittg posture, gait, or balance. Disorders of posture, gait and balance usually result from damageto the vermal area.Patientswith vermal damagemay be differentiated from those with a lesion of the posterior columns by the Romberg sign. B. Ataxia is defined as clumsinessor incoordination of muscle action. Ataxia was originally describedasa disturbanceof range,rate,and force of movement.Recently,thesedeficitshave been subdivided into severalcategoriesthat are not mutually exclusive. 1. Asynergy is the inability of different musclesto act together in a coordinatedfashion. 2. Dysmetria is the inability to stop a movement at the proper place. 3. Dysdiadochokinesia (adiadochokinesia) is the inabiliry to perform alternating movements, such aspronation and supination of the forearm, at a moderatelyquick pace. 4. Scanning dysarthria. During speech,patients divide words into syllables,thereby disrupting the melody of speech.Scanningdysarthria is causedby asynergyof the muscles responsiblefor speech. C. Abnormal ocular movements. As with other movementsof the body, there may be dysmetria. 1. When the eyestry to fix on a point, they may passit or stop too soon and then oscillatea few times before they settleon the target. 2. Nystagmus may be present,particularly with acute cerebellardamage.The nystagmusis often coarsewith the fast component usually directed towards the involved cerebellar hemisphere. D. Asthenia. Muscular strengthis diminished and musclesfatigue more easily.Astheniais usually observedacutely with damageto the cerebellum. E. Hlpotonia is a profound decreasein muscle tone that usually occurs with an acute cerebellar insult. The musclesfeel flabby on palpation and deep tendon reflexesare usually diminished. F. Intention tremor. Voluntary movementsare performed with a coarsetremor. For example, if a patient with a cerebellarlesion is askedto pick up a penny,a slight tremor of the fingers is evident and increasesasthe penny is approached.The tremor is barely noticeableor absent at rest.Note that intention tremor is causedby cerebellardysfunction,while resting tremor is characteristicof basalgangliadysfunction (e.g.,Parkinson disease).

ln a Nutshell of Common Symptoms Dysfunction Cerebellar . Ataxia . Dysmetria . Dysdiadochokinesia . Nystagmus . Hypotonia . lntention tremor

451

TheVisualSystem nervous system. inthehuman system sensory isperhaps themostsophisticated Thevisual system withthecentral connections oftheeyeanditsneuronal thestructure itsgreat complexity, Despite anatomy allows ofvisual system knowledge (CNS) A complete arewellunderstood. nervous system tumors, vascular damage, location of likely the determine to fielddefects to usevisual theclinician system. inthenervous or otherlesions

PARTS OFTHETHEEYE A. The sclera is the tough externallayer that cushionsand protectsthe eyeball. B. The cornea is a transparentstructure that lies anterior to the iris, pupil, and anterior chamber and is continuous posteriorly with the sclera.The cornearefracts most of the light rays. The lens is for fine tuning; the amount of refraction is proportional to the difference betweenthe indicesof refraction of the two media through which the light ray passes.Thus, more refraction occursat the air-corneainterfacethan at the aqueoushumor-crystallinelens interface. C. The aqueoushumor is an ultrafiltrate of plasmathat fills the anterior chamberof the eye.It lies betweenthe corneaand crystallinelens. D. The choroid is the vascular layer that lies between the retina (internally) and the sclera (externally).The choroid is heavilypigmented and absorbslight that passesthrough the retina so that it will not reflect back. E. The iris lies in front of the lens.The areanot coveredby the iris is the pupil. 1. The pupillary sphincter muscle consistsof circular muscle fibers and is innervated by cholinergic,postganglionic,parasympatheticfibers. Stimulation of thesefibers resultsin pupillary constriction (miosis). The pupillary sphincter muscle has muscarinic cholinergic receptors. 2. The radial dilator muscle is innervatedby adrenergic,postganglionic,sympatheticfibers. Stimulation of these fibers results in pupillary dilation (mydriasis). The radial dilator receptors. muscle fibers possessctr-adrenergic F. The crystalline lens is a transparentbody that doesthe fine tuning for the refraction of light rays.The equator of the lens is held in placeby suspensoryligamentsattachedto the ciliary body.

In a Nutshell sphincter Thepupillary thepupil muscle constricts of under thecontrol parasympathetic nergic choli dilator theradial stimulation; in dilates thepupil muscle crto sympathetic response stimulation. adrenergic

G. The ciliary body is formed in large part by the ciliary muscle.This smooth muscle,innervated by postganglionicparasympatheticfibers, is responsiblefor accommodation of the lens for near vision.

45'.

Neruous System

H. Vitreous humor is a gelatinous clear fluid that fills the cavity between the lens and retina. I. The retina is an evaginationof the diencephalon.The retina contains sevenlayersof neural elements;the photoreceptors (rods and cones)are locatedin the outermost layer.The macula is the area of the retina, located slightly lateral to the optic disc, that is responsible for central vision. Becausenearly all photoreceptorsin the macula are cones,this areahas the best acuity and color discrimination in the retina.

OPTIC PATHWAYS A. Passageof light rays. Light must passthrough the cornea,aqueoushumor, lens, and vitreous humor before reachingthe retina. It must then passthrough the inner six layersof the retina to reachthe photoreceptivelayer of rods and cones. B. Neural transduction 1. Photopigments in rods and cones absorb photons, and this causesa conformational changein the molecular structure of thesepigments. 2. This molecular alteration causessodium channelsto closeand a hyperpolarizationof the membrane potential of the rods and cones.

In a Nutshell Rods, cones

J Bipolar cells

J Canglion cells (axons formtheopticnerve) In a Nutshell Theopticchiasm contains fibers fromthenasal halfof theretina, andcarries information fromthelateral visual fields. Note Since thelensinverts the image ofthevisual field, visual inputs fromtheright sideof thevisual fieldtravel to theleftlateral geniculate nucleus andtheleftvisual cortex.

454

3. Rods and conesreleasemore neurotransmitter in the dark and lessin the light. C. Retinal connections 1. Rods and coneshave synapticcontactson bipolar cells that project to ganglion cells. 2. Axons from the ganglion cells convergeat the optic disc to form the optic nerve, which entersthe cranial cavity through the optic foramen.At the optic disc,theseaxonsacquire a myelin sheathfrom the oligodendrocftesof the CNS. D. Optic chiasm and optic tract 1. The optic chiasm is formed by decussatingfibers that originate from the nasalhalf of the retina. Fibersfrom the temporal retina project ipsilaterally. 2. The optic tract lies beyond the chiasm and carriesfibers from the temporal part of the ipsilateral retina and fibers from the nasalpart of the contralateral retina. Sincevisual stimuli in the left half of the visual field fall on the nasal half of the left retina and the temporal half of the right retina, the left half of the visual field is projected to the right hemisphere. Thus, each hemisphere receivesvisual input from the contralateral visual field. E. Central visual nuclei 1. Most fibers in the optic tract project to the lateral geniculatenucleus.Many fibers alsoterminate on cellsin the superior colliculi and pretectalarea.Theselatter terminations are important for visual reflexes. 2. The lateral geniculate body (LGB) is a laminated structure that receivesinput from the optic tract and gives rise to axons that terminate on cells in the primary visual cortex (striatecortex,Brodmann area17) of the occipital lobe. The pathwayfrom the LGB to the striate cortex is the visual radiation of the geniculocalcarinetract. F. Visual radiation 1. Medial fibers carry input from the upper retina (i.e.,the lower contralateralvisual field) and passdirectly from the LGB through the parietal lobe to reach the upper bank of the calcarinesulcus(cuneusgyrus) in the striate cortex.

Neuroanatomy: TheVisualSystem

2. Lat€ral fib€rs carry input ftom the lower retina (i.e.,the upper contralateralvisual field) and take a circuitous route from the I,GB tlrough Meyer loop in t]le temporal lobe to reachthe lower bank of the calcarinesulcus(lingual gyrus) in the striatecortex.

VISUAL CORTEX A. Primary visual cortex (striatecorto(, Brodmannarea17) l. The calcarinesulcus dividesthe striatecortexinto the: a. Upper cuneusgynrs, which receivesthe superiorfibers of the visual radiation (input for the upper retina and lower visual field) b. Iower lingual gynrs, which receivesthe inferior fibers of the visual radiation (input ftom the lower retina and upper visual field) 2. Stimulation of the prirnary visual cortex by a neurosurgeonin a consciouspatient producesthe sensationof seeingsimplepatterns(e.g.,spotsof light). B. Visualassociationcorter is distributedthroughoutthe entireoccipitallobeandin the posterior partsof th€ parietaland temporallobes.Theseregionsreceivefibersfrom the striatecort€x andintegratecomplexvisualinput ftom both hemispheres. Stimulationof thesevisualregions producesthe sensationof seeingcomplorvisualpatterns(e.g.,a face). by a neurosurgeon

ln I tt$.!t9lt Thecalorinesulcus(seenon themedialsurface of tE brain)dMdesthevisual cortexinto: . Cuneus gyrus(superior information fibers;receives fromthe lowervisual field)'and . Lingulagyrus(inferior fibers;receives information fromtheuppervisualfield)

TESIONS PATHWAYS OFIHEVISUAT A. ksions of the retina Destructionof the maculaproducesa centralscotoma.The maculais quite sensitiveto intenselight, trauma,aging,and neuotoxins. B. ksions ofganglion cell axons 1. Destruction ofan optic nerve producesblindnessin that eye.The pupil of that eyeconstricts when light is shined into the oppositeeye(consensuallight reflex) but not when light is shinedinto the blinded eye(absenceof direct light reflex). 2. Compressionof the optic chiasm,often the result of a pituitary tumor or meningioma, resultsin a lossof peripheralvision becausethe crossingfibers ftom the nasalretina are damaged.This field defectis calleda biternporal heteronyrnoushemianopia. 3. Destruction ofthe optic tract resultsin a lossofvisual input from the contralateralvisual field. For example,a lesionof the right optic tract resultsin a lossof input from the left visual field. This is calleda hornonymoushemianopia;in t}le oramplein FigureV-19-1, a left homonymoushemianopra. C. ksions of the visual radiations oroducevisual field defectssimilar to those of the ootic tract if all fibers areinvolved.

455

Neruous System

Temporal

Temporal lnversionof opticalimage

Note Thistypeoffigurehas historically beena USMLE favorite. Youshouldpractice predicting thevisual field defeGthatwouldresult from thevarious lesions.

ln a Nutshell

Defects

Optic nerve

oe oo

2. Rightnasal hemianopsia

Lateral geniculate body (LGB)

. Lesion ofthemacula + central scotoma

3. Bilateral heteronymous hemianopsia

. Lesion oftheopticnerve + ipsilateral blindness . Lesion oftheopticchiasm -+ bitemporal hemianopia (lossof peripheral vision, oftenresulting from pituitary tumors) . Lesion oftheoptictractA homonymous hemianopia . Lesion oftheoptic radiations inthetemporal lobe+ upper homonymous quadrantanopia . Lesion oftheoptic radiations intheparietal lobe+ lower homonymous quadrantanopia . Cortical lsionsproduce similar deficib aslesions of theopticradiations, butthere maybemacular sparing

456

oo

1. Anopseaof righteye (rightnasaland temporalhemianopsia)

oo

4,5,6.Left homonymous hemianopsia

Figure V-l9-1. Lesions of the visual pathways. 1. Lesions restricted to the lateral fibers in the visual radiation, usually involving the temporal lobe, result in a lossof visual input from the contralateralupper quarter of the visual field. For example,a lesion of the temporal fibers in the right visual radiation resultsin loss of visual input from the upper left quarter of the field (a left superior quadrantanopia). 2. Lesions restricted to the medial fibers in the visual radiation, usually involving the parietal lobe, result in a loss of visual input from the contralaterallower quarter of the field (a left inferior quadrantanopia). D. Cortical Lesions l. ksions of the primary visual cortex are equivalent to those of the visual radiation, although there is a greatertendencyfor macular (central) vision to be sparedwhen the lesion is localizedto the cuneusor lingual gyri at the occipital pole. 2. Lesions of the cuneus gyrus are equivalent to lesions restricted to the parietal fibers of the visual radiation; lesionsof the lingula are similar to lesionsof the optic radiations of the temporal lobe.

Neuroanatomy: TheVisualSystem

3. Large bilateral lesions of the primary visual cortex may affect all fields of vision. The pupillary light reflex is sparedin theselesionsbecausefibers subservingthe pupillary light reflex leave the optic tracts to terminate in the superior colliculi and pretectal area. The combination of blindness with intact pupillary reflexesis termed "cortical blindness." 4. Lesions of the visual association cortex produce visual agnosia in which there is no loss of acuity in any part of the visual field; rather, the perception of complex visual patterns is disturbed. For example,you might show a patient with visual agnosiaa pair of glasses and the patient would describethem as two circlesand a bar.

VISUAT REFTEXES A. Pupillary light reflex. When light is directed into an eye,it stimulates retinal photoreceptors and resultsin impulsescarried in the optic nerve.Someof thesefibers terminate in the pretectal area.Cells in the pretectal areasend axonsto the Edinger-Westphal nuclei on both sides.The Edinger-Westphalnucleus is the parasympatheticnucleus of the oculomotor nerve and givesrise to preganglionic parasympatheticfibers that passin the third cranial nerve to the ciliary ganglion. From there, 5o/oof the postganglionicparasympatheticfibers passto the constrictor (sphincter) muscle of the iris and result in pupillary constriction (miosis). Sincecellsin the pretectalareasupply both Edinger-Westphalnuclei, shining light into one eyeresultsin constriction of both the ipsilateralpupil (direct light reflex) and contralateral pupil (indirect or consensual light reflex).

ln a Nutshell Retina I

B. Accommodation-convergencereaction. This reaction occurs when an individual attempts to focus on a nearby object after looking at a distant object.While the precisepathwaysused in this reaction remain unknown, the occipital cortex appearsto be an essentialcomponent. The oculomotor nerve carries the efferent fibers from the accommodation-convergence reaction,which consistsof three components. 1. C,onvergenceresults from contraction of both medial recti, which p,rll the eyes to look toward the nose.This allowsthe image of the object to focus on the samepart of the retina in eacheye.Generalsomatic efferentsfrom the oculomotor nuclei supply the medial recti.

v

Pretectal area(midbrain) v

I

Edinger-Westphal nucleus (midbrain) v - ' l '

Lilrarygangil0n

2. Accommodation refers to the reflex that increases the curvature of the lens needed for near vision. Preganglionicparasympatheticfibers arisein the Edinger-Westphalnucleus and passin the oculomotor nerveto the ciliary ganglion.About 95oloof the postganglionic parasympatheticfibers from the ciliary ganglion supply the ciliary muscle.Contraction of this muscle relaxesthe suspensoryligamentsand allowsthe lens to increaseits convexity (become more round). This increasesthe refractive index of the lens, permitting the image of a nearby object to focus on the retina.

ln a Nutshell

3. Pupillary constriction (miosis) results from contraction of the constrictor muscle of the iris. A smaller aperture givesthe optic apparatusa greaterdepth of field.

. Convergence

C. An Argyll-Robertson pupil is a small pupil that is constant in size and is unaltered bylight or shade. Both direct and consensualreflexes are lost. The accommodation-convergence reaction remains intact. This type of pupil is often seenin casesof neurosyphilis; however, it is sometimesseenin patients with multiple sclerosis,pineal tumors, or rarely in vascular disease.The lesion site is not preciselyknown but is believedto occur near the afferentlimb of the circuits mediating pupillary light reflexes,perhapsnear the pretectalnucleus or the posteriorcommissure.

Pupillary .onir.i.to, muscle

Focusing fornearvision produces a triadof events:

. Accommodation . Pupillary constriction

In a Nutshell Argyll-Robertson Pupil . Pupils donotreact to light . Pupils when willconstrict focusing fornearvision . Mayresult fromsyphilis

457

TheDiencephalon portion isa prosencephalic derivative that Thediencephalon, themostrostral ofthebrainstem, (i.e., functions asa keyrelaybetween thelowerbrainstemandspinal cordandthetelencephalon ganglia). Allof thespecial of humans are"relayed" fromthe neocortex, limbic cortex, basal senses periphery Relayed isnota gooddescription through thediencephalon to reach theneocortex. of pass fromoneplace however, because thebaton tothenext, they theirfunction, theydonotsimply functions include thecontrol of autonomic and modify thebaton. Otherimportant diencephalic processes, in regulating themotorsystem. regulation of consciousness, andassistance endocrine thehypothalamus, theepithalamus, Thediencephalon canbedivided intofourparts: thethalamus, andthesubthalamus.

ANATOMY GROSS OFTHEDIENCEPHATON The diencephalon is surrounded by the telencephalonrostrally, dorsally, and laterally.The mesencephalonis locatedcaudally.Specificlandmarks are listed below. A. Caudal boundary is a line drawn betweenthe posterior commissureand the caudaledgeof the mammillary nuclei. B. Rostral boundary is the interventricular foramen (of Monro). C. Superiorboundaryis the choroid plexusof the thirdventricle and anterior columnsof the fornix. D. Inferior boundary is the exposedsurfaceof the diencephalon.From anterior to posterior,it is formed by the: 1. Optic chiasm 2. Optic tracts, which quickly diverge laterally 3. Infundibulum or the pituitary stalk, which connects the pituitary gland with the tuber cinereum,a small inferior swellingof the hlpothalamus 4. Mammill"ry bodies E. Medial boundary. The wall of the third ventricle divides most of the diencephalon into left and right halves.In 80o/oof the population, however, the left and right halvesof the thalamus are joined by the massaintermedia (interthalamic adhesion). F. Lateral boundary. The posterior limb of the internal capsule separatesthe diencephalon from the basalganglia.The internal capsuleis a large,heavily myelinatedtract consistingof corticofugalfibers that descendto the brain stem and spinal cord.

459

TheThalamus

Thesmallsizeofthethalamus belies itsimportance. Thethalamus serves asthemajorrelay forthe gustatory, ascending tactile, visual, auditory, andolfactory information thatultimately reaches the ganglia neocortex. Otherprojections derived frommotorareas suchasthebasal ofthebrain, and cerebellum, withinotherthalamic nuclei before synapse theyreach theircortical destinations. Still, primitive participate located intheolder, othernuclei region of thethalamus nearthemidline inthe regulation of states of consciousness. Although theprecise contribution ofthethalamus to eachof position remains these systems uncertain, thereisnodoubtthatit occupies a pivotal intheneural hierarchy.

GROSS ANATOMY The thalamusis an ovoid nuclearstructurethat bulg€sposteriorly (asa resultof the pulvinar). Th€rearetwo pairsof lateralswellingswhen the diencephalonis viewedin a transyersesection: the medial and lateralgeniculatenuclei. A. Bordersof the thalamus I . Medial border is the wall of the third ventricle. 2. Lateral border is the posteriorlimb of the internal capsule. 3. Anterior border is the interventricularforamen (of Monro). 4. Posterior border is the largeposterolateralnuclearmass,the pulvinar, which overliesthe superiorcolliculus. 5. Superomedialborder is the floor of the lateralventricle. 6. Inferior border is the hypothalamicsulcus. B. Principal fiber tracts running through or bordering the thalamus. 1. The external medullary larnina lies on the lateralborder of the tlalamus, just medialto the posteriorlimb of the internal capsule. 2. The internal rnedullary lamina divides the thalamusinto ventral, lateral, medial, and anterior portions, 3. The thalamic radiation (thalamocorticalfibers) is locatedon the lateralpart of the thalamus and sendsfibersto t}le cerebralcortex. 4. The stria terminalis is the principal effer€ntpathwayftom the amygdala.The stria terminalislieson the superolateralborderof the diencephalonbetweenthe thalamusandthe caudatenucleus.Someof thesefibersterminate in the anterior nucleusof the thalamus. while most terminatein the bed nuclei of the stria terminalis.

451

Nervous System

5. The stria medullaris is a midline structure that archesalong the superomedialsurfaceof the thalamus.The stria medullaris carries .rxonsfrom the anterior thalamic nuclei, the preoptic area,the globus pallidus, and the septal nuclei to the habenular nuclei (part of the epithalamus). 5. The mammillothalamic tract originates in the mamillary nuclei and terminates in the anterior nuclear group of the thalamus. The mammillothalamic tract is an important part of limbic circuitry.

THALAMIC NUCTEI Thalamic nuclei may be consideredby anatomic divisions,in which casethere are sevengroups of thalamic nuclei; or by functional considerations,in which casethere are four groups of thalamic nuclei. A. Anatomic divisions 1. Anterior nuclear group (part of the Papezcircuit) a. Input is from the mamillary bodiesvia the mammillothalamic tract and from the cingulate gyrus.

Note Theanterior nucleus and dorsomedial nucleus ofthe thalamus areinvolved with thelimbic system.

b. Output is to the cingulate gyrus via the anterior limb of the internal capsuleand to the habenularnuclei via the stria medullaris thalami. 2. Medial nuclear group (dorsomedialnucleus) a. Input is from other thalamic nuclei (centromedian,intralaminar, lateral group) and from the amygdala,prefrontal cortex, and temporal lobe. b. Output is to the prefrontal cortex and cingulate gyrus. 3. Midline nuclei. This diffi,rsegroup is located around the third ventricle and in the massa intermedia (i.e., the interthalamic adhesion).Input and output vary with various thalamic nuclei. Most nuclei have diffirseprojections to large areasof the cerebralcortex. 4. Intralaminar nuclei lie between the medial and lateral thalamic nuclei. a. Input is from the brain stem reticular formation and Brodmann areas4 and 6 of the frontal lobe. b. Output is to the putamen, the globuspallidus,aswell asto extensiveneocorticalareas. 5. Lateral nuclear group a. Lateral dorsal nucleus (1) Input is not known, but it is presumedto be similar to the anterior thalamic nuclei. (2) Output is to the cingulategyrus and parietal cortex. b. Lateral posterior nucleus (l) Input is possiblyfrom the ventral posterior nucleus. (2) Output is to the parietal cortex (Brodmann areas5 and7). c. The pulvinar is a large nuclear masslocatedposterolaterallyin the thalamus. ( 1) Input is from other thalamic nuclei, the superior colliculus,and the neocortex. (2) Output is to the parietal,temporal, occipital,and prefrontal cortex.The pulvinar is an important relay in the extrageniculatevisual pathway.

462

Neuroanatomy: TheThalamus

6. Ventral nuclear group a. Ventral anterior nucleus (\) (1) Input is from the globus pallidus, substantianigra, and other thalamic nuclei. (2) Output is to the premotor and prefrontal cortex, and other thalamic nuclei. b. Ventral lateral nucleus (Vr) (1) Input is from the globus pallidus, dentate nucleus of the cerebellum, and Brodmann areas4 and 6 of the frontal lobe. (2) Output is to Brodmann area4.

Note V^andV,receive motor projections ganglia. frombasal V,alsoreceives inputfrom cerebellum.

c. Ventral posterolateral (VPL) nucleus (1) Input somatosensoryand nociceptiveinformation ascendsvia the medial lemniscusand spinothalamictract. (2) Output is to Brodmann areas3, 1, and 2 of the parietal lobe. d. Ventral posteromedial (VPM) nucleus ( 1) Input is from the ascendingtrigeminal pathways. (2) Output is to Brodmann areas3, 1, and 2 of the parietal lobe (postcentralgyrus).

e. Ventralposteromedialnucleus,parsparvocellularis(VPM'.)

In a NuBhell VPLandVPMarerelaynuclei forascending sensory information fromthebody $/PL)andtheface(VPM).

(1) Input. Gustatory information comesfrom the nucleusof the solitary tract. (2) Output is to the dorsal half of the anterior insula. 7. Metathalamus (posterior thalamus) a. Medial geniculatebody (or nucleus)

In a NuBhell

( 1) Input. Auditory information ascendsfrom the inferior colliculus.

. Medial geniculate-audition

(2) Output. Acoustic radiations project to Hesctrlgyrus (transversetemporal gyrus).

. Lateral geniculate-vision

b. Lateral geniculate body (or nucleus) (1) Input is from the optic tract and superior colliculus. (2) Output. Geniculocalcarineradiation projectsto the striate cortex. B. Functional divisions 1. Midline and intralaminar nuclei receiveinput from the brain stem reticular formation. They appear to be important in mediating desynchronizationof the electroencephalogram (EEG) during behavioral arousal.Repetitiveelectrical stimulation of these nuclei can produce widespreadchangesin electricalactivity of the cortex.Damageto the posterior aspectof the central median nucleus (one of the intralaminar nuclei) can produce unarousablesleep.

ln a Nubhell Midline andintralaminar nuclei areinvolved in attention andbehavioral arousal.

2. Association nuclei, the lateral nuclear group and dorsomedial nucleus,receiveinput from other diencephalicnuclei and project to the associationareasof the cortex. The association nuclei probably integrate complex somatic, visual, and auditory inputs. 3. Specific sensory relay nuclei (i.e., the medial and lateral geniculatebodies,VPL, VPM, VPM".) receivesensoryinput and project in an organizedmanner to the primary sensory areasof the cerebralcortex. The somatic sensoryinput (i.e.,tactile, pain, temperature sensationfor the face)that reachesthe VPL nucleus (body) and VPM nucleus (face)projects to the primary somestheticarea (Brodmann areas3, 1, and 2) and the secondary somestheticareaof the cerebralcortex.

46t

Nervous System

4. Cortical relay nuclei (i.e.,anterior nuclear group, ventral lateral,part of the ventral anterior) receiveinput from well-defined subcortical areasand project to specific cortical areas.For example,the anterior nuclear group receivesinput from the mamillary nuclei of the hypothalamusand the hippocampus and sendsprojections to the cingulate gyrus of the cortex.

464

TheHypothalamus portion Thehypothalamus istheinferior ofthediencephalon andformstheroofandventrolateral wallsofthethirdventricle. Thehypothalamus iscomposed of numerous nuclei thathaveafferent andefferent connections withwidespread regions ofthenervous system, including thepituitary gland, theautonomic system, andthelimbic system. Thus, thehypothalamus ispartofa larger system of neural circuits thatcontain complex integrative mechanisms forregulating emotional reponses andothermotivated behaviors.

BOUNDARIES A. Medial boundary is at the third ventricle. B. Lateral boundary is in the subthalamicregion. C. Rostral boundary is at the lamina terminalis. The lamina terminalis is found near the midline, where the anterior neuropore closes.This is the only site where fibers from one cerebral hemispherecan crossto reachthe other hemisphere(the corpus callosumis derivedfrom the lamina terminalis). D. Caudal boundary is at the tegmentum of the midbrain. E. Dorsal boundary is at the thalamus. F. Ventral (inferior) boundary is an exposedsurface.

GROSS ANATOMIC DIVISIONS A. Rostrocaudal zones of the hypothalamus 1. The supraoptic zone is the most rostral (anterior). 2. The tuberal zone is the most intermediate. 3. The mammillary zone is the most caudal (posterior). B. Longitudinal zones of the hypothalamus 1. Periventricular znlneis the most medial. 2. Intermediate zotrc 3. Lateral zone

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HYPOTHATAMIC NUCTEI Dorsomedial

Paraventricular nucleus nucleus

Posterior nucleus

Thalamus

Preopticarea Anteriornucleus nucleus Suprachiasmatic Supraopticnucleus Opticchiasm

Arcuatenucleus lnfundibulum Hypophysis

Figure V-22-1.The hypothalamic nuclei.

A. The preoptic nucleus is located in the rostral hypothalamus near the walls of the third ventricle.

Bridgeto Endocrine System andsupraoptic Paraventricular nuclei ADHand synthesize oxytocin andtransport them pituitary, to theposterior from whichtheyarereleased. The mechanism of action ofthese hormones isdiscussed inthe Endocrine Physiology chapter of OrganSystems Book2 (Volume lV).

466

B. Nuclei of the supraoptic area. This region lies immediately posterior to the preoptic nuclei. Two nuclei of this area,the paraventricular and supraoptic nuclei, synthesizethe neuropeptides ADH and oxftocin. These neuropeptides are synthesizedby different neurons in the hypothalamus and are transported to the posterior pituitary, from which they are released. C. Nuclei of the tuberal region 1. Ventromedial nucleus 2. Dorsomedial nucleus 3. Arcuate nucleus 4. Lateral nucleus D. Nuclei of the mammillary region 1. Mammillarynuclei, 2. Posterior nucleus

which are located in the mammillary bodies

Neuroanatomy: TheHypothalamus

CONNECTIONS OFTHEHYPOTHATAMUS A. The medial forebrain bundle (MFB) carries both ascending and descending fibers that interconnect the hypothalamus with various limbic structures and tegmental and central gray regions of the brain stem. Many of the ascendingserotonergic,dopaminergic, and noradrenergic fibers ascendin the MFB. B. Fornix. This prominent fiber bundle arises largely from the hippocampal formation. It divides into two separatecolumns in the septal area. 1. Precommissural fibers. These axons terminate in the anterior hypothalamic area and septalnuclei. 2. Postcommissural fibers. These.xons terminate mainly in the medial mammillary nucleus, while some fibers passdirectly to the anterior nuclear group of the thalamus (the mammillary nuclei send a large projection to the anterior nuclear group of the thalamus). C. The dorsal longitudinal fasciculus carries afferents to the hypothalamus from the brain stem reticular formation and carries hypothalamic efferents to the midbrain, central gray, and tectum. D. Amygdaloid projections to the hlpothalamus 1. The stria terminalis is the largestefferent bundle from the amygdala.Thesefibers project to the bed nucleus of the stria terminalis, the medial preoptic area,and the ventromedial hypothalamic nucleus. 2. Ventral amygdalofugul pathway. Thesefibers project to the lateral preoptic area,the septal nucleus, and the nucleus of the diagonal band of Broca. E. The mammillothalamic tract originates in the mammillary nuclei and terminates in the anterior nuclear group of the thalamus. F. Tuberoinfundibular tract. These fibers originate largely from tuberal nuclei and terminate in the median eminence. These fibers carry releasing hormones (factors) that are synthesized in hypothalamic nuclei. The terminations of these axons are in closeproximity to the sinusoidal capillaries of the hypophyseal-portal system. The releasing hormones (e.g., thyrotropin-releasing hormone, TRH) enter thesecapillariesand passthrough the hypophysealportal veins to reach the secondarycapillary plexus in the anterior pituitary gland. G. Supraopticohlpophysial tract. This pathway carries axons that originate in the neurosecretory nuclei, the supraoptic nuclei, and paraventricular nuclei. Cells in thesenuclei synthesize oxftocin and antidiuretic hormone (ADH or vasopressin).Axons arising from these nuclei carry neurosecretory granules to the posterior pituitary gland, where they are releasedinto capillariesof the pars nervosa(posterior pituitary gland).

Bridgcto Physiology Tuberoinfundibular dopamine fibers inhibit thesecretion of prolactin fromtheanterior pituitary. Blockade of dopamine receptors by antipsychotic drugsincreases prolactin andcanproduce gynecoma$ia.

H. The retinohypothalamic tract originates in the retina and terminates in the suprachiasmatic nucleus. This pathway may be important for the entrainment of certain body rhythms to the 24-hour light-dark rycle (circadian rhythms).

467

NervousSystem

FUNCTIONS OFTHEHYPOTHATAMUS The hypothalamusis an important regulatorycenterfor the control of the endocrineand autonomic nervous systems,including temperature,hunger, thirst, sexual activity, and the emotional statusof the organism. A. Endocrine control 1. Regulationof hormone synthesisin the anterior pituitary gland 2. Synthesis,transport, and releaseof oxytocin and ADH B. Regulation of the autonomic nervous system 1. Hypothalamic areashaveimportant influenceson both sympatheticand parasympathetic functions. 2. Individuals with hypothalamiclesionsmay show a variety of emotional disorders,including rage and depressivereactions. C. Temperature control 1. The anterior hypothalamus sensesan elevation of body temperature and mediatesthe responseto dissipateheat. 2. Lesionsof the anterior hypothalamuslead to hyperthermia. 3. The posterior hypothalamussensesa decreaseof body temperatureand mediatesthe conservationof heat. 4. Lesionsof the posterior hypothalamuslead to poikilothermy (i.e., cold-blooded organisms). Thus, an individual with a lesion of the posterior hypothalamushas a body temperature that varieswith the environmental temperature. D. Ingestive behaviors 1. Food intake is largely controlled by the hypothalamus. Lesions of the ventromedial hypothalamus often result in obesity,whereaslesionsof the lateral hypothalamus produce severe aphagia. These observations originally led to speculation that the ventromedial hypothalamusis a satietycenterand the ventrolateralhypothalamus is a feedingcenter.The hypothalamus,however,is not organizedinto discretecenterscontrolling specificfunctions. There are complex and distributed neural circuits involving the hypothalamusthat integrate a variety of sensory motor, and gastronomic functions to regulate weight and feeding behaviors. 2. Osmoreceptors are sensitive to changesin osmolariry and influence the synthesis and releaseof ADH. 3. Lesions of the supraoptic nuclei lead to diabetesinsipidus, which is characterizedby polydipsia (excesswater consumption) and polyuria (excessurination). Thesesymptoms result from deficient ADH svnthesisand release.

468

Neuroanatomy: Ihe Hypothalamus

E.serualdisorders

, !!!.l!!S!g!f

1. C€rtainhypothalamic areasaresensitive to androgens and estrogens, whileotherarcas influencetheproductionof sexhormonesthroughtheir regulationof theanteriorpiturtary.

Hypothalamic Funclions '.'.. . ' Watey'salt balance viaADH

2. Priorto puberty,hypothalamic lesionsmayarrestsexualdevelopment, whileprecocious pubertyhasrarelybeenobserved.

' ReSulation ofautonomic nervous $Atem . Regulation ofbod temDerature

3. Afterpuberty,hypothalamic lesionsmayresultin amenorrh€a or impotenc€.

. Regulation ofingestive behavioy'food intake r

. Sexual maturation and childbirth

469

TheEpithalamus andSubthalamus Theepithalamus gland, consists ofthepineal qrcle, whichisinvolved in regulation ofthediurnal andthehabenular nuclei, whichrelayinformation frompartsofthelimbic system to thebrainstem. Thelastdiencephalic derivative, thesubthalamus, isinvolved withmotorfunction andiscovered in moredetailin theMotorSystem chapter.

EPITHATAMUS The epithalamusis the part of the diencephalonlocatedin the region of the posterior commissure that consistsof the pineal body and the habenular nuclei. A. The pineal body (epiphysis), a small, highly vascularizedstructure, is located closeto the posterior commissureand is attachedby a stalk to the roof of the third ventricle. 1. Internal structure. The pineal body contains pinealocytesand glial cellsbut no neurons. 2. Functions of the pineal body are incompletely understood. Pinealocytessynthesizemelatonin, serotonin, and cholerystokinin (CCK). The pineal gland plays a role in growth, development, and in the regulation of circadian rhythms. Environmental light regulates the activity of the pineal gland through a retinal-suprachiasmatic-pinealpathway. 3. Lesions a. In young males,pineal lesionsmay causeprecociouspuberty. b. Pineal tumors may causeobstruction of cerebrospinalfluid (CSF) flow and increased intracranial pressure.Large tumors may causecompressionof the upper midbrain and pretectalareaand the expressionof Parinaud syndrome (i.e.,impairment of conjugate vertical gaze,pupillary abnormaliry absenceof the accommodationreflex). B. Habenular nuclei are located superior and anterior to the pineal gland. Although the function of the habenularnuclei remainsunknown, they appearto act asrelaysbetweenthe limbic systemand the midbrain. The principal afferentprojection to the habenularnuclei is via the stria medullaris thalami. The principal efferent pathway is the fasciculus retroflexus, which projects to the interpeduncular nucleus.

SUBTHATAMUS The subthalamusis locatedbetweenthe thalamus (dorsally) and the midbrain (ventrally).Fibersof the internal capsulelie laterally.The subthalamusincludes the rostral portions of the red nucleus and substantianigra and the subthalamic nucleus itself. The subthalamic nucleus is connected reciprocally with the globus pallidus via the subthalamic fasciculus. Lesions of the subthalamic nucleusmay causehemiballismus, which consistsof violent, ballistic movements,usually restricted to the contralateralextremities,but possiblyinvolving the axial or facial muscles.

471

TheLimbicSystem

Thelimbicsystem isinvolved in thecontrol of emotion, attention, drives, andmemory. lt consists of group a diverse ofstructures, including thehippocampal formation, amygdala, nuclei, septal andthe cingulate andparahippocampal thalamus, andmedial ryri,aswellaspartsofthehypothalamus, tegmentum. Limbic structures haveafferent withotherlimbicstructures, andefferent connections (particularly withassociated areas of thecerebral hemispheres, andwithbrain$em$ructures the hypothalamus, theanterior anddorsomedial nuclei of thethalamus, andthereticular formation). (e.g., Dopaminergic, noradrenergic, andserotonergic fibers andvarious neuropeptides endorphins) influence thelimbic system. Various neuropeptides, mainly inthehypothalamus, bindto synthesized receptors oncellsin several limbicnuclei, especially thoseclose to theventricular sy$em. Therole remains oftheselimbicinputs undefined,

STRUCTURES OFTHETIMBIC SYSTEM The hippocampal formation extends along the floor of the inferior horn of the lateral ventricle and includes the hippocampus proper, the dentate gyrus, and the subiculum. The hippocampus proper and the dentate gyrus are characterizedby a three-layer cortex, the archipallium. A. Dentate gfrus. Granule cells, the main cell type of the dentate gyrus, project to pyramidal cells of the the hippocampus proper. The granule cells of the dentate gyrus do not project beyond the hippocampal formation. B. Hippocampus proper (Ammon horn, cornu Ammonis, CA) is divided into four fields (CAl, CA2, CA3, CA4) based upon the morphology and connectivity of the pyramidal cell layer. CAI is located closestto the entorhinal cortex. Pyramidal cells representthe output neuron of the hippocampal formation. The ventricular surfaceof the hippocampus is coveredby the alveus,which is formed by the axons of pyramidal cells located in the hippocampus and the subiculum. As the fibers of the alveusproceed medially, they convergeto form the fimbria and, finally, the fornix.

In a Nutshell from cellsoutput foramidal thehippocampus viathe fimbria andthenthefornix.

1. Afferent connections a. The hippocampus and dentate gyrus receive their largest input from the nearby entorhinal area,which, aspart of the parahippocampal gyrus, can be seenon the inferior surface of the temporal lobe. The entorhinal area receives afferents from the cingulate gyrus via the cingulum, almost all sensory association cortices, rnd several brain stem structures, including the locus coeruleus.

47'

NeruousSystem

In a Nutshell Themaininputtothe gyrus hippocampus/dentate isfromtheentorhinal cortex viatheperforant and pathways. alvear

b. Projectionsfrom the entorhinal cortex reachthe hippocampal formation via two routes. (1) Perforant pathway. Axons from the lateral entorhinal cortex perforate the subiculum and terminate in all parts of the hippocampus and dentate gyrus. (2) Alvear pathway. Axons from the medial entorhinal cortex enter the hippocampus by following the ventricular surface. c. Small projections from the septum and the contralateralhippocampus reachthe hippocampusvia the fornix. d. The hippocampus receivesmodulatory input from the raphe nuclei (serotonin), the locus coeruleus(norepinephrine),and the ventral tegmentalarea(dopamine).

2 . Efferent connections. The fornix is the major efferentpathway of the hippocampal formation. It is the large,C-shapedfiber bundle that coursesalong the undersurfaceof the corpus callosum.Almost all fibers in the fornix arisein the hippocampus and the subiculum. fu the fornix approachesthe anterior commissure,it divides into nvo unequal halves. a. The smaller,precommissuralpart descendsin front of the anterior commissureand terminatesin the septum. b. The substantiallylarger,postcommissuralportion projects to the septum, the mammillary nuclei, the anterior thalamic nucleus, the frontal cortex, the cingulate gyrus, the parahippocampalgyrus, and the mesencephalicreticular formation.

DG PP mf Sch Ent

= = = =

dentate gyrus perforant pathway mossy fiber Schaffer collateral entorhinalcortex

Figure V-24-1.Thetrisynaptic pathway of the hippocampus. (Modifiedwith permissionfrom ShepherdGM:The SynapticOrganizationof the Brain.NewYork,NY:OxfordUniversityPress,1990,p.360.)

474

Neuroanatomy: ThelimbicSystem

3. Intrinsic circuitry. Information reachingthe hippocampus is processedby a trisynaptic pathway that servesas a feed-forward loop. All synapsesare excitatory and use the neurotransmitter glutamate (FigureV-24-l). a. Granule cells in the dentate gyrus receive projections from the entorhinal cortex through either the perforant pathway or the alvear pathway.

In a Nutshell

b. Granule cells,in turn, send mossy fiber projections to the pyramidal cellsin the CA3 region of the hippocampus.

Cranule cellsreceive entorhinal cortex inputs, They project mossy fibersto CA3 pyramidal These cells. send axons outofthehippocampus viathefornix.

c. Pyramidal cells in the CA3 region project to areasbeyond the hippocampus via the fornix. Schaffercollateralsfrom these pyramidal cells provide feedbackto the CAI region of the hippocampus. C. Parahippocampalgyrus is the most medial convolution of the temporal lobe.It containsthe entorhinal and subicular areas. 1. Afferent connections. The parahippocampal gyrus receivesinput from the cingulate gyrus, sensoryassociationcortices,and brain stem structures. 2. Efferent connections. The parahippocampalgyrus projects to the hippocampus and to many areasoutside the hippocampusvia the fornix. D. The amygdala is an almond-shapednuclear mass located deep in the medial part of the anterior temporal lobe. 1. Afferent connections include inputs from the cingulategyrus, associationcortices,olfactory bulb, hypothalamus, thalamic nuclei (e.g., dorsomedial nucleus), pontine parabrachialnuclei, and reticular formation.

Note

2. Efferent connections a. The stria terminalis is the largest efferent projection from the amygdala.Most fibers terminate in the bed nuclei of the stria terminalis, while others passto the anterior hypothalamusor join the medial forebrain bundle.

Thestria is terminalis themajoroutputpathway oftheamygdala.

b. The ventral amygdalofugal pathway terminates in the hypothalamus, septum, and dorsomedialnucleusof the thalamus. c. The amygdalocortical and amygdalostriate projections are distributed to wide areas of the neocortexand ventral striatum. E. The septal nuclei (septalarea) are locatedmedially betweenthe anterior horns of the lateral ventricle. The septal area has reciprocal connectionswith the hippocampus,hypothalamus, and other brain stem structures. F. The cingulate gyrus is a long curved gyrus locatedon the medial surfaceof eachhemisphere abovethe corpus callosum. 1. Afferent connections are from many cortical association areas and from the anterior nuclear group of the thalamus. 2. Efferent connections are to the associationcortices,entorhinal area,amygdala,and certain thalamic nuclei.

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Neruous System

FUNCTIONS OFTHETIMBICSYSTEM The limbic system consists of a diverse group of structures that are strategically situated betweenthe neocortexand brain stem. Basicdrives and instincts (e.g.,hunger,sex,sleep)that are controlled primarily by the hypothalamus and other brain stem structures may be influenced by the neocortex via the limbic system.Similarly, these lower centersmay modifr cortical activity via the limbic system.The limbic systemis involved in emotion, memory, attention, and feeding and mating behaviors. A. Emotion. Papez(pronouncedPapz) describeda circuit between limbic structures and parts of the diencephalon that allows the cortex to influence the emotional state of the organism. The cortex is kept apprisedof the emotional stateof the animal through reciprocalconnections. It is now well acceptedthat the Papez circuit oversimplifies the role of the limbic system in modulating feelings, such as fear, anxiety, sadness,happiness, sexual pleasure, and familiarity; yet, it provides a useful starting point for understanding the system (Figure V-24-2).

Cingulum

Entorhinalarea of the parahippocampal

group Anterior nuclear

Mammillothalamic tract

Mammillarybodies of the hypothalamus

Figure V-24-2.The Papez circuit.

B. Memory. Severallimbic areas(i.e.,hippocampus,mammillarybodies, dorsomedialnuclei of the thalamus) appearto be important in the acquisition of new information. 1. Bilateraldamageto the medial temporal lobesin humans resultsin a profound lossof the ability to acquire new information. The classicdemonstration is provided by patient H.M., who receivedbilateral temporal lobectomiesin an attempt to manageintractable epilepsy.The exact sites necessaryto produce this anterograde memory deficit have not been fully elucidated,but almost certainly include the hippocampus. 2. The degreeof memory loss in Alzheimer and Pick diseasescorrelateswith the extent of degenerationin the pyramidal cell layer of the hippocampus.Electricalstimulation of the hippocampus may produce the sensationof d6jnvu or jamais vu, in addition to a variety of other feelingsand emotions.

476

Neuroanatomy: ThelimbicSystem

3. A memory deficit similar to that describedaboveis observedin patients with Korsakoff syndrome. Korsakoff syndrome is seen mainly in alcoholics who have a thiamine deficienry and often follows an acute presentation of Wernicke encephalopathy(ocular palsies,confusion,gait ataxia),which is alsorelatedto a thiamine deficiency.In WernickeKorsakoff syndrome, lesions are alwaysfound in the mammillary bodies and the dorsomedial nuclei of the thalamus. C. Aggression and docility. In some animals, lesions of the amygdala result in a marked decreasein aggressivebehavior; electrical stimulation, on the other hand, leads to a rage reaction. Becausestimulation of other limbic structures may produce rage responses,the amygdalashould not be considereda ragecenter.

ln a Nutshell Anterograde amnesia canbecaused by bilateral hippocampal lesions, ln Korsakoff syndrome, anterograde amnesia isassociated with thiamine deficiency and lesions ofthemammillary bodies.

BEHAVIORAT DEFICITS ASSOCIATED WITHDAMAGE TOTHELIMBICSYSTEM A. Kliiver-Bocy syndrome. Kluver and Bucy made bilateral lesions of the amygdala and hippocampusin monkeys.They describedthe following set of behavioralchangesas a result of theselesions,some of which overlap. 1. Psychic blindness. Objects in the visual field are treated inappropriately. For example, monkeys may approach a snakeor a human with inappropriate docility. 2. Hypermetamorphosis. Visual stimuli (even old ones) are repeatedly approached as though they were completely new.

In a Nutshell Kli.iver-Bucy Syndrome . Bilateral lesions of amygdala and hippocampus . Psychic blindness

3. Increased oral exploratory behavior. The monkeys put everything in their mouths, eating only appropriateobjects.

. Failure to recognize familiar objects

4. Hypersexuality and loss of sexual preference. The male monkeys mount anything in sight.

. Hypersexuality

B. Partial complex seizures (temporal lobe epilepsy, TtE) result from seizuresfocused in limbic portions of the temporal or frontal lobe. The seizuredischargeis often accompaniedby an epigastricsensation,fear,feeling of unreality, anxiety,and ddjn vu. In some patients,certain characteristicbehavioral changesdevelop during the long-term interictal period (i.e., betweenseizures),such as a deepeningof emotions, decreasedlibido, a tendenry to go on and on about each topic (viscosiry hypometamorphosis),increasedphilosophical or religious interests,excessive diaries and writings, irritability, and psychosis. C. Infections, tumors, drugs, and psychiatric illnesses

In a Nutshell Partial complex seizures originate inthetemporal lobe orfrontal lobe.Seizures are characterized bychanges in mood,oddsensations, or oddbehavior.

I. Papeznoted that involvementof the hippocampuswith rabiesinfection is associatedwith striking emotional changes,such as outbursts of rageand anxiety. 2. Tumors originating in limbic portions of the frontal and temporal lobes are known to causea variety of behavioral changesoften seenin psychiatricdisease. 3. Becausemany psychoactivedrugs affect limbic structures,thesemay be important sites for the pharmacologicaction of mood-altering and hallucinogenicdrugs. 4. Illnessessuch as mania, depression,and schizophreniamay be diseasesof the limbic system, although conclusive evidenceis lacking at present.

477

TheMotorSystem involuntary including movements, muscular skeletal forcontrolling isresponsible Themotorsystem are formotorcontrol responsible posture, Neural structures movements. andvolitional reflexes, ganglia, cerebellum, parts basal cortex, frontal of the include and theneuraxis throughout located cord. inthebrainstemandspinal fibertracts andtheirafferent of motornuclei andcollections thecorticospinal through sentfromthemotorcortex bysignals aremediated movements Volitional hornof inthebrainstemor intheventral in motornuclei whichterminate tracts, andcorticobulbar pyramidal modulated is system, the known as commonly ofthissystem, thespinal cord.Theoutput to the refers ganglia. thetermextrapyramidal Historically, andbasal fromthecerebellum byinputs suchas diseases, bydegenerative isillustrated ganglia, in motorcontrol anditsimportance basal disease. or Huntingon Parkinson

SYSTEM PYRAMIDAL The pyramidal systemis mainly concernedwith the production of skilledvolitional movements. A. Origin 1. Primary motor cortex (precentral gyrus, Brodmann area4) is comprised of pyramidal cellsin layersthree and five (including the giant pyramidal cells,the Betzcells),which give rise to about 30o/oof the pyramidal fibers. 2. Premotor area (Brodmann area6) givesrise to about 30o/oof the pyramidal fibers. 3. Parietallobe (Brodmann areas1,2,3,5) givesrise to about 40o/oof the pyramidalfibers. 4. Temporal and occipital lobes probably contribute a small percentageof pyramidal fibers. B. Projections. Axons of the pyramidal systempassthrough the posterior limb of the internal capsule.The internal capsuleis a large white matter structure, which carries afferentsand efferents to and from the cerebral cortex. After passing through the internal capsule, descendingcerebralpyramidal fibers enter the cerebralpeduncle. C. Termination 1. Corticobulbar fibers of the pyramidal system leave the cerebral peduncles at different brain stem levelsto supply the: a. Motor nuclei of the oculomotor (CN III), trochlear(CN IV), and abducens(CN VI) nerves,which supply the extraocularmuscles. b. Motor nucleusof the trigeminal nerve (CN V), which suppliesthe musclesof mastication. c. Motor nucleusof the facialnerve(CN VII), which suppliesthe musclesof facialexpression.

Note motorcortex Theprimary ontheprecentral islocated gyrus lobe. ofthefrontal ln a Nutshell Motorcortex

I

V Internal capsule (posterior limb) I I

V

peduncle Cerebral ,/\ ,/\ CorticobulbarhTramids fibers I (brain stem) V Corticospinal tract (spinal cord)

479

Neruous System

d. Motor nuclei of the glossopharyngeal(CN IX) and vagus (CN X) nerves,which supply the musclesof the pharynx and larynx. e. Motor nucleusof the spinal accessorynerve (CN XI), which suppliesthe trapeziusand sternocleidomastoidmuscles. f. Motor nucleusof the hypoglossalnerve (CN XII), which suppliesthe tongue muscles.

ln a Nutshell Mostcorticospinal fibers cross inthelowermedulla, then descend asthelateral corticospinal tract, which terminates intheventral horn.

2. Corticospinal fibers descend through the cerebral peduncles, and pass through the medullary pyramids. a. Roughly 80-90% of the corticospinal fibers cross in the medullary decussationand continue as the lateral corticospinal tract. These fibers terminate on lower motor neurons and interneurons in the contralateral (with respectto their cortical origin) half of the spinal cord. b. About l0-20o/oof the corticospinal fibers do not cross in the medulla but continue ipsilaterally as the anterior corticospinal tract. These axons cross shortly before they terminate,probably all on interneurons.

Note = neostriatum + putamen Caudate

Note Thecaudate bulges intothe lateral ventricle, forming iS lateral wall.

EXTRAPYRAMIDAT SYSTEM A. Overview. The basalganglia are prominent subcorticalnuclear masses,which are of telencephalic origin. They are located lateral to the thalamus with the internal capsulelying between.The basalgangliaconsistof the corpus striatum, i.e.,caudate,putamen, and globus pallidus. The substantianigra and subthalamicnuclei are sometimesincluded for functional reasons. B. The caudatenucleus is a C-shapedstructure that lies closeto the lateral ventricle throughout its course.The lateral ventricle lies medially,while laterallythe internal capsuleseparates the caudatefrom the lenticular (i.e.,putamen, globus pallidus) nucleus.Anteriorly, the caudate reachesits largestextent and is referredto asthe head of the caudatenucleus.The body of the caudateis posterior to the head and tapersinferiorly to form the tail, which is continuous with the amygdala. l. Afferents a. Corticostriatefibers arisefrom many areasof the neocortex;however,the largestprojection is from motor, premotor, and prefrontal cortices. b. Thalamostriatefibers arisefrom the intralaminar thalamic nuclei.

In a Nutshell Theneostriatum receives projections fromthecortex, thalamus, andthedopamineg nigrostriatal containin pathway (fromthesubstantia nigraparscompacta). In a Nutshell Theneostriatum projects to pallidus theglobus andthe parsreticulata. substantia nigra

480

c. Dopaminergic nigrostriatal fibers arisefrom the substantianigra. 2. Efferents a. Striatopallidalfibers terminate in the globus pallidus. b. Striatonigral fibers of the striatonigral tract terminate in the substantianigra. C. The putamen and the caudate nucleus collectively comprise the neostriatum. The putamen and globus pallidus were thought to look like a lens, and these two nuclei are collectively calledthe lenticular nucleus.The putamen lies lateral to the globus pallidus.They are separated by the external medullary lamina, which forms the medial border of the putamen, while the external capsulelies laterally.The putamen is the largestnucleus in the basalganglia.The afferentand efferentconnectionsof the putamen are similar to those of the caudatenucleus.

TheMotorSystem Neuroanatomy:

D. The globus pallidus (pallidum) makesup the medial portion of the lenticular nucleus. The external medullary lamina separatesthe pallidum from the putamen, while the internal medullary lamina divides the pallidum into medial (internal) and lateral (external) parts. 1. Afferents

Note pallidus ismedial; Theglobus islateral. theputamen

a. Striatopallidal fibers arise from the striatum and project to the globus pallidus. b. Subthalamopallidalfibers originate in the subthalamicnucleus and project to both segments of the globus pallidus. 2. Efferents a. Pallidothalamic fibers are as follows: (l) The ansa lenticularis is a bundle of pallidal efferents that proceed medially around the descendingfibers of the internal capsule. (2) The lenticular fasciculus (Forel field H2) carries pallidal efferents that pass through the internal capsuleand proceedmedially betweenthe zona incerta and the subthalamicnucleus. (3) The ansa lenticularis and lenticular fasciculus both carry efferents from the globus pallidus. On the medial border of the zona incerta, thesebundles merge to form the thalamic fasciculus, which terminates on cells in the ventral anterior, ventral lateral,and centromediannuclei of the thalamus. b. Pallidosubthalamicfibers project to the subthalamic nucleus.Thus, the globus pallidus and subthalamicnucleusare reciprocallyconnected. c. Pallidotegmentalfibers terminate in the midbrain tegmentum. E. The subthalamic nucleus is situated on the medial side of the ventral portion of the internal capsule.It is located rostral to the substantianigra and is consideredpart of the diencephalon. F. The substantia nigra is a darkly pigmented nucleus extending throughout the midbrain- It divides the cerebral peduncle into the crus cerebri ventrally and the tegmentum dorsally. l. Afferents. The main input to the substantianigra comesfrom the basalganglia. 2. Efferents a. Nigrostriatal fibers carry dopamine from the substantia nigra pars comPactato the caudate and putamen. This is the largest projection from the substantia nigra. Destruction of this pathway occurs during Parkinson disease. b. Nigrothalamic fibers terminate in the ventral anterior and the ventral lateral nuclei of the thalamus. G. Diseasesthat alter the function of the basal ganglia. The functions of the basal ganglia are poorly understood.It appearsto be involved in the coordination of movementsby relaying and integrating information concernedwith posture and volitional movements.Most of our knowledge about the basal ganglia comesfrom diseasestatesthat alter its normal functions.

Correlate Clinical pathway Thenigro$riatal in Parkinson degenerates to dopamine leading disease, intheneo$riatum deficiency motorproblems. andassociated

l. Parkinson's diseaseis characterizedbydegenerationof the substantianigra and by considerableneuronalloss.Clinical manifestationsof ParkinsondiseaseaPpearto result from destruction of the dopaminergic nigrostriatal pathway.Dopaminergic antagonists,such as the phenothiazinesor butyrophenones,ffioy result in a Parkinsoniansyndrome.

481

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In a Nutshell Symptoms of Parkinson Disease . Resting tremor . Bradykinesia . "Cogwheel" rigidity . Masked facies . Festinating (shuffling) gait In a Nutshell HuntingonDisease . Quick purposeless (chorea) movements . Writhing (athetoid) mOvements . Dementia, moodchanges

a. Tiemor is apparent during rest (resting tremor) and is attenuatedduring voluntary movements.This is the opposite of a cerebellartremor, which is most apparent during volitional movements.Neurosurgical lesions of the ventral lateral nuclei of the thalamus can relieve this tremor. b. Bradykinesia is manifested by a difficulty in initiating movements and by slownessof voluntary movements. c. Rigidity is due to increasedmuscle tone. This resultsin a stoopedposture,becauseit is more prominent in flexors. d. An expressionlessfacies ("maskedfacies")is observed. e. A festinating gait refers to an acceleratinggait during which individuals seemsto "chasetheir centerof gravity." 2. Chorea results from lesions of the basal ganglia.The term chorea is derived from the Greek word for "dance."It refersto involuntary movementsthat are purposeless,quick jerks that may be superimposedon voluntary movements.Choreais a frequent symptom in the following conditions. a. Huntington disease exhibits autosomal dominant inheritance. It is char acterized pathologicallyby severedegenerationof the caudatenucleusalong with degenerative changesin the putamen and cortex. In addition to chorea,thesepatients frequently suffer from athetoid movements,progressivedementia,and behavioraldisorders. b. Sydenhamchorea is a transient complication in some children with rheumatic fever. There is no residualdefect. c. Lesch-Nyhan syndrome resultsfrom a lack of the enrymehlryoxanthine-guaninephosphoribosyltransferase (HGPRT).This is inheritedby malesasa sex-linkedrecessive trait. Onsetusuallyoccursby 1 yearof age.Choreoathetosis occursalongwith decreased mental capaciryspasticparalysis,self-mutilation,and uric acid kidney stones. 3. Athetosis refersto slow, worm-like, involuntary movementsthat are most noticeablein the fingers and hands but may involve any muscle group. It is present in Huntington disease,and may be observedin any diseasethat involvesthe basalganglia.

In a Nutshell InWilson disease, copper accumulates intheliverand inthelenticular nucleus ofthe ganglia (hepatolenticular basal degeneration). KayserFleischer rings are pathognomonic. ln a Nutshell Hemiballismus refers to a violent flingmotion ofthe limbscontralateral to a subthalamic lesion.

4. Dystonia refers to a slow, prolonged movement involving predominantly the truncal musculature.Dystonia often occurs with athetosis.Blepharospasm(contraction of the orbicularis oculi causing the eye to close), spasmodictorticollis (in which the head is pulled towards the shoulder), and writer's cramp (contraction of arm and hand muscles on attempting to write) are all examplesof dystonic movements. a. Kernicterus (neonatal jaundice). Children who have had kernicterus may develop athetosisand dystonia.The basalganglia are severelyaffectedin this disease. b. Wilson diseaseresultsfrom an abnormality of copper metabolism,causingthe accumulation of copper in the liver and basalganglia.Personalitychanges,tremor, dystonia, and athetoid movementsdevelop.Untreatedpatients usuallysuccumbbecauseof hepatic cirrhosis. A thin brown ring around the outer cornea,the Kayser-Fleischer ring, may be presentand aid in the diagnosis.Penicillaminetherapy,initiated early in the course,provides excellentcontrol of the disease. 5. Hemiballismus resultsfrom a lesion of the subthalamicnucleus.It refersto a violent projectile movement of a limb. Hemiballismus is observedin the limbs contralateralto the involved subthalamicnucleus. 6. Tourette syndrome involvesfacial and vocal tics that progressto jerking movements of the limbs. It is frequently associatedwith explosive,vulgar speech.The basalgangliamay be involved and dopamine antagonistsare most commonly used to treat this disorder.

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of the GrossAnatomy Hemispheres Cerebral cortex, thewhite ofanouterconvoluted areeachcomposed hemispheres Thepaired cerebral lies Thefalxcerebri ganglia buried deepin eachhemisphere. andbasal thecortex, matter underlying Thelongitudinal thetwohemispheres. separates fissure, whichincompletely inthelongitudinal thetwo thatconneG fiberbundle themassive callosum, ventrally to thecorpus extends fissure andfunctionally. bothanatomically hemispheres,

BASAT GANGLIA Basalganglia include the neostriatum (caudateand putamen) and globus pallidus.

MATTER WHITE White matter forms the centralcore of the hemispheres'The nuclearmassesof the basalganglia are embeddedin the white matter of the cerebralhemispheres.Myelinatedfiber tracts are divided into threegroups: A. Projection fibers carry afferentand efferentinformation betweenthe cerebralcortex and otherpartsof the CNS(e.g.,thalamus,brain stem,spinalcord1. 1 The internal capsuleis a compactbundle of projection fibers,dMded into anterior and posteriorlimbs, shapedlike a V in horizontal sections,and continuouswith eachotJrerat the genu(FiguresV-26-1andv-26-2). a. The anterior limb containsthe following fibers: (1) Frontopontinefibers,or corticofugalfibers,originate in the frontal cortex and projectto the pons.

In a Nutshell is Theinternalcapsule of theanteriorand composed posterior limbsandthegenu, whichin horizontal cross assume a v-shape' seclions'

(2) Thalamocorticalfibers connectthe rnedial and anterior thalamic nuclei to the ftontal lobes.Thesefibersareseveredduring the surgicalprocedurecalleda preftontal lobotomy.

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Whitematterof cerebrum Column of fornix

Genu of corpus callosum Gray matter of cerebral cortex Anteriorhorn of lateral ventricle

Thirdventricle lnternalcapsule (anterior limb)

Septumpellucidum Head of caudate nucleus

Genuof internal capsule

Insularcortex

Lateralsulcus

Claustrum

I n t e r n a cl a p s u l e ( p o s t e r i o lri m b )

Putamen

P i n e a lb o d y

Globus pallidus

Lentiform nucleus

Superior colliculus Thalamus Inferior colliculus Tail of caudate nucleus

Vermisof cerebellum

Choroidplexus Posteriorhornof lateralventricle

Optic radiation

Cerebellar hemisoheres

Figure V-26-1.Transverse section of the cerebral hemispheres.

Clinical Conelate Lacunar infarcts of the posterior limbproduce contralateral motordeficis.

b. The genu contains corticobulbar fibers,which proiect to sensoryand motor nuclei of the brain stem. c. The posterior timb contains the following fibers: (1) Corticospinal fibers (2) Thalamocortical fibers from the ventral thalamic nuclei to the postcentral gyrus of the parietal lobe B. Association fibers interconnect different cortical areaswithin the samehemisphere. 1. The arcuate fasciculus connects auditory and language areas in the temporal lobe (Wernicke area) with Broca areain the frontal lobe.

4U

Hemispheres of theCerebral Anatomy Gross Neuroanatomy:

Caudatenucleus Genu of internalcapsule Corticobulbarand corticospinalfibers (headand neck)

Anteriorlimb of internalcapsule and Thalamocortical fibers corticopontine Putamen Globuspallidus (externalsegment)

Thalamus Globuspallidus (internalsegment) and Thalamocortical corticospinalfibers (trunkand extremities)

Posteriorlimb of internalcapsule

Figure V-26-2.Therelationship between the internal capsule and the thalamus and basal ganglia as seen in the horizontal plane.

2. The uncinate fasciculus connectsthe anterior parts of the temporal lobe with the orbital gyri of the frontal lobe. 3. Cingulum. This tract, which lies buried within the cingulategyrus, connectsthe medial part of the frontal and parietal lobeswith the parahippocampalgyrus and medial aspect of the temporal lobe. C. Commissural fibers interconnect correspondingareasof the two hemispheres. 1. The corpus callosum is the massivefiber bundle,located deepin the longitudinal fissure, that interconnectscorrespondingparts of the two hemispheres. 2. Theanterior commissure is locatedat the anterior junction of the fornix and corpus callosum. The fibers of the anterior commissureconnect the olfactory bulbs, the amygdala, and the middle and inferior temporal gyri of the two hemispheres. 3. The hippocampal commissure is formed by fibers connectingthe two fornices.Fibersof the hippocampal commissurelink the hippocampal formation and parahippocampalgyri of the two hemispheres. 4. The posterior commissure lies near the junction of the midbrain and the diencephalon but is not an interhemispheric commissure. Although some fibers are involved in mediating the consensualpupillary light reflex,its connectionsare not well understood.The posterior commissureis not the sole site for crossingfibers involved in the pupillary light reflex.

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CEREBRAL CORTEX A. Overview 1. The surface of the cerebral cortex is highly convoluted with the bulges or eminences referred to as gyri, and the spacesseparating the gyri called sulci. The term fissure is applied to sulci that are quite deep. 2. Lobes of the cerebrum are divided according to prominent gyri and sulci that are fairly constant in humans. a. The four main lobes of the cerebrum, named after the cranial bones that lie above them, are:frontal, parietal,occipital,and temporal. b. Two other lobesare sometimesdistinguished:the insula lobe and the limbic lobe. The insula lies deep within the lateral sulcus and is coveredby the lateral surfacesof the frontal, temporal, and parietal lobes. c. The limbic lobe was discussedpreviously. 3. Gross anatomy of the cerebrum is usually consideredfrom the lateral, medial, and inferior views.TWoprominent sulci on the lateral surfaceare key to understandingthe divisions of the hemispheres

In a Nutshell Thelateral (ofSylvius) fissure separates thetemporal lobe fromthefrontal andparietal lobes; (of thecentral sulcus Rolando) separates thefrontal andparietal lobes.

a. The lateral fissure (of Sylvius)separatesthe frontal and temporal lobesrostrally; further posteriorly,it partially separatesthe parietal and the temporal lobes. b. The central sulcus (of Rolando) is situatedroughly perpendicularto the lateral fissure and extendsfrom the superior surfaceof the hemispherealmost to the Sylvianfissure. The central sulcusseparatesthe frontal and the parietal lobes.On the lateral view of the hemispheres,all four major lobes may be seen. B. Lobes and major gyri 1. The frontal lobe is the largestlobe. It lies rostral to the central sulcusand superior to the lateral fissure. a. Major gyri ( 1) The precentral gyrus lies betweenthe precentral sulcusanteriorly and the central sulcusposteriorly. (2) The superior frontal gyrus is anterior to the precentral sulcus and separated from the middle frontal gyrus by the superior frontal sulcus. (3) The middle frontal gyrus lies betweenthe superior and the inferior frontal sulci and gyri. (a) The inferior frontal gyrus, which contains Broca speecharea,is located anterior to the precentral sulcus. Broca area is important for controlling motor functions in speech.Broca areais located in the left hemisphereof most righthanded individuals, but in left-handed individuals, it may be found in either (and occasionallyboth) hemispheres. (5) orbital gyri lie on the inferior porrion of the frontal lobe. b. Major functional divisions. The frontal lobes are also divided into severalareasbased upon functional considerations.

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Neuroanatomy: Gross Anatomy of theCerebral Hemispheres

(1) The primary motor area correspondsto the precentralgyrus. (2) The premotor area lies immediately rostral (anterior) to the primary motor area and includespart of the precentralgyrus. (3) The prefrontal area lies rostral to the premotor area.

2. The parietal lobe is located caudal to the central sulcus and superior to the lateral fissure. Posteriorly,it is continuous with the temporal and occipital lobes. The parietal lobe is usually divided into three main regions. a. The postcentral gyrus lies caudal (posterior) to the central sulcus. b. The inferior parietal lobule consists of the supramarginal and angular gyri. The supramarginalgyrus capsthe posterior end of the ascendingramus of the lateral sulcus.The angular gyrus surrounds the caudalend of the superior temporal sulcus.

ln a Nutshell gyrus Theprecentral ofthe frontal lobecontains the primary motorcortex; the po$central gyrus ofthe parietal lobecontains the primarysomatosensory cortex.

c. The superior parietal lobule lies immediately superior to the inferior parietal lobule. 3 . The temporal lobe is located ventral to the lateral fissure. a. It is divided by the superior and inferior temporal sulci into three gyri. (1) Superior temporal gyrus, which includesthe primary auditory cortex (2) Middle temporal gyrus (3) Inferior temporal gyrus b. On the medial surfaceof the hemisphere,two other parts of the temporal lobesare seen. (1) Parahippocampal gyrus

In a Nutshell gyrus Thesuperior temporal contains theprimary auditory cortex andWernicke area.

(2) Uncus 4 . The occipital lobe lies caudalto the temporal and parietallobes,abovethe tentorium. The boundary between the parietal and occipital lobes is determined by drawing a line betweenthe parieto-occipital sulcus,located on the medial surfaceof the cerebrum and the preoccipitalnotch, located at the lateral edgeof the cerebrum.On the lateral surface, the occipital lobe consistsof the lateral occipital gyri. On the medial surface,the occipital lobe is divided by the calcarine fissure into the cuneus superiorly and the lingual gyrus inferiorly. The primary visual cortex is located on the upper and lower banks of the calcarine fissure(FigureV-26-3).

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Central precentral Postcentral sulcus gyrus gyrus Superior parietallobule

Superiorfrontal gyrus Middlefrontal gyrus

Inferior parietallobule

Inferiorfrontal gyrus

Supramarginal gyrus

Broca'sarea

Angular gyrus

Lateralsulcus gyrus Superiortemporal Middletemporalgyrus Inferiortemporalgyrus

Pons Cerebellum

Medullaoblongata

Figure V-26-3.Lateral view of the right cerebral hemisphere.

C. Medial surface (FigureV-26-4) 1. The cor?us callosum is visible as a massive,C-shaped,white matter structure,which lies ventral to the cingulate gyrus and dorsal to the fornix. Fibers of the corpus callosum connect correspondingareasof the two cerebralhemispheres.From anterior to posterior,the corpus callosum can be divided into four parts: a. Rostrum b. Genu c. Body d. Splenium 2. Limbic lobe. Many of the parts of this lobe .ue seenon the medial surfaceof the hemisphere.

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Neuroanatomy: GrossAnatomy of theCerebral Hemispheres

Fornix lnterthalamic adhesion

Paracentral lobule Cingulate sulcus

Septum pellucidum

Cingulate gyrus

Corpuscallosum

Interventricular foramen Anterior commisure

Parieto-occipital sulcus

Third ventricle

Calcarine sulcus

Laminaterminalis

Pinealbody

Hypothalamus

Cerebral aqueduct

Opticchiasm Tubercinerum Hypophysis Mamillary body

Cerebellum Fourth ventricle

Figure V-26-4.Medial view of a cerebral hemisphere.

D. Inferior surface (Figure V-26-5) 1. Anteriorly, the orbital gyri are located on the inferior surfaceof the frontal lobe. The olfactory sulcus,within which the olfactory bulb and tract can be found, separatesthe lateral orbital gyri from the more medially located gyrus rectus. 2. Posteriorly, the occipitd and the temporal lobes dominate most of the remaining inferior cortical surface.In the intact brain, most of the occipital lobe is hidden by the cerebellum.

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Olfactorybulb Olfactory tract

Opticnerve(ll) Mammillary body

Oculomotor nerve(lll)

Crus cerebri Trochlear nerve (lV)

Abducens nerve(Vl) Facial nerve(Vll)

Trigeminal nerve (V)

Vestibulocochlear nerve(Vlll) Glossopharyngeal nerve(lX) Vagus nerve(X) Accessorynerve (Xl) Hypoglossalnerve (Xll) Cervicalspinalnerves

FigureV-26-5.Inferiorview of the brain.

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TheCerebral Cortex portion Thecerebral cortex, theoutermost ofthecerebral hemisphere, isa graymatter structure characterized bymanyconvolutions thatgreatly increase itssurface area. Each convolution or gyrus gyribydeepgrooves isseparated fromneighboring orsulci. About900/o ofthecortex iscomposed of a characteristic six-layer cellular column, whichiscalled the (paleopallium) isocortex or neocortex. Theolfactory cortex andhippocampalformation (archipallium) Themesocortex arethree-layered structures andtogether comprise theallocortex. is partsoftheparahippocampal gyrus intermediate between theneocortex andtheallocortex; and gyrus cingulate arecomposed of mesocortex.

STRUCTURE OFTHENEOCORTEX All of the neocortex contains a six-layer cellular arrangement,but the actual structure varies considerablybetween different locations. Based on these variations in the cytoarchitecture, Brodmann divided the cortex into 47 areas,but students need only familiarize themselveswith those discussedin this chapter.Eachof the six layersof neocortexhas a unique complement of cell types and fibers,which give it the appearanceof lamination (FigureY-27-l). A. Layer I, the molecular (plexiform) layer,is the outermost layer of the cortex and consistsprimarily of horizontally (tangentially)running nerve fibers. B. Layer II, the external granular layer, is made up of densely packed granule cells with dendrites that extend into the molecular layer and axonsthat passto deepercortical layers.

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Nervous System

Efferent Cortical Fibers I Molecularlayer

ll Externalgranularlayer

lll Externalpyramidallayer

lV Internalgranularlayer

V lnternalpyramidallayer

Vl Multiformlayer (layerof polymorphiccells)

Afferent Cortical Fibers

i

I

I I I

I

Figure V-27-1.The six-layered neocortex.

In a Nutshell . Layers lll andV contain pyramidal cells thatproject outofthecortex. . Layer lVreceives many ascending inputs.

C. Layer III, the external pyramidal layer,consistsof pyramidal cells of all sizes.Dendrites of thesecellsextendinto the molecularlayerwhile the axonsform efferentcortical fibers.These axons enter the underlying white matter and passto other regions of the samehemisphere (associationfibers),to the oppositehemisphere(commissuralfibers),or to other parts of the central nervous system(projection fibers). D. Layer IV, the internal granular layer, consistsmostly of small stellate (star-shaped)cells. Layer IV representsthe primary input layer for ascendingcorticopetalinformation. E. LayerV, the internal pyramidal layer,containspyramidal cellsthat vary from medium-sized to very large.Betz cells,the largestneurons in the body, are found in layerV of the primary motor cortex,which is located on the precentralgyrus. Pyramidal cellsof layer V represent the cellsof origin for association,commissural,and projection fibers. F. Layer VI, the multiform layer,consistsof spindle-shapedor fusiform cellsthat vary in size. Layer VI is the origin of corticothalamic projections that modulate ascendingcorticopetal information.

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Neuroanatomy: TheCerebral Corter

CORTICAT FUNCTION A. Motor control 1. The primary motor cortex (Brodmann area4) is locatedon the precentral gyms and the anterior wall of the central sulcus.About one-third of the corticospinal tract arisesfrom area4. a. The somatic musculatureof the body is representedacrossarea4 in an orderly fashion (FigureY-27-2).

-^N

Figure V-27-2.The motor homunculus. (1) The order from the fissureof Sylviusto the longitudinal fissureis: tongue,j"*, lips, eyelids,thumb, fingers,wrist, elbow,shoulder,and hip. (2) The knee, ankle, and toes are located on the medial bank of the precentral gyrus within the longitudinal fissure. b. Lesions of area 4 frequently result in contralateral weakness (paresis) and other deficits associatedwith an upper motor neuron lesion for the part of the body affected by the lesion.Impairment is most severefor volitional movementsof distal muscle grouPs.

2. The premotor area (Brodmann area 6) is located immediately rostral to the primary motor cortex. Electrical stimulation of the premotor cortex results in more complex movementsthan thoseproducedby stimulating adjacentparts of area4. While a stronger current is required, thesemovementspersist after ablation of area4. About one-third of the corticospinalfibers originate in area6.

3 . The supplemental motor cortex, another part of the premotor area,is located on the medial surfaceof the hemisphere.

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a. Stimulation of the supplementary motor cortex produces a variety of responses, including complex stereotypedmovements,postural changes,vocalization,rapid purposelessmovements,as well as pupillary dilation and other sympathetic responses. Stimulation of this area may result in bilateral movements. b. Highly processedsomatosensoryauditory, and visual information concerning the immediate extrapersonalspaceis relayedfrom Brodmann areas5 and 7 in the parietal lobe to premotor and supplementarymotor cortices.This information is used to create motor templatesor to choreographmotor sequencesthat are executedby the primary motor cortex. Electrophysiologicactivity in supplementaryand premotor corticesprecedethat of the primary motor cortex. 4. The frontal eye field (Brodmann area 8) is located in the caudal zone of the middle frontal gyrus. Stimulation of this arearesults in conjugate deviation of the eyestoward the oppositeside. B. Sensation.Regionsof the cerebralcortex that receivedirect projections from their respective thalamic relay nuclei are referred to as primary sensorycortex. The secondarysensory corticesreceivemost of their input from adjacentprimary sensorycortex with smaller contributions from other associationcorticesand some direct sensoryinput. 1. Overview a. Understandingof the primary areascomeslargelyfrom the work of Hubel and Weisel and Mountcastleon the primary visual and somatosensoryareas,respectively.In both systems,cellswithin a vertical column of the cerebralcortex are functionally related. For example,neurons in the striate cortex demonstrateremarkablespecificityin their responseto retinal stimulation. b. By comparison,the secondarysensoryareas,or sensoryassociationareas,are involved in more complex integration and analysisof sensoryinformation. Primary sensory areasmake their most significant intracortical connections with the secondary(or association)areasthat are adjacentto them. ( 1) The sensoryassociationareassend and receivefibers from the other hemisphere (commissuralfibers) and other areasof the samehemisphere(associationfibers).

In a Nutshell Allsensory neocortical projections for except relayinthe olfaction thalamus.

(2) All primary sensorycortices,except the olfactory cortex, receivetheir primary ascendinginput from the thalamus.Thesesystemsinclude touch, vision, audition, taste,pain, and balance. (3) The senseof olfaction is unusual in that its primary projection to the paleocortex bypassesthe thalamus. However, its projection to the neocortex, located on the orbitofrontal cortex, doespassthrough the mediodorsal nucleusof the thalamus. 2. Somatic sensory (somesthetic)areasreceiveinput from the contralateralbody half. a. The primary somatosensory area (SI) is located on the postcentral gyrus and the adjacentposterior wall of the central sulcusincluded in Brodmann areas3,l, and2. (1) The primary somatosensorycortex receivesinput from both superficialand deep receptorsvia the ventral posterior nuclei, which receivetheir ascendinginput from the trigeminothalamic tracts (ventral, posteromedial,VPM), medial lemnisci (ventral posterolateral,VPL), and spinothalamictracts (VPL). (2) The body and face are topographically organized on the postcentral gyrus (FigureV-27-3).

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Neuroanatomy: TheCerebral Cortex

Figure V-27-3.The sensory homunculus.

b. The secondary somatosensoryarea (SII) is located in the parietal lobe posterior to the postcentral gyrus, along the superior border of the Sylvian fissure.The second somatosensoryarea has a topographic organization and appearsto be functionally involved with both lemniscal and spinothalamic systems.

3 . Primaryvisual cortex (Brodmann area 17;Vl) receivesdirect input from the opposite half of the visual space.The central part of the visual field, however,is representedin the primary visual areaof both hemispheres. a. The primaryvisual area is locatedalong the banks of the calcarinesulcus.The sensory afferentsfrom the lateral geniculatebody terminate largely in layer IV of the striate cortex. A similar terminal pattern is observedfor thalamic projections to the primary somestheticand auditory areas. b. The secondaryvisual area (Brodmann areas18 [V2] and 19 tV3]) lies adjacentto area 17 in the occipital lobe. 4. Auditory areas of each hemisphere receiveauditory input from both ears that is relayed by the medial geniculatebody to the primary auditory area. a. The primary auditory area (Brodmann area4l and some of 42) is located on the transversegyri (Heschl gyri) on the superior surfaceof the superior temporal gyrus. Although there is some tonotopic organization of input in the primary auditory area, it is not asdiscreteasthat of the cochlea.Eachhemispherereceivesbinaural input, but soundsreachingthe contralateralear are more pronounced. b. The secondary auditory area (Brodmann area22) is located adjacent to the primary auditory areain the superior temporal gyrus. 5. The primary gustatory area is located within the dorsal half of the anterior insula.

ln a Nubhell Primary is visual cortex located around thecalcarine lobe; fissure oftheoccipital primary cortex isin auditory gyri(of thetransverse Heschl), located onthe gyrus. superior temporal

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Nervous System

6. The primaryolfactoryarea include the pyriform, periamygdaloid,and entorhinal cortices. C. Higher order processing in the prefrontal cortex (Brodmann areas9-12). Some,but not all, of the abilities that distinguish humans from other animals reside in the prefrontal cortex. The prefrontal cortex lies rostral to the premotor area (Brodmann area6) and frontal eye fields (Brodmann area S) in the frontal lobe. The prefrontal cortex develops late phylogenetically and is quite extensivein humans.

In a Nutshell prefrontal Bilateral cortex produce lesions distinct personality (apathy, changes inappropriate behavior, inability to planforthe future).

1. The prefrontal cortex has extensiveconnections with the dorsomedial nucleus of the thalamus, hypothalamus, anterior half of the cingulate gyrus, part of the limbic system,anterior lobe, and associationareasof the parietal and the occipital lobes.Someauthors have suggestedthat the prefrontal cortex representsthe site of personaliry in the individual, while others considerit the abstract-thinkingpart of the brain. There is support for both of theseviews. However, other cortical areasare certainly involved with both personality and abstractthought. 2. The orbital gyri of the prefrontal cortex appear to play a role in the socialization of certain autonomic functions and emotions. Bilateral lesionsof the orbital gyri may lead to incontinence and to the releaseof sexual or aggressiveimpulses in responseto environmental stimuli. 3. Bilateral lesions of the dorsolateral prefrontal cortex lead to deficits of surveillance,emotional arousal,and orientation to relevant stimuli, which are manifested clinically by apathy and neglect. 4. Lesions that involve both the orbital and dorsolateral prefrontal cortices (e.g., prefrontal lobotomy, which in the past was used to treat psychotic patients), produce a combination of symptoms. Thesepatients usually show only slight changeson formal cognitive testing although their personalitiesundergo striking changes.Apathetic one moment, they maybecomeirritable and aggressive or boisterousand lewd the next moment, if triggered by some environmental stimulus. D. Functions related to cerebral dominance. Despite the apparent anatomic similarity of the two cerebral hemispheres,certain functions are localized in one hemisphere more than the other. The correlation between handednessand the so called dominant hemisphere is high, but is not perfect, especiallyin left-handed individuals. l. Language a. Broca discoveredthat lesioning a given area of one hemisphereproduces a striking aphasia (a deficit in languagecomprehensionor production not resulting from an attentional,sensory or motor deficit), while lesioningthe sameregion of the opposite hemisphere causesno observable deficit. This was the first evidence that language function is lateralized in the brain.

ln a Nutshell people Mo$righthanded havespeech lateralized to the lefthemisphere. Left-handed people arelikely to useeither therighthemisphere or both hemispheres forlanguage.

b. Approximately 90-95o/o of the population is considered right-handed; of these, 9G99o/ohavelanguagecapacitieslargelyrestrictedto the left hemisphere.Approximately 70o/oof left-handers, however, have most language functions in the left hemisphere. Approximately l5o/orestrict languagemostly to the right hemisphere.Approximately l5o/oof the left-handershavelanguagefunction in both hemispheres. c. Aphasia is likely to follow damageto either hemisphere in a left-hander. However, the deficit is usually lessseverethan a similar lesion in the left hemisphereof a right-handed individual. Recoveryof languagefunction also is better in individuals who are lefthanded. d. There are three cortical areasthat are intimately involved in languageand speech.

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Neuroanatomy: TheCerebral Cortex

( 1) Broca area,the part of the premotor cortex intimately involved with language,is locatedon the inferior frontal gyrus,anterior to the "face" areaof the motor cortex. The Broca areaproducesmotor templatesusedby the primary motor cortex for the production of speech.The Broca areaalso plays a role in languageproduction involving complex syntax.A lesion of this areaproducesa Broca aphasia (motor or expressiveaphasia), which is characterizedby sloq effortful speech,(i.e., patients are nonfluent). This dysarthric speechis often called telegraphic becauseit containsnouns and verbswithout the usual grammatic structure contributed by small connecting words (e.g.,and, or, but). Most patients with Broca aphasia comprehend well and, aware of their disabiliry are often depressedand irritable. A right-sided hemiparesis(in right-handers)of the lower face and arm may accompanyBroca aphasiaas a result of the proximity of the Broca areato the faceand arm representationwithin the primary motor cortex. (2) The Wernickeareais the auditory associationcortexlocatedon the posterior part of the superior temporal gyrus, next to the primary auditory cortex. The Wernickeareais involved in learning patternscorrespondingto different types of auditory stimulation. A lesion of this arearesultsin Wernicke aphasia (receptive or sensoryaphasia)in which the comprehensionof language(spokenand written) is severelyimpaired. Patientswith Wernickeaphasiaspeakfluently and often volubly; however,their speechis often indirect (circumlocutory) and contains incorrect word usages(paraphasias).Wernicke aphasicsusually have no hemiparesisand are not depressed;indeed they are often euphoric. Becausesome of thesepatientsmay becomeagitatedand paranoid,their bizarre speech,abnormal behavior, and lack of neurologic signs may lead to an incorrect diagnosisof a functional psychosis.The arcuate fasciculus is a white matter tract situateddeep in the parietallobe,connectingthe Wernicke and Broca areas.A lesion of the arcuate fasciculusproduces a conduction aphasia,which is characterizedby paraphasias,poor object naming, and a severedeficit of repetition and of fluent speech,which is often circumlocutory. (3) The angular gyrus is locatedin the parietal lobe,just abovethe posterior part of the superior temporal sulcus.It is a higher order associationcortex, which has connectionswith somesthetic,visual, and auditory associationcortices.In the dominant hemisphere,the angular gyrus plays an important role in reading, writing, calculation, planned movements, finger naming, and right-left orientation. Lesionsof the angular gyrus may lead to an abnormality of any or all of these functions. Damage to the angular gyrus also may result in severe anomic aphasia,which is characterizedby word-finding difficulties in spontaneous speech.Not all anomic aphasias,however,result from dominant parietal lobe lesions.

In a Nubhell BrocaAphasia . Expressive aphasia . Speech isnonfluent . Comprehension is preserved

In a Nutshell Wernicke Aphasia . Receptive aphasia . Speech isfluentbut meaningless . Comprehension is impaired severely In a Nutshell (caused Inconduction aphasia bya lesion ofthearcuate is fasciculus), repetition impaired withonly severely mildimpairment of outputor comprehension.

2. Spatial orientation appearsto be largely a parietal lobe function, although the frontal lobe is alsoinvolved.The nondominant hemisphere(i.e.,contralateralto the one controlling language)is consideredto be more important in tasksrequiring spatial orientation.

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Neruous System

3. Constructional ability requires much of the cortical apparatus.However,the parietal and frontal lobes are the most important regions.Again, the nondominant hemisphereis consideredmore important in thesetasks.The nondominant parietallobe (i.e.,the right parietal lobe in a right-handed individual) is probably the single most important site. But it is certainly not the only one involved. In copying figures, patients with right-hemisphere lesionsmake scatteredand fragmented drawings with faulty orientation and loss of spatial relations. Patientswith left-hemisphere lesions preservethe spatial relations and orientation of the figure but make simplified copiesshowing a grosslack of detail. 4. Emotion. Experiments on normal individuals and clinical evidence from patients with destructiveand epilepticlesionssuggestthat the right hemisphereplaysa more important role in emotion than the left hemisphere.For example,patients with a left hemiparesis (damage to the right hemisphere) are usually less concerned about their deficit than patientswith a right hemiparesis.

In a Nutshell Unilateral sensory neglect is oftendueto lesions ofthe parietal contralateral lobe.

5. Denial and neglect syndromes,including Anton syndrome (denial of cortical blindness), anosagnosia(denial of hemiplegia),and sensoryneglect(neglectof one side of the body or of the environment) representthe most striking clinical deficits.Right-handedpatients with permanent denial or neglectalmost alwayshave damageto their right hemisphere, usually within the parietal lobe. (Frontal lobe lesions may produce a temporary loss of attention to stimuli in the contralateralhalf of space.)The mechanismof thesesyndromes appearsto be that the right parietal and frontal lobes are "dominant" for surveillance of and orientation to the immediate extrapersonalspace.An intact right hemisphere(i.e., left hemispherelesion) is able to scanboth halvesof spacewhile an intact left hemisphere is only able to attend effectively to the right half of space,thus neglecting the left. a. In patients with sensory neglect, the neglect is usually on the left side of right-handed patients and is manifestedby the patient dressingonly half the body, shaving half the face,or copying or drawing the right side of a figure. When askedto fill in the numbers on the faceof a clock, the patient may producethe clock facein FigureV-27-4. b. Patientswith bilateral damageto the occipital lobe may not recognizeor admit their loss of sight (Anton's syndrome). c. Patientswith damageto the nondominant hemisphere (i.e., usually the right side) deny the hemiplegiaexpressedon the left side of the body (anosagnosia). 6. Other higher cortical functions and syndromes

ln a Nutshell Apraxia istheinability tocarry outskilled motor acts, assuming thatmotor, sensory, andlanguage functions areintact.

a. The ability to calculateis most frequently impaired with lesionsof the parietal lobe in the dominant hemisphere.The parietal lobe, however,is not the only lobe involved in numeric computations. b. Apraxia is the failure to carry out learned movements that cannot be attributed to a deficit of attention, comprehension,sensation,strength,or coordination. For example, a patient cannot salute to command yet can repeat the salute of the examiner (although some may also be unable to imitate learned movements).Praxis may be affectedby lesions of the dominant parietal or frontal lobes involving the language areas,resultingin a bilateral apraxia.Lesionsof the corpus callosumin a right-hander may "isolate" the nondominant hemisphere from languagecenters,resulting in an apraxia of the left limbs. c. Agnosia is a failure of recognition in the absenceof a sensorydeficit. The three main types are visual, tactile, and auditory agnosia.These are most often the result of a lesion in the associationcortex of the given sensorymodality. Bilaterallesionsmay be necessaryfor auditory and visual agnosias.

498

Neuroanatomy: TheCerebral Cortex

.A t

6 7

$ \o9/

Figure V-27-4.Rendition of a clock face drawn by a patient who expresses sensory neglect.

d. Alexia is an acquired brain lesion that producesa severeimpairment of reading.Alexia is different from dyslexia,which is a developmental disorder of reading in individuals with normal intelligence. Although the most common lesions giving rise to alexia involve the Wernicke area or the angular gyrus, patients with Broca aphasiaalso show difficulty understanding material with complex grammar. Pure alexia (without aphasia or writing difficulty) resultsfrom a lesion destroying the left occipital lobe and the posterior portion of the corpus callosum, which connects the occipital lobes. With this lesion, information presentedvisually is unable to reachthe intact languageareasof the left hemisphere. 7. Corpus callosum syndromes. Lesions of this commissural pathway produce only subtle deficits. a. Lesions of the anterior portion of the corpus callosum disconnect the right frontd and anterior parietal lobes from the language areasin the left hemisphere. The left hand may be unable to perform learned movements,to command (apraxia),to write language (agraphia), or to name objects that are placed in the hand and touched but not seen.The right hand is unaffected. b. Iesions of the posterior portion of the callosum result in pure alexia if combined with damageto the left visual cortex.

499

BloodSupply to theBrain

it requires 200/o oftheorygen Thebrainmakes uponly20/o of themassofthebody;however, to thebrainbya Theheartdelivers about750mlof bloodperminute carried bythebloodsupply. circulation regions Although somecollateral thatserve circumscribed ofthebrain. system ofarteries generally results in lossof arteries orocclusion of specific exists inthecircle ofWillis, damage neural functions. specific

ARTERIAT SUPPTY The brain is suppliedby the two internal carotid arteriesandthe two yertebralarteries.Roughly one-third of the arterial blood is carriedby eachcarotid and one-third through the vertebrals. On the base(or inferior surface)of the brain, branchesof the internal carotidsand the basilar Oinical Conelah to form the circle of Willis. The circleof Willis lies within the subarachnoid artery anastomose of a vesselin $e space.This arterial anastomosisallowscollateralcirculationbetweenthe individual arterialter- I Rupture circleof Willisproduces a ritories(FigureV-28-1). subaractrnoid hemorrhage' A. The internal carotid artery arisesftom the bifurcation ofthe commoncarotidand entersthe skull through the carotid canalin the petrousbone, It ent€rsthe subarachnoidspaceand terminatesby dividing into the anteriorandmiddle cerebralarteries.Major arteriesoriginateftom , tlre intemal carotid. i. The ophthalnic ntery entersthe orbit through the optic canal and suppliesthe eye, including the neuralelernents(i.e.,retina,optic nerve). 2. The posterior communicating artery arisesnearthe termination of the intemal carotid ' posteriorlyto join tlre posterior cerebralartery.This is part of the circle , artery and passes of Willis.

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Superior parietal lobule

Anteriorcerebral artery

Superior frontal gyrus

Posterior cerebral

Frontal pole

artery Middlecerebral

artery Temporal pole

lnferior temporal gyrus

Figure V-28-1.The Distributions of the Cerebral Arteries: 1 3 . The anterior choroidal artery runs posteriorly and terminates in the choroid plexus of the lateral ventricle. Branchesmay help supply the optic tract, lateral geniculatebody, internal capsule,and the crus cerebri.

In a Nutshell Theanterior cerebral artery supplies: . Medial surfaces ofthe hemispheres . Anterior andsuperior portions ofthefrontal and parietal lobes . Anterior portions ofthe ganglia, basal internal capsule, andcorpus callosum

4. The anterior cerebral artery is the smaller terminal branch of the internal carotid artery. It is connectedto the opposite anterior cerebralartery by the anterior communicating artery (part of the circle of Willis). a. Areas supplied by the anterior cerebral artery include: ( 1) The medial surfaceof the frontal and parietal lobes (this includes the "leg area" of the precentraland postcentralgyri) (2) The anterior four-fifths of the corpus callosum (3) Approximately I inch of the frontal and parietal cortex on the superior aspectof their lateral surface (4) Anterior portions of the basalganglia and internal capsule b. Occlusion of the anterior cerebralartery may result in the following defects: ( 1) Paralysisof the contralateralfoot and leg (2) Sensoryloss in the contralateralfoot and leg (3) Urinary incontinence,which usually occurswith bilateral damage

502

Neuroanatomy: BloodSupply to theBrain

(4) Ideomotor apraxia of the Ieft limbs with involvement of the anterior portion of the corpus callosum. Ideomotor apraxia occurs becausethe left hemisphere (languagedominant) has been disconnectedfrom the motor cortex of the right hemisphere.

Pericallosal artery

Callosomarginal artery

Corpus collosum

S pl e n i u m

Posterior cerebral artery Cuneus

Frontalpole

Superior cerebellar artery

Orbitalartery Anteriorcerebralartery lnferiortemporalgyrus

Anterior inferior cerebellar artery Posterior inferior cerebellar artery

Basilarartery Vertebralartery lnternalcarotidartery

Figure V-28-2.The Distributions of the Cerebral Arteries: ll 5. The middle cerebral artery is the larger terminal branch of the internal carotid. a. Areas supplied by the middle cerebral artery include: (1) The bulk of the lateral surfaceof the hemisphere.Exceptionsare the superior inch of the frontal and parietal lobes,which are supplied by the anterior cerebral artery,and the inferior part of the temporal lobe and the occipital pole, which are supplied by the posterior cerebral artery.

ln a Nutshell Themiddle cerebral arteries supply thelateral surfaces of thehemispheres, theposterior limboftheinternal capsule, ganglia. andpartofthebasal

(2) Part of the internal capsuleand basalganglia b. Occlusion of the middle cerebral artery may result in the following defects: ( 1) Paralysisof the contralateralface,arm, and leg (2) Sensoryloss in the contralateralface,arm, and leg (3) Aphasia (e.g.,Broca,Wernicke,conduction, and anomic tfpes) when the dominant hemisphere (usually the left hemispherefor right-handed individuals) is affected (a) Left-sided neglectwith damageto the right hemisphere(usually the parietal lobe) (5) Homonymous hemianopia or quadrantanopiafrom damageto the optic radiation

ClinicalCorrelate Strokes frequently occurin middle cerebral artery territory.

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Neruous System

B. Vertebral artery. This artery is a branch of the subclavianthat ascendsthrough the foramina of the transverseprocessesof the rostral six cervicalvertebrae.It entersthe posterior fossa by passingthrough the foramen magnum. Eachvertebral artery contributes a branch to the anterior spinal artery. The vertebral arteries continue up the ventral surfaceof the medulla, and at the caudalborder of the pons,join to form the basilar artery. 1. Branchesof the vertebral arterv include the: a. Meningeal branches b. Anterior spinal artery c. Posterior spinal artery (this may also arise from the posterior inferior cerebellar artery.)

ln a Nutshell of a vertebral artery Occlusion symptoms of mayproduce cerebellar or medullary dysfunction.

d. Posterior inferior cerebellar artery, which is the largest branch of the vertebral. Occlusion of this artery may produce the lateral medullary syndrome. e. Medullary branches, which along with the posterior inferior cerebellarartery, supply most of the medulla. 2. Occlusion of a vertebral artery may result in either a medial or lateral medullary syndrome,in addition to signsand symptoms of cerebellardysfunction. C. The basilar artery is formed by the joining of the two vertebrals in the caudal pons. It ascendsalong the ventral midline of the pons and terminatesnear the rostral border of the pons by dividing into the two posterior cerebralarteries. 1. Branchesof the basilar artery include the: a. Labyrinthine artery, which follows the course of the eighth cranial nerve and supplies the inner ear. b. Anterior inferior cerebellarartery, which suppliespart of the pons and the anterior and inferior regions of the cerebellum. c. Superior cerebellarartery, which suppliespart of the rostral pons and the superior region of the cerebellum. d. Pontine branches,which supply much of the pons via perforating and circumferential vessels. e. Posterior cerebral artery. This artery is formed by the terminal bifurcation of the basilar artery.It anastomoseswith the posterior communicating artery in the circle of Willis.

ln a Nutshell Theposterior cerebral artery pole,the supplies theoccipital inferomedial temporal lobes, thethalamus, andthe nucleus. subthalamic

(1) Areas supplied by the posterior cerebral artery include the occipital pole and inferior temporal lobe on the lateral surfaceof the cerebral cortex, the occipital lobe and posterior two-thirds of the temporal lobe on the medial surfaceof the cerebralcortex, and the thalamus and subthalamicnucleus. (2) Occlusion of the posterior cerebralartery resultsin a homonymous hemianopia of the contralateralvisual field. Central (macular) vision is often spared. 2. Occlusion of the basilar artery may result in the following signsand symptoms: a. Diplopia and various gazepalsies b. Upper motor neuron lesionsfrom corticobulbar and corticospinaltract involvement c. Cortical blindness,sparing the pupillary light reflex d. Coma from involvement of the thalamus,midbrain, and pons e. Cerebellarsymptoms

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Neuroanatomy: BloodSupply to theBrain

D. The circle of Willis (circulus arteriosus) is an arterial anastomosislocated at the baseof the brain. The anterior part of the circle lies in front of the optic chiasm,while the posterior part is situated just below the mammillury bodies. The circle of Willis is formed by the terminal part of the internal carotids;the proximal parts of the anterior, middle, and posterior cerebral arteries;and the anterior and posterior communicating arteries.This arterial network allows for excellentcollateral circulation. Collateralsthrough the circle of Willis will compensatefor an occlusion of an individual artery especiallyif it occurs gradually (Figure V-2S-3).

VENOUS SUPPTY The veins and venous sinusesof the brain contain no valves.The veins are located in the subarachnoid space,while the venous sinusesare located between the two layersof the dura mater. A. Superficial (external) cerebral veins drain the cortex and the more superficial white matter. They mainly follow the sulci, lyttrg between the gyri, and drain into the superior sagittal, transverse,and cavernoussinuses. B. Deep (internal) cerebral veins. There is one in eachhemisphere,formed by the union of the thalamostriateand choroid veins.Beneaththe posterior portion of the corpus callosum,the two deep cerebral veins unite to form the great cerebral vein (of Galen), which drains into the straight sinus.

Note granulations Arachnoid inthe superior sagittal sinus reabsorb CSFintothevenous circulation.

Middle cerebral

Superior cerebellar (cut) Basilar Anteriorinferior cerebellar

Vertebral

Posteriorinferior cerebellar

Anteriorspinal

Figure V-28-3.Arterial Supply of the Brain

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Neruous System

C. Venous sinusesform where the meningeal and periosteal layers of the dura mater separate. The cerebral veins drain into these sinuses, which drain into the internal jugular vein. Emissary veins form anastomosesbetween the venous sinusesand the veins external to the brain. Diploic veins run between the inner and outer tables of the skull and communicate with the venous sinusesand extracranial veins via the emissaryveins. 1. The superior sagittal sinus is located in the midsagittal plane along the upper margin of the falx cerebri. It drains into the confluence of the sinuses.Arachnoid granulations are found primarily in the walls of the superior sagittal sinus. They absorb the cerebrospinal fluid (CSF) into the venous circulation. 2. The inferior sagittal sinus is located in the midsagittal plane, along the lower margin of the falx cerebri. It terminates by joining with the great cerebral vein to form the straight sinus at the junction of the falx cerebri and tentorium cerebelli. 3. The straight sinus is formed by the union of the inferior sagittal sinus and the great cerebral vein. It usuallyterminatesby draining into the confluenceof the sinuses(or into the transversesinus). 4. The occipital sinus is found in the attached border of the tentorium cerebelli. It drains into the confluenceof the sinuses.

Clinical Correlate Thecavernous sinuses drain valveless ophthalmic and paranasal veins. Infection can fromthefaceintothe spread producing cavernous sinuses, infection andthrombosis.

506

5. The confluence of the sinusesis formed by the union of the superior sagittal,straight, and occipital sinuses.It drains into the two transversesinuses. 6. The transverse sinuses drain venous blood from the confluence of the sinusesand the superior petrosalsinus into the sigmoid sinuses. 7. The sigmoid sinusesdrain into the internal jugular vein at the jugular foramen. 8. The cavernoussinusesare located on either side of the body of the sphenoidbone. This sinus receivesblood from some of the cerebral veins, ophthalmic veins, and the sphenoparietalsinus. It drains into the transversesinus via the superior petrosal sinus, into the internal jugular vein via the inferior petrosal sinus, and laterally into the pterygoid plexus.

Nervous Physiology System

Thenervous system coordinates theactivities ofthebodyviaa series of extremely complex operations. lt receives andprocesses sensory information, organizes andinitiates responses to incoming information, andplays animportant roleinthemaintenance of homeostasis. Each of these diverse functions ismadepossible, atthecellular level, because oftheexcitability of nerve cell properties membranes. Thischapter reviews theelectrophysiological of neurons, anddetails the functions ofthesystems theycomprise, including thesomatic andautonomic nervous systems, the somatosensory system, andthespecial senses.

FEATURES GENERAT OFNEURONAL FUNCTION A. Resting membrane potential refers to the difference in electric potential between the intracellular and extracellularspaceof a neuron at rest. In most neurons,an electricalpotential differenceof about -60 mV exists(the inside of the cell is negativerelativeto the outside). l. Resting membrane potential (V,) is formed becauseof the differential distribution of ions and the selectivepermeability of the cell membrane. The major cellular ions are sodium (Na*), potassium(K*), calcium (Ca2*),chloride (Cl ), and organic anions (A-), comprised mostly of proteins and amino acids. The distribution of the major ions in mammalian nerve and muscleis shown in TableV-29-I.The nerve cell membrane actsas a physicalbarrier to the diffi.rsionof ions through its channels,which are ion-selective. The resting membrane potential is formed largelybecausethe neuron is permeableto K* and impermeableto intracellular anions.K* flows down its electrochemicalgradient,leaving a net negativechargeinside.An electrochemicalgradient consistsof a concentration gradient and an electricalgradient. ThbleV-29-1. Distribution of the major ions in mammalian nerve and muscle. Ion

Cytoplasm

K+ 140 mmol/l Na+ 2 mmol/l Ca2+
Extracellular Fluid

Nernst Potential

4 mmol/l 142mmol/l 2 mmol/l 120mmol/l

-93 mV +65 mV +120 mV -89 mV

a. Concentration gradient is the force that drives ions to diffrrse acrossa membrane so that the intracellular and extracellularconcentrationstend to equalize.

507

Nervous System

b. Electrical gradient is the force that drives ions to diffrrse acrossa membrane so that intracellular and extracellular chargestend to equalize. 2. Example. Tirke the example of a cell membrane selectivelypermeable to K+ only (Figure

v-29-1).

il+

ffi

Intracellular

ffi+ Extracellular

Figure V-29-1.A membrane selectively permeableto potassium.

a. The positively charged Kn ions diffuse acrossthe cell membrane becauseof the concentration gradient,leavingthe impermeant negativechargebehind. Thus, as K* ions flow down their concentration gradient, an electrical gradient is developedwhose force is opposedto that of the K* ion concentrationgradient. b. The more K+ ions that passthrough the membrane,the larger the electricalgradient. The processstops (equilibrium is achieved)when the magnitude of the electrostatic force is equal and opposite to that of the concentrationgradient. c. The equilibrium condition with K+ as the only permeant ion can be expressedin the Nernst equation as follows:

r-:#r"#l: in which EK*= K* equilibrium potential;R - gasconstant(8.32llmol x K); T = temperature in degreesKelvin; Z - valence of K* (+1); F = Faraday'sconstant (96,500 coulombs/molof positivecharge);[K*]o = externalK* concentration;and [K*]1= internal K* concentration.At 37"C,RT1ZF- 26 mY, and convertingto log,o,the equation = -93 mV. Varying the K+ concentration gradient by becomesE6- - 60 mMog rc 41140 increasing or decreasingthe external K+ concentration changesthe value of EK.. The Nernst potential for the other ions can be calculatedin a similar fashion with the values given (seeThbleV-29-l). Glial cellsvery closelyapproximate Es. and are thought to be selectively permeable, primarily to K+. Most neurons, however, have a membrane potential different from Eg, and must, therefore,be permeableto other ions besidesK+.

Note V,is largelydetermined by [K.]i because thecellmembrane is muchmorepermeable to K. thanto otherions.

508

3. Flux studies show that nerve cells are permeable to K+, Na*, and Cl . Active transport is responsiblefor maintaining the Na* and K* concentrationsat the level in ThbleV-29-1. This metabolically active system is the Na-K pump, which is Na*- and K*-dependent adenosinetriphosphatase(ATPase).This pump maintains the concentration gradient of thesetwo ions so that there is a low [Na.]i and a high [K.]1.Also, the permeability in the resting membrane is fixed so that the K* permeability is high relative to Na+.When the net flux of chargeacrossthe cell membrane is zero,V, = V- (membrane potential). At E6. (*93 mV), K* ions are in equilibrium, but there is an influx of Na* ions.As the membrane

Physiology

becomesmore positive, there is an increasingK* efflux and a decreasingNaninflux. At -60 mV the nerve cell V., the two fluxes are equal, and there is no net flux acrossthe membrane. The Na-K pump preventsthe dissolution of the ionic gradient by activelytransporting Na* out of the cell and K+ into the cell. The cell at rest is diagrammatically pictured in FigureV-29-2.

J(+

Na+ <J(+

il

n

FR\ vg*

lntracellular

n

J(+ I I I Na+J

Ditfusion downelectroconcentration gradient

Na+

Extracellular

Figure V-29-2.The Na-K pump.

a. Although the Nernst equation exampleaboveconsideredK* asthe only permeant ion, in actualiry V- ir determinedby more than one ion; eachion influencesV- by means of its concentration gradient as well as its permeability (P). This can be expressedin the Goldman equation as follows:

RT v-:

F

P*[K.]o * P""[Na*]o + Po[Cf]r

I"

P*[K.], * P,o"[Na*]t+ Po[Cl ]o

Note It'ssufficient to knowthatthe equation represents Coldman a combination of Nernst equations for K.,Nar,andCl-.

b. The Goldman equation weights the Nernst equation for each ion by a relative permeability factor (P.) for that ion. B. Biologic structure and electrical properties 1. Membrane structure accountsfor the electricalpropertiesof the membrane.The current fluid-mosaic model of the biologic membrane structure is shown in Figure V-29-3. The membrane matrix is composed primarily of a bilayer of phospholipids with the hydrophilic (water-soluble) ends facing the aqueous milieu (the extracellular and intracellular fluids) and the hydrophobic (water-insoluble) ends facing the interior of the membrane (lipophilic interior). It is acrossthis membrane that the voltage difference is established.Thus, the lipid bilayer forms an insulating layerin contactwith aqueousphases,which are good conductors.Sincea potential differenceexistsacrossthe membrane,it actsas a capacitor.

509

NervousSystem

nn nnnn)mnn UKUU),q uu Figure V-29-3.The lipid bilayer with embedded proteins.

2. Membrane proteins. Randomly distributed within the membrane are a number of proteins embeddedwithin the membrane.Someof theseembeddedproteins are responsible for the activetransport ionic pumps. Other membraneproteins provide channelsor pores for ionic movement (the passivetransfer of ions acrossthe membrane). Ion channels exhibit a property known as selectivity:channelsare more permeableto some ions than to others.The easewith which an ion can passthrough a channelis relatedto the hydrated sizeand chargeof the ion, aswell as the sizeand internal chargedenvironment of the channel itself.

In a Nutshell Voltage-gated Na.andK. channels areimportant in potential propagation. action Voltage-gated Ca,.channels areimportant in neurotransmitter release.

In a Nutshell potential A neuron's threshold thatis 0,) isthepotential required forgenerating an potential action attheaxon hillock.

5t0

3. Ion channels a. The permeability of many channelsappearsto be regulated.For example,the neuron contains "gated" Nan and K* channelsthat open and close in responseto changesin charge differences(voltage) acrossthe membrane. There are gated channelsthat open and closein responseto other stimuli, such asneurotransmitters(ligand-gatedion channels). There are also channelsfor other ions, most importantly Ca2*,which are voltagesensitiveand are involved in the releaseof neurotransmitters. b. Topographicdifferencesin the distribution of channelsalso exist in the neuron. For example,Ca2*channelsare more denseat axon terminals,where Ca2ninflux is important in neurotransmitter release.AIso, dendrite, cell body, and axon hillock membraneshavemore types of gatedchannelsthan the axon membrane. C . Stimulus and action potential. Many cells exhibit strictly passive electrical properties in which the resistivepropertiesof their membranesremain constant.In contrast,neuronspossessthe ability to regulatetheir resistances asa function of their membranepotential; that is, the membrane has channelsthat are mostly closedin the resting statebut can open as the cell depolarizesin responseto some externalstimulus. 1. Threshold. A stimulus that depolarizesa membrane to the point of electricalinstability has reachedthreshold. The threshold intensity is the minimum intensity of stimulating current that is necessaryto produce an action potential (Figure V-29-4). The action potential fails to occur if the stimulus is subthresholdin magnitude. Any stimulus at or abovethe thresholdintensity resultsin the sameaction potential with constantamplitude (all-or-noneresponse).

Physiology

E

+50

(d .F

0

c o o o o c (d L

-o E o

Stimulating current 0-r

msec f|l4

strength stimulus lncreasing

Figure V-29-4.The action potential.

2. Current pulses a. Hyperpolarizing current pulses, which polarize the membrane to an even greater level than the resting membrane polarization, are those that introduce negativeions or removepositiveions from within the axon (anodalcurrent). Sucha pulsemovesthe potential further awayfrom the threshold voltage and, thus, increasesthe threshold stimulus required to causean action potential. b. Depolarrzingcurrent pulses,which supply positivechargesto the inside of the membrane (cathodal current), can cause passivechangesin the membrane below the threshold level of depolarization (up to approximately 10 mV depolarization). c. Impulse initiation. When the membrane depolarization reaches10 mV or more (threshold),the magnitude of the responseis greaterthan would be expectedfrom the magnitude of the applied current (FigureV-29-5).There is now activeparticipation of the membrane in which the movement of ions overwhelmsthe repolarizing process, and an action potential is initiated. The potential can reach+40 mV and subsequently repolarizesbelow the resting potential. (The action potential continueseven when the depolarizingcurrent is discontinued.)

ln a Nutshell in a change Depolarization: of inside that the V- such thecellislessnegative. a Hyperpolarization: inV, suchthatthe change is inside oftheneuron morenegative.

mV+40

Threshold- 55 RP-60

-70 Current

Figure V-29-5.lmpulse initiation and depolarization.

5ll

Nervous System

In a Nutshell Na.flowsinward during the earlyphase oftheaction potential, causing depolarization oftheneuron. ln thelaterphase, K.flows outward, leading to hyperpolarization ofthecell.

3. Ionic movements in the impulse. The impulse, which consistsof a rapid depolarization followed by a repolarization, is produced by an early inward current of cations (positive ions), followed by a late but long-lastingoutward current (Figure V-29-6).Selectivepharmacologic blockade of separatevoltage-sensitiveconductancechannelshas shown that the ionic fluxes consistof an early and rapid influx of Na* (G,u")along its concentration gradient followed by a later K* efflux (G*) along its gradient. Actually, the net driving forceson ions crossingthe membrane are a result of both the concentration and electrical gradientsfor that ion. Sincethe equilibrium potential for a given ion is that potential providing an electrical driving force that exactly balancesthe chemical driving forces arising from the concentration gradients (Nernst equation), the net driving force on an ion lies in the difference betweenV," and E.o.For example,for K*, Va.iuingfo.."= I" x R" = I"/G"

x dri'ingfo...afld Vd.iuingfo...= V- - E*; and I* = G*

(V. - E*) = GK[-65- (-90)] = G.(+25)o. Similarly,I*u = G*"(V_ - ENu)= GN"[-65- (+50)] = G*,(-115),. At rest, G* and G*" are so low that only slow leaks occur.

Outward current Current0

0 Inward current TimeFigure V-29-6.lonic movements during the impulse.

4. An action potential can thus be explained in terms of changesin the membrane ionic conductances,as follows:

Note Theinfluxof Na.isvoltagedependent; if V,isnot reached, Na.permeability is notincreased andtheaction potential cannot begin.

In a Nutshell Positive feedback activates moreandmoreNa.channels potential astheaction begins.

a. Below threshold depolarizations,little or no changein G*" and G* occurs, and the membranebehavespassivelyas a capacitor;that is, below the threshold level of depolarization, membrane properties are not affected. b. When the threshold level of depolarization is reached,G*" risesvery rapidly in the first 2 msec (sodium activation). The rise in Na* conductanceis produced by an opening of voltage-gatedNa* channelsthat are usuallyclosed,enablingthe membraneto act as a resistor,that is, permit current flow of Na* accordingto the net driving force (Figure V-29-7). This increasein G*uis voltage-dependent:the greaterthe degreeof depolarization, the greaterthe rise in G*". c. The increasein G*uthus resultsin a regenerativeor positive feedbackcycle,sincethe greaterthe conductance,the greaterthe Na+current, or I*"; that is, the greaterthe Na* influx, the further the depolarization;and the greaterthe depolarization,the greater the increasein Na+ conductance.Figure V-29-8 illustratesthis feedbackcycle.

E"": V, - V" : 60log I*" : G*" (V. - EN")

512

[Na.]" tN*],

Physiology

With the increasedNa* movement through the membrane, the action potential is able to approachE"u.Note that reducing the concentrationgradient for Na* (i.e., increasing internal Na* concentration) reducesthe action potential maximum and the slope of the action potential upstrokebecausethe E*. is lowered,lowering I*".

T i m e .-# Figure V-29-7.Conductance changes during the action potential.

Increasein Grua

lncreasein lrua(Na+influx)

Figure V-29-8.Positive feedback cycle (Hodgkin cycle) for rising phase of action potential. d. The action potential ends rapidly (falling phase) partly becauseG,uureachesa peak value in a few milliseconds and then falls. This is Na* inactivation. e. Na* and K* activationbegin nearly simultaneously.Na* activation leadsto rapid depolarization. Na+ inactivation begins as the action potential approaches+50 mV and continues after the action potential peaks.K+ activation is still occurring at this point. f. Throughout the action potential, G" rises,indicative of K* activation.This rise, however,is much slower than Na+ activation, becausethe membrane K* channelsopen more slowly than the Na* channels.G" rises steadily to a peak that coincides with the onsetof Na* inactivation.This resultsin a large outward I* flow, and the membrane is repolarized.G* remains elevatedfor an extendedperiod of time, so that the action potential, in its falling phase,approachesE" evenmore closelythan in the resting condition. Thus, it undershootsthe resting potential. (The membrane is hyperpolarized

Note of theaction Atthebeginning potential, bothNa*andK* open; areactually channels take simply theK*channels to open(andthus longer well begins hyperpolarization afterNa*-dependent depolarization).

515

Neruous System

for a time until the resting potential is restored).The Na-K pump continually restores the ionic gradientsnecessaryfor the membrane potential at rest: Ix = Gr (Vm - EK). Note that although there is no K* inactivation, the eventsfollowing the rise of G" result in a termination of the G" becauseof the negativefeedbackrycle initiated by the K* efflux (FigureV-29-9).These eventsaccount for the falling phaseof the action potential.

Decreasein Gx

Decreasein 16(K efflux)

Figure V-29-9.Negative feedback of K+ activation. (1) Note that the thresholdthus representsthe minimum depolarizationto start conductancechanges.Separatechannelsexist for Na* and K*. (2) Na* channelis blockedby tetrodotoxin (TTX),leading to zeroNa* conductance. (3) K. channel is blocked by tetraethylammonium (TEA), leading to zero Kn conductance. E. Refractory periods, hnrerpolarizaton, and recovery. A neuron is refractory to stimulation at two phasesduring and following the action potential becauseof the changesin ion conductances.

In a Nutshell Theabsolute period refractory isthattimeduring whichNa. channels cannot reopen, regardless ofV,.Therelative periodisthattime refractory inwhich Narchannels can open,butV,isharder to attain dueto K-dependent hyperpolarization.

l. Absolute refractory period, at the peak and first half of the falling phaseof the action potential, is a period during which a secondstimulus, no matter how strong, cannot initiate another impulse (Figure V-29-10A). Becauseof the Na* inactivation, a secondstimulus cannot again elevateG*", as is required for the beginning of a secondaction potential. Furthermore, G* is still elevatedthrough the falling phase,causing an outward I*, which would neutralize the effect of an inward I*u on the state of polarization. 2. Relative refractory period, immediately following the absoluterefractory period, is the phasein which Na+ inactivation is ending and G* is diminishing and reaching the rest value (Figure V-29-10B). At this point, a stronger-than-normal stimulus can initiate another action potential. 3. Following the termination of the action potential, the membrane is in a state of hyperpolarization. Sincethe membrane is further awayfrom the threshold level of depolarization necessaryto cause the changesin G*u needed for action potential initiation, the membrane is hlperpolarized. 4. Changes in ionic concentration gradients occur during the action potential. With each action potential, severalpicomoies(10-tt mol) of Na+enter the cell,and severalpicomoles of K* leavethe cell. To maintain the concentration gradientsnecessaryfor the functioning of the neuron (the restingpotential and, indirectly,the action potential), energymust be supplied by the cell'smetabolism to power the Na-K pump.

5t4

Physiology

,a , I

I I

, ,

I f

,

a

I I I I I

'r+

Absolute

I I t I

AbsoluteRefractoryPeriod

RelativeRefractoryPeriod Figure V-29-lO.A, Absolute refractory period; B, relative refractory period.

F. Propagation of the action potential l. The discussionthus far has applied to the membrane action potential, that is, the electrical changesfor a given site (cylindrical portion) of the membrane as the action potential passesthrough it. The region was considereduniform, and longitudinal currents were ignored. 2. When an impulse moving along an axon is discussed,however,this is a propagatedaction potential, involving both local circuits and longitudinal currents.The patch of membrane undergoing the action potential provides the stimulus for (depolarizes)the region of membrane immediately aheadof it. 3. Figure V-29-11 showsan axon conducting an action potential at a given instant in time. a. Notice that the potential difference distributed spatially at successivepoints along the membranein one instant of time is the sameasthe potential differenceat a singlespapoints in time (just asthe standingwavealong a rope is tial location acrosssuccessive generated). (1) Considerthe two points shown, A and B. At B, the action potential is at its maximum, V- = +40; while A, which is just aheadof the action potential, is still at the resting potential, V- = -60 mV.

515

Nervous System

Membranepotentials along the axon at a giveninstantin time

Figure V-29-11.Propagation of the action potential.

(2) The potential differencesbetweenthesetwo points, both at the inside and outside of the membrane,resultsin the current flows shown (a local circuit).

In a Nutshell Saltatory conduction occurs alongmyelinated neurons by jumping fromnodeto node.

(3) By drawing off positive chargesfrom the outside of the resting membrane at A and neutralizingnegative chargesinside the membrane at A, the resting region is depolarizeduntil it reachesthreshold,when Na* activation occursand the membrane at A undergoesthe action potential. b. With myelinated axons, the spatial distribution of local currents is altered because myelin is an effective insulator and current flow through it is negligibte. Thus, the action potential at any given point can be effective in setting up membrane current flow further downstream. c. Depolarization in such axonsjumps from one node of Ranvier (where there is a gap in myelination) to the next node. The currents at the active node depolarize the node directly ahead to the threshold level. This is known as saltatory conduction and is much more rapid than simple conduction along unmyelinated axons (Figure V-29-I2). In both unmyelinated and myelinated axons,the greater the diameter of the axon, the greaterthe speedof conduction.

ri rl

myelin

I node of Ranvier Figure V-29-12.Saltatory conduction.

5t6

Physiology

4. Although an axon can conduct impulses in either direction in vitro, conduction usually occurs in one direction in vivo. a. Synapsespermit transmissionin one direction only. b. Once initiated, a moving impulse does not depolarizethe region of axon behind it becausethat areais hyperpolarizedor refractory; the impulse spreadsin the forward direction only. 5. Orthodromic impulses are those that occur in the normal direction of conduction of an axon. Antidromic impulses are those conductedin the direction oppositeto the normal or usual direction; these can be initiated experimentally. 6. Gradation of sensoryimpulse strengthis possible,sincemany axonswith different thresholds are presentat the samesensorylocation. As the stimulus strengthincreases,axonsof higher and higher thresholdscan be excitedto fire, and the cumulativeelectricalresponse increasesuntil all axons are excited by the maximal stimulus. 7. Recorded action potentials from nerves represent a summation of the all-or-none responsesof eachof the axons. 8. Mixed nervesare composedof families of axon and dendrite fibers with a variety of conduction speeds(TableV-29-2). a. The greaterthe diameter of a given nerve fiber, the greater its speedof conduction. Myelin also increasesthe speedof conduction.

Table V-29-2.Classification of mammalian nerve fibers. Conduction tfpe

Alternate name

Diameter (pM)

Myelin

velocity (meters/sec)

Ia

Acr

16-22

Yes

7O-I2O

Muscle spindle afferents, motor nerves

2-16

70-120 35-70

Golgi tendon organs Muscle spindle (nuclear chain), touch, pressure,hairs, vibration

Fiber

Function

Ib II

AB

6-tZ

Yes Yes

III

A1

2-6

Yes

10-35

Muscle spindle efferents

III

4.6

2-6

Yes

1240

B

<3

c

0.5-1.5

Yes No

3-15 0.5-2.0

Pain, temperature Autonomic preganglionic Pain, temperature,sympathetic,

w

postganglionic

b. Compound action potentials are observedin mixed nervesbecauseof the different conduction speedsof the fibers present.Each fiber is at a different stagein its action potential rycle at any given point along the nerve, and hence the compound action potential has multiple peaks.

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NeruousSystem

SYNAPTIC TRANSMISSION A synapseis the specializedareawhere one neuron communicateswith another (Figure V-29-13). Morphologically, synapsescan be divided into bridged junctions and unbridged junctions. Chemical synaPses are responsiblefor most neurotransmission;the separation(synaptic cleft) is about 30 nm. Electrical synapses(gap junctions) mediate electricaltransmissionand are separatedby a gap of about 2 nm (20 A). Thesetypes of synapsesare rare in vertebrates. A. Pre- and postsynaptic properties

Note

l. When an action potential reachesthe presynapticterminal at the tip of an :Lxon,it activatesvoltage-dependentCa2*channelsthat arelocalizedin the axon terminal membrane. Ca2*influx into the nerve terminal triggers the fusion of synaptic vesicleswith the plasma membrane and the releaseof neurotransmitter from the vesiclesinto the synapticcleft.

Nicotinic AChreceptors always leadtodepolarization because theypermitNa*to enterthecell.

2. When acetylcholine(ACh) is releasedinto the synaptic cleft, it either binds to receptors on the postsynapticmembrane or is inactivatedby an acetylcholinesterase (AChE) within the cleft. Neurotransmitterssuch as catecholaminesare taken back up into the nerve terminal via uptake carriers. a. Two moleculesof ACh bind to the nicotinic ACh receptor. b. Thesechannelsare equally permeableto both Na* and K* and stightly permeableto Ca2*.Thus, when the channel opens,both Na* and K* flow down their concentration gradients.The flow resultsin potential changein the postsynapticmembranebecause there is a net flow of Na* ions into the cell,owing to the greaterelectricalgradient driving Na* flux than that for the movement of K*.

Dendrites

Node of Ranvier Presynaptic neuron

Figure V-29-13. The synaps e.

The movement of Na* into the postsynapticneuron generatesan excitatory postsynaptic potential (EPSP)with magnitude dependentupon the number of ACh channels that are opened. Since there are few voltage-gatedchannelsin the dendrites or

5t8

Physiology

soma of the typical neuron, the EPSPmust be conductedelectrotonicallyto the beginning of the axon (axon hillock), which containsmanyvoltage-gatedchannelswith low threshold.The action potential will be generatedhere if the EPSPstill exceedsthreshold, and will be conducted backwards over the soma as well as down the axon of the postsynapticcell. 3. Inhibitory postsynaptic potentials (IPSPs) hyperpolarize the membrane potential as a result of a ligand-gatedmechanism in which K* channelsare opened by a neurotransmittor. An IPSP may also be causedby an inward flux of Cl . 4. Synaptic potentials summate to allow depolarization to occur. Inhibitory as well as excitatory input is involved. Certain presynapticfactors are responsiblefor controlling neurotransmitter release.TWotfpes of summation are:

Note + Onlyif thesumof EPSPs IPSPs isgreater V, than can potential anaction be generated bytheneuron.

a. Spatial summation, which is the summing of simultaneous inputs from different presynapticneurons with eachsynapticinput occupying a different areaon the postsynaptic cell membrane b. Temporal summation, in which the additive effect on the postsynaptic neuronal membrane potential is causedby the repeatedrapid firing of a presynapticneuron B. Calcium in presynaptic control. Calcium is critical for transmitter releaseand couples the action potential to transmitter secretion. 1. During depolarization,Ca2*channelsare openedto allow Ca2*to move down its concentration gradient into the cell and allow transmitter release. 2. Lowering extracellularCa2*concentration reducessynaptictransmission,and increasing extracellularCa2*concentrationenhancestransmitter release. 3. By selectivelyblocking Nan influx with tetrodotoxin (TTX) or K* efflux with tetraethylammonium (TEA) and artificially depolarizing the presynaptic membrane, it can be demonstratedthat transmitter releaseis not dependenton either of thesemechanisms. C. Neuromuscular junction. Observation of a nerve-muscle synapse,a model for synaptic transmission,revealsspontaneouspotentialsin the end plate, or postsynapticregion, which are calledminiature end-plate potentials. 1. Increaseor decreaseof availability of ACh, the neurotransmitter for the nerve-muscle synapsepermits observationof the effect on the miniature end-platepotential. 2. Thesepotentialsare enhancedby drugs such as neostigmine,which inhibits the hydrolysis of ACh by AChE. 3. They are abolishedby drugs such as D-tubocurarine, which blocks the nicotinic ACh receptor p ostsynaptically. 4. Normally, the miniature end-platepotential is about 0.5-1.0 mV in amplitude. However, a smaller number of ACh moleculesproducesa potential chargemuch smallerthan this. 5. Theseobservationsand othersled investigatorsto concludethat ACh is releasedin a packet of up to 5 x 103ACh molecules,and these packetsare stored and releasedfrom the nerve terminal by specializedsynapticvesicles. 6. Synapticvesiclesfusewith the inside surfaceof the presynapticmembrane at specificrelease sites.During an action potential, Ca2nis brought into the nerve terminal and there facilitates a fusion of the vesicular and terminal membranes,which increasesthe probability that a given quantum of transmitter is released.Sinceeachsynapticvesiclecontainsa fixed quantity of ACh (up to 5 x 103molecules),neurotransmissionoccursin a quantal manner.

519

Neruous System

D. Synaptic plasticity. The effectivenessof a synapsecan be altered by changing the amount of Ca2+that comesinto a terminal, and this allows synaptic plasticity. Long-term potentiation (tTP) is an important example of neuronal plasticity,which is thought to be the biologic basisfor learning and memory. E. Morphology of chemical synapses.The synapseis traditionally defined as the region of the transmitting neuron where transmitter is releasedto the receptor region of the receiving neuron. Although this is often describedas axon-to-dendrite, neurons are in reality more variable; axons can communicate directly with the soma or with an axon of the postsynaptic cell.The distanceand areainvolved in a synapsedetermine how directedthe information will be. The nerve-skeletalmuscle synapsecan be used as an exampleof a directed synapse. Neuroendocrinecells are examplesof the least directed neurons, releasinginto the bloodstreamhormones that act on target cellsat a distance.The morphology of the neuromuscular synapse(neuromuscularjunction) is detailedbelow: 1. Vesiclesare stored in the presynapticterminal and are the structural unit responsiblefor quantal releaseof neurotransmitter.The activezone is the areawhere presynapticthickening occurs. These thickenings are dense bars with synaptic vesiclesalong each side, located directly above the postsynapticfolds in the muscle. During an action potential, synapticvesiclesare releasedby the processof exocytosis.Individual vesiclesact independently, and for each vesicle undergoing exocytosis,one quantum of transmitter is released.After exocytosis,the vesiclemembrane is rerycled.The neuromuscularjunction contains about 10,000ACh receptorsper squaremicrometer of membrane at the postsynaptic site. The receptorsare localized primarily in the plasma membrane of the junctional folds. 2. Many synapsesoperate in a directed manner similar to that of the neuromuscular synapse.The autonomic nervous system(ANS) doesnot havethe samespecializationfor directed transmitter release.In the postganglionicneuron of the ANS, the synaptic gap may be aswide as400 nm (comparedto 25 nm for the neuromuscularsynapse);there are no denseprojections where the vesiclesalign presynaptically,and the vesiclesdo not show a preferred orientation toward a particular surface membrane. Apparently this allows a widespreadeffect by the particular neurotransmitter. 3. The presynapticterminal can form a synapsewith the postsynapticcell in a variety of places.Known contact sites(with the presynapticelementnamed first) include: a. Axosomatic b. Axodendritic c. Axoaxonic d. Dendrodendritic e. Somatosomatic 4. The location of the synapseinfluencesthe type of effect it has. For example,axoaxonic synapsesare far from the trigger zone of the postsynaptic cell and, therefore, have little effect on the threshold of the neuron but do control the amount of transmitter released by the presynapticterminal; however,axosomaticcontacts are closeto the trigger zone and directly influence the threshold of the postsynapticnerve cell. 5. The number of inputs is also important in determining the final output. Typically,neurons havea number of synapticinputs. The Purkinje cell of the cerebellum,for example, has up to 80,000 synaptic inputs, including both excitatory and inhibitory, and both strong and weak inputs.

520

Physiology

a. The function of the synapsedependson manyvariables,including location, size,proximity of other synapses,and inhibitory and excitatorysynapses. b. Functional segregationoccurs,which meansthat certain inputs affect only a particular site of the postsynapticcell and some inputs are capableof overriding all others. F. Chemical transmission summarized. Chemical transmission may be visualizedas occurring in severalsteps. 1. The transmitter is synthesized,the substanceis stored,and then it is released,interacting with receptorsof the postsynapticmembrane.The transmitter is then removed from the synaptic cleft. 2. For a substanceto qualiff as a neurotransmitter,it must meet the following criteria: a. The neuron synthesizesthe substance. b. It is releasedfrom the presynapticterminal in an amount sufficient to exert its effect. c. Its action can be mimicked with exogenousapplication of the substance. d. A mechanismexistsfor removing the substancefrom the synapticcleft. G. Neuronal differentiation. Classically,it was taught that a mature neuron is differentiated so that only one neurotransmitter is synthesized,stored,and released.We now know that neurotransmittersmay coexistin a single neuron. 1. Tiansmitters a. ACh is usedby motor neurons of the spinal cord at the neuromuscularjunction. It is also the transmitter for all autonomic preganglionicneurons and of parasympathetic postganglionicneurons.ACh is located throughout the brain, and it is thought to be highly concentratedin the substantiainnominata region of the basalgangliawith diffuse projections from this areaplaying some role in memory. b. Norepinephrine is the transmitter in postganglionicneurons of the ANS. In the CNS, norepinephrine-containingneurons are prominent in the locus ceruleus,which projects diffirsely to the cortex, cerebellum,and spinal cord and is involved in alerting mechanisms. c. Dopamine-containing cells are found in the substantianigra, the midbrain, and the hypothalamus.From these regions they project to the striatum, limbic cortex, and pituitary stalk, respectively. d. Serotonin is located primarily in the raphe nuclei of the brain stem with projections throughout the cortex and spinal cord. e. Glutamate, glycine, and GABA are amino acidsthat also serveas neurotransmitters. (1) Glutamate is the primary excitatory neurotransmitter of the CNS and is found in many locations. (2) Glycine is an inhibitor in the spinal cord. (3) GABA is responsible for the inhibition in the basal ganglia, the cerebellar Purkinje cells,the spinal cord, and certain cortical relays. f. Severalpeptides are now felt to be probable neurotransmitters.Among these are vasoactiveintestinal polypeptide (VIP); substanceP; the endogenousopiates(i.e., Fendorphin, met-enkephalin,leu-enkephalin,adrenocorticotropichormone (ACTH); insulin; glucagon; neurotensin; thyrotropin-releasing hormone (TRH); luteinizing hormone-releasinghormone (LH-RH) ; vasopressin;bradykinin; oxFtocin;and others.

521

Neruous System

2. Receptors. A given transmitter is not intrinsically excitatory or inhibitory. Effects are a result of the interaction of the transmitter with the specific receptor, and the receptor determines if the transmitter will be excitatory or inhibitory. For example,ACh can excite some synapsesbut inhibit others. a. The receptor is a protein that facesoutward in the membrane of the postsynaptic neuron. The nicotinic ACh receptor-complex,which is a type of ligand-gatedion channel, consistsof two components: ( 1) A binding component (2) An ionophore component (a channel in the membrane through which ions flow) b. In this example,ACh binding produces a conformational changein the receptor,thus opening the ion channel. c. Somereceptorsdo not work by changesin ionic permeability but alter the metabolism of the postsynapticcell (e.g.,provoke the synthesisof secondmessengers such asryclic adenosinemonophosphate[cAMP] or ryclic guanosinemonophosphate[cGMP]). d. Once a transmitter binds to a receptor,there must be a way of disposingof the transmitter to end the signal. This can be done by enzymatic degradation, re-uptake by the presynaptic cell, or through diffrrsion of neurotransmitter away from the receptor. H. Diseases of the neuromuscular junction. Certain diseasestates occur as a result of dysfunction of the synapse. 1. Postsynaptic diseasestates

ln a Nutshell gravis Mya$henia isa disease inwhichautoantibodies tothe AChreceptor inactivate receptors attheneuromuscular junction, resulting in muscle generally weakness. Symptoms worsen withrepeated useof themuscle.

ClinicalCorrelate Succinylcholine isa depolarizing blocker used asa skeletal muscle relaxant. Adm inistration initially results in muscle fasciculations, followed by paralysis. flaccid

a. Myasthenia gravis is the best understood diseaseinvolving disordered function of chemicalsynapses. (1) An autoimmune syndromecausedby antibodiesto the nicotinic ACh receptorat the neuromuscular junction, resulting in muscle weaknessthat often affects the eyesbut can also affectthe limb and respiratory muscles.The weaknesscan vary from day to day and tends to be worse after prolonged use of a particular muscle.The antibodiesto the receptorsprobably causea decreasednumber of functionalACh receptors.It is not known why all musclesare not affectedequally,nor why spontaneousexacerbationsand remissionsoccur. (2) Therapy consistsof anticholinesterase(anti-ChE) medication, which preventsthe degradation of ACh at the synapseby AChE, making more ACh availableto the functioning receptors;and immunosuppressionwith steroids,cytotoxic agents,or other methods,which works by attacking the underlying causesof the disease. b. Curare, a deadly poison, effectively competes with ACh for receptor molecules. Although it binds to the receptor,it fails to causethe cation channelsto open, preventing postjunctional depolarization. Since curare is a competitive antagonist,the effect can be reversed. c. cr-Bungarotoxin (from snakevenom) is a noncompetitive inhibitor; that is, it binds irreversibly to ACh receptors. d. Depolarizing blocking agents (e.g., succinylcholine) compete with ACh for receptor sites;however,they do open the cation channels.At the sametime, they desensitizethe muscle to ACh (the binding may be lessreversiblethan ACh binding) so that end-plate potentials are smaller. e. Anticholinesterases (e.g., edrophonium [reversible], diisopropyl phosphorofluoridate [DFPJ,parathion [irreversibleinsecticide]) bind to AChE and, thus, slow down

522

Physiology

or stop ACh hydrolysis and removal from the neuromuscular junction. This first lengthensthe time of action of ACh, resulting in larger and longer end-plate potentials (and enhancedneuromusculartransmission,hencespasms).Secondarily,there is a depolarizingblock of neuromusculartransmission. 2. Presynaptic dysfunctions

ClinicalCorrelate Eaton-Lambert diffenfrom gravis mya$henia inthataffected musdes improve withuse.

a. Eaton-Lambert syndrome is clinically similar to myastheniaexceptthat patients tend to get stronger rather than weakerafter repeateduse of a muscle.The defectis presynaptic in ACh releaseand the receptoris normal. b. Clostridium botulinum toxin (botulism, bacterialtoxin) actson the motor nerve end plate, causinga blockagein the releaseof transmitter, resulting in quick paralysisof skeletalmusculature and death by respiratory failure. c. Black widow spider venom causescomplete releaseand depletion of ACh from the nerve ending at the skeletalneuromuscular junction. Clinically, the effect is muscular spasms. I. Smooth muscle synapse.The smooth muscle neuroeffectorjunction may be cholinergic or adrenergic. 1. The synapticcleft is much smaller (10-20 pm) than in a skeletalneuromuscularjunction, and no secondaryfolds are present. 2. Cholinergic nerve terminals have the sametype of synapticvesiclesas in skeletalmuscle neuromuscularjunctions. 3. Adrenergic terminals have dark, dense-coredvesicles containing norepinephrine. Inactivation occursby reuptakeof transmitter by the nerve ending. 4. Tiansversetubules (T tubules) are absentin smooth muscle.

(ANS) AUTONOMTC NERVOUS SYSTEM The ANS consistsof efferent (motor) neurons to viscera,cardiac and smooth muscle, and glands.It adjuststhe amplitude of visceral activity and coordinatesactivities of different viscera. Note that unlike skeletal muscle, visceral effectors are usually autonomous; smooth muscle spontaneouslycontracts without neural innervation by spontaneousdepolarization of the membraneto threshold or in responseto direct mechanicalstimuli (stretch).However,without the ANS, the visceraare not modulated or coordinated. A. Anatomic organization 1. CNS centersof the hypothalamusand brain stem,especiallythe reticular formation, contain the controlling neuron cell bodies,i.e., the sitesof autonomic regulation. 2. Peripheral organization consistsof two motor neurons in series.

52t

Neruous System

Intermediolateral horn

Postganglionic fiber (unmyelinated)

Motoraxon

ganglion Skeletal muscle

Preganglionic fiber (thinlymyelinated)

Spinalcord (crosssection)

Figure V-29-14.Spinal autonomic system.

a. Preganglionic neuron in the CNS sendsout a slow-conducting slightly myelinated fiber that synapseswith another neuron outside the CNS,locatedin a peripheral ganglion, a cluster of neurons (FigureV-29-14). b. Postganglionic neuron sends out a very slow-conducting unmyelinated postganglionic fiber, which slmapseson the effector organ. Becausethesepre- and postganglionic fibers conduct so slowly (especiallythe postganglionic) and becausetwo synapsesare involved, autonomic nerve conduction is 100 times slower than skeletal motor conduction (FigureV-29-15).

Sympathetic

Parasympathetic

fiber Shortpreganglionic Longpreganglionic fiber

Long postganglionic fiber -

ACh Smoothmuscle

NE

fiber Shortpostganglionic ACh

Figure V-29-15.Microanatomy of pre- and postganglionic autonomic nerves.

B. Sympathetic nervous system originates in the intermediolateral cell column (lateral horn of spinal gray matter) in spinal segmentsTl to L2 (thoracolumbar). 1. Preganglionic fibers leavethe spinal cord, togetherwith motor neurons from the anterior horn, to form the ventral roots. The sympatheticpreganglionicsimmediately leavein a white ramus (myelinated)to join the sympatheticchain.

524

Physiology

2. Sympathetic chain (one on each side of the spinal cord, running parallel with it) consists of the cell bodies of the postganglionic neurons, known as the paravertebral ganglia. The chain runs along the entire length of the spinal column (although preganglionic fibers supply it only from Tl to L2) and innervates viscera in the entire body. Each presynaptic neuron synapseswith manypostsynapticneurons (divergence),and eachpostsynapticcell body receivesinput from many preganglionicfibers (convergence).Not all preganglionic fibers terminate by synapsingin the sympathetic chain.

ln a Nubhell Thesympathetic chain allows activation of thesympathetic system throughout thebodyin synchronous, coordinated fashion.

a. Splanchnic nerves pass through the chain without synapsing,ending in a neuron plexus such as the celiac ganglia. b. Nerves to the adrenal medulla also pass through the sympathetic chain without synapsing,ending in neuroendocrine cells in the medulla (analogousto postganglionic neurons). 3. ACh is the chemicaltransmitter betweenpreganglionicand postganglionicneurons;thus, the preganglionicneuron is referredto as a cholinergic neuron. 4. Small dopaminergic neurons called small intensely fluorescent (SIF) cells regulate sympathetic ganglia.The SIF releasetheir transmitter into the ganglionic blood vessels.SIF cellsare innervatedby preganglioiccholinergic fibers (FigureV-29-I6).

Norepinephrine

Figure V-29-16.Fine structure of sympathetic ganglia.

5 . Organization. Postganglionic neurons in the sympathetic system have long axons running from the gangliato the peripheral visceraby one of two paths: a. Gray ramus, leading back to the peripheral (spinal) nervesby which they reach the somatic musculature b. Vascularroute, along the major blood vessels(e.g.,carotid plexus) to reachthe areas servedby the blood vesselsas well as innervating the smooth muscle lining the vessel 6 . Norepinephrine (also called noradrenaline) is the usual chemical transmitter of the sympathetic postganglionicfiber. Theseare,thus, noradrenergicneurons;exceptionsinclude sympatheticpostganglionicneurons to sweatglands and to some of those causingdilation of blood vesselsin skeletalmuscle,which are often cholinergic. 7. Effectors include all smooth muscle;glandsand viscera,notably the heart, spleen,adrenal medulla; musculatureand glands of the gastrointestinaltract and bladder; smooth muscle of blood vessels,sweatglands,and hair follicles;and iris and ciliary musclesof the eye. a. Superior cervical ganglion, the uppermost ganglion of the sympathetic chain, serves the uppermost structures:those in the head and neck,including the lower four cranial nerves,the pharynx, the efiernal and internal carotid arteries,and the superior cervical cardiac nerve.

In a Nutshell Norepinephrine isreleased by mostpostganglionic neurons of thesympathetic nervous system. Exceptions include the sympathetic cholinergis (whichinnervate glands sweat andskeletal muscle vasculature) andtheadrenal (which medulla release epinephrine inaddition to norepinephrine). ClinicalCorrelate A lesion ofthesuperior ganglion cervical leads to Horner syndrome.

525

Neruous System

b. Middle and inferior cervical ganglia (known as the stellate ganglion when these are fused) serve the heart and lungs through spinal nerves C5-C8 and T1, and blood vesselsand skin of the uppq extremities. c. Thoracic chain ganglia and the celiac (prevertebral) ganglion send fibers to the entire gastrointestinal tract up until the left colic flexure (upper colon). d. Lumbar and sacral clnin ganglia (and the mesenteric plexus, another prwertebral ganglion receiving preganglionic fibers via a splanchnic nerve) send fibers to the digestive tract below the left colic flexure, including the rectum, and to smooth muscle and glands of the bladder, uterus, and external genitalia. F-g-ltq!gl! nervoussystefi Sympathetic functionscanbe viewedas resDonses Io $ress.

8. Funcion is coordination of all involuntary effectors for emergency or stress responses. The system can act as a unit to achieve a state of excitement; a. cardiac outDut rises as a result of increased contraction force and rate. b. The oxygen content ofblood rises as a result of dilation of the bronchi. c. Blood supply to the brain is increased, while t}lat to the digestive tract is d€creas€d. d. Contractile activity in the gastrointestinal tract is decreased. e. Smooth muscle in blood vesselsto musculature (vasodilators) is stimulated, as are piloerector muscles to hairs in the skin and vasoconstrictors of cutaneous blood vessels. f. Sympathetic innervation to the liver causes a rise in blood glucose by stimulating glycogenolysis. g. Inneryation to the adrenal medulla causesreleaseof epinephrine. h. Dilators of the pupil are activated. C. Parasympathetic n€ryous system originates in the cranial (preganglionic neuron soma in the brain stem nuclei of cranial nerves III, \rll, IX, and X) and sacral (the intermediate column ofthe spinal cord, segments52, 53, 54) divisions. l. Preganglionic fibers, unlike those of th€ sympathetic system, terminate in ganglia close to t}le innervated structure; hence, the preganglionic fibers are very long, whereas the postganglionic fibers are very short. a. Parasympathetic ganglia are found in or near the innervated organs. There is little divergence or convergence of synaptic innervations. b. ACh is the chemical transmitter for the preganglionic fibers, or cholinergic neurons. These synapsesare always excitatory but the postganglionic neurons do not always excite. Sometimes, there are postganglionic sympathetic receptors within parasfmpathetic ganglia (especially in the gastrointestinal tract) that inhibit traasmission by stimulating cr-adrenergic receptors on the postganglionic parasympathetic fibers. 2. Postganglionic neurons are short, secrete ACh (thus are also cholinergic), but are ftequently inhibitory.

Itotc Bothpre and postganglionic parasympathetic neurons releaseACh

:. nararynparhetic patlnvays consist of distant innervations to particular viscera.Unlike rympatlrctic neurons,the distribution is not to the entire body but is limited to f]'e following: a' oculomotorPath (1) Preganglionic oculomotor nucleus (midbrain) is connected via cranial nerve III to the ciliary ganglion. (2) Postganglionic connection is ftom the ciliary ganglion to ciliary muscle and sphincter pupillae.

526

Physiology

b. Salivary gland innervation (1) Preganglionic connection is from the superior and inferior salivary nuclei (medulla oblongata) via cranial nervesVII and IX. Fibers from cranial nerve VII synapsein the submandibular ganglion, whereasthose from IX synapsein the otic ganglion. (2) Postganglionic fibers from the submandibular ganglion supply submandibular and sublingual salivaryglands,whereasfibers from the otic ganglion supply the parotid gland. c. Vagus (cranial nerve X) path (1) Preganglionic fibers connect the dorsal nucleus of the vagus (medulla), via the vagusnerve,to peripheral gangliain numerous viscera(heart, esophagus,stomach,intestinesthrough the left colic flexure). (2) Postganglionic fibers run short distances from the ganglia to the sites of innervation. d. Sacralparasympathetic neurons from 52, 53, and 54 segmentsof the spinal cord send axonsout with the correspondingsacralnerves,exiting at the sacralplexusto synapse in the walls of pelvic viscera,including the uterus, genitals,bladder,lower colon, and rectum. Note that parasympatheticfibers do not innervate any blood vesselsor visceral structuresin the skin (sweatglands and hair follicles). 4. Important parasympathetic functions include activation and coordination of digestive, reproductive, and excretory functions. Note that the parasympatheticactivities are not relatedfunctionally, and therefore,the different componentsare usually controlled independently.Parasympatheticfibers:

ln a Nubhell Parasympathetic fibersdo not innervate bloodvessels, sweat glands, pili orarrector muscles; thesestructures receive unopposed sympathetic input.

a. Stimulate the gastrointestinalmusculature (increasedperistalsis[mainly CN X-the vagusnerve]) b. Stimulate salivary glands (mainly CN VII and IX-the nerves,respectively)

facial and glossopharyngeal

c. Open the sphinctersin the gastrointestinaltract d. Activate digestion e. Have an inhibitory effect on the heart (slowing the rate and force of contractions [vagusnerve]) f. Stimulate the bladder to contract and stimulate defecation(vagusnerve) g. Constrict the pupils (CN Ill-oculomotor

nerve)

h. Causeerection (sacralparasympathetics) 5. Receptorsdetermine the nature of the postsynapticeffect. a. Adrenergic receptors are sensitive to catecholamines (e.g., dopamine, norepinephrine, epinephrine,isoproterenol). (1) Alpha receptorshavesensitiuttyto epinephrine,norepinephrine,and isoproterenol; causeexcitatoryresponsesin postsynapticsympatheticcells (e.g.,contraction); and are blocked by phenorybenzamine, dihydroergotamine, and phentolamine. (2) Beta receptors have sensitivity to isoproterenol, epinephrine, and norepinephrine; are usuallyinhibitory exceptin the heart muscle,where they increase rate and force; and are blocked by propranolol and metoprolol.

ln a Nutshell Adrenergic Receptors . cr:generally excitatory . p: excitatory atheart, inhibitory elsewhere

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Neruous System

In a Nutshell Receptors Cholinergic . Nicotinic AChR: atskeletal muscle, autonomic ganglion; always excitatory . Muscarinic AChR: at postganglion iceffector sites

b. Cholinergic (ACh) receptors ( 1) Nicotinic receptors are found at synapsesbetween pre- and postganglionic sympathetic and parasympatheticfibers and also at neuromuscularjunctions (nicotine mimics the effect of ACh). They are alwaysexcitatory. They can be blocked by curare (especiallyat the neuromuscular junctions) and hexamethonium (especiallyat ganglia),but they are not blocked by atropine. (2) Muscarinic receptors are found at postganglionic parasympathetic synapseson effectors. They are inhibitory or excitatory (muscarine mimics the effects of ACh) and are blocked by atropine but not by curare or hexamethonium. c. Tonic activity is the slow level of autonomic activity that is alwayspresent,for example, continual stimulation of the sinoatrial (SA) node at a moderaterate from both the vagus and sympathetic fibers. Both autonomic systemshave tonic rates of firing, originating from higher centersin the brain. This enablesfiner control, since the tonic level can be increasedor decreased. 6. Coordination of sympathetic and parasympathetic systems a. When both systemsinnervate the samecell or tissue,they usually have opposite effects (e.g.,innervationof the SA node). b. The autonomics may createopposing activity through excitation of antagonistic pairs of effectors,for example,innervation of antagonisticmuscles (sphincter pupillae is innervated parasympathetically,whereasdilator pupillae is sympathetically innervated). Both systemsexcite the effectorsto contract, but paired effectorshave opposite activities. c. Synergisticeffects are found where the two systemsaugment each othet for example, dual innervation to salivary glands,both excitatory.

SOMATIC SENSORY SYSTEM A. Sensory receptors are the structures that confer awarenessof the external environment. The information receivedcomesfrom the external world and from within the body. Sensorysystems can be divided into three categoriesbased on the source of the signals to which they respond. 1. Exteroceptivq those sensitiveto the external environment, such as vision, hearing, skin, and chemical senses 2. Proprioceptive: those that provide information about the relative position of body parts to one another or the body position in space 3. Interoceptive: the functional monitoring of internal body events,such as blood pressure

B. Somatic sensory system is involved with the stimuli that affect the body surfaceor deep tissues and combines all three categoriesof sensory systems(unlike vision, which is entirely exteroceptive). l. Four submodalities of the somatic sensory system a. Touch-pressure sensation, or the sensitivity to mechanical stimulation of body surfaces b. Position sense,or the sensitivity to mechanical changesin musclesand joints

528

Physiology

c. Thermal sensations,which render responsiveness to cold and hot stimuli in the environment d. Pain sensation, or sensitivity to noxious stimuli 2. Receptors.Each submodaliry is mediatedby a particular receptor:

In a Nubhell

a. Nociceptors, which mediatepain, are connectedto A6 and C fiber axons. ( 1) Strong mechanicalstimulation activatesmechanicalreceptors(e.g.,sharp objects).

Painreceptors arefreenerve endings ofA6andCfibers.

(2) Temperaturesgreaterthan 45"C stimulate heat receptors. (3) Pain receptorsmediatedbyA6 fibers sensestimuli perceivedasabrupt and sharp. Slow pain sensationis mediatedby C fibers and is perceivedasa sickening,burning sensation. (a) Mixed receptorsrespondto various fypes of noxious stimuli. b. Cold and warm receptors mediate thermal sensation and are connected by A6 and C fibers. c. Mechanoreceptorsmediatetouch and pressure.They are classifiedas: (1) Rapidly adapting, responding only at onset and termination of stimulus. The fibers are connected by AB and AD axons. Examples of rapidly adapting mechanoreceptorsare hair follicle receptors,Meissner corpuscles(located in as the palms), and Pacinian corpuscles(located in subcuta|1:r|xr:,:*.,:r.n (2) Slowly adapting, responding continuously to a stimulus. They are mediatedby AB fibers.Type I slowly adapting mechanoreceptorsare punctile receptivefields that fire irregularly with, for example, maintained indentation of skin. Type II mechanoreceptorsproduce regular dischargein responseto maintained pressure.An example is Ruffini end organ in hairy skin. Flutter, or low-frequenry sinusoidal mechanical stimulation, is mediated by hair follicles and Meissner corpuscles.Vibration, or high-frequencymechanicalstimulation, is mediatedby Paciniancorpuscles. d. Afferent muscle fibers and joint afferents mediate position senseand kinesthesia. C. Spinal cord pathways for sensation 1. Functionally specific receptorsconnect to anatomically discretelocations in the spinal cord and brain stem.Information is processedfrom the peripheryvia afferentnerve fibers to peripheral nerves to plexus to spinal nerves to dorsal root. At the plexus, the afferent fibers are regrouped so that a single spinal nerve receivesafferentsfrom severalperipheral nerves.The spinal gray matter is divided into nuclei that are important for sensation (FigureV-29-17). a. The posterior marginal nucleusintegratesafferentinformation. b. The substantiagelatinosaactsas a relayfor pain and temperature. c. The nucleusproprius integratessensoryinformation in conjunction with descending control. d. Clarke nucleusrelayslimb position to the cerebellum.

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Neruous System

Posteriormarginalnucleus Substantiagelatinosa Intermediolateral nucleus

Nucleusproprius Clarke'snucleus

Motor nuclei

FigureV-29-17.Spinal cord sensory nuclei.

2. Spinal white matter contains myelinated rxons. These major ascendingsensory systems include the following: a. Dorsal columns, large-diameter axons, carry discriminative touch, vibration, and joint and limb position sense.Fibers here ascend to the nucleus gracilis and the cuneate nucleus in the lower medulla. These fibers cross and then ascend in the contralateral medial lemniscus to terminate in the thalamus. b. Anterolateral pathways carry pain, temperature, and crude touch sense. (1) The cells of origin to the anterolateralcolumns are in the dorsal horn, i.e., the columns are postsynaptic fibers to the primary afferent fibers. The fibers crossin the spinal cord. (2) The major termination of this pathway is in the thalamusvia the spinothalamic tract. c. Spinocerebellar tracts involved in coordination control by the cerebellum are also located in the lateral columns. Thesetracks carry unconsciousproprioceptive information.

3 . Anterolateral and dorsal column systems converge at the ventral posterior lateral nucleus (VPL) of the thalamus. The anterolateral system also projects to the thalamic intralaminar nuclei, which are thought to play a role in arousal.The VPL sendsprojections to the cerebral cortex. 4 . Body surface is representedschematicallyon the cortex (Figure V-29-18). This can be found by direct stimulation of the cortex, which leads to tactile sensationsof tingling, numbness,or pressurein a correspondingpart of the opposite side of the body.

550

Physiology

FigureV-29-18. Sensoryhomunculuson postcentralgyrus.

D. The eye. FigureY-29-I9 showsthe major anatomic featuresof the eye. l. Pupil a. This structure regulates light entering the eye. lts size ranges from 2-8 mm (can reduceentering light by a factor of 16). b. The constrictor pupillae has parasympathetic innervation. c. The dilator pupillae (radial dilator) has sympathetic innervation. d. Light entering one eyecausesconstriction of the contralateral pupil (consensuallight reflex); the reflex is mediated via Edinger-Westphalnuclei,located in the midbrain.

ClinicalCorrelate Onesymptom oftertiary syphilis isArgyll Robertson pupil. lnthiscase, thereflex pupillary constriction to lightis lost,butthecon$riction that occurs during accommodation (light-near ispreserved dissociation).

e. Pupillary constriction occurs when focusing for near vision (accommodation). It is mediated via a different pathway from the light reflex. 2. Lens: accommodation-convergence reflex a. The lens is unique in that its refractive powers can be changed.Viewing a near object causesconstriction of the ciliary muscles to thicken the lens. At the same time the medial recti contract to direct the gazemedially. This reflex is mediated via oculomotor nuclei and the visual cortex.

ln a Nubhell Whenfocusing ona near object, a triadof events occur: (l) Lensaccommodation (2) Pupillary con$riction (3) Eyeconvergence

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NeruousSystem

Choroidcoat Retina Pupil Lens

Fovea------=Blind sRot--_.__,_

Figure V-29-19.The eye.

b. Note that the lens is not the primary refractivecomponent of the eye.Approximately 75o/oof the refraction of incident light is performed by the cornea. 3. Retina. The retina containstwo types of photoreceptors,rods and cones.

ln a Nutshell Rhodopsin absorbs lightand induces a conformational change intheretina, whichin turnalters visual cellpermeability to Na*.

5t2

a. Rod cells are long and slenderand contain numerous stackedmembranous disks in their outer portions. The membranescontain the pigment rhodopsin, which consists of the light-trapping protein, scotopsin, and the vitamin A derivative,ll-cis-retinal (retinene,).In the absenceof light, rod cellsare somewhatpermeableto Na* through channelsthat remain open in the presenceof cytoplasmic cGMP. As long as these channelsremain open, Na* diffrrsessteadilyinto the cells,causingthem to be slightly depolarized(the Na' is pumped out of the cell by an electrogenicNa*/K* pump). This inward flux of Na* is referred to as dark current. When light rays impinge upon the rod cells,they are absorbedby the rhodopsin. The 1l-crs-retinal component isomerizes to "all-trans-retinal," which dissociates from the scotopsin, converting it to metarhodospin II. Each molecule of metarhodopsin II thus generatedactivatesthe membrane disk-bound G-protein, transducin, which, in turn, activatesa phosphodiesterasethat converts cGMP into the noncyclic 5'-GMP. The reduction in cGMP decreases the Na* pe,:meabilityof the membrane,causingit to becomehyperpolarized. Thus, light activation of photoreceptor cells induces a hyperpolarization of their membranes. b. Conesproduce visual acuity and color vision. There are three types of cone cellswith eachphotoreceptorsensitiveto either blue, green,or red light. They contain iodopsin, which has a similar pathwayof decomposition and regenerationas rhodopsin. c. Propertiesof rods and conesare summarizedin ThbleV-29-3.

Physiology

Thble V-29-3. Properties of rods and cones. Properties

Rods

Cones

Type of vision Sensitivity Location Acuity Convergence (receptors,neurons) Pigments Color vision

Scotopic High Peripheral Low High

Photopic Low Central (mainly foveal) High Low

Rhodopsin No

3 pigments-identitiesunclear Yes

d. Chemical changesecondaryto light in the photoreceptorscausesa changein the permeability of the plasma membrane (decreasein Na* conductance),which causesan electricalresponseof slow hyperpolarizationin the receptorcell. 4. For subsequentsynapticevents,five classesof neurons in the retina havebeen identified (FigureV-29-20).

In a NuBhell

a. Receptors(rods and cones)do not generateaction potentials (i.e., they are nonspiking neurons). In the dark, they are continually depolarized (excited) and releasea transmitter that hyperpolarizes(inhibits) the bipolar cell.

Rodsandconesare not excitedwhenstruck by light.Rather, they arehyperpolarized and

b. Bipolar cells are also nonspiking neurons. In the dark they are hyperpolarized, which Typ.r of bipolar cells prevents the releaseof excitatory I t L 'r ' transmitter at the synapse. include:

!|:.tt^::^t-t}]:^" neurotransmftter release.

(1) Depolarizing bipolar cells,which depolarizein responseto central (direct) illumination and hyperpolarize in responseto surround (indirect) illumination. They connectwith on-center ganglion cells. (2) Hyperpolarizing bipolar cells hyperpolarize in direct illumination and depolarize in surround illumination. They connect with off-center ganglion cells.

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Amacrine tt" *a

I

4\

-t'il: ^

Figure V-29-20.Schematic of retinal cell synapses.

c. Ganglion cells are ultimately responsible for transmitting visual information to the brain. In on-line pathways,the bipolar cell synapsesdirectly with the ganglion cell. There are three types of ganglion cells: (1) Largecells (30-40 pm diameter) (2) Medium cells(10-15 pm diameter) (3) Small cells (lessthan 10 pm diameter) d. Axons stream from the ganglion cell toward the optic disk, to the optic nerve, then to the optic tract. e. Horizontal cells and amacrine cells are local-circuit neurons of the retina. (1) Horizontal cells are involved in off-line pathways from the receptor to the ganglion and mediate antagonismat the bipolar cell level. (2) Amacrine cells generate action potentials and synapseon bipolar cells and ganglion cells. 5 . Visual fields a. Nasalvisual field projectsto the temporal retina. b. Temporalvisual field projectsto the nasalretina. c. Superior visual field projectsto the inferior retina.

554

Physiology

d. Inferior visual field projectsto the superior retina. e. Fibers from the contralateralnasalretina (temporal visual field) and the ipsilateraltemporal retina (nasalfield) project to the ipsilaterallateral geniculatenucleusin the posterior thalamus;that is, the left visual field is projected to the right lateral geniculate,and vice versain an orderly fashion.There are six layersin the lateral geniculatenucleus: (1) Layers6,4, and,l receiveprojections from the contralateralnasalretina. (2) Layers5, 3, and 2 receiveprojections from the ipsilateraltemporal retina. f. The superior colliculus and pretectum also receiveretinal projections. 6. Visual cortex a. Anatomy. Brodmann arealT is the primaryvisual cortex.It receivesaxonsof the optic radiation from the lateral geniculate (which had received projections from the contralateral visual field). (1) The inferior retinal fibers (superior visual field) project to the inferior visual cortex. (2) The superior retinal fibers (inferior visual field) project to the superior visual cortex. The visual cortex is organized in a laminar fashion as shown in Figure

v-29-2r. b. Pf"-idal cells of the visual cortex are the source of projections from cortical areas in Brodmann area 17 to other areasof the brain. c. Stellate cells of the visual cortex are responsiblefor local integration of visual input. 7 . Physiolo gy of visual pathways a. Receptive fields. Retinal ganglion cells are never quiescent. There are two types of receptivefields (FigureV-29-22).

Afferent connection

Efferent connection Highercorticalareas

Lateralgeniculate Superiorcolliculus Lateralgeniculate Figure V-29-21.Organization of visual cortical layers.

555

System Neruous

Off center

On center

Figure V-29-22."On-center" and "off'center" fields.

(1) On-center type, which have a central excitatory zone and inhibitory surround. Shining light in the center of an on-center receptive field causesan increasein ganglion cell spontaneousfiring. Shining light in the periphery of an on-center receptivefield inhibits the cell's firing. Diffilse light is ineffective.Therefore, cells read contrasts. (2) Off-center type, which exhibit an inhibitory center and excitatory surround. Small spots of light are effective in the retina and the lateral geniculate but are not as effective as a stimulus in the striate (visual) cortex. b. T\yo major groups of cells are found in the visual cortex simple and complex. (1) Simple cells have discreteinhibitory and excitatory zoneslarger than that of the retina (Figure Y-29-23); for example, a rectangular excitatory zone in a particular axis is flanked by rectangular inhibitory zones.

+ _l+l-

+ + +l_

Figure V-29-23."Simple" cell fields.

(2) Complex cells have larger receptive fields than the simple cells. There are no clearly defined excitatory and inhibitory zones,but there are critical axesof orientation.A significant input to complex cellscomesfrom simple cells. c. Function of the striate cortex is twofold. (1) It combinesinput from the two eyes. (2) It breaksdown information into short line segmentsof various orientations. 8 . Peristriate cortex (Brodmann areas18 and 19) is responsiblefor further elaboration of information from area17.

556

Physiology

E. Ear (sensation and transmission of sound). Sound waves entering the ear cause the eardrum (tympanic membrane) to vibrate, which causesthe ossiclesto produce pressure changesin the fluid of the inner ear.Ossiclesfunction in impedance matching, thus increasing the efficienry of sound conduction from air into fluid. 1. Tympanic reflex is elicited by loud sounds. Two muscles, the tensor tympani and the stapedius, contract and lock the ossiclesinto place, preventing damage to the delicate inner ear. However, latenry for the reflex is 4G-160 msec, so the reflex cannot protect againstshort, intensesoundssuch as pistol shots. 2. Cochlear vibration. The structure that actually transducesphysical forces into bioelectric phenomena is the organ of Corti, which restson the basilar membrane (Figure V-29-24). a. Organ of Corti consistsof hair cells innervated by branches of CN VIII. The hairs of the hair cells are embedded in the tectorial membrane. Deformation of the hairs, produced by movements of the underlyirg basilar membrane, generatesaction potentials in the eighth nerye fibers.

In a Nubhell Waves of perilymph move thebasilar membrane, which inturntriggers haircells of theorganof Cortito fire.

Scalavestibuli

Scala media

Basilarmembrane S p i r a ll a m i n a

S pir algan g l i a

M odio l u s CranialnerveVlll

Figure V-29-24.The cochlea.

b. Basilar membrane. The movement of the stapesproduces pressurewaveswithin the perilymph of the scalavestibuli. This results in the displacement upward and downward of the basilar membrane (Figure V-29-25).

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Neruous System

Reissnermembrane

Tunnel Striavascularis

Tectorialmembrane

Scalamedia

In n e rh a i rc e l l s Spiralligament

Spiralganglion

Outerhaircells Basilarmembrane

Modiolus

Arch of Corti

Figure V-29-25.Fine structure of the cochlea.

In a Nutshell Tonotopic 0rganization . Base + highpitch . Apex+ lowpitch

(1) For any given frequenry of sound, there is a location of the basilar membrane that is displacedmaximally. Since the base,or stapesend, of the basilar membrane is 100times lesscompliant (i.e.,stiffer) than the apex,or helicotremaend, higher-pitched sound produces maximum displacement closer to the base whereaslower-pitched soundsmaximally displacethe apex (FigureV-4-26).

o

E J

= E E

Distancefromstapes Figure V-29-26.Differential length of basilar membrane response to varying frequencies.

(2) Sincedifferent parts of the basilar membrane respond maximally to different frequencies,different hair cells are displaced,and therefore, different eighth nerve fibers are activated. (3) Increasingthe intensity of the sound causesan increasein the displacementof the basilar membrane and an increasein the rate and number of firing eighth nerve fibers.

3 . Cochlear microphonics. If an electrode is placed on or near the cochlea,fluctuations in potentialsthat reproducethe shapeof the waveof the sound stimulus can be recorded.If an amplifier and speakerare connectedto the electrode,a reproduction of the sound being played to the ear will be broadcast from the speaker.

558

Physiology

4. Central auditory pathways. CN VIII fibers terminate in the cochlear nucleus of the medulla in a tonotopic organization.From here,crossedand uncrossedfibers passin the lateral lemniscus pathway to the inferior colliculus, the medial geniculatebody, and then to the superior temporal gyrus. Although sound representation is bilateral in the auditory cortex,an individual hemisphereis concernedprimarilywith localizingsound from the contralateralauditory hemisphere. 5. Vestibular system a. Each semicircular canal (Figure V-29-27) contains an enlarged region called the ampulla, which contains the receptor organ, the crista ampullaris. The receptor contains hair cellswhose processesare embeddedin a gelatinous cupula. Distortion of the cupula by movement of endolymph results in either hyperpolarization or depolarization of hair cells,dependingon the direction of movement.

Figure V-29-27.The semicircular canals.

b. Rotary accelerationin any plane causesa senseof rotation oppositeto the direction of endolymph displacement.Further, a senseof rotation toward a crista is stimulated by heat and awayfrom a crista by cold.

In a Nubhell

c. Utricle (and the saccule) contain receptors called maculae, which contain hair cells whose apical processescontain stonescalled otoliths. These are also embeddedin a gelatinousmass.A movement of endolymph causesdepolarization of some hair cells and hyperpolarizationof others.The utricle and sacculesensestatic positioning (e.g., tilting of the head) and also respondsto linear acceleration.

Thesemicircular canals eachcontain a crista ampullaris, whichdetects angular acceleration.

d. Central connections are via the eighth nerve to the vestibular nuclear complex in the medulla. This afferent input is important in mediating many positional reflexesthat are not part of consciousprocessing.

Theutricle andsaccule contain maculae, which gravitational pull sense andlinear acceleration.

F. Pain 1. A6 fibers are small, finely myelinated fibers that transmit sensationsof sharp,pricking pain. Their conduction speedis 5-30 m/sec. 2. C fibers are small, unmyelinated fibers. Their conduction speedis 0.5-2.0 m/sec.These bare axons are activated by high-intensity mechanical,chemical, and thermal (greater than 45'C) stimulation. They transmit long-lasting,burning pain.

559

Neruous System

3. A6 and C fibers travel to the spinal cord, where they synapseon neurons in the dorsal horn. 4. SubstanceP (a peptide) is the mediating transmitter of C fiber afferentsat central synapses. 5. Spinal pain prorections (spinothalamic tract) synapseat numerous brain stem levels as well as the thalamus. Some brain stem connections include the tegmental reticular formation, the superior and inferior colliculi, and the periaqueductal gray matter. 6. Thalamic projections synapsein the ventroposterolateralnucleus (VPL) of the thalamus. 7. Gate control theory of pain. This theory proposes to explain the mechanism by which other stimuli can alter levels of pain. It is thought that sensory afferents (other than pain fibers) inhibit incoming pain afferentsin the dorsal horn. This might explain why rubbing on a sore spot helps relieve pain. 8. Analgesia. Central stimulation in certain areas can produce inhibition of pain, not through a disruption of pain afferents,but through active inhibition of afferent volleys. a. Stimulation of the periaqueductalgray region near the serotonergicdorsal raphe nucleus leadsto releaseof an opiate-like neurotransmitter responsiblefor the pain inhibition. b. At least nine opiate-like substancesare currently identified.

Note actin peripheral Endorphins analgesia in partbypreventing P therelease of substance fromC-fiberafferent terminals.

(1) The enkephalins,endorphins, and dynorphins may serve as neurotransmitters for pain inhibition and other central processes. (2) Pain inhibition also appears to be dependent on the serotonin system. Endogenousopiate releaseis induced by serotonin stimulation, and exogenous narcotic analgesiais blocked by serotonin depletion. G. Olfactory system l. Receptor elements in olfactory epithelium. There are hair cells whose processesare bathed in a special fluid that dissolvesgaseousstimuli. The unmyelinated axons of these cells penetrate the cribriform plate and then form the olfactory nerve. Thesebipolar cells are the primary neurons of the olfactory system (Figure V-29-28).

epithelium Olfactory (haircell-
Fiberof olfactory nerve Glomerulus

Granulecell

Mitralcell

bulb Olfactory Olfactorytract Medial olfactory

striae

Lateralolfactory striae

Olfactory "ort"r/, The olfactoryapparatus. FigureV-29-28.

540

Physiology

2. Olfactory bulb is the site of termination of the ipsilateral olfactory nerve. At the surface of the bulb are numerous glomeruli, the sites of the first synapses. a. Mitral cells are the major elements of the olfactory bulb. Each has a major dendrite, which synapseswith an olfactory nerve. The axons of mitral cells form the olfactory tract, which synapseswith granule cells. b. Granule cells are the most numerous cells in the olfactory bulb. They have several basaldendrites and a single,long, apical dendritic process.They synapsewith mitral cells.Granule cells have no axons. c. Tufted cells also receiveolfactory nerve axons and sendaxonsthrough the olfactory tract. 3. Sensation of odor quality a. Receptor tnres. Olfactory receptors show a wide range of sensitiviry but no specific receptor types havebeen isolated. (1) Someexperimentshave demonstratedodor specificitiesin mitral cells. (2) Some have suggesteda place-encodingmechanismwhereby the odor perceived is determined, at least in part, by the distance the stimulus molecules travel before coming to rest on the olfactory epithelium. b. Odor classification (1) Seven-odor theory assertsthat camphoraceous,musky, floral, pepperminty, ethereal, pungent, and putrid odors can account for all smells. While this is somewhatanalagousto the well-establishedfour-tastetheory, no neural basisfor this classificationhasyet been found. (2) Stereochemical theory holds that odiferous molecules "fit" into functioning groups and specificreceptorsaccordingto molecular sizeand shape.

In a Nubhell Interaction between olfactory haircells andodor-producing molecules leads to signal production andtheperception of smells.

4. Olfactorytracts project to the olfactory cortex, the paraterminal gyrus, and the amygdala. The olfactory systemis the only sensorysystemthat doesnot have a relay in the thalamus. H. Thste 1. Receptors.There is a pore at the apex of the taste bud that admits the stimulus solution (FigureV-29-29). Here the stimulus comesin contact with the gustatoryprocessesof the receptor cells,and receptorpotentials are generated. 2. Encoding. There are four primary tastes:sweet,salty,bitter, and sour. All portions of the tongue respond to all four tastes,but certain areasare more sensitivethan others to one of the primary tastes. 3. Pathways (Figure V-29-30) a. Thstesensationsfrom the anterior two-thirds of the tongue travel with the facial nerve

(cN vII). b. Tastesensationsfrom the posterior one-third of the tongue travel with the glossopharyngeal nerve (CN IX). c. Thstesensationsfrom the pharynx (e.g.,epiglottis) may be carried by the vagusnerve

(cNx).

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Neruous System

Tastepore

I

6/6t0\@

(t

Axons of cranial Sustentacularcell

- I€IV€S Vll, lX, or X

Receptorcell Figure V-29-29.The taste bud.

4. Perception of taste. Much of the perception of subtlety of taste is actually interpreted through the olfactory sense.A wide range of tastescan be perceivedthrough the four tfpes of tastebuds, but if accessto the olfactory receptorsis blocked,tasterangebecomes limited. Conversely,a strong odor influencesthe interpretation of taste(e.g.,it is difficult to tastean apple while smelling a banana).

lnternalcapsule

Thalamicnucleus (vPM)

Epiglottis

Nucleusof tractussolitarius

Fasciculussolitari

Figure V-29-30.Central pathways for taste perception.

542

Physiology

MOTOR SYSTEM A. Cortical centers 1. Primary motor cortex (precentralgyrus, Brodmann area4) controls skilled movements on the contralateralside and provides maintenanceof muscle tone. Some 600/oof pyramidal tract fibers originate here.The large pyramidal tract neurons are partially responsible for voluntary movement on the contralateralside of the body, while the small pyramidal tract neurons maintain muscletone. a. Stimulation experimentshaveproduced the homunculus pictured in FigureV-29-31. Direct cortical stimulation does not produce orderly movementsbut isolatedmuscle twitches. Area4 representsnot the origin of skilled movements,but rather the "keys" of a piano that are pressedby other centers.

v,r-

E3:E .==5 P'f

6r

EYe\id

s

Figure V-29-31. The motor ho munculus of the precentral gyrus.

b. The pyramidal tracts were once thought to be essentialto all but the grossestmovements.However,area4 sendsout extrapyramidalfibers.Experimentshaveshown that the only impulses carried exclusivelyby the pyramidal tract fibers are those for the highest order of skilled movements(e.g.,individual movementsof fingers).

2. Premotor cortex (Brodmann area 6, anterior to precentral gyrus). Removal of this area causesspasticity.Skilled movements are affected only in that the resultant spasticity makesthem more difficult to execute.

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NeruousSystem

3. Supplementary motor cortex (anterior and inferior to Brodmann area 6) is involved in coordination of eye movements. Removal causesspasticity. B. Upper and lower motor neuron lesions 1. Upper motor neuron refersto motor cortices,internal capsule,and pyramidal and other descendingmotor tracts. Characteristicsof lesions affecting this type of neuron are describedbelow.

ln a Nutshell UpperMotorNeuron Lesion Symptoms . Hypertonicity . Hyperreflexia . Positive Babinski LowerMotorNeuron lesion Symptoms . Hypotonicity . Hyporeflexia

a. Spasticityorhypertonus of affectedmusclesresultingfrom a releaseof the tonic inhibition of the brain stem facilitatory information leads to gamma neuron excitation. Thus, hyperactivity of gamma fibers causesan exaggeratedresponseto the stretch of muscle spindles. b. Hnrerreflexia (e.g.,ankle clonus) is also due to increasedgamma activity. c. Patterned paralysis typically affectsthe flexors of the legs and the extensorsof the arms among others. d. Positive Babinski sign is an exaggerateddorsiflexor withdrawal of the foot in response to stimulation of the outer edgeof the plantar surface. e. Decerebration resultsultimately in a set of symptoms singular to upper motor neuron lesions.There is first a period of "spinal shock,"during which all responsesare profoundly depressed.Following this period, extensorhypertonus,decerebraterigidity, and hyperactive reflexesare observed. 2. Lower motor neuron refers to ventral horn cells and their associatedperipheral fibers. Characteristicsof lesionsaffectingthis type of neuron are: a. Flaccidity. The tone in musclesis abolished,sincealpha motor neuronsare destroyed. b. Segmental paralysis. There is no functioning organization of the paralysis.Muscles are paralyzedaccordingto which spinal segmentsor peripheral nervesare destroyed. c. Hyporeflexia. Reflexesare diminished or abolished,since alpha motor neurons are destroyed.Nociceptive stimuli may still be perceivedif sensorypathwaysare intact. d. Muscle wasting occursas a result of atrophy secondaryto lack of innervation. e. Fasciculations are contractions of motor units resulting from repetitive firing of dying motor neurons.Thesecan be observedgrossly. f. Fibrillations are random contractions of muscle fibers that are dying becauseof lack of innervation, which causesspontaneouselectricalactivity. Sinceonly small portions of musclesare contracting asynchronously,fibrillations usually cannot be observed grossly. C. Functions of basal ganglia in movement l. Mechanism. Information about the physiology of the basal ganglia has been obtained from stimulus and ablation studiesand from the study of diseasesbelievedto affect the basalganglia (Figure V-29-32).

544

Physiology

f;*'l crult+l Substantia

I

GABA

(-)

GABA (-)

Figure V-29-32.Basal ganglia and their connections. DA = dopamine;Glu - glutamate. a. Parkinsonismis associatedwith loss of neurons from the pars compactaof the substantia nigra, whosetransmitter is dopamine. (1) Major characteristicsof parkinsonism are "pill-rolling" tremor at rest (L7 cycles per second),"cogwheel"joints resulting from increasedtonic action of alphamotor neurons, and difficulty in the initiation of skilled movements (finesia). (2) Partial alleviation of the symptoms and signsof parkinsonism may be obtained with anticholinergics, which presumably block some of the excessiveACh releasedby the uninhibited striatum; by r-dopa, the immediate precursor of dopamine; and by bromocriptine, a dopamine agonist. b. Huntington choreais associatedwith damageto the striatum and decreasedlevelsof GABA; in this respectit is a physiologic opposite of parkinsonism. Characteristicsof chorea include hyperkinesia (i.e., excessive,spasmodic,and involuntary movements [choreoid movements]). c. Lesionsof the subthalamic nucleus result in hemiballismus (violent flinging of the contralateralarm). d. Stimulation of the basal ganglia often results in the performance of complex movements, such as locomotion and chewing.Thus, the theory hasbeen advancedthat the basal ganglia contain the stored information necessaryfor initiating and directing complex movements. D. Functions of the cerebellum in motor control 1. Cerebellum receivesfast inputs on motor activity via the spinocerebellarand corticopontocerebellartracts. Thus, it can make quick, constant correctionson motor activities while they are in progress. a. Paleocerebellum consistsof the vermis and intermediate region. This is the dominant portion of many mammals,but not in primates. (1) Its major inputs are from the spinocerebellartracts. (2) Its major outputs are to brain stem nuclei. (3) It is concernedwith the maintenanceof tonus in postural musclesand coordination of locomotion; thesefunctions are traditionally ascribedto the anterior lobe of the cerebellum.

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Neruous System

b. Neocerebellum consistsof the hemispheresand part of the intermediateregion. It is the dominant portion in primates,including humans. (1) Functions. Its major outputs are to thalamic nuclei I ventral anterior thalamic nuclei (VA) and ventrolateral nucleus of the thalamus (W) via the dentate nucleus.It coordinatesmotor activity originating in the cortex, involving such processesasrelaxationof antagonistmusclesprior to contraction of agonistsand feedbackon muscle position. The functions of the neocerebellumhave traditionally been ascribedto the posterior lobe of the cerebellum. (2) Damage to the neocerebellumtypically resultsin adiadochokinesia,or inability to perform rapidly alternating movements; decomposition of movement, the breaking up of complex motions into simple, mechanicalcomponentsthat can be individually monitored; and intention tremor, a coarsetremor that appears when an attempt is made to perform skilled movements,usually associatedwith overshooting and undershooting causedby inadequate monitoring of muscle position. c. Archicerebellum, or vestibulocerebellum, consists of the flocculonodular lobe and part of the uvula. (1) Its major inputs are from the vestibularnuclei. (2) Its major outputs are to vestibularand fastigialnuclei. (3) It functions in the maintenanceof equilibrium and the adjustmentof eyemovements and posture to the body's position in space. (4) Lesions here result in walking disturbances,head rotation, and nystagmus (rapidly alternating eyemovments). 2. Cerebellar cortex containsa representationof the body that can be mapped in a manner similar to that usedfor the cerebralcortex.Although electricalstimulation producesmuscle contraction, the function of the somatotopicrepresentationis not for the initiation of contraction. It probably representsan internal plan of body musculaturefor purposesof planning and regulatingmovement. E. Motor dysfunction syndromes are summarizedin TableV-29-4.

546

Physiology

Thble V-29-4. Motor dysfunction syndromes. Involuntary and Disordered Movements

Reflex

Marked (denervation tYPe)

Fasciculations may occur

Diminishedto absent

Absentor slight (disusetype)

Absentor secondaryeffects

Usuallynormal

Iesion

Loss of Power

Tone

Atrophy

Lowermotor neuron

Specificmuscles and/or muscle groupsaffected

Flaccid

Upper motor neuron,also called"pyramidal" or "corticospinal"

Spasticity Specificmove("claspknifd') mentsor entire extremity affected

Basalganglia, clinically referred to asextrapyramidal

Difflculty initiating movem€nt, but when muscle is activated, strengthusually normal

Rigidity (leadpipe, Absent cogwheel)in parkinsonism; hlpotonia in choreicdisorders

Cerebellar

Strengthnormal

H)?otonia

Absent

DeePtendon Involuntary reflexincreased; movements present,suchas clonal pathologic reflex (e.9., restingtremor, drorea athetosis, Babinskisign) often pr€s€nt; dystoni4 ballismus.Lossof asso- superficialreflex ciat€dmovem€nts.decreased Characteristically disturbedgait (e.g.,"shuffIing," "dancing") Dysm€tria, Deeptendon intentiontemor, normal dysdiadochokinesia,dyssynergia, ataxicgait

DISTURBANCES SPEECH A. Dysarthria is a defectin motor output involvedin speaking,physiologicallynot very different ftom any other motor distutbance. B. Aphasiasarespeechdiffrculties(or absenceof speech)not relatedto motor disorders'A simplified classificationof theseabnormalitiesfollows. l. Broc. (motor) aphasiais due to lesionsin the inferior frontal gyrus.In this condition, tllere is no comprehensiondeficit,but the patienthasprofound word-finding difficulties, and speechis nonfluent. 2. Wernidre (receptive)aphasiais due to lesionsin tle posterior portion of the superior temporalgyrus.In this condition thereis no motor deficit,but the patient cannotunderstandwhat h€ or shehears.Speechis fluent but containsParaPhasias. 3. Conduction aphasiais due to lesionsin the fibers betweenBroca and Wernickeareas. Patientswith this type of lesionhavetrouble convertingauditory input to verbaloutput (i.e.,repeating).

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Neruous System

RETTCUTAR (RAS) ACTTVAT|NG SYSTEM ln a Nubhell

RAS is a collection of innumerable nuclei contained in the brain stem reticular formation.

. Stimulation A. Nonspecific input. Collateralsfrom the visual, auditory olfactory, and other sensorysystems oftheRAS terminate on the RAS in such a manner that the specific sensorymoddity is eliminated. The results inCNS arousal, RAS thus functions to causegeneralizedarousal as opposed to interpreting specific sensory experienced most commonly information. asthewaking $ate. B. Output from this region projects to the (nonspecific) intralaminar thalamic nuclei aswell as . Powerful sensory stimuli directly to the cortex. The intralaminar nuclei project diffirsely to the cortex. canactivate theRAS;thus, painthatwakes a patient C. Stimulation of the RAS or the nonspecific thalamic nuclei results in desynchronization of the electroencephalogram(EEG) with subsequentarousal.Thus, intense visual, auditory or fromsleep isclearly severe. painfrrl stimuli causeexcitation (via their collateral branches) of the RAS with the result that the subject is aroused or alerted.

ETECTROENCEPHATOG RAM(EEG) An EEG is the recording of the spontaneouselectrical activity of the brain. Activity is present throughout the life of an individual; hence, a flat-line EEG recording may be one basis for declaring a person dead (brain dead).Artifact usually preventsan adequateflat-line reading, and the bedside clinical examination is acceptedin many states as adequatefor declaring an individual brain dead. A. EEG electrodes are either bipolar or unipolar and in the caseof the latter, the ear is usually used as the theoretically indifferent (distant) electrode.The electrodesmay be taped to the surfaceof the skull or inserted slightly under the skin in the form of needles. 1. In a person relaxed,with their eyesclosed,the dominant EEG wave is the alpha (o) wave with a characteristicfrequencyof 8-12lsec and an amplitude of about 50 pV. 2. Opening the eyesresults in "alpha blocking," with the replacement of the alpha wavesby rapid,low-voltage beta (F) waveswith a characteristicfrequencyof 14-60/sec. a. Sensory input (usually in the form of light) or mental activity results in this alpha blocking. b. RAS stimulation also results in desynchronization. 3. During sleep,the alpha wavesare replacedby slower (<4/sec) wavescalled delta (6) waves. 4. Theta (o) waves(4-8lsec) are normally present in children, but if they are observedasthe dominant wave in adults, cerebral diseaseis usually indicated. B. EEG patterns may be changedby hormones or drugs. 1. Catecholaminesproduce EEG desynchronizationand arousalby decreasingthe threshold of RAS neurons. 2. Barbiturates produce "spindles" and excessbeta activity.

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Physiology

C. Low-frequencystimulation of the nonspecific thalamic nuclei results in synchronizedactivity of the cortex (8/sec).The amplitude of the wavesfluctuates in a waxing and waning manner. This phenomenon is referredto as recruitment. 1. Intracellular recordings from cells in the thalamus show that low-frequency stimulation of the nonspecificnuclei elicit short EPSPs,which spreadover a wide area of the thalamus. This, in turn, causesa synchronousoscillationof cortical neuronsspreadover a wide area.This rhythmic EPSP-IPSPphenomenon is referred to as the "thalamic pacemaker," and it is believed to be the basis for EEG synchronization. 2. When a thalamic neuron fires,it may alsobe sendingan impulse down a collateralthat synapseson an inhibitory interneuron. This interneuron terminates on the original thalamic neuron and hyperpolarizesit. Thus, we havean EPSPfollowed by * IPSP(FigureY-29-33).

Recurrent collateral Thalamic neurOn+

Inhibitory interneuron Figure V-29-33.Organization of recurrent collaterals and inhibitory interneurons.

D. Clinical use of the EEG 1. The EEG can localize tumors, hematomas,and infarcts, although brain magnetic resonance,computerizedradiographic,and positron emissiontomography are more sensitive. 2. It is useful for discriminating among certain seizureand metabolic disorders.For example, petit mal (absence)seizuresare characterizedby a pattern of periodic 3-Hz spikeand-wave activity. Uremia and other metabolic encephalopathiesare characterized by intermittent high-voltagetriphasic waves.

STEEP The sleep-wakecycleundergoesEEG changesduring life, from a polyphasicpattern in the newborn to a biphasic pattern in the child (night-time plus afternoon sleep) to the generally monophasic circadian adult rhythm. Sleepis an activefunction of the brain and has different stagesthat are controlled by different neurochemical systems. A. Stagesof sleep 1. Wakefulness, characterizedby p waves 2. Non-rapid-eye-movement sleep (NREM) is characterized by progressively slower frequency and high-voltageactivity on the EEG asthe individual passesinto a deepersleep. NREM sleepis divided into stagesI to 4, stage4 being the deepestsleep.During stage4, heart rate, blood pressure,and respiratory rate decline, while gastrointestinalmotility increases.Muscle tone is maintained.

549

Neruous System

3. Rapid eye movement (REM) [paradoxical sleep] first occurs about 90 minutes after the onset of sleep.REM is characterizedby the dreaming state, although thought processes occur during all stagesof sleep.Normally, an individual progressesfrom stage I to stage 4 in an orderly fashion, then back to stage 1 in the reverseorder, then to REM; the cycle then repeats.After two or three rycles, stages3 and 4 may be bypassed,but typically there are about five periods of REM per night.

ln a Nutshell During REM, theEEC resembles thewaking state; autonomic toneincreases, and skeletal muscles areparalyzed.

a. REM is further characterizedby: (1) EEG desynchronization(low-voltage,fast activity) (2) Increasedbrain temperature (3) Inhibition of head,neck, and skeletalmuscles (4) Increasedheart rate (5) Increasedblood pressure (6) Increasedrespiratory rate b. REMs appearto be driven by phasicbursts of electricalactivity from the pons, oculomotor nuclei,lateral geniculatenuclei, and the visual cortices,calledpontine-geniculate-occipitalspikes(PGO). B. Sleepand the RAS 1. Earlyexperiments led to the discoveryof this system. a. A surgicaltransectionat the midbrain (originally of a cat) leadsto a stateof sleepwith high-voltage, slow-wave EEG activity. b. A surgicaltransectionat the caudalmedulla and spinal cord (alsooriginally in the cat) leadsto continued normal sleep-wakecycles. 2. Specificlesions followed the transectionexperiments. a. Lateral brain stem tegmental lesions that severthe ascendingsensorysystem do not affect sleep. b. Midline brain stem lesions result in behavioral stupor.

ln a Nutshell Experimentation hasshown thatreticular formationactivity keeps thebrain"awake," and parts thatactivity of other of thebrainstemarerequired to induce sleep. isnota Sleep passive phenomenon.

3. Conclusions a. These experiments led to the conclusion that ascendingprojections of a tonically active reticular formation keep the forebrain awake,which in turn led to sleepbeing viewed as a passivephenomenon. b. Further experimentsrevealedthat certain areasof the brain stem must be active to induce sleep.If the caudal brain stem is anesthetizedselectively,a sleeping cat will wake up, and synchronous EEG activity is replacedby desynchronousactivity. C. Sleepand neurotrasmitter systems 1. Serotonin. The midline medulla raphe nuclei contain cellsrich in serotonin projections. Serotonin is thought to be important in mediating NREM sleep.Damageto those nuclei result in insomnia. 2. Nucleus of the solitary tract is also in the medulla. This area is probably important for helping to induce sleep,but damagedoesnot causeinsomnia. 3. Locus ceruleus is rich in noradrenergiccellsand was previously thought to be responsible for inducing REM sleep,but selectivepharmacologic blockade has disproved this hypothesis.

550

Physiology

4. Cholinergic neurons The pontine gigantocellulartegm€ntalfield containsneuronsrich in ACh that influenceREM sleep. 5. Roleof neumtransmitt€r syst€msin sleepis not known,but undoubtedlya combination of inhibitory and ercitatory mechanismsinterplay to producethis sleep.

SPECIAT FUNCTIONS A. Control of body weight 1. Ventromedial nud€us (VMN) of the hypothalamus.Bilaterallesionsin this part of the brain result in hyperphagiaand obesity;thus,the \{Ir4N is the "satietycenter." 2. Lateral hypothalamus. Lateral lesions in this area result in hypophagiaand loss of appetitq thus,lateral hypothalamusis the'eating center." 3. Glucoserec€ptorspresentin the cellsofthese nuclei monitor the level of circulatingglucosein order to producethe appropriater€sponse.

In a Nubhell Hypotralamic Lesions . VMNlaion -+ hyperphagia . LateEllesionJ trypophagta

B. Tenperature regulation 1. Posterior hnnthalamus respondsto cold by producing shivering,vasoconstrictionof skin vessels, and piloerection("goosebumps"). 2. Anterior hypothalarnusrespondsto excessive heatvia sweating,panting,and vasodilatation of skinbloodvessels. 3. Rec?tors monitoring body temperatureseemto be locatedprimarily in the anterior or preoptic areaof the hlaothalamus. c. Innervation of urinary bladder

ln a ltubhell ' llli:";.110"*"t" ' Anteriorhypothalamus c00lsv0u'

l. I\uo functional units of musclesof th€ bladder a. Detrusor, which forms the bulk of the muscularisof the bladder.It extendsdown the urethra, forming the intemal sphincter.In serieswith the cells of the detrusor ar€ numerousstretchrec€ptors,whoseaxonstravelwith spinalnervesS2-S4. b. Trigone, formedby muscularextensionsfrom the uretersthat encirclethe neckof the bladder 2. Autonomic innervation a. Syrnpatheticflow to bladderis from segmentsT11 to L2. B€ta (inhibitory) receptors predominatein the detrusor,and alpha (excitatory) receptorspredominatein the trigone. Thus, sympatheticstimulation causesthe contraction of t}le trigone and relaxationof the detrusorthat occursduring filling. b. Paraspnpathetic flow to the bladder arisesfrom segmentsS2-S4,primarily 53. Para,sympathetic stirnulationcaus€s contractionof the detrusor,resultingin mictruition, 3. Micturition involvesbladderdistention,which reflexlycauses: a. Parasympathetic stimulation b. Depressionof rympatheticinhibition c. Inhibition of somatic efferentoutput to the externalurethral sphincter,causingits relaxation

551

Neruous System

D. Innervation of genitalia 1. Erection resultsfrom parasympatheticstimulation via the pudendal nerves,which originate at segmentsS2-S4. 2. Emission (transmissionof semento the posterior urethra) is under sympatheticcontrol. The outflow fibers arisefrom segmentsT12,L1, andL2. 3. Ejaculation (expulsion of semenfrom posterior urethra through the externalmeatus) is brought about by contraction of the bulbocavernosusmuscle in responseto stimulation by the internal pudendal nervesthat arisefrom Sl and 52. 4. Innervation of the clitoris, the female homologue of the male penis, has preciselythe same sensoryinnervation as the penis with the same neural connectionsto the brain. Mechanicalstimulation of thesesensorynervesservesas a prelude to the centrally mediated orgasmin both male and femalesystems.In the male, this frequently,but not necessarily,accompaniesemission. 5. The G spot, found in the roof of the proximal vagina about 7 cm from the orifice, is alwayspresent although not alwaysfunctional. It is derived from homologous origins of the male prostateand mechanicalstimulation may contribute to the centrally mediated orgasmin females. 6. Copulation-induced ovulation, while common in mammals with estrous-inducedsexual receptiviry it is rare in anthropoids and humans in particular. It occasionallyoccurs in humans and is thought to be initiated by clitoral stimulation and mediatedcentrally.

552

Nervous Pathology System proceses genetic Thenervous isaffected slstem byallofthesame thataffedother organ systems: malformations, degeneration, infectious diseaset vascular insufficiency, andneoplasms. (CNS) Degenerative disorders ofthecentral nervous system areoften duetotheaccumulation of produG, (e.9., metabolic fromaninherited Tay-Sachs sometimes disorder disease) andsometimes froma problem acquired ormanifested later inlife(e.g., Alzheimer disease). Agreat dealofprogres hasbeen made indetermining themolecular basls ofthese diseases. Prenatal testnowexist for predisposing Tay-Sachs disease, Huntingon disease, andeven fora genotype toAlzheimer disease. Vascular disease isofprimary importance intheCNS. Again, arteriosclerosis andib attendant risk pathology, laclonarethemostcommon cause ol vascular insufficienry andib resultant $roke. protozoal, Infectious diseases oftheCNS canhave viral, bacterial, orlungal etiologies. Some ofthe "slow virus" diseases such askuruhavenowbeen shown to beduetoDrions, which areDroteins thatmayfoldintomore thanoneconfiguration.

h a Nubhell t"u,ont' il#tu;!'t*"tn . Nissl substance dissolution . Cytoplasmic eosinophilia

NONSPECIFIC NEURONAT AND GUALCHANGES The following terms describe conditions that may be seen alone or in combination in many disorders that affect tle central nervous system (CNS). They are presented here togetler for convenience, but will be discussed again throughout the chapter,

. Nuctearconcensa.on (pyknosis)

A Neuronal loss is the endpoint of many diseaseprocess€s.It usually requires at least a 30% loss of neurons before it is observable by light microscopy. In many cases,neuronal loss is accompanied by fibrous gliosis. B. Ischemic neuronal damage is an acute process that most commonly follows anoxia. It is characterized by retraction of the cell body (sorna), disappearance of Nissl substance,cftoplasmic eosinophilia, and nuclear pyknosis (condensation, often with hyperchromasia). C. Neumphagia refers to neuronal phagocytosis, which often occurs with viral infections; the degenerating neuron is surrounded by monocftes and microglia (CNS macrophages). D. Central chromatolysis (axonal reaction) refers to tlre reaction of tle cell body following a lesion of the lower motor neuron (LMN) axon. The soma swells, Nissl substancedisappears (especially around the nucleus), and there is peripheral displacement of the nucleus. E. Neuronal atrophy results from a variety of slowly progressive degenerative processes,The soma shrinks, and tlere is increased cFoplasmic basophilia, nuclear pyknosis, and increased neurofibril and lipofirscin pigment (the "wear and tear" pigment, which accumulates in degenerating and aged neurons and other tissues).

555

l{eruousSystem

ln a Nubhell process isthescaninS Cliosis oftheCNS. Clialscars are (and formedbya$rocytes sometimes byfibroblasts).

F. Gliosis. In gliosis, injury to the CNS stimulates hypertrophy and hyperplasia of astrocftes shortly after exposureto a variety of noxious agents.The cell body, nucleus,and processesof the astrocfte swell. In the chronic stage,glial fibers accumulate as the cell body shrinks. Roughly 5 days after infarction, swollen astrocyteswith eosinophilic cytoplasm proliferate around the necrotic lesion.

DEGENERATIVE DISORDERS OFTHECNS Degenerativedisordersof the CNS are a mixed group of disordersthat tend to begin insidiously and progressgradually.They may causedementia,disordersof movement and posture,ataxia, weakness,or sensorychanges. A. Alzheimer diseaseis the most common form of dementia. Presenileand senile forms have been distinguishedon the basisof age,although both sharecommon clinical and pathologic featuresand are consideredtogether. 1. Incidence. Most casesoccur after the ageof 40. The prevalenceat the ageof 60 is roughly 5o/o,rising to about 40o/oat age 85. There is a female predominance.The averagelifespan after diagnosisis 7 years. 2. Etiology remains unknown, although it has been ascertained that genetic factors are involved in a small number of cases.To date, mutations have been identified in the amyloid gene on chromosome 21. A specific isotype of apolipoprotein E (ApoE ) on chromosome 19 has alsobeen associatedwith the disease. 3. Clinical features. Early symptoms include impairment of short-term memory, abstract thinking, problem solving, and visuospatialorientation, as well as emotional and social changes(e.g.,irritability). Symptomsprogressand are later accompaniedby aphasiaand apraxia; ultimately, the patient enters a vegetativestate. 4. Pathology a. Grossly, diffrrse cortical atrophy occurs with relative sparing of primary motor and sensoryareas.Gyri are thin and sulci are wide. Hydrocephalusex vacuo (a secondary increasein cerebrospinalfluid [CSF] from lossof parenchyma)also occurs.The brain losesan averageof 200 g over the courseof the disease. b. Microscopically, neuronal loss occurs mainly in the cortex but also in many subcortical nuclei. The following featuresare characteristic,though not pathognomonic. (1) Neurofibrillary tangles are intracytoplasmic,skein-like structurescomposedof paired helical filaments;they are best seenwith silver stains (FigureV-30-1).

554

Pathology

Fig u re V-30-1. Neurof i bri Ilary tan gle: Bielschowsky stain (m icroscopic).

(2) Granulovacuolar degeneration describessmall cytoplasmicvacuolescontaining a central granule. (3) Senileplaques are abnormal, enlarged,presynapticaxon terminals surrounding a central core of extracellularamyloid-like substance;they are best seenwith silver stains. (4) Hirano bodies are found in some cases. c. It hasbeenproposedthat lossof cholinergicneuronsin the nucleusbasalisof Meynert is in part responsiblefor memory impairment and other cognitive deficits.

B. Pick diseaseis a rare form of dementia,which causeslobar atrophy (affectingboth grey and white matter), predominantly in the frontal and temporal lobes.Familial casesare common. 1. Clinical features. In the early stages,frontal lobe personality changes(e.g.,loss of social graces)are prominent; later, memory loss and other characteristicsignsof dementia occur.

In a Nutshell Alzheimer Pathology . Cross atrophy cortical . Microscopic changes - Neurofibrillary tangles - Senile plaques - Hirano bodies

2. Pathology a. Grossly, atrophy of frontal and temporal lobes occurs.

ln a Nutshell

b. Microscopically, severeneuronal loss and gliosis are found. Pick bodies are intrarytoplasmic spherulescomposedof paired helical filaments;they are best seenwith silver stains.

Pick disease issimilar to Alzheimer disease, butwith atrophy localized tothefrontal andtemporal lobes.

C. Parkinson disease(paralysisagitans)is an idiopathic disorder that usually begins after age 40 and afflicts lo/oof the population older than 50. 1. Clinical features include bradykinesia (difficulty initiating and slownessof voluntary movement), rigidiry resting tremor, flexed posture, expressionless(masked) facies,and festinating (shuffling) gait. Dementia may occur. 2. Etiology. Symptoms are primarily from dopamine depletion in the caudateand putamen, the termination of the nigrostriatal tract. The causeof death of substantianigra dopaminergic neurons is unknown. Dementia is thought to be secondaryto degenerationof cellsin the nucleusbasalisof Meynert, similar to Alzheimer disease.The diseaseis usually sporadic. 3. Pathology a. Grossly, depigmentation of the substantia rigta (which contains the somata of dopaminergic neurons from which the nigrostriatal tract originates) and locus ceruleus is evident.

555

Neruous System

ln a Nutshell Parkinson Symptoms . Bradykinesia . Rigidity . Resting tremor

b. Microscopically, there is degenerationof pigmented neurons and gliosis of the substantia nigra and locus ceruleus;L"toy bodies (intracytoplasmic eosinophilic structures) are present. 4. Parkinsonism includes disorders displaying the clinical features of Parkinson disease. This classificationis now recognizedas encompassingseveralroutes of pathogenesis.The final common pathwayfor the recognizedetiologieslisted below is thought to be nigrostriatal dopamine depletion or blockadeof postsynapticreceptors.Causesinclude:

. Festinating gait

a. Neuroleptics(e.g.,phenothiazines)

. Masked facies

b. Encephalitis,particularly viral

. Dementia

c. Carbon monoxide/manganesepoisoning

Parkinson disease is characterized bya lossof dopaminergic neurons inthe nigra, substantia which projects to thestriatum (caudate nucleus and putamen).

d. Strokes

Bridgeto Microbiology

e. Methylphenyltetrahydropyridine(MPTP), which is found in some syntheticheroin 5. Tleatment a. L-Dopa, a dopamine precursor, is usually used in combination with carbidopa, a peripheral dopamine decarboxylaseinhibitor. b. Bromocriptine is a postsynapticdopamine agonist. c. Amantadine stimulatespresynapticdopamine release. d. Anticholinergics (e.g.,benztropine) reducecentral cholinergic neurotransmission.

Recall thatamantadine isalso usedforprophylaxis against influenza A virus.

e. Deprenyl (selegiline,Eldepryl) is a selectiveMAO-B inhibitor used in Parkinson therapy. D. Huntington diseaseis characterizedby autosomal dominant inheritance, choreoathetosis, and dementia. The gene mutation on chromosome 4 is an expandedtrinucleotide tandem repeatthat increasesfrom generationto generation. 1. Incidence.The onset is usuallybetween25 and 55 yearsof ageand tends to be about the same in each afflicted familv.

ln a Nutshell Huntingon disease isan autosomally dominant disease characterized bythe degeneration of neurons of thecaudate nucleus. The geneislocalized to theshort armof chromosome 4.

2. Pathology a. Grossly,there is striking degenerationof the medium-sized,spiny neuronsof the caudate nucleus with lesssevereinvolvement of the putamen and cerebralcortex. b. Microscopically, neuronal loss and gliosis are present. E. Progressivesupranuclear palsy is a degenerativedisorder characterizedbyophthalmoplegia (affecting vertical before horizontal gaze),pseudobulbar palsy, axial dystonia, and bradykinesia.Mild dementia often develops. l. Incidence. Onset is usually betweenthe fifth and seventhdecadesof life. 2. Pathology a. Grossly,there is widespreadneuronal loss and gliosisin subcorticalsiteswith sparing of the cerebraland cerebellarcortices. b. Microscopically, neurofibrillary tanglesare often present;theseare morphologically distinct from those seenin Alzheimer disease. F. Friedreich ataxia is an inherited disorder (usually autosomalrecessive). 1. Incidence. Onset is usually betweenages5 and 25. 2. Clinical features.Most patientsare unable to walk within 5-10 yearsof onset becauseof progressiveataxia.Associatedfeaturesinclude pescavus(hollowing of the instep),diabetes,

556

Pathology

kyphoscoliosis,diminished proprioception, tremors, decreasedor absent tendon reflexes, Babinski sign, and cardiomyopathy. 3. Pathology. The spinal cord is atrophic with loss of fibers in the spinocerebellarand corticospinal tracts and posterior columns. There may be cell loss in the dorsal root ganglia and in certain spinal, brain stem, and cerebellarnuclei. G. Motor system diseaserefers to a group of overlapping degenerativedisorders characterized by some combination of muscle weakness,atrophy, and spasticity; these symptoms result from loss of motor cellsin the spinal cord, brain stem, cerebralcortex, and cerebellum.These disorders include amyotrophic lateral sclerosis (AIS; Lou Gehrig disease). H. Cerebellar atrophy includes both a familial and nonfamilial form. There is degeneration of the superior parts of the cerebellarvermis as well as the hemispheres.It is characterizedby ataxic gait, followed by dysarthria and limb tremor. Pathologically,there is complete loss of Purkinje cells in affected areasof the cerebellarcortex.

VASCULAR TESIONS A. Cerebral infarction refers to necrosisof neural parenchyma secondaryto inadequateblood or oxygen supply.

Clinical Correlate ln ALS, bothupperandlower motorneurons degenerate. Symptoms aremixed: atrophy andfasciculation indicate lowermotorneuron paralysis, degeneration; spastic increased muscle tone,and hyperreflexia indicate upper motorneuron degeneration.

1. Etiology a. Thrombosis usually results from atherosclerosis.Diabetes,smoking, family history, age,hypertension,and alcohol are important risk factors.Thrombosis is also caused by arteritis, vasculartrauma, and a hypercoagulablestate.It usually occurs in largeand medium-sizedvessels. b. Emboli may arisefrom a mural thrombus of the left ventricle, aortic or carotid plaques, septic emboli, and fat and air emboli. They usually occur in medium-sized vessels. c. Lacunar infarcts are cluesto the occlusion of deep penetrating arteriesand are asso* ciated with hypertension.They are named for small cavities(lacunes)formed in the deep white or grey matter. 2. Clinical features vary with etiology and location. a. Thrombosis follows a variable course, often stuttering and often preceded by transient ischemic attacks (TIAs), which causefocal neurologic dysfunction lasting up to 24 hours. (1) In the internal carotid territory, patientsexperiencecombinations of monocular blindness,hemiparesis,hemisensoryloss,visual field loss,and languagedisturbance if the thrombosis occurs in the dominant hemisphere.The left hemisphereis dominant in almost all right-handed people and in a large fraction of left-handed people.

In a Nubhell Thrombotic infarG, characterized bypermanent neural damage, areoften preceded byTlAs, whichare temporary syndromes resembling mini-strokes.

(2) Vertebrobasilar thrombosis causesa variable combination of vertigo, diplopia, facial numbness,weakness,nauseaand vomiting, dysarthria,ataxia,and bilateral or alternating hemiparesisor sensoryloss. b. Emboli often produce their maximal deficit within 1 minute; signs and symptoms depend on the specific arterial territory affected. 3. Pathology. Infarcts are characterizedas anemic (pale),hemorrhagic,or lacunar.

557

Neruous System

a. Anemic infarcts (l) Grosspathology (FigureV-30-2). There are no changesfor the first 4-8 hours. From 8-48 hours, edematousswelling of white and grey matter occurs.From 210days,the tissuebecomessoft and mushy (liquefaction).After weeks,cavitation takesplace.

Figure V-30-2.Old infarct in left parietal lobe of brain (gross). (2) Microscopicpathology (FigureV-30-3).From 6-12 hours,thereis disorganization of cytoplasm and nuclear chromatin; ischemic neurons stain redder with eosin than do normal neurons. By 48 hours, neutrophils accumulate.By 72-96 hours, there is aggregationof macrophages.After weeks,there is astrocytosis, leading to fibrillary necrosis.

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558

Pathology

b. Hemorrhagic infarcts (1) Gross pathology. Theseinfarcts fypically involve the grey matter, causingmany petechialhemorrhagesthat may becomeconfluent. Reperfusionof the damaged vesseldue to the migration of an embolus or from collateralflow resultsin leakageof red cells (RBCs). (2) Microscopic pathology. Many macrophagescontain hemosiderin during the healing phase. c. Lacunar infarcts (1) Gross pathology. Lacunar infarcts are small, ranging from 3 or 4 to 15 mm; they are generallyseenin deepportions of the brain where arteriolesareoften hyalinized. (2) Microscopic pathology. Lacunar infarcts also show pigmented macrophages, suggestingat leastminute hemorrhages. B. Intracranial hemorrhage. Bleeding within the cranial cavity may occur in the epidural, subdural, or subarachnoid spaces,or in neural parenchyma.Epidural and subdural hemorrhagesare discussedunder trauma (FigureV-30-4). 1. Intraparenchymal bleeds are usually the result of hypertension (called hypertensive,primary, or spontaneousintracerebral hemorrhage) and are the most common causeof death from stroke.

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ln a NuBhell lntraparenchymal bleeds, often caused byhypertension, are themostcommon cause of stroke fatality.

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Figure V-30-4.Massive right intracerebral hemorrhage (gross). a. Pathology. Half of thesehemorrhagesoccur in the basal ganglia and internal capsule; the remainder occur in the central white matter, thalamus, cerebellum, and pons. Hypertensivehemorrhagesare often large.Lobar hemorrhagesare located near the surfaceof the hemispheres;they are associatedwith arteriovenousmalformations, amyloid angiopathy, blood dyscrasias(but not with hypertension), and may occur without known cause.If hemorrhageis chronic, hemosiderin-ladenmacrophagesare present. b. Ctinical features ( 1) There is a suddenheadacheand abrupt onset of neurologic deficit. (2) Edema may be massive,and herniation can occur.

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Nervous System

(3) The CSFis usuallybloody,especiallyin hypertensivehemorrhagewith dissection of blood into the ventricular system.

ln a Nutshell Ruptured berryaneurysms are themostfrequent cause of subarachnoid hemorrhage; at theyoften occur bifurcations oftheanterior circle ofWillis.

2. Saccular (berry) aneurysms are the most common causeof nontraumatic subarachnoid hemorrhage. a. Etiology is usually attributed to congenital defectsin the arterial media, acquired factors such as atherosclerosisand hlryertension,or both. b. Incidence. These are rare before puberty and are found in L1o/o of routine autopsies after age25. There is a female predominance. c. Pathology. (1) Ninety percent of saccularaneurysmsare in the anterior part of the circle of Willis, especiallyat bifurcations. In order of frequenry, sites of rupture are the posterior and anterior communicating arteriesand the bifurcation of the middle cerebral artery. (2) Most aneurysmsarebetween0.4-1.0 cm; rupture is more common in aneurysms greaterthan 1.0 cm. Rupture occurs in l5-20o/oof berry aneurysms.

ClinicalCorrelate Patients withsubarachnoid hemorrhages oftendescribe having the"theworst headache of mylife."

(3) Bleeding occurs into the subarachnoid space and may dissect into neural parenchymaor causea stroke (from vasospasm).Blockageof arachnoid granulations by blood products may impair CSFreabsorptionand produce communicating hydrocephalus. d. Ctinical features. Rupture usually causessevereheadache,which may be followed by no deficit or may be followed by coma. Rupture often occurs during exertion but may occur spontaneously.Patients with saccular aneurysms have a higher incidence of polyrystic kidney diseaseand coarctation of the aorta. C. Arteriovenous malformations (AVMs) are developmental abnormalities (non-neoplastic) that directly connect arterial and venouscirculations without capillaries.Thesefistulae vary in size and may be found throughout the CNS. Ninety percent are found in the cerebralhemispheres.There is a male predominance.Although present at birth, symptoms (e.g.,headache, seizure,focal deficit, hemorrhage) usually occur between the agesof 15 and 40. Contrastenhancedcomputed tomography (CT) and arteriography are often diagnostic. Hemorrhage into the parenchyma,subarachnoidspace,or both, is the most important complication.

BRAINTRAUMA In a Nutshell . Concussion + no structural damage . Contusion -> "brain bruise" fromblunthead trauma

A. Concussion is a transient paralysisof cerebralfunction immediately after head trauma (ffpically a blunt, nonpenetrating injury such as a blow with a fist) that is not associatedwith structural damage. Although impairment of consciousnessis brief, symptoms (e.9., headache,dizziness)may persist.Duration of post-traumatic amnesiais the bestindex of the severity of injury. B. Contusion is a bruise of the brain parenchyma that typically involves the summit of the gyrus. The bruise produces a wedge-shapeddefect of necrosisand petechialhemorrhages with the base near the meninges and the apex towards the white matter. The bruise may occur beneaththe point of trauma (coup lesion), on the opposite site of the brain (contrecoup lesion), or on both sides.Contrecoup lesions often occur at siteswhere the brain is adjacentto bony prominencesor dural folds (e.g.,anterior temporal lobes). C. Skull fractures may be of no clinical significance,or they may be responsiblefor important sequelae,including contusion (usually with depressedfractures), CSF leakage(meningeal tear), or epidural hematoma (vasculartear).

560

Pathology

1. Linear fractures are seenaslucent lines with well-definedborders.Both tablesof the skull are involved. 2. Depressedfractures causeindentation of the skull and are often associatedwith contusion. 3. Compound fractures havea communication with the outside through an associatedtear of the scalpor paranasalsinuses.Osteomyelitismay develop. 4. Basilar skull fractures are usuallylinear and may not be seenon x-ray. CSFleak and cranial nerve palsiesmay develop. D. Hemorrhage following headtraumamay occur into the epidural,subdural,or subarachnoid spacesor within the parenchymaof the brain. 1. Epidural (extradural) hemorrhageoccurs into the spacebetweenthe dura and the skull; bleeding may arise from arteries,veins, or both. Most casesfollow trauma to the lateral skull, resulting in laceration of the middle meningeal artery, although frontal and occipital lesionsalso occur. Skull fracture is present in 80-900/oof cases.Classically,the head trauma is associatedwith momentary loss of consciousness, followed by a lucid (asymptomatic) period of 1-48 hours. The patient then developssymptoms of elevatedintracranial pressure(e.g.,headache,changesin mental status,nausea,vomiting) and possibly focal findings (e.g., hemiparesis).Herniation of the medial temporal lobe, coma, and death may result if the collection of blood is not surgicallyevacuated.Although the classic history is usually presentedin test questions,it is important to note that up to 50o/oof patients have no initial loss of consciousness, and roughly 600lohad an injury for which they did not seekmedical attention. 2. Subdural hematoma resultsfrom bleeding into the spacebetweenthe dura and arachnoid. a. Acute subdural hematomas almost always result from severehead trauma, causing tears in the bridging veins; they are associatedwith contusion. Largehematomasare usually fatal; smaller ones may lead to symptoms after a latent interval of days to weeks.Tieatment consistsof surgicalevacuationof the clot. b. Chronic subdural hematoma. The diagnosisof a chronic subduralhematomais often difficult becausemany patients are elderly or alcoholic, and head trauma may be minor or forgotten. Anticoagulation and coagulopathy are predisposing factors. Symptomsmay developweeksto months after trauma. Headache,drowsiness,asymmetric signs,and fluctuation of symptoms are often present.Herniation, coma, and death may result from compressiveeffectsof an enlarginghematoma. 3. Subarachnoid hemorrhage results from bleeding into the spacebetween the arachnoid and pia (i.e., subarachnoidspace).Severehead trauma or rupture of an aneurysm can produce subarachnoidhemorrhage. 4. Intracerebral hemorrhage results from bleeding into the parenchyma of the brain. Although this is an unusual complication of head trauma, it is presentin almost half of fatal cases.Bleedingmay occur acutely or be delayedhours to weeksafter trauma. The mechanismof delayedhemorrhageis not known. E. Hypothalamic and pituitary lesions secondaryto trauma are more common than was previously realized.The lesionsare ischemic,hemorrhagic,traumatic, or necrotic and are often associatedwith temporoparietalblows and fracturesof the middle cranial fossa.Thesetraumatic injuries seldom presentwith a clinical syndrome of hormone deficienry in the acute post-traumatic period.

ln a Nutshell . Epidural hematomas lie between theskullandthe dura.Dueto theirarterial origin, theygrowrapidly andconstitute a serious emergency. . Subdural hematomas lie between theduraandthe arachnoid. Theyoriginate fromthebridging veins andtherefore develop more slowly thandoepidural hematomas. ClinicalCorrelate Because of cortical atrophy dueto age,bridging veins are morefragile intheelderly. persons Thus, elderly are moremorelikely to develop subdural hematomas thanare y0unSer persons.

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Neruous System

F. Traumatic spinal cord lesions 1. Etiology. Tiauma may be penetrating (producing laceration and hemorrhage) or compressive(causingcontusion and ischemia).Vertebralbodies may or may not be displaced. 2. Clinical features include weakness,parasthesias, and paralysis,dependingon the level of the spinal cord involved. 3. Pathology. The injured cord undergoesnecrosisand hemorrhage and then, ultimately, cavitation and gliosis. G. Complications of trauma 1. Acute complications include brain edema,herniation, hydrocephalus,and infection. 2. Chronic complications include post-traumatic epilepsy,white matter degeneration,and delayedintracerebralhemorrhage.

ClinicalCorrelate

BRAINHERNIATION

ThreeFrequent Sitesof CNS Herniation . Uncus (under tentorium cerebelli)

Brain herniation is the displacement of cerebral tissue outside of its usual compartment through cranial or dural openings.The cranial cavity is divided by dural septaeinto several compartments.Herniation is usuallythe result of a masslesion or brain swellingthat resultsin a pressuregradientbetweencompartments.Damageusuallyresultsfrom direct compressionof brain or blood vesselsor from obstructivehydrocephalus.

. Cerebellar (through tonsils foramen magnum) . Cingulate gyrus (below falx cerebri)

In a Nutshell . Vasogenic edema + interstitium swells . Cytotoxic -> edema cells swell

BRAINEDEMA Cerebral edema is an important complication of many neurologic diseases.There are three types of brain edema. A. Vasogenicedema resultsfrom increasedpermeability of endothelial cellsin brain capillaries.It occurswith trauma, infarction, tumor, infection, hemorrhage,and lead encephalopathy. Osmotic diuresis (e.g., mannitol) reducesthe volume of normal brain tissue acutely, while steroidsreduceedemain tumors and abscesses. B. Cytotoxic edema results from the swelling of neurons, glia, and endothelial cells in brain capillaries.It occurs with infarction, hypoxia, or hypo-osmolarity. Osmotic diuresis (e.g., mannitol) reducesthe volume of normal brain tissueacutely,but steroidsare ineffective. C. Interstitial edemaoccursin obstructivehydrocephaluswith leakageof CSFinto the periventricular white matter. Tieatment of hydrocephalusby a shunt is the only effective therapy.

In a Nutshell NormalPressure Hydrocephalus . Dementia . lncontinence . Ataxia . Normal pressure CSF

HYDROCEPHATUS A. Overview. Hydrocephalusis a generalterm that refersto an increasedvolume and/or pressure of CSF.It results in dilatation of the ventricular system. 1. Types a. Normal pressure hydrocephalus is a chronic, progressivedisorder of unknown pathogenesis,characterizedby dementia,incontinence,gait disturbance,and normal CSFpressure. b. Hydrocephalus ex vacuo refers to ventricular dilatation resembling typical hydrocephalus;it is produced by cerebral atrophy (Figure V-30-5). Hydrocephalusmay,

562

Pathology

therefore, be thought of as arising from two general phenomena: it may arise when excessfluid production causesneural tissue to atrophy and the ventricles to expand, or it may result when neural tissue atrophies from Alzheimer diseaseor fibrosis in dementiapugilistica (boxer dementia) and fluid under normal pressurefills the resultant enlargedspaces.

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c. Communicatinghydrocephalus is a syndrome of ventricular dilatation due to hydrodynamic abnormalities,such asCSFoverproduction (in which the normal flow of CSF within the ventricular systemis preserved)or impaired CSF absorption. d. Noncommunicating hydrocephalus occurs as a result of obstruction within the ventricular system(e.g.aqueductalstenosis).

Note Noncommunicating hydrocephalus may occur whentheaqueduct of Sylvius isob$ructed.

Pathology includes ventricular dilatation, edema of the periventricular white matter, and atrophy of white matter with relative preservation of grey matter.

3 . Etiology a. Congenital malformations (e.g.,Arnold-Chiari, Dandy-Walker, aqueductal stenosis) may all lead to noncommunicating hydrocephalus. b. Obstruction by mass lesions (e.g., tumors, AVM, aneurysm, inflammatory lesions) leadsto noncommunicating hydrocephaluswhen the obstruction is strategicallyplaced. c. CSF overproduction by choroid plexus papillomas produces communicating hydrocephalus. d.Impaired CSF absorption resulting from arachnoiditis or meningitis also produces communicating hydrocephalus.

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Neruous System

TUMORS A. Overview 1. Types.CNS tumors may be classifiedasprimary or secondary.Secondarytumors include metastaticor craniovertebralbone tumors. Primary tumors may be divided by tissue of origin. 2. Incidence. Neoplasm is the secondmost common causeof mortality from intracranial disease(strokeis first). CNS tumors are found in about lo/oof routine autopsiesand constitute roughly 9o/oof all neoplasms. a. Neural tube gliomas include astrocftomas,glioblastomas,ependymomas,oligodendrogliomas,medulloblastomas,ganglioneuromas,and certain pineal tumors. b. Neural crest tumors include meningiomas,schwannomas,and neurofibromas. c. Mesodermal tumors include CNS lymphomas, hemangioblastomas,lipomas, and chordomas. d. Ectodermal tumors include craniopharyngiomasand pituitary adenomas.

Note produce Brain tumors symptoms directly, byinvading indirectly, tissue, or by increasing intracranial pressure. ClinicalCorrelate SignsandSymptoms of Increased Intracranial Pressure . Headache . Nausea andvomiting . Papilledema . Autonomic changes

e. Germ cell tumors include germinomasand teratomas. 3. Location. Intracranial tumors may be supratentorial or infratentorial (posterior fossa). Infratentorial tumors comprise70o/oof intracranialtumors in children and30o/oin adults. Intraspinal tumors may occur outsidethe dura (epidural) or within the dura (intradural). Intradural tumors may be extramedullary (e.g., meningioma) or intramedullary (e.g., astrocytoma). 4. Clinical syndromes. Brain tumors produce progressivecerebraldysfunction. Symptoms may be generalized(if they result from diffr,rsecompromise) or focal.Sincethe volume of the intracranial cavity is fixed, tumor growth and edemamay causecompressionor displacement of parenchymaas well as increasedintracranial pressure.Obstructive hydrocephalusmay result from a block in normal CSFflow. Elevatedintracranial pressuremay produce headache,nausea,vomiting or papilledema,and autonomic changes(e.g.,hypertension, bradycardia,respiratory changes).Pressuregradients in different intracranial compartmentscan lead to brain herniation. Focal symptoms include aphasia,hemiparesis, and visual field cuts. Generalizedor focal seizuresoccur in roughly 35o/oof brain tumors. Behavioralchangesare common. Stroke-likesyndromesmay result from hemorrhageinto a tumor. B. Astrocytoma and glioblastoma multiforme. Tumors of astrocytesare divided into astrorytoma, anaplasticastrocytoma,and glioblastomamultiforme. Glioblastomais discussedseparately below. 1. Astrocftoma

In a Nutshell . Adults -+ supratentorial astrorytomas . Children -+ infratentorial astrorytomas

554

a. Incidence.Astrocytomasmake up 25o/oof all gliomas.Incidenceis dependenton location, and men outnumber women 2:1. ( 1) In adults, cerebralastrocytomaspredominate. (2) Adolescentstend to get pilocytic astrocytomasof the optic chiasm, hypothalamus, and third ventricle. (3) In children, the most common tumors are pilocytic astrocytomasof the cerebellum and pons.

Pathology

b. Pathology

ln a Nubhell

(1) Grossly astrocytomasare slow growing, and they tend to infiltrate, calcifr, or form pseudorysts. (2) Microscopically, different histologic forms, dependingon the degreeof anaplasia, are evident; well-differentiated forms lack mitotic figures. c. Clinical features. There is a slow onset of headache, neurologic impairment, or epilepsy; symptoms depend on location. Impairment may not progressfor many years,or it may undergo rapid progression.The rapid phaseis usually associatedwith anaplastictransformation with worseningprognosis(death within months to years).

Clioblastoma multiforme is generally grows cerebral, rapidly,andis uniformly fatal. quickly It spreads to the meninges, butrarely beyond.

d. Prognosis dependson differentiation and location. There is a better prognosis for cerebral and cerebellarastrocytomasthan for pontine astrocytomas.Overall, there is a 70o/oI-year survival and a 30o/oS-yearsurvival with surgery and radiotherapy. 2. Glioblastoma multiforme is a highly anaplastic astrocytoma with necrosis. a. Incidence. Glioblastoma multiforme makes up 550/oof all glial tumors and 20o/oof aX, intracranial tumors. The peak incidenceis betweenages40 and 60. Men are afflicted more frequently than women. b. Pathology (1) Grossly,glioblastomasoccur most frequentlyin the cerebralhemispheres(particularly the frontal and temporal lobes). Multicentric gliomas occur in roughly 5olo of cases.They are fairly well defined but not encapsulated.Local spreadis rapid, and meningeal involvement common; extraneural metastasesare very rare. Necrosis,hemorrhage,and cysticdegenerationmay occur (FigureV-30-6).

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Figure V-30-6.Glioblastoma multiforme (gross).

(2) Microscopically, there is increasedcellularity with pleomorphic astrocytescontaining hyperchromatic nuclei; giant cells and mitotic figures may occur.

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c. Prognosis.Glioblastomamultiforme is uniformly fatal with a median survival time after diagnosis of 6-9 months, a l-year survival of roughly 25o/o,and a 2-year survival of about 10o/o.Treatmentsthat may prolong survival include surgical resection,radiation therapy,and chemotherapy(especiallynitrosoureas).

In a Nutshell Pinealtumors mayresult in noncommunicating hydrocephalus, visual deficits, andParinaud syndrome (paralysis gaze). of upward

C. Pineal tumors usually occur in young men betweenthe agesof 10 and 40. Thesetumors produce symptomsby compressingadjacentstructures,including the midbrain (which may causeParinaud syndrome [i.e.,paralysisof upward gazeassociatedwith other ocular abnormalities]), the aqueductof Sylvius (which causesobstructivehydrocephalus),and the optic pathways or the hypothalamus (which cause delayed or premature puberty and other endocrine abnormalities).Both radiation therapy and surgerymay be helpfrrl. 1. Germinomas account for roughly half of all pineal tumors. They are histologically malignant and invasive,but they may be cured by radiation therapy, as may all germ-cell neoplasms. 2. Pinealomas include the benign pinealocytomasand the malignant pinealoblastomas, which may metastasizethrough the CSF. D. Medulloblastomas 1. Incidence. These are a common brain tumor in childhood, accounting for 25o/oof all intracranial tumors in this agegroup. The peak incidenceis betweenthe agesof 2 and 10, with a male predominanceof 2:1. 2. Pathology a. Grossly, medulloblastomas usually arise in the midline of the cerebellum (i.e., the vermis) but may arise in a cerebellarhemisphere(especiallyafter age 5). The tumor usually extends into the fourth ventricle, often spreading throughout the space,with positive CSF cftology in roughly 40o/oof cases.Extracranial metastasismay occur, especiallyafter craniotomy. b. Microscopically, medulloblastomas are hypercellular and composedof homogeneous cells with frequent mitotic figures. 3. Clinical features. Typically, a young child presents with signs of increased intracranial pressure (from obstructive hydrocephalus) and gait ataxia. 4. Prognosis. The combination of surgery,radiation therapy, and chemotherapy has resulted in a S-yearsurvival of 20-50o/o. E. Meningiomas are benign tumors derived from arachnoid cells.

Note Meningiomas arebenign but dangerous dueto mass effects. Theydo notinvade braintissue, butmayerode nearby bonebycompression.

In a Nutshell Psamomma bodies are calcified, layered structures foundin meningiomas.

566

1. Incidence. Meningiomas make up 15oloof intracranial and 25o/oof intraspinal tumors. The peak incidenceis betweenthe agesof 35 and 60, and there is a 2:1 ratio of women to men. 2. Pathology a. GrosslS the most common sites in the cranium are the parasagittalregion, lateral cerebral convexiry and falx cerebri; spinal tumors are usually thoracic and are found along the lateral part of the cord. They are usually well limited and may compressbut not invade the parenchyma.Penetrationof the dura may produce hyperostosis,bone destruction,or both. b. Microscopically, a characteristic"whorling" pattern of cellsis often present.If the center of the whorl is calcified or hyalinized, thesefeaturesare called psamornma bodies. 3. Clinical features. Depending on tumor location, patients may experienceheadachesand focal or generalizedsigns.Surgicalresectionis often successful;the postoperativerecurrence rate is about 15olo.

Pathology

F. Pituitary adenomas are the most common pituitary tumor. 1. Incidence. They make up 10oloof intracranial tumors.

Clinical Correlate

2. Pathology

Pituitary adenomas often present withbitemporal hemianopsia dueto compression of themedial opticchiasm.

a. Grossly, pituitary adenomas are usually well circumscribed, but they may be locally invasive. b. Microscopically, basedon their affinity for histologic stains,thesetumors maybe classified as basophilic,acidophilic, or chromaphobic;the last of theseis the most common fype. 3. Clinical features. Most adenomas secretehormones: prolactin in about 600/oof cases, growth hormone in 10o/o, ACTH in 10olo,and rarely TSH, LH, and FSH. Signsand symptoms result from endocrine imbalancesplus local compressionor invasion; symptoms may include visual field or cranial nerve (III, IV, V or VI) deficits. 4. Prognosis. If caught early, surgical cure is possible.

ln a Nutshell

G. Metastic tumors. CNS metastasesmay be divided into four groups. 1. Skull and dural metastasesare usually seenwith carcinomas of the breast,prostate, and lung, and with neuroblastomas. 2. Intracerebral metastasesaccount for roughly 25o/oof intracranial tumors; they are present in almost 20o/oof patients with systemic cancer.Lung and breast carcinoma are the most common sources,followed by renal cell and gastrointestinaltract carcinomas. Multiple metastases are presentin7}o/oof cases.Metastasesare usuallywell-definedmasses,but they may have the histologic appearanceof the primary tumor or of poorly differentiated cancer.

Metastic tumors represent 250/o of all CNStumors.They oftenarise fromlung,heart, skin,andhematopoietic cells.

3. Spinal metastases(usually epidural) are present in roughly 5o/oof patients with systemic cancer. 4. Leptomeningeal metastasesresult from the dissemination of systemiccancerin the subarachnoid spaceand leptomeninges.The most common sourcesare carcinomasof the breast,lung, and genitourinary tract, melanoma,leukemia,and lymphoma. H. Oligodendrogliomas are tumors of myelin-forming cells of the CNS. l. Incidence. Oligodendrogliomas make up 5olo of all gliomas. The peak incidence is betweenthe agesof 30 and 50. There is no sexpreference. 2. Pathology a. Grossly, these tumors form well-defined massesthat may undergo cystic degeneration, calcification, or hemorrhage. Most are in the cerebral hemispheresand involve both grey and white matter. b. Microscopically, they are composed of cells with small central nuclei encircled by cytoplasm.The histologic appearancedoes not correlatewith neoplastic activity. Some may contain featuresof astrocFtomas. 3. Ctinical features. Most are slow-growing tumors that often present with seizures.

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Neruous System

I . Schwannomas 1. Incidence. Thesecomprise 7o/oof intracranial tumors. Incidencepeaksbetweenthe ages of 20 and 60 with a 2:1 ratio of women to men.

ln a Nutshell arebenign; Schwannomas results mostof thepathology fromcompression, most ofCNVlll commonly (acoustic neuroma).

2. Pathology. Schwannomasare benign encapsulatedtumors that compressbut do not invade; malignant changeis rare. They may involve any of the cranial or spinal nerves.The most common intracranial site is the eighth cranial nerve (CN VIII) [i.e., acoustic neuroma]. Schwannomasusually form single tumors; however,when associatedwith von Recklinghausenneurofibromatosis,multiple schwannomasare common, including bilateral acousticneuromas. 3. Clinical features. Acoustic neuromas usually arise in the internal auditory meatus; early symptoms are tinnitus and diminished hearing. Compressionnear the cerebellopontine angle may produce facial and trigeminal nerve dysfunction; later, it may produce brain stem and cerebellarcompromise.

I. Neurofibromas arebenign tumors that are composedof fibroblastsand Schwanncells.They may occur along cranial,spinal,or peripheral nerves(many are cutaneous).Multiple tumors are usually present; most cases are associated with von Recklinghausen syndrome (neurofibromatosis),which featuresautosomaldominant inheritance, caf6au lait spots,and multiple neural tumors.

ln a Nutshell Neuroblastomas arefoundin children andarehighly malignant.

K. Neuroblastoma is a rare tumor derived from ganglion cell precursors that may arise anywhere in the cerebralhemispheres. l. Incidence.Neuroblastomasare encounteredin children ranging in agefrom 2 months to 9 years. 2. Pathology a. Grossly, tumors are well defined with extensive areasof hemorrhage, necrosis, and rystic degeneration. b. Microscopically, there is a densenetwork of poorly differentiated cellswith a variable fibrous connectivetissuebackground. The tumor is malignant and, despite sharp borders, infiltrates adjacentbrain and often invadesleptomeningesand the CSFpathways. L. Ependymoma can occur wherever ependymal cells or their "nests" are found. 1. Incidence. Ependymomasare more common in children. They most often originate in the fourth ventricle and are the most common intramedullary glioma of the spinal cord. 2. Pathology a. Grossly, tumors are well circumscribed and noninfiltrating growths that are highly cellular. b. Microscopically, the cells often form a perivascular rosette pattern that is diagnostically usefrrl. 3. Clinical features.Ependymomasoften causesymptomsof increasedintracranial pressure secondaryto obstructivehydrocephalus. 4. Prognosis. The tumors rarely undergo malignant transformations and, in these cases, may seedthe CSF pathways.Long-term prognosis is poor becausethey are difficult to excise,and the remaining cellsare not particularly radiosensitive. M. Craniopharyngiomas 1. Incidence. Craniopharyngiomasmake up 3o/oof all brain tumors. They are the most common supratentorialtumor in children.

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Pathology

2. Pathology. They have a smooth surface.Internally, they are often calcific and arise from squamous cell restsin the pituitary stalk (Rathke pouch). Frequently,they have cystscontaining cholesterol crystals. 3. Clinical features. Most produce symptoms by compressingthe optic chiasm or hlryothalamus. 4. Prognosis. Early surgical intervention can lead to cure, although recurrencesare common. Severingthe pituitary stalk is a risk leading to panhypopituitarism. N. Lymphomas 1. Incidence. Lymphomasmake up 0.4o/oof primary brain tumors. They may be metastatic to or primary in the CNS. They are often perivascular or periventricular. They are much higher in incidencein AIDS patients.

In a Nubhell Tumors inChildren . Astrocytomas . Medulloblastomas . Neuroblastomas . Ependmonas . Craniopharyngiomas

2. Pathology a. Grossly,lymphomas may form multiple nodules or diffirse infiltration with a periventricular predilection. b. Microscopically, sheetsof lymphoma cells,almost alwaysof B-cell origin, are present. Frequently,the cells are found in perivascular cuffs. 3. Clinical features. Lymphomas causesymptoms similar to other space-occupyinglesions. They are very sensitiveinitially to steroids and radiation, but recurrence is virtually universal,especiallyin immunocompromised hosts. O. Miscelklneous tumors 1. Colloid cysts are tumors of uncertain origin. Smooth, thin-walled rysts filled with a hyaline substanceattach to the septum pellucidum, fornix, choroid plexus, or walls of the third ventricle. They may become symptomatic in early adult life if they obstruct the foramina of Monro, presenting as a sudden headacheor drop attack. 2. Arachnoid cysts are developmental abnormalities of the arachnoid membrane formed by hyperplastic arachnoid cells and collagenous tissue filled with a clear, CSF-like fluid. Preferential locations include cerebral hemispheres and posterior fossa, sella, and suprasellar regions. They may become symptomatic if they enlarge enough to compress adjacent structures and/or causeobstructive hydrocephalus. 3. Intracranial lipomas are often incidental findings on CT scan;they may exhibit characteristic outer-edge calcification, giving them an eggshellappearance.They occur in the corpus callosum and upper brainstem aswell asthe spine. If symptomatic, they may cause seizures,mental abnormalities, or other midline developmental abnormalities.

569

NervousSystem

NEUROCUTAN EOUS DISORDERS Neurocutaneousdisordersor "phakomatoses"arelocalizedtumors and/or tumor-like lesionsof the skin, eye,and nervous system. A. Neurofibromatosishasbeendescribedabove.Neurofibromasrarelybecomeneurofibrosarcomas. 1. Incidence.In the generalpopulation, 1/3,000individuals are affected.Fifty percent have autosomaldominant inheritance,and 50o/oareapparentlyspontaneousmutations. 2. Clinical features include: a. Caf6,au lait (pigmented skin lesions) spots b. Neural tumors (e.g.,neurofibromas) c. Lisch nodules (benign, pigmented hamartomasof the iris)

ln a Nutshell vonHippel-Lindau Disease . Autosomal dominant

B. T[rberoussclerosisinvolvesmultiple organsbut commonly presentsas a result of CNS disease,seizures,and mental retardation. Adenoma sebaceumof the face,ashleafspots, shagreen patchesof skin, and subungual angiofibromata may be evident. Multifocal areasof cerebralcortex may be involved with "tubers,"which are potato-like massesof giant neurons and astrocytes.The condition is associatedwith giant-cell astrocytomas,gliomas, and gangliogliomas,and rarely involvesthe infratentorial CNS or spinal cord. C. Retinocerebral angiomatosis (von Hippel-Lindau disease)is an autosomal dominant disorder involving:

. Hemangioblastomas

1. Hemangioblastomas of the retina or cerebellumwith other hemangioblastomasin the cerebrum or spinal cord

. Pheochromocytoma

2. Abdominal masses,such as pheochromocytoma

. Renal, pancreatic, hepatic cysts

3. Cysts of the kidney, pancreas,and livet and renal cell carcinoma

. Renal cellcarcinoma in up to 500/o of patients

D. Encephalofacial angiomatosis (Sturge-Weber syndrome) involves the association of an extensive capillary-venous malformation of one cerebral hemisphere with an ipsilateral cutaneous port-wine stain (nevus flammeus) in the trigeminal region of the face. Neuroblastomasare associated,and glaucoma may be present on the affected side. The affectedbrain is atrophied, and the cortical gyri may exhibit "railroad track" calcification radiologically. There may be associatedangiomatosis of the lung, intestine, and ovary. Clinically, the patient presentswith hemiparesisand seizurescontralateralto the lesion.

MATFORMATTONS ANDINTRAUTERTNE/PERINATAI LESIONS A. Dysraphic states are malformations that result from incomplete closure in the neural parenchymaor its coverings.

ln a Nutshell Failure oftheneural tube to close mayresult in anencephaly, spina bifida, or meningomyelocele. The failure maybeassociated withmaternal folate deficiency, especially during earlypregnancy.

570

1. Anencephaly is a lack of brain formation, resulting from failure of closureof the neural tube at the level of the encephalon.The fetus is alwaysnonviable. 2. Spina bifida occulta is dysraphismof the bony spinal canal alone. It is detectableonly radiologically. 3. Meningocele is a saccularmalformation resulting from protrusion of the meninges-but not the spinal cord-through a defectof the bony canal. 4. Meningomyeloceleis the sameasa meningoceleexceptthat neural tissueis containedinside the sac.This lesion is frequently seenin associationwith Arnold-Chiari malformation.

Pathology

5. Encephaloceleis a saccularmalformation that resultsfrom protrusion of the meninges and brain tissuethrough a defectin the skull. B. Arnold-Chiari nalformation is a highly complexand poorly understoodmalformation.It is alwaysassociatedwith low-lying, gliotic cerebellartonsilstlat herniatetlrough the foramen maSnum. 1. Pathology.It is associated with a number of featuresin variouscombinations,including: a. Kinking of the medulla b. Aqueductalstenosisor atresia c. lvlloDraln malormauon

ln a Nubhell

d. Hydrocephalus

TheArnold-Chiari

e.spinabifida

isesentiallv li!]lnitt meningomyelocele, whh

f. Meningomyelocele 2. Pathogenesis.Symptomsare usuallyproducedby the hydrocephalusor by the development of a secondarycervicalryrirx, The extentof the malformation is variable. C, Dandy-Walkersyn&ome is a poorly understoodconstellationof malformations,including cerebellarvermishlpoplasia or aphasiahydrocephalus,and a largefourth ventricular cyst. D. Syringomyeliais the progressivedevelopmentof a cysticintramedullary cavity,usuallyin the cervicalcord. It may be idiopathic, or secondaryto trauma, hemorrhage,infarcdon, or developmentalanomaly.It maybe associat€d witl intramedullaryneoplasm.

hydrocephalus andtonsillar herniation In a Nutshell Syringomyelia isa cy$ic cavitation in thesDinal cord. especially cervical segments.

E. Agenesisof the corpuscallosum resultsin a singlecerebralventricle.It is usuallyassociated with mental retardationand other malformations. F. Hydranencephaly,In this condition, thin gliotic sacsfilled with CSFreplacetlre cerebra.l hemispheres. The brain stemand cerebellumarerelativelypreserved.It is possiblycausedby obstruction of carotid artery flow during fetal development. G. Porencqhaly is an intracranial cyst that communicateswith both the subarachnoidand intraventricular spaces. H. Holoprosencephalyis a failure of division of the forebrain,resultingin a single,largeherniwith trisomy 13and,to a lesserdegree,with spherewith a singleventricle.lt maybe associated tdsomy18. I. Anhinencqhaly is failure of developmentof the olfactory region of the brain and nasal portion of the face. ]. Periventricular leukornalacia is the most common finding following prematurity with resultantintraventricularhemorrhage,hypoxia-ischemia,or both.

DEMYETINATING DISEASES Demyelinationmayoccur primarily (asin multiple sclerosis)or secondaryto Walleriandegeneration dueto axonaldeath. A Multiple sclerosis(MS) l. Incidence a. MS usuallypresentsbetweenthe agesof 20 and 40. b. Thereis a slight femalepredominance.

571

NewousSystem

c. Prevalenceis increasedin cooler,higher,and temperatelatitudes of both the Northern and Southern hemispheres;individuals who relocatebefore adolescenceassumethe risk of the new climate. d. There is both familial and human antigen leukocyte (HlA)-linked geneticclustering.

ln a Nutshell Thecourse of multiple sclerosis ischaracterized by spontaneous appearance and remission ofsymptoms.

2. Clinical features a. The course is characterizedby spontaneous exacerbations and remissions. b. Ninety percent of patients develop pyramidal tract dysfunction (hyperreflexia,weakness,spasticity).Dysfunction is generallymultifocal. c. Cerebellardysfunction (e.g.,dysarthria,tremor, ataxia) is also common. d. Disturbancesof extraocularmusclesresult from lesionsof the medial longitudinal fasciculus;disturbancesof visual acuity result from lesionsof the optic nerve. e. CSF examination shows a very slight mononuclear pleocytosis(usually only during exacerbations)and an elevated proportion of immunoglobulin (IgG) that shows an oligoclonal pattern on electrophoresis.Thesemoleculesare synthesizedin the CNS. 3. Etiology. There is a presumedautoimmune etiology,possiblyinfluencedby a viral infection. Antibodv to measlesvirus is often detectedin the CSF.

In a Nutshell Crossly, MSbrains show plaques of demyelination (composed of immune cells andglialcells) inthe whitematter.

4. Pathology a. Grossly, plaques are evident in the white maffer (frequently periventricular) or in the corpus callosum.They are also found in the optic nervesand spinal cord. b. Microscopically, plaquescontain a margin of lymphocftes,lipid-laden macrophages, and reactiveglial cellssurrounding a central areathat is without myelin or oligodendrocytes.Older, inactive plaquesare predominantly gliotic. B. Devic disease(neuromyelitis optica) refers to demyelination confined to the optic nerves and spinal cord. It is characterizedby blindness,paralysis,and loss of sphincter control. C. Postinfectious/postvaccinial encephalomyelitis l. Pathology. This form of demyelinating diseasecausesacute widespread,perivenular demyelination associatedwith mononuclear infiltration; infiltration follows certain viral illnessesand vaccinations. 2. Etiology is thought to be autoimmune (rather than primary) destruction of myelin by viral infection of the neurons.

In a Nutshell Cuillain-Barre syndrome isan autoimmune,postinfectious, peripheral demyelinating disorder. Limbparalysis and autonomic failure mayresult.

572

D. Guillain-Barrd syndrome is a demyelinating illness of autoimmune etiology that affects peripheral nerves following certain viral illnessesor vaccinations. It usually presentswith limb weakness,but facial and ocular muscles may be involved early. Guillain-Barr6 syndrome may causecomplete paralysis,autonomic dysfunction, and respiratory failure. CSF protein gradually becomes markedly elevated. Symptoms usually resolve completely, but prolonged respiratoryassistance maybe required.Peripheralnervesshow demyelinationand an accumulationof lymphocytesand macrophages.

Pathology

TEUKODYSTROPHIES Leukodystrophiesresult from defectsin myelin metabolism. A. Metachromatic leukodystrophy (MLD: sulfatide lipidosis) is an autosomal recessivedefect of aryl sulfatase A. In the absenceof this enzyme, lipids with sulfate groups accumulate in cells,interfering with their function. Thesemolecules are particularly toxic to the CNS. 1. Incidence. It usuallypresentsbefore age4,but rare adult forms exist. 2. Ctinicalfeatures are impaired speechand motor development,blindness,deafness,seizures, and rigidity. Adults have dementia, movement disorders, or both more frequently than children. 3. Pathology a. Grossly, the brain may exhibit only firm, grey,rubbery white matter deficient in myelin. b. Microscopically, sulfatide-containing macrophagesare abundant in the brain as well as in the liver and kidneys. c. CSFprotein is increased,and nerve conduction velocity is slowed. B. Krabbe disease(globoid cell leukodystrophy) is an autosomal recessivedeficiency of galactocerebroside-p-galactosidase that involves only the brain and peripheral nerves. 1. Clinical features. The diseaseusually presentsbetween 3 and 6 months with irritabiliry mental and motor decline, blindness,and decerebrateposturing. Accumulation of the toxic lipid psychosinehas been invoked as the major neurotoxic lesion in the disorder. Death usually occurs before age2. 2. Pathology a. Grossh white matter is reduced in volume and is abnormally firm with small cavitations. b. Microscopically, myelin is decreased,and many large macrophages are filled with periodic acid-Schiff (PAS) - positive galactocerebroside. C. Adrenoleukodystrophy is an X-linked recessivedisorder associatedwith accumulation of long-chain cholesterol esters in the white matter and adrenals. 1. Clinical features include behavioral disturbance, blindness, and ataxia. Usually, adrenal insufficiency is not clinically obvious but can be documented by laboratory examination (ACTH stimulation test). 2. Pathology a. Grossly, central white matter is demyelinated and destroyed. b. Microscopically, macrophagescontain sudanophilic, PAS-positivematerial (the longchain cholesterolesters).

METABOTIC DISORDERS aminoacidemias, Metabolic disorders include the sphingolipidoses,mucopolysaccharidoses, and deficarbohydratemetabolism disorders,Reyesyndrome,Wilson disease,lupofuscinoses, cienry states. A. Sphingolipidoses include many diseasescategorizedas storage diseasesand leukodystrophies. They are usually categorizedby a descriptive term (or eponym), by the enzyme deficiency,or by the accumulated material.

57',

NervousSystem

1. Specific diseases a. Niemann-Pickdisease is due to sphingomyelinasedeficiency;sphingomyelin accumulates. b. IGabbe diseaseis due to galactocerebrosidase deficiency;galactocerebrosideaccumulates. c. Metachromatic leukodystrophy is due to aryl sulfatasedeficienry; sulfatide accumulates. d. Gaucher diseaseis due to glucocerebrosidase deficiency;glucocerebrosideaccumulates. e. Fabrydiseaseis due to o-galactosidase deficienry;ceramidetrihexosideaccumulates. f. Tay-Sachsdiseaseis due to hexosaminidase A deficiengr;GMr-gangliosideaccumulates. 2. Pathology. Atl of these disorders are characterrzedby distention of the reticuloendothelial cells with stored material, resulting in neuronal enlargement and dysfunction, hepatosplenomegaly, and marrow infiltration. 3. Clinical features are usually characterizedby delayeddevelopmentwith progressionto mental retardation and motor impairment. 4. Diagnosis is confirmed by specificenzymatic activiry assayor by characterizationof the material accumulated.Restriction fragment length polymorphism analysisof DNA in utero is now availablefor severalof thesedisordersand is diagnostic.

B. Mucopolysaccharidoses are enzymatic defects that lead to the accumulation of glycosaminoglycansin the brain and viscera,often with concomitant excretionof accumulated material in urine. 1. Specific diseases a. Hurler syndrome is a defectin cr-r-iduronidase. b. Hunter syndrome is an X-linked recessivedefectin iduronosyl sulfatase. c. Sanfilippo syndrome is causedby a defectin either heparan sulfataseor N-acetylglycosaminidase. 2. Clinical featuresinclude combinationsof mental retardation,hepatosplenomegaly, skeletal changes,and corneal clouding. 3. Pathology shows accumulation of glycosaminoglycansin neurons and in organs other than the brain.

ClinicalCorrelate Screening for phenylketonuria isdoneperinatally. lf the disease isdiscovered early, itsmanifestations maybe prevented byrestricting the dietary intake of phenylalanine. lf not,the patient willprobably need to beinstitutionalized.

C . Aminoacidurias 1. Phenylketonuria is a defect in phenylalanine hydroxylase.Mental retardation may develop, but it can be preventedby a diet low in phenylalanine. 2. Homocystinuria is due to a defectin cystathioninesynthetase.Clinically multiple thromboembolic infarcts may occur. Restriction of dietary methionine together with pyridoxine supplementationmay be helpful. 3. Maple syrup urine diseaseis a defect in branched-chainketoacid decarboxylase. Mental retardation,seizures,and death occur before the secondyear of life.

D. Carbohydrate metabolism disorders 1. Hypoglycemia is defined as low serum glucose. a. Incidence. It usually occurs in diabeticson insulin, but it is also seenwith insulinomas and chronic liver disease. b. Clinical features. Hypoglycemia causes encephalopathywith delirium or coma, stroke-likedeficits,and seizures.

574

Pathology

c. Pathology. Focal,diffirse,or laminar cortical necrosismay be evident.The cerebellum may show loss of Purkinje cells. 2. Famitial myoclonic epilepsy (Lafora disease)is a rare autosomal recessivedisorder. It causesmental deterioration, seizures,and myoclonus. Intraneuronal inclusions (Lafora bodies,which are complex sugarpolymers) may be present. E. Other metabolic disorders 1. Reyesyndrome

Clinical Correlate isseenmost Reye syndrome given in children frequently varicella aftera recent aspirin (chickenpox) or influenza infection.

a. Incidence. This syndrome occurs sporadically in children following viral illnesses (frequently varicella),usually in associationwith aspirin ingestion. leading b. Clinical features include acutefever,vomiting, seizures,alteredconsciousness to coma, and alteredliver function with hyperammonemia. c. Pathology.Pathologicfindings are possiblythe result of a mitochondrial abnormality induced by the antecedentviral illness.There is acute cyototoxic cerebraledema and prominent fatty changein the liver. 2. Wilson's diseaseis an autosomaldisorder of copper metabolism. a. Clinical features include movement disorders,personality change,dysarthria, and liver dysfunction.It may be treatedwith the copper chelatorpenicillamine. b. Pathology (1) Grossly, the brain is shrunken (especiallythe basal ganglia) and cavitated. Kayser-Fleischerrings (green-browndepositsof copperin Descemetmembrane near the limbus of the cornea) are essentiallydiagnostic.Liver changesinclude fatty change,hepatitis,cirrhosis,and massiveliver necrosis. (2) Microscopically, the changesin the liver are similar to other forms of fatty change,hepatitis,cirrhosis,or necrosis.Copper accumulationin hepatocytescan often be demonstratedwith specialstains.Serum copper levelsmay be low normal, or high, dependingon the stageof the disease.

ln a Nutshell ischaracterized Wilson disease basal changes, byhepatic ganglia and degeneration, rings around Kayser-Fleischer lt canbetreated thecornea. withpenicillamine.

DISORDERS ANDTOXIC NUTRITIONAT A. Thiamine (vitamin 81) deficiency. Thiamine is crucial to cellular energy production. Deficienry is due to dietary insufficiency; in the United States,deficiencyis usually due to the malnutrition of chronic alcoholism. Two neurologic diseasesresult: 1. Beriberi peripheral neuropathy is an axonal degenerationwith secondarydemyelination. It is causedby an unknown mechanism. 2. Wernicke encephalopathy is charactertzedby confusion, ocular disturbance,and ataxia of gait. a. Pathology (l) Grossly, there are lesions of the mammillary bodies; less frequently, the periventricular grey matter of the pons, midbrain, and thalamus degenerates. (2) Microscopically, pathology involves variable necrosis of neurons, axons, and myelin associatedwith small perivascularhemorrhages.

ln a Nutshell of Neurologic Sequelae Deficiency Thiamine . Beriberi: peripheral neuropathy . Wernicke-Korsakoff: gait,andeye memory, disturbances; movement mammillary important bodylesions

b. Korsakoff syndrome is characterized by a profound short-term memory deficit. Critical lesionsarelocatedin the dorsomedialnucleusand the mammillarybodiesof the thalamus.

575

Neruous System

ln a Nutshell Vitamin B,,deficiency results in CNSandPNSpathology dueto bothdemyelination andaxonal degeneration.

In a Nutshell Effects of Ethanol . Wernicke-Korsakoff syndrome . Cerebellar andpontine degeneration . Peripheral polyneuropathy

B. Vitamin 812 deficiency is almost alwayssecondaryto malabsorption rather than to dietary deficiency (except in strict vegetarians).The most common causeis pernicious anemia, which resultsin pathology in the peripheral and optic nervesaswell asin the spinal cord and brain. In the spinal cord, these changes are termed subacute combined degeneration and involve the posterior and lateral white matter tracts, more often in the lower cervical and upper thoracic cord. Spongydegenerationof myelin sheathsgivesway to degeneration of myelin and axonswith secondarywalleriandegenerationof fiber tracts.Disturbing paresthesias are the most frequent clinical symptoms. Optic nerve and cerebralpathology are not well characterized.The associatedperipheral neuropathy involvesboth axonal degeneration and demyelination. C. Ethanol. Pathology is usually the result of nutritional deficienry, hypoxia, or hepatic disease. fuide from Wernicke-Korsakoffsyndrome,the following diseasesmay accompanyalcoholism. 1. Alcoholic cerebellar degeneration causescerebellaratroph5 predominantly in the anterior superior vermis,particularly affectingthe Purkinje cells.It occursmainly in men and is characterizedby severeataxia of the lower extremities. 2. Central pontine myelinosis is a condition of lo calizedpontine demyelination. It may also be seenin severemalnutrition and with suddenshifts in serum sodium. It may be asymptomatic or causeseverebrain stem dysfunction, quadriparesis,coma, and death.

. Fetal alcohol syndrome

3. Alcoholic polyneuropathies are characterized by axonal degeneration of peripheral nerves,gradual developmentof paresthesias, weakness,and pain.

Clinical Correlate

4. Fetal alcohol syndrome (FAS) describesfetal damageresulting from alcohol use during pregnancy. The amount required to produce the syndrome remains controversial. Featuresof the syndrome include mental retardation, microcephaly, incoordination, hypotonia, irritabiliry hyperactiviry and a characteristicfacies.

poisoning Methanol istreated withethanol; ethanol competes withmethanol for alcohol dehydrogenase and prevents theformation of formaldehyde.

D. Methanol intoxication produces metabolic acidosis (with an anion gap) and visual disturbances. Pathologically, the brain, retina, and optic nerve are edematous, and the external ganglion cells and optic nervesdegenerate.The metabolism of methanol to formaldehyde (and lessso,to formic acid) is responsiblefor the ocular toxicity.

INFECTIOUS DISORDERS A. Bacterial infections l. Acute pyogenic meningitis a. Pathogenesis. Infectious agents are relatively specific to the patient's age, although overlapoccurs. (1) For neonates,Escherichiacoli, Group B Streptococciand Listeria monoqttogenes predominate. (2) For infants and children, Streptococcus pneumoniaeis the most common infectious causein those that have receivedthe vaccine for H. influenzae.H. influenzae will predominate in nonvaccinatedchildren. (3) In young adults,Neisseriameningitidlscausesthe mostcases. (a) In the middle-agedand elderly,Pneumococcuspredominates. b. Clinical features include fever, malaise, headache,nuchal rigidiry photophobia, and altered mental status.Laboratory tests show elevatedCSF pressure,high CSF neutrophil count, high CSFprotein, and low CSFglucose.

576

Pathology

Note

c. Pathology (1) Grossly the brain becomesvery edematous,and herniation may occur.Meningeal vesselsarecongested,and the subarachnoidspacecontainsexudate.Ventriculitiswith resultant exudatecoating the ependymal surfacesof the ventricles and aqueduct may obstruct the flow of CSFand causeacutehydrocephalus.Cerebralinfarcts of variable sizemay occur; they are much more frequent in neonatesthan adults. (2) Microscopically, polymorphonuclear leukocytes are the initial cells in the exudate;they are later replacedby mononuclear cells.The outermost cortex reveals microglial proliferation and neuronal swelling.Intimal proliferation in arteries and fibrin thrombi in veins may occur. (3) Pathologic sequelaeare more frequent in children and neonates.Theseinclude cavitary lesionsfrom old infarcts; chronic hydrocephalusfrom meningealfibrosis; subdural effi.rsions;and visual loss, deafness,and vestibular disturbances from involvement of the corresponding cranial nerves. The WaterhouseFriderichsen syndrome (which includes adrenal hemorrhage and infarction) occursin severecasesof meningococcalmeningitis with sepsis.It can also occur in casescausedby Pneumococci,H. influenzae,and Staphylococci.

Meningitis isaninflammation not layers, ofthemeningeal parenchyma. thebrain

tn a Nubhell Waterhouse-Friderichsen Septicemic syndrome: meningitis meningococcal infarcls. withadrenal

2. Brain abscessesarelocalized,walled-off areasof intraparenchymalpurulent exudate. may result from: a. Etiology. Brain abscesses ( 1) Extensionof otitis, mastoiditis,or sinusitis (2) Contamination of surgicalwounds (3) Penetratinghead injuries

FigureV-30-7.Cerebralabscess(gross).

577

Neruous System

#, ;,,'w*

.

ft'l

.*, .,. ,W

wt'

,,

:

.:

, tft;.

:. ]::

g:'

,i:il.':'

"ffi r#,

t?.; i:l

r

,&i

Figure V-30-8.Cerebral abscess (microscopic).

(4) Hematogenousdisseminationfrom infected heart and lung sites

In a Nutshell Cerebral abscess isa localized parenchymal infection walled offfromtherestofthebrain. Symptoms maybefocalor generalized.

ln a Nutshell Tertiary syphilis involves the meninges andbrain parenchyma aswellasthe spinal cord(tabes dorsalis).

b. Pathology varieswith time. During the initial "cerebritis,"the lesionsconsistof small necrotic foci infiltrated with acuteand chronic inflammatory cells.In time, the central portion of the lesion consistsof purulent exudateand liquified debris,surrounded by inflamed granulation tissueand by a collagenousconnectivetissue"capsule."The surrounding brain is edematousand eventually becomes gliotic (Figures V-30-7 and v _ 3 0 _ 8 ). c. Clinical features. There may be focal or generalizedsigns.Death follows herniation or, more rarely,rupture with ensuing meningitis and ventriculitis. d. Pathogenesis.Common organisms include anaerobic streptococci, staphylococci, Bacteroides, Gram-negativebacilli, and,less often, Nocardia, and Citrobacter. 3. Neurosyphilis (tertiary syphilis) follows an asymptomaticmeningitis. a. Meningovascular syphilis involvesinfiltration of meningesand vesselswith chronic inflammatory cells; the resultant arterial fibrosis and infarction is responsiblefor many of the clinical manifestations,such as hydrocephalusand cranial nerve palsies. b. General paresis is charactertzedby meningealfibrosis and atrophy; it is most severe in the frontal and temporal lobes.Histologic examination revealsneuronal loss,astrocytosis,rod-shapedmicroglial cells,and spirochetes. c. Thbes dorsalis involves thoracolumbosacralchronic meningeal inflammation with initial injury to dorsal roots and secondarydemyelinationof the dorsal columns. 4. Neurotuberculosis resultsfrom hematogenousdisseminationof tuberculosis.It is characterizedby a thick exudateat the baseof the brain or over the dorsal surfaceof the spinal cord. Arteries encasedwith exudatedevelop obliterative arteritis that can lead to infarction, while exudateand fibrosis at the brain's baseresult in hydrocephalus.The exudate contains caseousnecrosisin acutecases,while in more chronic cases,it is composedof a denseinfiltration of chronic inflammatory cells.Large,discretetuberculosisgranulomas are calledtuberculomas and consistof caseousmaterial,surrounded by a fibrous capsule lined by multinucleatedgiant and chronic inflammatory cells.

578

Pathology

5. Sarcoidosis is not of infectious origin but is a systemic granulomatous disease that commonly involvesthe lungs, lymph nodes,skin, eyes,liver, salivary glands,and bones. The central and peripheral nervous systemare lesscommonly involved.The CNS lesions consist of a granulomatous meningitis preferentially at the base of the brain with resultant visual disturbances, hypothalmic-pituitary dysfunction, and cranial nerve palsies.The lesions consist of compact aggregatesof epitheloid cells,macrophages,and multinucleated giant cells without frank caseation.Occasionally,parenchymal sarcoid granulomasare found in the brain; thesemimic primary or metastatictumors.

Note frequently Condido in infections causes immunocompromised hosts.

B. Mycotic infections occur commonly in patients with neoplasia,immunosuppression,and organ transplants. 1. Candidiasis is the most often encountered fungal infection at autopsy of the CNS. Virtually all casesresult from hematogenousdisseminationfrom distant sitesin colonized The organismsappear as a patients. Lesionsare composedof multiple small abscesses. mixture of yeastand pseudohyphae,a pathognomonic characteristicof Candida. 2. Aspergillosis is the secondmost common fungal infection of the CNS encounteredat autopsy. It results from initial infection through inhalation of airborne spores with hematogenous dissemination to the brain. Thus, these infections rarely occur without especiallyin the lung. The lesionsaremultiple, hemorrhagic,and overt infection elsewhere, necrotic, and the organism'spropensity for vascularinvasion leads to frequent cerebral infarction.

ln a Nutshell lesions ofthe Aspergillosis from CNSresult spread. hematogenous tends to invade Aspergillosis andcause vascular walls infarction. cerebral

3. Mucormycosis may occur as a regional infection involving the nose,sinuses,and brain (as in uncontrolled diabetes),or asa systemicdiseasewith hematogenousdissemination in compromised hosts. Lesions include purulent meningitis, cerebritis,and infarction secondaryto arterial invasion and thrombosis. 4. Cryptococcosis.Approximately 50o/oof casesoccur in immunocompetent individuals. Inhalation of spores,followed by hematogenousspread,leads most often to meningitis. The degreeof meningealexudatevaries widely; rarely,large intraparenchymalgranulomas may develop. C. Parasitic infections 1. Toxoplasmosis a. Acquired toxoplasmosis is causedby the protozoan Toxoplasmagondii. Acutely, there is destruction caused by intracellular, crescent-shapedtrophozoites. Chronically, intracellular cystscontaining organismsare formed and may remain viable in brain and muscle for years.Normal or immunocompromised adults acquire the organism by consumption of poorly cookedmeat or by contamination with fecesfrom infected cats.In severecases,the brain is littered with multiple large foci of necrosisand many encystedorganismsand free trophozoites.

ln a Nutshell through T.gondiiisacquired withcatsor infected contact cause meat. lt isanimportant in bothhost of CNSinfection it cancross andfetus(since theplacenta).

579

Neruous System

ffi\:

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ffi

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# Figure V-30-9.Toxoplasmacysts in the brain (microscopic).

b. Congenital toxoplasmosis complicates nearly 40o/oof primary infections in pregnanry. A maternal infection during the second to sixth month of gestation may result in infant convulsions, intracerebral calcification, hydrocephalus,and chorioretinitis. Brains show microglial nodules, trophozoites, rysts, necrosis,mineralization, and a mixed inflammatory response,resulting in secondary vasculitis and hydrocephalus (FigureV-30-9). 2. Cysticercosis results from infection by enrysted larvae of the pork tapeworm, Taenia solium. The organism invades the skin, muscle, eye, and brain. In the brain, the larvae involve the meninges, parenchyma (with cysts), and ventricular system.The brain surrounding the cysticerciibecomesinflamed and necrotic.Secondarymeningealinflammation, vasculitis,and hydrocephalusare common. D. Viral infections

Clinical Correlate CSFFindings in Meningitis Bacterial Viral

Fungal

wBG tt Protein tt

1 t

1 1t

Glucose J Pressure 1tt

normal normalto 1

J tl

Normal: WBG G-5lymphocytes,0 PMNs Protein 15-45mg/dl Glucose 45-85mg/dl(50-700tof plasma glucose Pressure 7G-180 mmH,O

1. Meningoencephalitis may be caused by many agents, but the morphologic features are similar. a. Pathology. The brain is edematous,containing focal areasof necrosisand even hemorrhage. The meninges,subarachnoid space,and neural parenchyma are infiltrated by lymphocytes, plasma cells, and histiocytes; polymorphonuclear leukocytes are transiently numerous at the onset of infection. Microglial nodules of chronic inflammatory cells may be scatteredthroughout, and perivascular cuffs of mononuclear cells are common. Neuronophagia(dying neuronsphagocytizedbyinflammatory cells)is present. The specific diagnosis rests on isolation of the virus and serologic studies rather than on conventional histopathology. b. Enteroviruses are common causesof viral CNS infections. Prior to immunization, poliomyelitis was a prominent example. Today, coxsackievirus (especially group B) and echovirusesare common. c. Arenaviruses are associatedmost commonly with lymphocytic choriomeningitis. d. Arboviruses produce Eastern,Western,Venezuelan, St.Louis, fapanese,and California encephalitis.The St. Louis variety is common in older individuals and carriesa mortaliry of 20o/o.

580

Pathology

e. Paramlaroviruses (1) Mumps causesmeningitis in nearly 25o/oof patients.A rare meningoencephalitis that appearsto be immune-mediated may occur. (2) Measles (rubeola) is responsible for many cases of postinfectious encephalomyelitisand, in a rare, persistentform, subacute sclerosing panencephalitis (SSPE).SSPEmainly affects children, causing personality changes, myoclonus, electroencephalographic (EEG) abnormalities, and death. Pathologicatly,SSPEis characterizedby Cowdry A inclusions, which are red inclusions in nuclei that take up at least half the diameter of the nucleus and are surrounded by a clear halo. They are seenin neurons or glial cells,along with a perivascular mononuclear infiltrate, fibrillary gliosis, and neuronal atrophy. They are alsooften seenin herpesvirus infections.Histochemicalstudiesidentiff measlesantigen in the inclusion bodies.With regard to the pathogenesisof SSPE,damageis causedby an immune reaction to the measlesvirus. f. Rubella virus causes the congenital rubella syndrome: low birth weight, cardiac defects,cataracts,chorioretinitis, and neurologic abnormalities. g. Rabiesvirus causespain and paresthesiaat the original wound, followed by abnormal behavior, hyperactiviry autonomic dysfunction, and laryngeal muscle spasm. Negri bodies (eosinophilic,oval cytoplasmicinclusions) are characteristic.

ln a Nutshell = rabies Negribodies

In a Nutshell isoftena encephalitis Herpes lt is resultof HSV-Iinfection. withacyclovir. treated

h. Herpesvirus ( I ) Herpes simplex is the most common causeof sporadic encephalitis,which can be fatal if untreated.Pathologicchangeshavea predilection for the frontal and temporal lobes. Herpes encephalitisis responsiveto specific therapy with aryclovir in many cases.Cowdry A inclusionsmay sometimesbe seenon brain biopsy. (2) Varicella zoster produces a benign cerebellar ataxia and postinfectious encephalomyelitis.The latter entity is characterizedby perivenular demyelination. Latent virus may persist in sensory ganglia; reactivation leads to herpes zoster (shingles),which commonly affectsthoracolumbar dermatomesand the ophthalmic division of the trigeminal nerve. (3) Cytomegalovirus may involve the cerebrum with disseminated"glial nodules" that consist of nodular infiltrates of histiocytes; these are usually seen in immunosuppressed individuals. Large, intranuclear inclusions may be seen along with cytoplasmicinclusions. 2. Transmissible subacute spongiform encephalopathy is thought to be causedby viruslike agents(prions) with a very long incubation period ("slow viruses"). a. Creutzfeldt-Jakob disease(CID) (1) Clinical features include personality changes, incoordination, myoclonus, dementia,and death (within 3 years). (2) Pathology showsstatusspongiosus(vacuolization) in the cortex and basalganglia, atrophy, and fibrillary gliosis. Characteristically,there is no inflammatory reaction.

Bridgeto lmmunology a without Prions areproteins They nucleic acidcomponent. oralternate byvariable arise of class of a particular folding proteins. Thisvariable normal causes themto folding "crystallize" producing easily, plaques. folding Thevariable pattern sothese isverystable, proteins infectious, appear thegastrointestinal surviving andcausing tractif ingested proteins to "crystallize" normal withthemwhentheyare intothebrain. absorbed

b. Kuru affectstribal people of the mountains of Papua,New Guinea.The incidencehas greatly diminished sincethe practiceof cannibalismhas ceased. ( l) Clinical features include ataxia,tremor, and death (within 1 year). Dementia is not prominent.

58t

NeryousSystem

(2) Pathology.Lesionsare asin CJD; they aremost prominent in the cerebellumand striatum. Kuru plaques(spiculesarrangedaround an amyloid body) are present in 600/oof cases. 3. Progressivemultifocal leukoencephalopathy is a demyelinating disease,causedby small DNA papovaviruses(JC virus and SV40), that typically occurs in adults with depressed cell-mediatedimmuniry. Beginning insidiously,focal deficits progressto death within 46 months. Pathologically,multiple areasof demyelination involve white matter and contain lipid-laden macrophagesand reactiveastrocytes.OligodendrocFtescontain intranuclear inclusion bodies. Enlarged astrocyteswith bizarre nuclei are common.

NEUROPATHOTOGY OFAIDS The majority of autopsiedAIDS caseshave pathologic findings in the neuromuscularsystem, including primary findings of HIV infections and secondaryabnormalities due to complicating conditions.Thesepatientsmay haveabnormalitiesin one or many structures,including the peripheral nerves,meninges,and the cNS (brain, spinal cord, or both). A. Peripheral nerve abnormalities in AIDS 1. Incidence. The actual incidenceof peripheral neuropathy associatedwith HIV seropositivity remains controversial, and numbers range from less than 25o/oto almost I00o/o. Symptomsare usually presentearly in the courseof the disease. 2. Types a. The most common neuropathy is demyelinating and segmental with endoneurial inflammatory infiltrates.This entity maybe either acuteor chronic with areflexia(distal and proximal), symmetric weakness,and sensoryloss.Motor symptoms are more prominent than sensory. This condition frequently responds to treatment with steroids and can even resolvespontaneously. b. Others. Patients may also experience distal symmetrical polyneuropathy with sensorysymptoms more prominent than motor (mild inflammation with diffuse loss of axons),mononeuritis multiplex, and inflammatory polyradiculopathy. B. Meningeal abnormalities in AIDS l. Incidence. Abnormalities of the meninges in AIDS are usually secondary to other syndromes (including cytomegalovirus infection, neurosyphilis, toxoplasmosis,cryptococcosis,and bacterialinfection). 2. Pathology is inflammatory with increasedprotein and cells;inflammation and CSFfindings dependon the primary cause. C. Spinal cord abnormalities in AIDS

ln a Nutshell MostH|V-positive patients develop a diffuse CNS pathology thatisdirectlyHIVrelated;they arealso susceptible to focal opportu nistic infections.

582

l. Incidence. Approximately 25o/oof HlV-positive individuals have a vacuolar myelopathy on autopsy.This is the most common finding, but other patientshaveevidenceof inflammation secondaryto viral infection (usually herpesor CMV). 2. Pathology. There is spongiform white matter degeneration (resulting from swelling within the myelin) without inflammation. Patientspresentwith symptoms of spinal cord dysfunction referable to motor and sensory tracts, including ataxia, spasticity, and incontinence.CSFprotein and cell count are normal.

Pathology

D. Brain abnormalities in AIDS 1. Incidence. Up to 75o/oof HlV-positive individuals have some form of diffrrse neuropathology in the brain. Many AIDS patients are demented,albeit some just mildly, at the time of death. There are, however,severaldifferent forms of neuropathology that are associatedwith dementia.In addition, there are patientswho have,either aloneor in combination with one of the diffirse neuropathologicentities,a focal abnormality as a complication of HIV infection. Much of the diffuse neuropathologyis directly HlV-related, whereasthe focal lesionsare diseasesthat also occur in non-AIDS patients,but to which HlV-infected patients are susceptiblebecauseof their immune deficits. 2. Types a. AIDS dementia/encephalitis with multinucleated cells (MNCs). This is the neuropathology most directly related to AIDS. The clinical course is characterizedby a progressivedementia.Neuropathology is remarkablefor direct evidenceof infection of macrophagesand microglia with the HIV virus, destruction of white matter, and multinucleated cells (likely comprised of microglia and other cells).MNCs are consideredby someto be pathognomic of HIV encephalitis.Simultaneousinfection with CMV is extremelycommon and is probably a contributory causeto the neuropathology.The neurons themselvesdo not appearto be directly infectedby the HIV virus.

In a Nutshell Multinucleated inAIDS cells dementia/encephalitis arethe result of HIVinfection ofthe brainmicroglial cells(monoryte may derivatives). CMVinfection contribute aswell.

b. AIDS dementia without MNCs accounts for approximately 50o/oof the identified CNS pathology; only a minoriry of these brains demonstrate direct HIV invasion. Clinically, thesepatients also demonstratea progressivedementia,but usually not as severeas those describedabove.There is destruction of white matter, but MNCs are not present. c. Lesionsassociatedwith AIDS, but not directly causedby the HIV virus, n&y be infectious or noninfectious. Noninfectious diseasesinclude primary CNS lymphoma, infarcts secondary to vasculitis, and embolic infarcts (sometimes secondary to a peripheral infection). Infectious diseasesinclude toxoplasmosis,mycobacteria,herpesvirus,CMV alone,HHV8 which causesKarposi sarcomaand the JC virus (leading to progressivemultifocal leukoencephalopathy).Lesscommon agentsinclude various fungi (e.g.,Aspergillus,Candida) and Cysticercus.

585

theAutonomic DrugsAtfecting Nervous System nervous system to altertheautonomic areeffective asa result oftheirability Manytherapeutic agents (e.9., (ANS)Clinical diseases hypertension, include thetreatment ofcardiovascular uses ofthese drugs glaucoma, knowledge ofthebiochemi$ry and A basic andbronchial a$hma. cardiac anhythmias), physiology thepharmacology of isusefulin understanding nervous system oftheANSandthesomatic Thischapter reviews the agents. therapeutic ofthemostappropriate these drugs andintheselection areclassified according totheir Thedrugs biochemical, andphysiologic aspects oftheANS. anatomic, primary agonists and andcholinergic agonists andantagonists mechanism ofaction: adrenergic pharmacology including themechanism isdiscussed, ofeach subclass of drugs Thebasic antagonists. toxicities, andcontraindications. therapeutic uses, organ andtissue effects, ofaction,

INTRODUCTION A. Neuroanatomicaspects.The autonomicnervoussystem(ANS)-also calledthe vegetative, involuntary, or visceralnervoussystem-is the division of the peripheral-n:t_l::::L,T that inn€rvatessmooth muscle,cardiacmuscle,and glands.The coordinatedactivity of the il,rt" mi"r# ANS and endocrinesystemis vital to the maintenanceof ho-.r"*ir ""tironment. Both systemsexert effectsthat are predominantlyinvoluntary and unconscious. The hypothalamusis the chief integrativecenterfor both the ANS and the endocrinesptems.The entericnervoussystemis a collection of neuronsin the wall of the gastrointestinal tract. The somaticnervoussystem(alsocalledthe voluntary nervoussystem)innervates skeletalmuscle.

In a Nubhell . Autonomic = system ,. vegetative andinvoluntary . Somatic sv$em= voluntary

585

Neruous System

1. Pre- and postganglionic neurons. Tiansmission of motor impulses from the central nervous system(CNS) to the viscera occurs in the ANS through a chain of two neurons. This is in contrast to the somatic nervous system,which innervates skeletalmuscle by a single myelinated axon from a CNS neuron. a. The preganglionicneuron hasits cell bodylocated in the brain stem or spinal cord. The lightly myelinated preganglionic fiber passesthrough either a cranial or spinal nerve to reach an autonomic ganglion,where it synapseswith the postganglionicneuron.

In a NuBtell Parasympathetic System . Craniosacral . Longpreganglionic fibers . Shortpo$ganglionic fibers Sympathetic System . Thoracolumbar . Shortpreganglionic fibers . Longpostganglionic fibers

b. The unmyelinated postganglionic neuron innervates effector cells (i.e., smooth muscle, cardiacmuscle,and glands). 2. Parasympathetic and sympathetic divisions. The ANS is subdivided into two segments-the parasympathetic and sympathetic systems.These divisions have cell bodies locatedin different regions. a. The parasympathetic or craniosacral division arisesfrom the brain stem via cranial nerves III, VII, IX, X, and sacralportion (S2-S4) of the spinal cord. In general,the parasympathetic system has long preganglionic and short postganglionic fibers. Ganglia lie near or within the organsbeing innervated. b. The sympathetic or thoracolumbar division arises from the intermediolateral cell columnsof the thoracic(T1-T12) and the lumbar (L1-L3) regionsof the spinalcord. In general,the sympatheticsystemhas short preganglionic and long postganglionic fibers, with most ganglia within the two paravertebral(sympathetic) chains; a few gangliaare prevertebralor terminal.

B. Neurotransmitters of the autonomic and somatic nervous systems

ln a Nutshell Cholinergic Transmission . Allpreganglionic parasympathetic and sympathetic . Allpostganglionic parasympathetic . A fewpostganglionic patheti sympath etic(sym c cholinergia) . NMJofthesomatic nervous system Adrenergic Transmission . Mostpostganglionic (NQ sympathetic . Adrenal (EPl, medulla NE)

586

I. Localization of neurotransmitters. A schematic of the neurotransmitters and receptors in the autonomic and somatic nervoussystemsis presentedin FigureV-31-1. a. Cholinergic neurons. Preganglionic neurons of both the parasympathetic and sympathetic systemsreleaseacetylcholine(ACh). Postganglionicparasympatheticfibers and somaticneurons to the neuromuscularjunction (NMI) alsoreleaseACh. All neurons releasingACh are called cholinergic nerve fibers. b. Adrenergic neurons. In contrast, most postganglionic sympathetic neurons release norepinephrine (NE) and are referredto asadrenergicnerve fibers.Exceptionsare the sympathetic cholinergic neurons that innervate the sweat glands and that mediate dilatation of skeletal muscle blood vessels,and the adrenal medulla releasesboth epinephrine(EPI) and NE (FigureV-31-1).

Pharmacology: DrugsAffectingtheANS

Somatic Nervous System

Sympathetic "Thoracolumbar"

Note . N^,neuronal nicotinic receptors, arepresent ganglia intheperipheral andadrenal medulla. ' Nm' muscle nicotinic receptors, on arepresent skeletal muscle.

Epinephrine 'fi-t:'l::::'"'

NordKineffiTrine Adrenergic

\z\

Adrenergic

t:ceeto2

{""otoj

-

Ace@rlbholine

/\7\ Muscarinic

{t"ot?

Effectororgans * Exception:There is sympatheticcholinergic(acetylcholine) stimulation of the sweatglandsand of the skeletalmusclevasculature.

FigureV-31-1.Neurotransmission and receptorsof the autonomic and somaticnervoussystems.

c. Other neurotransmitters associatedwith the ANS are dopamine,which is releasedfrom dopaminergicneurons and actsto dilate the renal vasculature,and epinephrine,which is releasedfrom the adrenal medulla. Many autonomic neurons which is releasecotransmitters (mostly peptides),which modulate the activity of the primary transmitter. 2. Synthesis, storage, release, and metabolism of neurotransmitters. Since autonomic drugs act by altering neurotransmission,it is important to understandthe synthesis,storage,release,and mechanismsfor terminating the action of the neurotransmittersof the autonomic and somatic systems(FigureV-31-2).

587

Neruous System

Cholinergic

Muscarinic

receptor Acetvl '+ CoA crrjine

ChAT :-ji+' Ach

Muscarinic receptor

\

Nicotinic receptor C hol i ne

Tyrosine Adrenergic cr2receptor

In a Nutshell . Choline + acetyl CoA+ = ChAT) ACh(enzyme . ACh+ choline + acetate = (enzymeAChE)

In a Nutshell Tyrosine J('l Dopa

J(rr Dopamine

JGr NE J(or EPI (l) Tyrosine hydroxylase @ Dopadecarboxylase p-hydroxylase* (3) Dopamine (4) PNMT *Note:Step3 occuninsynaptic vesicles; therestoccurinthe cytoplasm.

588

ChAT ACh AChE TH

= = = =

Choline acetyltransferase Acetylcholine Acetylcholinesterase Tyrosine hydrorylase

DD DA DpH NE

= = = =

Dopa decarborylase Dopamine Dopaminep-hydroxylase Norepinephrine

Figure V-31-2.Characteristics of cholinergic and adrenergic neurotransmission.

a. Acetylcholine (ACh) is synthesizedand releasedby cholinergic neurons in preganglionic autonomic fibers, postganglionic parasympatheticfibers, and a few sympathetic postganglionicfibers.ACh is synthesizedin the cytosol of the presynapticterminal from acetylCoA and choline by the enzyme,choline acetyltransferase (ChAT). (1) Following synthesis,ACh is sequesteredin synaptic vesicles.Depolarization of the axon terminal resultsin exocytosisof ACh. (2) The action of ACh is terminated by hydrolysis to choline and acetateby the (AChE), which is presentin the synapse. enryme acetylcholinesterase (3) Choline is taken up by the nerve terminal through an active transport mechanism and may be reusedfor ACh synthesis.Choline uptake is the rate-limiting step of Ach synthesis. (a) In addition to inactivation by AChE, ACh and synthetic analogs may be hydrolyzedby a plasma enzyme,calledplasmaor pseudocholinesterase (butyrylcholinesterase). b. Catecholamines are 3, -dihydroxybenzene(catechol)derivatives.Norepinephrine is synthesizedand releasedby adrenergic neurons, most postganglionic sympathetic neurons,and the small amounts from the adrenalmedulla.Epinephrine is synthesized from norepinephrine in the adrenalmedulla. (1) Tyrosineis taken up by adrenergicand dopaminergic neurons and hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This is the ratelimiting step in catecholaminesynthesis.

Pharmacology: DrugsAffectingtheANS

(2) DOPA is decarborylated to dopamine by dopa decarboxylase (r-aromatic amino acid decarboxylase), a pyridoxal phosphate-dependent enzyme. Dopamine is taken up into storagevesicles. (3) In adrenergic fibers, dopamine is further hydroxylated to norepinephrine by dopamine p-hydroxylase. This step occurs in synaptic vesicles. (a) In the adrenal medulla, norepinephrine is converted to epinephrine by phenylethanolamine-N-methyltransferase. (5) Releaseof catecholamines is similar to that of ACh, involving calcium influx through voltage-dependentchannels,causingfusion of the vesiclesto the plasma membrane and exocFtosisof the neurotransmitter along with adenosinetriphosphate (ATP), enzfmes,and cotransmitters.

In a Nubhell . Therate-limiting stepfor is catecholamine synthesis tyrosine hydrorylase. . Theratelimiting stepfor AChsynthesis ischoline uptake. . Adrenergic neurotransmission is terminated byreuptake.

(6) A sodium-dependentactive reuptake processis the primary method of terminating catecholamine action. Present on catecholaminergicnerve terminals, theseproteins retrieve catecholaminesfrom the synaptic cleft.

. Cholinergic neurotransmission is terminated byAChE.

(7) Once back in the nerve terminal, the catecholaminemay be reusedor metabolized by monoamine oxidase (MAO). MAO is found on the outer membrane of mitochondria. High levels are found in liver, kidney, and nerve terminals. There are two forms: MAO-A and MAO-B.

In a Nubhell

(8) A secondmetabolic enzfme, catecholO-methyltransferase(COMT) is located primarily in the cytoplasm; high levels are found in the liver and kidney, with lesseramounts found near adrenergicsynapses. 3. Receptors. Neurotransmitters produce their effectsby binding sterospecificallyto receptors located on the cell membrane. These receptors are either linked to G proteins (that regulate phospholipase C, adenylateryclase, or K* channel activity), or are ligand-gated ion channels. ?ableV-3f -1. Cholinergic receptors in the autonomic and somatic neryous systems. Receptor Classification

PrimaryActivity

Location

Mr

Gn-linked

StimulatesphospholipaseC, forming DAG and IPr; increasesCa2+

Nerve endings

M2

G,-linked

Activates K+ channels; inhibits adenylatecyclase

Heart and nerve endings

M3

Gn-linked

StimulatesphospholipaseC, forming DAG and IPr; increasesCa2+

Glands,smooth muscle,and endothelium

NN

Ion channel

Na+ influx; depolarization

Ganglia and adrenal medulla

NM

Ion channel

Na+ influx; skeletalmuscle contraction

Neuromuscular junction

Definitions: Go = Go G protein; Gi = G inhibitory protein; DAG = diacylglycerol;IP, = inositol 1,4,5-triphosphate.

AChreceptors Nicotinic Muscarinic

tl

ligand-gatedC protein cation channel coupled ln a NuBhell lmportant Locations of Muscarinic Receptors . Parasympathetic neuroeffector sites . Neuroeffector sitesof the sympathetic cholinergia (e.g., glands) sweat . Onendothelial cellsof (these bloodvessels sites arenotinnervated) lmportant Locations of Muscarinic Receptor Subtypes ' M,-neural ' Mr-heart . M,-smooth muscle, glands endothelium,

589

Nervous System

a. Cholinergic receptors are divided into two types: muscarinic and nicotinic (Table v -3 1 -1). (1) Muscarinic receptors were named becausethis receptor classwas found to be stimulatedby the natural analog,muscarine.Muscarinic receptorsare locatedon auto-nomic effector cells(heart, smooth muscle,vascularendothelium, exocrine glands),presynapticnerve terminals, and in selectedareasof the CNS.

ln a Nutshell lmportant Locations of Nicotinic Receptors . Allperipheral ganglia (Np) . NMJ(NM)

(2) Nicotinic receptors, which are stimulatedby nicotine, are located at autonomic ganglia,the neuromuscularjunction, and in the CNS. b. Adrenergic receptors are divided into cr- and B-adrenoceptorsubtypes(TableV-3I-2). The a and B receptorsare further subdividedinto a"1,d2, F,, F, and Br. (1) ar-adrenoceptors are locatedin vascularand other smooth muscle,and glands.

lmportant Locations of Adrenergic Receptors

(2) q-adrenoceptors are primarily found on presFnaptic nerve terminals to reduce norepinephrinerelease(negativefeedback),in somesmooth muscle,and in the CNS.

' a,-arterioles

(3) Br-adrenoceptorsare locatedin the heart and kidney.

. 02-presynaptic (inhibitsneu rotra nsm itter release) . F,-heaq kidney . Fr-lungs, skeletal muscle vasculature ' F,-fat

( ) Br-adrenoceptorsare located on vascularand bronchial smooth muscle. (5) A p3-adrenoceptorhasbeen localizedin adiposetissue. (6) The primary dopaminergic receptorfound in the periphery is the Dr-dopaminergic receptor subtype. C. Autonomic physiology. Most visceralstructuresreceiveboth parasympatheticand sympathetic input. As a rule, theseinputs have opposite effects.Functions of the parasympathetic systemare best summarized by "rest and digest,"while the sympatheticsystemis used for "fight or flight." The physiologic effectsof the ANS are describedin TableV-31-3, which is divided into cholinergic and adrenergiceffects.

ThbleV-31-2. Catecholaminergic receptors in the autonomic nervous system. Receptor

Classification

Primary activity

Location

crr

Go-linked

StimulatesphosopholipaseC, forming IP, and DAG; increasesCa2+

Vascularand other smooth muscle, glands

az

G,-linked

Inhibits adenylateryclase

Presynapticnerve endings,smooth muscle

It

G,-linked

Increasesadenylateryclase

Heart, kidney

9,

G,-linked

Increasesadenylateryclase

Bronchial and other smooth muscle, vasculature

F,

G,-linked G,-linked

Increasesadenylateryclase Increasesadenylateryclase

Adipose

D1

Renalvasculature

Definitions:Go=GoGprotein;Gt=Ginhibitoryprotein;Gr=Gstimulatoryprotein;IPr=inori,ot 1,4,5-triphosphate;DAG = diacyglycerol.

590

Pharmacology: DrugsAffectingtheANS

D. Sites of pharmacologic intervention. The sites at which drugs affect the ANS are: 1. Inhibition of neurotransmitter synthesis 2. Stimulation or inhibition of neurotransmitter release 3. Interferencewith neurotransmitter storage 4. Interferencewith neuronal reuptakeof neurotransmitters 5. Inhibition of the metabolism of the neurotransmitter 6. Activation or blockadeof neurotransmitter receptors

AGONISTS CHOTINERGIC A. Classification l. Direct acting (receptoragonists) a. Muscarinic agonists(e.g.,bethanechol,pilocarpine) b. Nicotinic agonists(e.g.,nicotine) c. Muscarinicand nicotinic agonists(e.g.,acerylcholine,carbachol) 2. Indirect acting a. Inhibitors of cholinesterase(e.g., edrophonium, neostigmine, physostigmine,pyridostigmine,echothiophate,malathion, parathion) b. Stimulatorsof ACh release(e.g.,black widow spider venom)

ln a Nubhell . Adrenergic produces system (a,) or vasoconstriction (8,), vasodilatation stimulates theheart(B,), relaxes bronchial smooth (p,),reduces muscle gastrointestinal toneand (cr,F),anddilates motility (cr,). thepupils . Cholinergic system reduces heartrate(M,),causes (M,), bronchoconstriction ga$rointestinal increases (M,)andgastric motility (M,), acidsecretion constricts thepupils ofthe eye(M,), increases (M,),and secretions produces skeletal muscle (Nr)and contraction po$ganglionic nerve (N,'). stimulation

B. Choline esters(e.g.,acerylcholine,bethanechol,carbachol) 1. Mechanism of action. Choline estersact by direct activation of cholinergic receptors. 2. Pharmacologic properties, using ACh as the prototype a. Cardiovasculareffects include vasodilation (through endothelium-derived relaxing factor,EDRF; EDRF is nitric oxide) and a decreasein heart rate and force of cardiac contraction. b. Smooth muscleeffectsinclude an increasein gastrointestinaltone and motility, bronchoconstriction, contraction of the ureter and bladder, uterine contraction (only slight in humans), miosis, and accommodationfor near vision. c. Increasein secretionsinclude salivation,lacrimation,sweating,gastrointestinalsecretions, and bronchiolar secretions.

Note Muscarinic receptors onblood vessels arenotinnervated. So, administration of a muscarinic antagonist hasnoeffect on vasculature; a muscarinic agonistcauses vasodilatation viaEDRF.

d. There is alsostimulation of the motor end plate at the neuromuscularjunction.

591

Nervous System

Thble V-3 I -3. Autonomic physiology. Effector organs

Adrenergic stimulation

Arterioles Abdominalviscera,pulmonary, Constriction(o), dilatation(Fr) renal Skeletalmuscle

Constriction (s), dilatation (Fr)

Endothelium

N/A

Veins Heart Sinoatrial (SA) node Atria Atrioventricular (AV) node Ventricles

Constriction (cr,), dilatation (Fr)

Bronchialsmoothmuscle Intestine Tone and motility Bladder Detrusor muscle Sphincter (internal) Male genital function

Uterus Nonpregnant Pregnant Eyes Ciliary muscle Pupillary constrictor muscle Radial dilator muscle Metabolic function Liver Liver Adipose Kidney

Cholinergic stimulation Slight dilatation Contraction (muscarinic,M), if endothelium is stripped away Releasesendothelial relaxation factor (EDRF) [Mr],leading to vasodilatation N/A

Increasedheart rate (Fr) Increasedconduction and contractility (8,) Increasedconduction and automaticity (8,) Increasedcontractiliry automaticiry and conduction (F,)

Decreasedheart rate (Mr) Decreasedcontractility (Mr) Decreasedconduction (Mr) N/A

Relaxation(Br)

Contraction (Mr)

Decrease(cr,,c[r, 9,, Fr)

Increase(Mr)

Slight relaxation (Fr) Contraction (cr,) Ejaculation (cr,)

Contraction (Mr) Erection (M)

Relaxation(Br) Contraction (cr,), relaxation (Br)

N/A N/A

Relaxation for far vision (Fr) N/A Contraction (mydriasis) (cr,)

Contraction for near vision (Mr) Contraction (miosis) (Mr) N/A

(cr/Fr) Gluconeogenesis (crlBr) Glycogenolysis Lipolysis(Br) (F,) Reninrelease

N/A N/A N/A N/A

3. Specific agents a. ACh acts at both muscarinic and nicotinic receptors. When given parenterally, its effects are too widespread, and it is too rapidly metabolized by acetyl and plasma cholinesterases(ChEs) to be an effective therapeutic agent.ACh is available topically as a short-acting miotic. b. Bethanechol actsprimarily on muscarinic receptorswith some seleaivity for those in the gastrointestinaltract and urinarybladder.It doesnot readily crossthe blood-brain barrier. (1) Indications for use include nonobstructive atony of the bladder and atonic bowel or gastrointestinal distention with no obstruction.

592

Pharmacology: DrugsAffectingtheANS

ThbleV-3l-4. Comparison of properties of choline esters. Muscarinic Effects

Nicotinic Effects

Crosses into CNS

Acetylcholine Yes Bethanechol No

Yes Yes*

Yes No

No No

Carbachol

Yes

Yes

No

Susceptibility to AChE

No

Use Miotic Atony of ileus/ bladder Miotic

*Mainly in gastrointestinaltract and urinary bladder Definitions: AChE = acerylcholinesterase; CNS = central nervous system

(2) Side effects may include overactivity at other muscarinic receptors,including gastrointestinaldistress,sweating,bronchoconstriction, salivation, and cardiovasculardepression. 4. Contraindications to the useof muscarinicagonistsinclude peptic ulcers,bronchial asthma, and hyperthyroidism. C. Cholinomimetic alkaloids (muscarineand pilocarpine) 1. Muscarine is a natural alkaloid derived from a variety of speciesof wild mushrooms (Amanita muscaria,Inocybe, Clitocybe).Itactsby selectivelystimulating muscarinicreceptors. Symptoms of intoxication result from overstimulation of the parasympatheticsystem. Treatmentis with atropine, a muscarinic antagonist. 2. Pilocarpine is a natural alkaloid from a South American shrub. It is a muscarinic agonist. It is used topically in the eyesfor narrow angle and open angle glaucoma to increasethe outflow of aqueoushumor, and thus to reduceintraocular pressure.It is alsousedto treat xerostomiaby inducing salivation.Adversereactionsinclude spasmof accommodation, nausea,abdominal pain, sweating,and, at high doses,bradycardia. D. Autonomic ganglionic agonists: nicotine and lobeline 1. Mechanism of action. Nicotine binds to the cxsubunit of nicotinic receptors,producing an increasein sodium influx. Prolongedactivation leadsto blockade of effectorresponse (known as"depolarizingblock"). 2. Pharmacokinetics. Nicotine is highly lipid soluble and is well absorbedfrom the gastrointestinal tract, skin, and lungs. Eighty to ninety percent is inactivated in the liver. Metabolitesare excretedin the milk of nursing mothers who smoke. 3. Pharmacologic properties. Autonomic effectsare unpredictablesinceboth sympathetic and parasympatheticganglia are stimulated; also,following initial stimulation, nicotinic receptorsbecomedesensitized. a. CNS effects include (with increasing doses) irritabiliry tremors, and convulsions. Initial tachypneacan be followed by respiratory collapse.Nauseaand vomiting can occur by stimulation of the chemoreceptortrigger zone.

In a Nubhell Adverse reactions of muscarinic agonists include spasm of accomodation, gastrointestinal upset, g,bronchoconstriction, sweatin andbradycardia.

Clinical Correlate Pilocarpine, whichisspecific formuscarinic receptors, is usedinthetreatment of glaucoma andxerostomia.

Note Nicotinic first agonists stimulate, thendesensitize nicotinic receptors, resulting in depolarization block.

b. Cardiovasculareffectsat low dosesinclude an increasein heart rate, cardiac output, total peripheral resistance,and blood pressure. c. Gastrointestinal effects include an increase in motility, nausea, vomiting, and increasedacid secretion. d. Glandular effectsinclude an increasein secretions.Nicotine causesthe releaseof catecholaminesfrom the adrenalmedulla.

59r

Nervous System

4. Indications for use. Nicotine is availableby gum and as a transdermal patch to help individuals stop smoking by reducing withdrawal symptoms.Lobeline, a lesspotent analog, is availablein tablet form as a nicotine substitute. 5. Side effects and toxicity a. Acute poisoning includes nausea,vomiting, abdominal pain, diarrhea, headache,confusion, impaired vision and hearing, palpitations, cardiovascularcollapse,and seizures. b. Chronic toxicity with the use of tobacco includes toleranceand addiction. Nicotine may exacerbatepeptic ulceration,hypertension,and cardiacarrhythmias.Smoking is associatedwith respiratory and cardiovasculardiseaseand cancer. E. Cholinesterase inhibitors 1. Classification.The cholinesterase inhibitors are subdividedinto three major classes(with prototfpe drugs listed). a. Alcohol (e.g.,edrophonium) b. Carbamates(e.g.,physostigmine,neostigmine,pyridostigmine,demarcarium,carbaril)

ln a Nutshell AChE lnhibitors . Short-acting: inhibitor competitive (e.g., edrophonium) . Intermediate-acting: carbamylating inhibitors (e.g., physostigmine, pyrido$igmine) neostigmine, . Long-acting: phosphorylating inhibitors (DFP, echothiophate, parathion) malathion,

c. Organophosphates(e.g.,DFR echothiophate,malathion, parathion, soman) 2. Mechanism of action. All of these agents act by binding to the active site of the cholinesterases, thus inhibiting the metabolism of acetylcholine. a. Edrophonium is a competitiveinhibitor of acerylcholinesterase.It alsostimulatesnicotinic receptorsat the neuromuscularjunction. It hasa short duration action of 5-15 minutes. b. Carbamateestersinhibit AChE by carbamylatingit. This bond is more resistantto hydrolysis than acetylated enzymes (as produced by ACh). Pyridostigmine and neostigmineare alsoweak agonistsat cholinergic receptors.The duration of action is 0.5-6 hours. c. Organophosphatesbind to cholinesterase, which producesa phosphorylatedenzyme that is very stable and which hydrolyzes at a very slow rate. Phosphorylated enzyme undergoes"aging" in which one of the oxygen-phosphorousbonds breaks,further strengtheningthe phosphorylated enzymecomplex. Once aging occurs,inhibition is irreversible. 3. Pharmacologic properties. The effectsof thesedrugs are due primarily to a buildup of acetylcholinein cholinergic synapses,causing enhancedstimulation of muscarinic and nicotinic receptors. 4. Indications for use (with prototfpe drugs) a. Postoperativeparalytic ileus and neurogenicbladder are treatedwith neostigmine.

ClinicalCorrelate inhibitors Cholinesterase are usedto diagnose andtreat gravis, myasthenia an autoimmune disorder in whichantibodies target the nicotinic AChreceptors in the junction. neuromuscular

594

b. Physostigmine (alone or in combination with pilocarpine) and echothiophate are used to treat glaucoma. c. Pyridostigmine and neostigmine are used for chronic therapy in myastheniagravis (these drugs may be combined with muscarinic blockers to reduce side effects). Edrophonium is used to diagnosemyastheniagravis. d. Cholinesteraseinhibitors (neostigmine,pyridostigmine) are usedby anesthesiologists to terminate the action of curare-likedrugs used during surgery. e. Physostigminehas been used to treat overdoseof drugs with antimuscarinicproperties (e.g.,atropine, tricyclic antidepressants).

Pharmacology: DrugsAffectingtheANS

f. There has been limited successin the treatment of Alzheimer diseasewith physostigmine. Thcrine is available for the treatment of cognitive deficits associatedwith the disease.It is a noncompetitive, reversibleAChE inhibitor and partial agonist at musinhibitor carinic receptors. Donepezil is another recently approved acerylchonisterase used for Alzheimer disease. g. Somecarbamates(e.g.,carbaryl) and organophosphates(e.g.,malathion, parathion) are used asagricultural insecticides. 5. Side effects and toxicity a. Toxicitiesof cholinesteraseinhibitors include peripheral and central muscarinic and nicotinic manifestations.Symptoms may occur accidentallydue to drug overdoseor exposure to agricultural insecticides. Some organophosphate compounds (e.9., soman, tabun) were specifically designed for use as chemical warfare agents due to their extremely rapid "aging" to the enryrr'e.

Note gases Manynerve are choli nesterase inhibitors.

( 1) Muscarinic effectsinclude bronchoconstriction,miosis,excessive secretions(i.e., lacrimation, salivation,sweating),diarrhea,urinary incontinence,vasodilatation, and bradycardia. (2) Nicotinic manifestations include tremors, skeletal muscle fasciculations,and depolarization blockade of skeletalmuscle, including the diaphragm. (3) CNS stimulation includes convulsions followed by respiratory and cardiovascular collapse. b. Treatment of cholinesteraseinhibitor-induced toxicity includes the following: ( 1) Orygen is given by mechanicalrespirator,if necessary, to combat the respiratory paralysis. (2) Atropine is given to block the muscarinic effectsof excessiveACh. (3) Pralidoxime (2-PAM), a cholinesterasereactivator,has high affinity for the phosphorus and binds to the organophosphate,thus freeingthe enzyme.This is effective only before aging has ocurred.

ClinicalCorrelate Agents used in acetylcholinesterase inhibitor overdose: . Atropine . Pralidoxine (2-PAM)

(4) Diazepam (or another benzodiazepine) is given, if necessary,to control seizure activitv.

NERG ICANTAGON ISTS CHOTI A. Classification. For therapeutic purposes,cholinergic antagonistsare divided into two major categories. 1. Muscarinic receptor blockers (e.g.,antimuscarinics, anticholinergics) 2. Nicotinic receptor blockers (e.g.,ganglionic blocking drugs, neuromuscular blockers) B. Muscarinic receptor blockers are also known as antimuscarinics, anticholinergics, parasympatholytics, and atropine-like agents. The drugs include the natural alkaloids atropine and scopolamine,and the semisyntheticand synthetic analogshomatropine, benztropine, and ipratropium, propantheline, diryclomine, tropicamide, trihexpyhenidyl, and glycopyrrolate.

595

NervousSystem

Note Atropine andrelated agents withAChforthe compete muscarinic receptor. Their blockade issurmountable.

Note Current antimuscarinic drugs arenonselective fortheM,-M, subtypes. Thequaternary amines cross lipidbilayers poorly andtherefore tendto actlocally. Forthisreason, (aquaternary ipratropium amine) isusedasaninhalant to dilate thebronchi

1. Mechanism of action. All the agents are competitive, reversible antagonists of ACh at muscarinic receptors.As previously mentioned, there are various subtypesof muscarinic receptors.Current therapeutic agents are relatively nonselective.Dicyclomine and triheryphenidyl have some selectivityfor M, receptorsin binding studies.Pirenzepineand telenzepineare M, selectiveantagoniststhat are not yet availableon the market. 2. Pharmacokinetics.Atropine is a tertiary amine that crossesthe blood-brain barrier. It has a duration of action of 4-8 hours. When used topically,ocular effectsmay last 3 or more days.Shorter-actingantimuscarinics(e.g.,tropicamide) are preferred for eye examination. Quaternary compounds, such as those used for gastrointestinaleffects,have minimal CNS properties. 3. Pharmacologrcproperties.The peripheraleffectsof theseagentsaredue to blockadeof muscarinic receptorsin the ANS. a. Reduction in salivation,lacrimation,bronchial secretions,sweating,and gastrointestinal secretionsoccur. b. Pupillary dilatation (mydriasis)and rycloplegiaoccur. c. Relaxationof bronchial smooth musclecausesbronchodilatation. d. There is an initial reduction in heart rate, followed quickly by a more prolonged increasein heart rate. e. There is decreasedgastrointestinalmotility, resulting in constipation. f. There is relaxation of the bladder wall, resulting in urinary retention.

In a Nutshell Antimuscarinic effects include: . Decreased secretions . Mydriasis andcycloplegia . Bronchodilatation . Tachycardia . Decreased Cl motilitv . Urinary retention . Amnesia anddelirium

g. Nonquaternary antimuscarinic agentsare used in the treatment of Parkinson disease and motion sicknessand may causesedation,amnesia,and delirium. h. There is blockadeof the effect of muscarinic agonists. 4. Indications for use.Muscarinic receptorantagonistshavemany important therapeuticuses. a. Atropine, homatropine, and tropicamide are usedto produce mydriasisand rycloplegia. b. Ipratropium is usedto dilate the bronchi, and atropineis usedasa preanestheticto prevent bronchospasm and laryngospasm.These agents are, therefore, usefi.rl with bronchial asthmaand chronic obstructivepulmonary disease(COPD). c. Diryclomine and glycopyrrolateare usedto treat diarrhea,gastrointestinalspasm,and as adjuncts in ulcer therapy. d. Dicyclomine and glycopyrrolateare used to relievethe symptoms of transient rystitis and bladderspasms. e. Benztropine,bipericien,and triheryphenidyl are used to reducethe relative excessof cholinergic activity and are,therefore,useful in Parkinson disease. f. Scopolamineis used to prevent motion sickness. g. This group of drugs is alsousedin the treatment of bradycardiaand acutemyocardial infarction in patients with excessivevagal activify. h. Muscarinic receptor antagonists are also used in the treatment of toxicities of cholinesteraseinhibitors. 5. Side effects and toxicity. Signs of toxicity of antimuscarinic drugs include dry mouth, dry eyes,mydriasis,tachycardia,hot and flushed skin (due to cutaneousvasodilatation), elevated body temperature (atropine-fevet due to inhibition of thermoregulatory sweating),constipation,urinary retention, and blurred vision.

596

Pharmacology: DrugsAffectingthe ANS

a. Elderly patients are susceptibleto drug-induced glaucomaand urinary retention. b. Infants and young children are susceptibleto hyperthermia. c. CNS toxicity includes sedation,agitation, amnesia,and delirium. d. Contraindications include patients with glaucoma and elderly men with prostatic hypertrophy. e. Tieatment of overdoseis symptomatic and includestemperaturecontrol with a cooling blanket, seizurecontrol with diazep?fl, and possibleuse of physostigmine. C. Nicotinic receptor blockers are divided into ganglionic blockersand neuromuscularblockers. 1. Ganglionic blockers are mostly of historic interest. They were originally used in treatment of hypertension, but have been replaced by more effective, less toxic drugs. Tiimethaphan is still used intravenouslyin the treatment of hpertensive emergencyand for controlled hypotensionduring surgery. a. Specific agents (1) Hexamethonium, the prototype for this group, is a quaternary ammonium compound that selectivelyblocks nicotinic receptorsat ganglia,not at the neuromuscular junction.

In a Nutshell Nicotinic receptor subtypes

(N.,) Skeletal Canglia (Nr) muscle

(2) Trimethaphan is a competitivenicotinic (N*) receptorblocker. (3) Mecamylamine is anotherexampleof a ganglionicblocker.

Clinical Correlate

b. Pharmacologic properties. Effects at organ systemsinclude the following: (1) Mydriasis and cycloplegia (2) Decreasein arteriolar and venomotor tone, causinghypotension and moderate tachycardia (3) Reducedgastrointestinalmotility and secretions (4) Urinary hesitancyand impaired erection (5) Reduction in sweating,salivation,and lacrimation 2. Neuromuscular blocking drugs are used to produce muscle paralysis in patients during surgery and mechanical respiration. The drugs are subdivided into nondepolarizing and depolarizingblockers. a. Nondepolarizing neuromuscular blockers (e.g., tubocurarine) compete with acetylcholine for the nicotinic receptor site (NM), thus blocking the effect of acetylcholine. Becausetheir effectis surmountable,increasingthe concentrationof ACh at the receptor site by administration of an AChE inhibitor reversesthe action of these drugs (Table

v_31_s). b. Depolarizrngneuromuscular blockers (e.g.,succinylcholine)bind to nicotinic receptors, causingan initial depolarizationthat may lead to fasciculations.Failure to repoIarizeleadsto musclerelaxationand paralysisin which the membraneis unresponsive. PhaseI block is characterizedby continuous depolarization.This proceedsto a phase II (desensitization)block and muscle paralysis.Succinylcholine-inducedblock is not overcome by AChE inhibitors; in fact, they enhance its efflect.Succinylcholineis

Trimethaphan istheonly ganglionic competitive nicotinic receptor antagonist lt isused usedtherapeutically. to treatacutesevere hypertensive andfor crises in controlled hypotension sur8ery.

ln a Nutshell . Nondepolarizing neuromuscular blockers are competitive inhibitors of (N")receptors. nicotinic . Depolarizing neuromuscular blockers (N") stimulate thenicotinic prolonged receptors, but inactivates depolarization andleads these receptors block. to depolarization

hydrolyzedby plasma cholinesterases.

597

Neryous System

Table V-3 f -5. Characteristics of neuromuscular blockers.

Drug

Duration (min)

Effect on Ganglia

Effect on Heart (M, Muscarinic Receptor)

Nondepolarizing agents Tubocurarine Atracurium Mivacurium Pancuronium Vecuronium

100 30 15 150 30

Blockade None None None None

None None None Blockade None

Depolarizing agent Succinylcholine

7

Stimulation Stimulation

Stimulation of Histamine Release (M, Muscarinic Receptor)

Yes Small Small None None

Small

In a Nutshell c. Side effects and toxicity

Acetylcholinesterase inhibitors reverse theeffeGof nondepolarizing blockers, butenhance theeffects of depolarizing blockers.

Clinical Correlate Thecombination of succinylcholine andgeneral anesthetics maycause malignant hyperthermia; treatwithdantrolene.

(1) Adverse reactions include respiratory depression and prolonged apnea, histamine release,hypotension,bronchospasm,disturbancein cardiacrhythm, and hyperkalemia (succinylcholine). (2) Succinylcholine,given along with halothane, may produce malignant hlperthermia (treatedwith dantrolene). D. Other cholinergic blockers 1. Hemicholinium blocks the activetransport of choline into the cholinergicnerveterminal, thus reducing the synthesisof acetylcholine.It is currently used as a laboratory tool. 2. Clostridium botulinum neurotoxin blocks the releaseof ACh. It is best known for its potential to causerespiratory paralysisand death following accidental ingestion as a food contaminant.

ADREN ERG rCAGON rSTS(SYMPATH OMIMET|CAGENTS) A. Mechanism of action. Adrenergic agonists can be classified as direct acting or indirect acting. Direct-acting agonists, including the endogenous catecholamines,bind directly to adrenergic (or dopaminergic) receptors. Indirect-acting agents derive their sympathomimetic effects by acting presynaptically to stimulate release of endogenous catecholamines,or by blocking the reuptake of catecholaminesinto the presynaptic nerve terminal. There are some agents that exert their effects by a combination of direct and indirect mechanisms.FigureV-31-3 lists the drugs accordingto their specificmechanismof action. B. Pharmacokinetics. The endogenous catecholamines-norepinephrine, epinephrine, and dopamine-are rapidly metabolized by COMT and MAO. Thesecompounds are ineffective orally and have a short duration of action following parenteral administration. Agents like amphetamine are orally effective.Many are not catecholaminesand are resistant to MAO, COMT, or both.

598

Pharmacology: DrugsAffectingtheANS

C. Pharmacologic properties are summarizedin the insert in FigureV-31-3 and ThbleV-31-6. 1. Cardiovascular effects a. Constriction of blood vesselsin the skin and spleenby stimulation of o,-adrenoceptors increasesthe total peripheral resistanceand may causereflex bradycardia. b. Stimulation of central clr-adrenoceptors(by clonidine) reducessympatheticoutflow and reducesblood pressure. c. Direct stimulation of the heart through B,-adrenoceptorsproducesan increasein rate and force of contraction. d. Vasodilatationis due to stimulation of Br-adrenoceptors,which reducesperipheral resistanceand blood pressure. e. Dilation of renal and splanchnicvasculatureis causedby stimulation of D,-dopaminergic receptors. f. Becauseof cardiovascularreflexes,drugs that increasetotal peripheral resistance(TPR) causereflex bradycardia,and drugs that reduceTPR leadto reflex tachycardia.Thus, the net effect on heart rate and blood pressureis due to both direct and indirect efifects.

In a Nutshell . 0tr Constricts many bloodvessels . a2'.Decreases sympathetic outflow . 0,r Increases heartrate; increases forceof contraction ' 9r: Dilates skeletal muscle vasculature; bronchodilatation

2. Relaxationof bronchial smooth muscleis causedby stimulation of Br-adrenoceptors. 3. Alpha agonistsproduce mydriasis. 4. Gastrointestinalmotility and tone are reducedby stimulation of o- and p-adrenoceptors. 5. pr-agonistsrelax the uterus (usefrrlto treat premature labor). 6. o-agonistsincreasesphincter tone of the bladder,and Br-stimulation relaxesbladder wall smooth muscle. 7. Norepinephrine and other catecholaminesdo not cross the blood-brain barrier. Amphetamine and sympathomimetic agentsthat enter the CNS have stimulatory effects. Theseinclude reducedfatigue,insomnia, decreasedappetite,and anxiety. D. Indications for use l. Alpha,-agonists (e.g., phenylephrine) are used for their vasoconstrictingproperties to produce vasoconstrictionfor local hemostasis,to increasethe duration of action of local anestheticsat the injection site, to maintain blood pressurein spinal shock, to produce nasaland ophthalmic decongestion,and to produce mydriasis. 2. Nphar-agonists (e.g.,clonidine) are used in treatment of hypertensionto reducecentral sympathetic outflow. 3. Beta,-agonists(e.g.,dobutamine) are usedto increasecardiacoutput and maintain blood flow to the tissuesin shock.

599

Neruous System

Indirect acting Tyramine Amphetamine lncreaserelease *Ephedrine of norepinephrine *Metaraminol Cocaine(blocks

Nonspecific Norepinephrine(o1= o2;

Fr'> 0z) (or = crz= Fr= Fz) Epinephrine

>> o) Dopamine(Dt = D2 > *Ephedrine(at = uz = Fr = Fr 0z)

9z Terbutaline Albuterol Metaproterenol Ritodrine

Adrenergic Receptors (major effects) cr,1Vasoconstriction,increasesblood pressure,stimulatesglycogenolysis,and mydriasis stimulatesplateletaggregation, cr2 Decreasesnorepinephrinerelease(presynaptic), vasoconstriction, inhibitslipolysis,and inhibitsinsulinsecretion 9r Increasesheart rate and force of contraction,stimulatesrenin release p2 Vasodilatation, relaxationof uterinesmoothmuscle,increased bronchodilatation, glucagon,and increasedglycogenolysis p3 Stimulateslipolysis D1 Relaxationof renaland splanchnicvasculature * Have both direct and indirecteffects

Figure V-31-3. Adrenergic agonists.

In a Nutshell . cr,-Agonists areoftenused aslocalvasoconstrictors. . q-Agoni$s areusedto lower bloodpressure. . p,-Agonists areusedto increase cardiac output. . B,-Agonists areusedfor broncochodilatation and uterine relaxation . Indirect acting agents are usedfornarcolepsy. . Ephedrine isusedasa bronchodilator.

600

4. Betar-agonists(e.g.,terbutaline) are used to produce bronchodilatation in patients with bronchial asthmaand (e.g.,ritodrine) to relax uterine smooth musclein pregnantwomen near term. 5. Indirect-actingagents (e.g.,amphetamineand analogs)are usedin narcolepsy,attentiondeficit disordet and in diet therapy to suppressappetite (amphetamineis no longer used for this). 6. Mixed-acting drugs (ephedrine) are used for vasoconstrictionand bronchodilation.

ADREN ERGIC ANTAGON ISTS(SYMPATHOTYTICS) A. Mechanism of action. Adrenergicantagonistscan be classifiedbasedon their mechanismof action: ct-adrenoceptorantagonists,B-adrenoceptorantagonists,and adrenergic neuron blockers,as describedin FigureV-31-4 and TableV-3I-7. B. Alpha-adrenergic receptor antagonists are subdivided based on their selectivity and reversibility. 1. Nonselective, irreversible (long-acthg) agents. Phenoxybenzamine irreversibly blocks o,- and or-adrenergicreceptorsby forming a covalentbond with the receptor.

Pharmacology: DrugsAffectingthe ANS

Table V-3f -6. Selectedproperties of adrenergic agonists.

Drug

Pharmacolog. Properties

ClinicalUses

Toxicity

Ineffective orally; does not enter CNS; usually given intravenously; and inactivated by COMT and MAO

Hemodynamic shock (not drug of choice)

Ischemiaand necrosis at injection site may causehlpertension in patient with hyperthyroidism

Epinephrine

Ineffective orally and does not enter CNS

Bronchial asthma,allergic anaphylaxis,cardiac arrest;to produce hemostasis;and to enhancelocal anesthetics

Anxiety,tremot irritabiliry headache, dizziness,tachycardia, hypertension,angina, and palpitations

Dopamine

Does not enter CNS

Shock;oligouria due to decreasedrenal bloodflow; to increaserenal bloodflow (low doses);to increasemyocardial contractility and heart rate (moderatedoses);to increase systemicblood pressure,heart rate,and forced contraction; and to reducerenal bloodflow (high doses)

Decreasedrenal perfusion,ischemia, local necrosis,tachycardia,angina,and hypertension

Nasaldecongestant, hlpotension mydriatic; to prolong local anesthetic; and to terminate PATs

Hlpertension, headache, and tissuenecrosis

Endogenous catecholamines Norepinephrine

o-Adrenergic agonists Phenylephrine(o,) Increasesblood pressureand TPR, reflex bradycardia,and resistantto COMT Methoxamine (4,)

Vasoconstriction and reflex bradycardia

Hypotension (especiallyduring Similar to phenylephrine anesthesia);and to terminate PAIs

Clonidine (ar)

Hypotension,sedation,reduced sympathetic oudow; rapidly entersbrain; and is administered orally and transdermally

Hypertension,opiatewithdrawal, andbenzodiazepinewithdrawal

p-Adrenergic agonists Isoproterenol(B,, B2) Increasesheart rate and contractiliry relaxesbronchial and gastrointestinalsmooth muscle, and is administered intravenourly ot inhaled. Metabolized by COMT, metabolized poorly by MAO.

Sedation,dry mouth, orthostatichpoten-

ffi'i.'#1"*'tunction' Bronchial asthmaand bradycardia Thchycardia,palpitations, headache, anginalpain, and cardiac arrhythmias

Dsfnitiorri CNS : c€ntra.l nervous syst€m; COMT = cat€chol O-methyltra$ferasej PATS= parcxtsmal atdal tachycardias.

MAO = monoamin€ onda!€; TPR = total peripheral resistancei and

(Continued)

601

Neruous System

Note Phenoxybenzamine isanirreversible used cr-antagonist inthetreatment of pheochromocytoma.

a. Pharmacologic effects. Catecholamine-inducedvasoconstriction is blocked, thus decreasingblood pressure.Phenorybenzamineproducestachycardiaby two mechanisms: through cardiovascularreflex, and by inhibiting negativefeedbackby blocking presynapticautoregulatorycrr-receptors,thus stimulating norepinephrine release. b. Indications for use include pheochromocFtoma, hlpertensive crises secondary to adrenergicagonist or MAO inhibitor overdose,in presurgicalmanagement,autonomic hyperreflexia,and prophylaxis of Raynaudphenomenon.

ThbleV-3f -6. Selectedproperties of adrenergic agonists (cont'd).

Drug

Pharmacologic properties

Clinical uses

Toxicity

Dobutamine (B,)

Positiveinotropy but less increasein heart rate

CHF; promotes increased output with little change in myocardial orygen demand

Thchyarrhythmias angina,hypertensln

Metaproterenol (M), (Fr), terbutaline(T), albuterol (A), and ritodrine (R)

Active orally and inhalation; resistantto COMT

Bronchospasm/asthma (M, T, A); delaysdelivery in premature labor (T and R)

Nauseaand vomiting, tachycardia,palpitations, hypertension, and tremors

Stimulatesreleaseof norepinephrine,dopamine, and serotonin increasesblood pressure, reflexly decreases heart rate, readily entersCNS, D-isomer has greaterCNS effects

Narcolepsyand appetite suppression(short-term)

Restlessness, dizziness, insomnia, impotence, headache,tremor delirium, paranoia, cardiacarrhythmias, hypertensivecrises, and arrhythmias (with MAO inhibitors)

Indirect-acting adrenergic agonists Amphetamine

Tyramine

Mixed-acting adrenergic agonists Ephedrine

Metaraminol

Presentin red wines,beer,cheese, None and chocolate;stimulatesrelease of norepinephrine and dopamine

In combination with MAO inhibitors, it can lead to a sympathetic crisis,which is potentially fatal.

Stimulatesreleaseof norepinephrine and dopamine; some direct receptor stimulation; stimulatesCNS; resistantto COMT and MAO

Bronchospasm/asthma, hypotension

Hypertension,insomnia, and tachyphylaxis

Stimulatesnorepinephrine release;cr-agonist;increases blood pressure;reflexly decreasesheart rate; doesnot enter CNS

Hypotension and associated PATs

Similar to norepinephrine

Definitions:CNS : central neryous system;COMT = catecholO-methyl-transferase;MAO = monoamine oxidase;TPR = total peripheral resistance; and PATs= paroxysmal atrial tachycardias.

602

Pharmacology: DrugsAffectingthe ANS

c. Side efifectsand toxicity. Adverse reactions include sedation, orthostatic hypotension, tachycardia,nasalcongestion,nausea,abdominal pain, and inhibition of ejaculation. 2. Nonselective reversible (short-acting) agents. Phentolamine competitively and reversiblyblocks cr,- and crr-adrenergicreceptors.Phentolamineis shorter acting than phenoxybenzamine.

Adrenergic neuron blockers Reserpine I Decrease GuanethidineJ norepinephrine release Nonspecific Phenoxybenzamine Phentolamine

Selective crr blockers Prazosin Terazosin Doxazosin

Selective az blockers Y o h i mb i n e ldazoxan

Selective Br blockers Acebutolol Atenolol Metoprolol Esmolol

Figure V-31-4. Adrenergic blockers. Table V-31-7. Comparison of B-adrenergic receptor antagonists.

Drug

Receptors blocked

Sympathomimetic activity

Local anesthetic activity

Therapeutic uses

Acebutolol Atenolol

F, F,

-r

+

Arrhythmias

None

None

Hypertension and angina pectoris

Esmolol Labetalol Metoprolol

p,

None

Arrhythmias

cr,,B,,B, I,

None

None + +

Nadolol

F,,F,

None

None

Hypertension and angina pectoris

Pindolol

F,,9,

+

-1-

Hypertension

Propranolol F,,F,

None

+

Hypertension,angina pectoris, and arrhythmias after myocardial infarction

Timolol

None

None

Hypertension, arrhythmias after myocardial infarction, and glaucoma

0,,9,

f

Hlpertension Hypertension,angina pectoris,and arrhythmias after myocardial infarction

605

NeruousSystem

Note Phentolamine isa reversible nonselective ntagonist cr-a usedinthetreatment of pheochromocytoma. ClinicalCorrelate (e.g., Selective cr,-antagonists prazosin) areusedinthe treatment of hypertension withminimal increase in heart rate. Terazosin isalsousedfor prostatic benign hyperplasia.

a. Indications for use include hypertensive crises associatedwith pheochromocFtoma and prevention of dermal necrosisfollowing extravasationof an o-adrenergicagonist. b. Side effects and toxicity. Adverse reactions include tachycardia,arrhythmias, angina, orthostatic hypotension, gastrointestinalstimulation (aggravatespeptic ulceration), nausea,vomiting, abdominal pain, and diarrhea. 3. Selectivecr,-antagonists.Prazosin,terazosin,and doxazosinare competitive, reversible blockersof cx,-adrenoceptors. a. Pharmacologic properties include vasodilatation in both arterial and venous beds, thus reducing both afterload and preload. The major advantageover nonselectivecrblockers is that they produce less tachycardiaand renin releasedue to lack of crrpresynapticreceptorblockade.Sometolerancedevelopswith chronic use. b. Indications for use include hypertension, congestiveheart failure (CHF), Raynaud phenomenon,and preventionof urinary retention in men with prostaticenlargement. c. Side effectsand toxicity. Adversereactionsinclude a "first-dose effect" (marked postural hypotension 30-90 minutes following the initial dose,which may lead to fainting), palpitations,dizziness,headache,and nasalcongestion. 4. Selective cr2-antagonists.Yohimbine and idazoxan are used primarily in research.They increasethe releaseof norepinephrine. C. Beta-adrenergrcreceptor antagonists (ThbleY-3I-7; FigureV-31-4).

Note names endin B-blocker "olol."Notethatlabetalol is alsoancr,-blocker.

1. Classification. Beta-adrenergicreceptor antagonistsare classifiedaccordingto three properties(TableY-31-7;FigureV-31-4). a. Selectivity. Some of the B-antagonists(e.g., propranolol) act on both B,- and Brreceptors.Other antagonists(e.g.,atenolol, metoprolol) are selectiveB,-antagonists. This selectivityhas two advantages:to treat patients who also havebronchial asthma (no blockade of B, in bronchial smooth muscle) and to prevent peripheral vasoconstriction (no blockade of B, in vasculature).Labetalolis a nonselectiveB-blocker,but it alsoblocks cr,-receptors,thereforehaving lesseffect on the vasculature. b. Intrinsic sympathomimetic activity. Pindolol and acebuodol,besidesblocking Breceptors,havepartial agonistactivity.They causelessslowing of the heart, lessbronchoconstriction,and lessalteration of serum lipids than other B-blockers.

ClinicalCorrelate Therapeutic Useof B-Blockers . Treatment ofglaucoma . Treatment of hypertension . Treatment ofarrhythmias . Reduction ofpostMl mortality . Migraine prophylaxis . Stage phobias fright/social

604

c. Local anesthetic activity (membrane-stabilizingactivity). This property is useful in the treatment of cardiac arrhythmias and is partially responsiblefor their effectiveness.It is a disadvantagewhen used topically in the eye. 2. Pharmacokinetics. The B-adrenergicblockersvary in their bioavailability,lipid solubility, and duration of action. Propranolol has low bioavailability due to first-pass metabolism.It is also lipid soluble,producing CNS effects.Some agents(e.g.,pindolol) havehigher oral bioavailability.Newer drugs (atenolol and nadolol) with lower lipid solubiliry havelessCNS side effects.Nadolol is the longest acting blocker (half-life up to 24 hours), while esmolol has a half-life of only 10 minutes. 3. Indications for use a. Aqueoushumor formation in the eyeis reducedin patients with glaucoma. b. Cardiac output and renin secretionare reducedin patientswith hypertension. c. Atrioventricular (AV) nodal conduction and automaticity of cardiactissuearereducedin patientswith tachyarrhythmias.

Pharmacology: DrugsAffectingtheANS

d. A depressanteffect on the heart reducesoxygen deficit and thus pain in patients with angina pectoris. e. Beta-antagonistsare used prophylacticallyfor migraine headache. f. Their CNS effectsreduce tremor and anxiety. g. This classof drugs is used as adjunctive therapy in hyperthyroidism becauseof their cardiac depressantand antianxiety effects. 4. Side effects and toxicity a. Bradycardia,A-V nodal block, CHF, and exacerbatedperipheral vasculardiseasemay occur. b. Bronchial asthmais exacerbatedin susceptiblepatients. c. Sedation,fatigue,and insomnia may occur. d. Symptoms of hypoglycemia in a diabetic patient (tachycardia, anxiety, and tremor) may be masked. D. Adrenergic neuron blockers are drugs that act presynapticallyto block the storageor release of catecholamines. 1. Reserpineblocks the reuptake of catecholamines(e.g.,norepinephrine, dopamine) and serotonin into the storagevesiclesin adrenergic neurons. This leads to neurotransmitter depletion. It is still available,though it is little used in the treatment of hypertension. In addition to peripheral sympatholytic effects,reserpine produces CNS depressanteffects. 2. Guanethidine enters the presynaptic adrenergic termin"l by the catecholamine uptake process.Once in the nerve,guanethidinedisplacesnorepinephrine from the storagevesicles.The norepinephrine is then metabolized to inactive products by MAO, and thus, the nerve terminal is depleted of neurotransmitter. Guanethidine also prevents the releaseof norepinephrine.The drug works only in peripheral neurons.It doesnot crossthe bloodbrain barrier. Guanethidine is used in patients with severehypertension and has a prolonged action.

ClinicalCorrelate (evenB,AllB-blockers selective be ones) should patients usedwithcarein with (e.9., lungdisease asthma, (blocks COPD) anddiabetes premonitory symptoms of hypoglycemia).

In a Nutshell thenerve Cuanethidine enters terminal bytheNEreuptake NEfrom carrier anddisplaces synaptic vesicles, leading to NEdepletion. lt alsoprevents release of NEintothesynapse. It therefore lowers blood pressure. blockers Uptake (e.g.,tricycl nts) icantidepressa prevent guanethidine's actions.

605

the DrugsAffecting System CentralNervous nervous inthecentral neurotransmission drugs thatactbyaltering There aremanytherapeutic forsurgery setting general (CNS). agents usedin a hospital anesthetic include These drugs system of in the treatment drugs used procedures, agents, antiepileptic sedative-hypnotics, or medical (e.g., psychiatric anxlety, disorders (e.g., parkinsonism), usedin anddrugs motordisorders thereisa better psychosig. hasexpanded, of brainfunction Asknowledge depression, moreeffective of newer, andthedevelopment agents ofthese ofthemechanisms understanding pharmacology of these drugs. basic reviews the Thissection agents.

ANESTHETICS GENERAT Generalanesthesiais a statecharacterizedbydrug-induced perceptualabsenceof all sensation. All generalanestheticsare administeredby inhalation or intravenousinjection and are classified by the route of administration (TableV-32-l). A. Overview 1. Characteristicsof the ideal anestheticagent are listed below. It is important to note that no single anestheticcan achieveall of the characteristicslisted; therefore,a combination of severaldrugs is used to achievethis goal (balancedanesthesia).Drug combinations may include a primary anestheticagent (e.g.,isoflurane) with a preanestheticagent for sedation(e.g.,a benzodiazepine),a rapidly acting agentfor induction (e.9.,nitrous oxide, thiopental), a skeletalmuscle relaxant (e.g., succinylcholine),and an analgesicfor pain (e.g.,morphine). a. Rapid, pleasantinduction and recoveryof anesthesia b. Rapid changesin the depth of anesthesia c. Adequateskeletalmuscle relaxationto perform surgery d. Production of amnesia e. Ability to provide analgesia f. A wide safetymargin g. Nontoxic

607

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Thble V-32-1. General anesthetic agents. InhalationalAnesthetics

IntravenousAnesthetics

Nitrous oxide Halothane Enflurane Isoflurane Desflurane Methoryflurane Sevoflurane

Barbiturates(thiopental) Benzodiazepines(diazepam,midazolam) Ketamine Propofol Etomidate

2 . Depth of anesthesiais directly proportional to the partial pressure(inhalation agents)or the drug concentration (intravenous agents)that is in the CNS. The rates of induction and recovery area function of how quickly the anestheticlevelschange.Factorsthat determine the CNS partial pressureof inhalational agentsinclude: a. Concentration of anesthetic agent in the inspired mixture b. Alveolar ventilation rate (increasing the rate of ventilation increasesthe rate of induction, particularly with high solubility anesthetics)

Note (blood-gas Blood solubility partition coefficient) is proportional inversely to the rateof induction.

In a Nutshell (when Atequilibrium the partial pressures of thegasin differentbodycompa rtments areequal), = Solubility

[Anesthetic]o,ooo [Anesthetic]ru,

c. Solubilig of anesthetic agent in the blood. The lesssoluble an agent is in the blood, the quicker the rise in partial pressureand the more rapid the induction. A soluble agent usesthe blood as a reservoirby dissolvingin the blood and does not reach the brain asrapidly as an insoluble agentbecauseit takeslonger for the partial pressureto rise. The blood-gas partition coefficient reflects the relative solubility of an agent for blood versusair. The lower the blood-gaspartition coefficient,the more insoluble an agentis in blood and, thus, the fasterthe induction of anesthesia. (l) Desflurane:0.42 (2) Nitrous oxide:0.47 (3) Sevoflurane:0.67 (4) Isoflurane:1.4 (5) Enflurane:1.8 (6) Halothane:2.3 (7) Methoxyflurane 12.0 d. Alveolar to blood transfer, which is affected by the ventilation-perfusion ratio e. Loss of anesthetic from arterial blood to tissue, which is a function of the partial pressuregradient,perfusion, and partition coefficient 3 . Stagesof anesthesia.The stagesof anesthesiaprovide signs noted with increasingCNS depression,based on the effects of the classicanesthetic,diethyl ether. Though most newer anestheticsact more rapidly and are combined with other agentsthat may mask these stages,these signs of anestheticdepth are usefirl in understanding the effects of generalanesthetics.

608

DrugsAffectingthe CNS Pharmacology:

a. Stage I (analgesia) starts from the point of induction and lasts until loss of conthere is also a loss of pain sensation. sciousness; b. Stage2 (excitement,disinhibition) startsfrom the end of stage1 to surgicalanesthesia. This stagemay be associatedwith autonomic instabiliry airway irritation, excessivemuscle activity, rapid eyemovement, and vomiting. c. Stage3 (surgical anesthesia)consistsof four planes. (1) Plane I is from the onset of the return to regular breathing until the loss of eye movement.

( ) \ Plane 2 is from the cessationof eye movement until the initiation of intercostal muscleparalysis.

( 3 ) Plane 3 is from the initiation of intercostalmuscleparalysisuntil completion. ( 4 ) Plane 4 starts with complete intercostalparalysisand ends with diaphragmatic paralysis. d. Stage4 (respiratory collapse) lastsfrom diaphragmaticparalysisuntil cardiacarrest. 4 . Elimination of inhalational anesthetics a. Ideally,gaseousanestheticsareentirely eliminated by exhalation.In actuality,th.y may be metabolizedin part by the liver, leading to the formation of toxic metabolites.The less metabolism there is, the safer the anesthetic.The percent of each agent metabolizedis enflurane:2olo;isoflurane: methoxFflurane:70o/o;halothane:l5-20o/o;sevoflurane:2-5o/oi and nitrous oxide:0.004o/o. desflurane:0.02o/o; 0.2a/o; b. The rate of recoveryis partly dependenton the partition coefficient of the gas.The partition coefficient (which is approximately 1 for lean tissue) may be quite high for fat, leading to sequestrationin the fat and delayingrecovery. 1

Potency of inhalational anestheticsis inverselyproportional to the minimum alveolar concentration (MAC), the amount of anestheticneededto induce immobility in 50% of individuals following a noxious stimulus. MAC is dependentonly on the specific agent used.Increasedpotenry correlateswith increasedlipid solubility (or hydrophobic properties). Be awarethat MACs are additive when combining agents.MACs of inhalational anesthetics (from the least potent) are: nitrous oxide: >100o/o;desflurane: 6-70/o; and methoxyflurane:0.l6oio. enflurane:l.7o/o;isoflurane:l.4o/o;halothane:0.75o/o;

6 . Mechanism of action. The exactmechanismof action for the effectsof inhalational general anestheticsis not understood. a. Since the potency of the agent correlatesto the lipid solubility, these agents are thought to disrupt neuronal transmissionby intercalatinginto the lipid bilayer,leading to ion channeldysfunction.Nternation in various receptorfuntion is another possible mechanism. b. Analgesia,producedby someof theseagents,is due to a decreasein the activity of neurons in the substantiagelatinosain the dorsal horn of the spinal cord. c. Other stagesof anesthesiaare due to complex effectson higher brain regions.

Note Atequilibrium, Partition [Anesthetic],'rrr. coefficient [Anesthetic]o,ooo

ln a Nutshell r0lencY *

I MAC

Because theMACfornitrous l00o/0, thisdrug exceeds oxide intothe bringa patient cannot stage when surgical alone. administered ln a Nutshell are anesthetis Ceneral into thought to intercalate cell neuronal andexpand thusdisrupting membranes, transm ission. synaptic

609

Nervous System

B. Inhalational anesthetic agents 1. Halothane a. Pharmacologic properties (1) Halothane is a halogenatedgasand a potent anesthetic.

Note

(2) Cardiovasculareffectsinclude myocardial depressionwith reducedcardiacoutput and reduced renal and splanchnic blood flow. Halothane sensitizesthe myocardium to catecholamines,which can lead to tachyarrhythmias. (3) Respiratorydepressanteffectswith reducedtidal volume are dose-dependent.

produces Halothane cardiovascular depression and sensitizes theheartto the arrythmogenic effects of catecholamines.

(4) Cerebralblood flow increases,leadingto possibleincreasesin intracranial pressure. (5) In skeletalmuscle,halothaneproducesminimal relaxationvia CNS effects,but it increasessensitivityto neuromuscularblockers. (6) In the kidneys, halothane decreasesthe glomerular filtration rate (GFR) and renal blood flow. (7) In the liver, halothane decreasessplanchnicand hepatic blood flow. It can produce postoperativehepatitis. b. Pharmacokinetics. About 80o/oof halothane is eliminated via the lungs in 24 hours; approximately 15-20% is metabolizedby hepatic cytochrome P-450 over 2-3 weeks; bromine, chloride, and trifluoracetic acid appearin the urine as metabolites. c. Indications for use. Halothane is a potent anesthetic.Its use is precluded in neurosurgical casesbecauseit increasesintracranial pressureand in obstetric casesbecauseit inhibits activelabor by relaxing uterine smooth muscle.It is usefrrlfor pediatric surgery.

€linical Correlate

d. Side effects and toxicity

Halothane isassociated with posta nesthesia hepatitis ("halothane hepatitis").

(1) Halothaneis associated with hepatitis,2-5 dayspostanesthesia. It is characterizedby tissue necrosis,abnormal liver function tests,and eosinophilia.This is most often seenafter multiple exposures.Incidenceis low (1:10,000)but it is fatal in approximately50o/oof thesepatients.

In a Nutshell

(2) Malignant hnterthermia occurs with halothane and other halogenatedinhalational anesthetics.It is characterizedby a rapid rise in body temperature with massiveincreasesin oxygen consumption and metabolic acidosis.This is a rare but fatal condition unless it is aggressivelytreated with cooling measuresand dantrolene,which reducescalcium releasefrom the sarcoplasmicreticulum, thus blocking thermogenic skeletalmuscle activity.

Malignant hyperthermia may occur withgaseous anesthetics, especially when usedin conjunction with succinylcholine. lt istreated withdantrolene.

In a Nutshell Enflurane causes less cardiovascular sideeffects thanhalothane, butit can produce seizures.

2. Enflurane a. Pharmacologic properties are similar to but lesspotent than halothane. ( I ) Cardiovasculareffectsinclude dose-dependentmyocardialdepression(lessthan halothane) and lesssensitizationto catecholamines.Therefore,it is lessarrhythmogenic. (2) In the CNS, enflurane has been associatedwith the production of seizuresand elevatedintracranial pressure. (3) Enflurane producesmore respiratory depressionthan halothane. (a) Skeletalmuscle relaxation is greater than with halothane. Enflurane potentiates neuromuscularblockers. (5) In the kidney, enflurane reducesthe GFR and renal blood flow.

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Pharmacology: DrugsAffectingthe CNS

b. Pharmacokinetics. About 80o/oof enflurane is excretedunchanged by the lungs, and 2o/ois metabolized in the liver. c. Indications for use. Enflurane is considereda good general anestheticagent,although it is not administered to patients with seizureconditions or renal dysfunction. d. Side effects and toxicity. Adverse reactions include postoperative hepatitis, seizures, renal toxicity, and malignant hyperthermia. 3 . Isoflurane. Isoflurane is an isomer of enflurane and is, thus, a potent anestheticagent. Pharmacologicproperties are similar to enflurane. a. Pharmacologic properties (1) In the cardiovascularsystem,it producessome myocardial depression,but it is not arrhythmogenic. (2) It producesa dose-dependentrespiratory depressionand respiratory irritation on induction. (3) In the CNS, isoflurane does not produce seizure activity and it decreases intracranial pressure,making this a preferredagentfor neurosurgery. b. Side effects and toxicity. Adverse reactions are similar to but less severethan with halothane;malignant hyperthermia is possible. 4. Desflurane. This is a new agentthat is similar in pharmacologicpropertiesto isoflurane, but it has a more rapid rate of induction. 5 . Methoxyflurane. This agent is not commonly used because of nephrotoxicity. Pharmacologicpropertiesare similar to halothane.Cardiacarrhythmias arelesscommon, but the drug may produce nephrotoxicity from the releaseof fluoride and oxalate. Induction and recovery areslow becauseof its high solubility. 6. Sevoflurane. This is the newest inhaled anesthetic.Induction and recovery is rapid. It is potentially nephrotoxic; hepatic metabolism produces fluoride ions and exposureto carbon dioxide absorbantsin anesthesiamachinesproducescompound A, which causesrenal damage in rats. However, sevoflurane has not been reported to cause renal damage in humans. 7. Nitrous oxide (laughing gas) a. Pharmacokinetics. This drug is quickly eliminated by the lungs; it has little or no metabolism.

Note Metabolites of methoxyflurane renal failure. maycause

Note isoflurane, Nitrous oxide, desflurane, andsevoflurane arethemostcommonly anesthetis usedinhalational intheUnited States.

b. Pharmacologic properties (1) Nitrous oxide decreasesmyocardial contractility and increasescirculating catecholaminelevelsand the myocardialresponseto them. The net result is increased cardiacoutput and mean arterial pressure.

ln a Nutshell

(2) Only mild depressionof respiration is produced.

. Coodinducing uq:T

(3) In the CNS, nitrous oxide preservesautoregulationof blood flow, thereforeproducing no increasein intracranial pressure.It doesnot relax skeletalmuscle.

. Coodanalgesic

c. Indications for use. Nitrous oxide is used alone for dental and obstetric procedures. It is a rapid-acting agent,providing good analgesia.However,surgicalanesthesiacannot be achievedwith nitrous oxide alone becauseof its low efficacy.It must be usedin combination with other inhalational agents.

Nitrous oxide(Nr0):

. Mustbeusedin withother combination anesthetics to produce surgical anesthesia

6ll

Neruous System

d. Side effects and toxicity. Nitrous oxide can causediffusional hypoxia, particularly at the end of administration. Supplementalorygen can be given to avoid tissuedamage. Long-term abuse by health care professionalshas led to toxicity, including parethesias, tolerance,and addiction.

Clinical Correlate Thiopental isuseful for induction ormaintenance forshortprocedures. Note Barbiturates actattheirown binding siteonCABA^ receptors to potentiate CABAs activity. At highdoses, they canstimulate thereceptor directly, causing severe CNS depression. Note

C. Intravenous anesthetic agents. Severalchemical classeshavebeen used as intravenous anesthetics:barbiturates,benzodiazepines, opioids, ketamine,and propofol. 1. Barbiturates include thiopental, thiamylal, and methohexital. Thiopental is an ultrashort-acting barbiturate, which is the prototype of this group. Loss of consciousness occurswithin 30 secondsof intravenousadministration. Recoveryoccurswithin 30 minutes following a single intravenousdose. a. Mechanism of action. Barbituratesact by enhancingthe effectsof y-aminobutyric acid (GABA), an inhibitory neurotransmitter. GABA binds to the GABAAreceptor,which is a ligand-gated chloride channel, to increasechloride influx, which hyperpolarizes the cell. Barbiturates also bind to the GABAA receptor and increasethe duration of Clchannelopening. b. Pharmacologic properties of the ultra-short-acting barbiturates are listed below. (1) CNS effectsinclude suppressionof the brain stem reticular activating system,a hyperalgesiceffect,and decreasedcerebralblood flow and metabolism. (2) Barbituratesproduce myocardial depressionand increasedvenouscompliance. (3) Theseagentsdepressthe respiratory center.

Whereas N,0isa good analgesic, barbiturates are gesic (intensify hyperal pain).

c. Pharmacokinetics. Thiopental's action is terminated by redistribution from the brain to adipose and lean tissues.The drug is ultimately metabolized in the liver. d. Indications for use. Theseagentsmay be usedto induce anesthesiaor maintain anesthesiafor short proceduresby continuous intravenousinfusion. They produce a rapid and pleasantinduction and recovery,with minimal arrhythmogenicity.

ClinicalCorrelate Benzodiazepines areuseful in shortdental andmedical procedures. Theyenhance CABA activity atCABA^ receptors. Overdose is reversed byflumazenil, a benzodiazepine receptor antagonist. ln a Nutshell Neuroleptic Analgesia . Fentanyl anddroperidol . Dissociated, butconscious

e. Side effects and toxicity. Adverse reactions include cough, respiratory depression, laryngospasm,bronchospasm,and precipitation of porphyria. 2. Benzodiazepines include midazolam, diazepam,and lorazepam. (The pharmacology of theseagentsis discussedlater in this chapter.)Theseagentsare used in high dosesintravenously in conjunction with inhalational agentsor opioids. They produce anxiolysis, sedation,hypnosis,unconsciousness, and amnesia. 3. Opioids include morphine and fentanyl.Theseagentshavebeen used as analgesicsboth preoperativelyand postoperatively.They havealsobeen usedin combination with nitrous oxide and droperidol, a neuroleptic agent,to produce neuroleptic anesthesia.Opioids are good adjuncts to anesthesiain cardiac surgery becausecardiac output is maintained. Fentanyl is more potent and shorter acting than morphine. Effects of overdose are reversedby naloxone, an opioid receptor antagonist. (Complete pharmacology of the opioids is discussedlater in this chapter.) 4. Ketamine a. Pharmacologic properties

Neuroleptic Anesthesia . Fentanyl,droperidol, andNrO

(1) Ketamine is a dissociative anesthetic characterized by sedation, analgesia, amnesia, and immobility associatedwith feelings of dissociation from the environment. It increases CNS blood flow and intracranial pressure and preserveslaryngeal reflexes.

. Leads to unconsciousness

(2) It blocks NMDA glutamatereceptorsin the cortex and limbic system.

612

DrugsAffectingthe CNS Pharmacology:

(3) CNS sympatheticstimulation producesincreasedheart rate, cardiacoutput, and increasedblood pressure. (4) Ketamine may increaseintraocular pressure. b. Pharmacokinetics. Ketamine is lipophilic and rapidly distributes to vascular organs. c. Indications for use. Ketamine is used for anesthesiain children, young adults, and outpatients. d. Side effects and toxicity. Ketamine has a high incidence of postoperativebehavioral phenomena (e.g., delirium), especiallyafter the age of 25. It is contraindicated in patientswith hypertension,psychiatricdisorders,or glaucoma.

ln a Nutshell isa dissociative Ketamine to anesthetic andisrelated phencyclidine (PCP, angel NMDA dust). lt blocks glutamate Ketamine receptors. causes anemerSence upon excitement-delirium awakening.

5. Propofol. Though the two drugs are not structurally related,the pharmacologyof propofol is similar to thiopental. It producesa rapid induction and even more rapid recovery than thiopental. It is commonly usedas an anestheticin outpatient surgeryand as a comIt is usedin ambulatory patientsand for sedationin intenponent of balancedanesthesia. sive care units. The drug can causemarked hypotensionduring induction and can cause apneaand bradycardia. 6. Etomidate. This is used for rapid induction and as a part of balanced anesthesiafor shorter procedures. It produces minimal cardiovascular and respiratory depressant effects.It is associatedwith a high incidenceof nauseaand vomiting, myoclonus,and pain on injection.

ANESTHETICS LOCAL A. Overview 1. Characteristics of ideal local anesthetics a. They should reversiblyblock nerve conduction, producing no permanent damageto the nerve. b. They should not irritate the tissueat the site of application. c. They should have minimal toxicity when absorbedinto the systemiccirculation. d. They should have a rapid onset of action. e. They should have a duration long enough to allow treatment to occur. 2. Chemistry a. Local anestheticsconsist of an aromatic ring (lipophilic group), a hydrophfic group (usuallya tertiary amine),and a linking intermediatechain (esteror amide) (TableV-32-2). Thble V-32-2. Local anesthetic agents. Ester-TypeAnesthetics

emide-TypeAnesthetics

. . . .

. . . . . .

Cocaine Procaine Tetracaine Benzocaine

Lidocaine Bupivacaine Mepivacaine Etidocaine Prilocaine Ropivacaine

Note . Lidocaine isalsoan antiarrythmic. . Cocaine canalsoproduce CNSeffeGandincrease bloodpressure.

Mnemonic have an"i" Amides before the"caine."

6t5

NervousSystem

b. The type of linkage altersthe pharmacologiccharacteristicsand metabolic pathway. c. The more lipophilic the drug, the longer its duration of action, the more potent, and the more toxic.

ClinicalCorrelate

d. Local anestheticsare weak baseswith a pK" of 8-9. They are usually marketed in watersoluble hydrochloride salts.Local anestheticspenetrate nerve cell membranes in their uncharged form. Once inside, they become protonated and block the voltage-gated Na* channel.

3 . Pharmacokinetics Vasoconstrictors are coadministered withlocal anesthetia to increase the duration ofaction andto limit systemic absorption.

a. Routes of administration. Local anestheticsmay be administered topically, through local injection into the skin or specific nerve plexes,through epidural or subdural injection (in spinal anesthesia),or intravenously (lidocaine) when used as a cardiac antiarrhythmic agent. b. Systemic absorption depends on the site of administration and degree of drug-tissue binding. Vasoconstrictors, suchasepinephrineand phenylephrine,may be addedto a local anestheticsolution to decreaseregionalblood flow and, thus, reducesystemicabsorption. This increasesthe duration of action and minimizes systemicadversereactions. c. Elimination ( I ) Ester-type anestheticsare degraded by plasma cholinesterasesand hepatic esterases. (2) Amide-type anestheticsare primarily metabolized by liver amidases.Caution must be usedwith patients in renal failure.

ln a Nutshell Local anesthetia stopnerve conduction byblocking voltage-gated Na.channels. In a Nutshell Thesmaller thediameter and thelessmyelinated anaxon is,themoresusceptible it isto localanesthetics. Fortunately, painfibers aresmall and either unmyelinated orlightly myelinated. In a Nutshell LocalAnesthetic SideEffects . Cardiovascular depression . CNSexcitability, then depression . Hypersensitivity reactions

6t4

(3) Metabolitesare excretedin the urine. 4. Mechanism of action. Local anestheticsinhibit both the generation and conduction of action potentials.Local anestheticsblock voltage-gatedNa* channelsby binding to the intracellular side of the channel. These drugs are frequenry (or use) dependent-they stop conduction fasterif the nerve is rapidly firing becausethey bind to open or recently inactivatedchannelsbetter than they bind to resting channels. 5 . Pharmacologic properties a. Small,unmyelinatedfibers areblocked first; rapidly firing fibers areblocked more easily than nerveswith a slower firing rate. (l) Neurons are blocked in the following order: autonomic, sensory,then motor. (2) Sensorymodalitiesareblocked in the following order: pain, cold, warmth, touch, then deep pressure. b. Local anestheticagentsdepressmyocardial irritability, prolonging the effective refractory period and conduction time. Lidocainehasbeen used asan antiarrhythmic agent basedon theseeffects.Myocardial depressioncan alsobe an adverseeffectof overdose. Local anestheticsalso produce vasodilatation. c. In general,local anestheticscauseCNS stimulation by initially depressinginhibitory neurons. Central stimulatory effects may be followed by CNS depression.Effects include dizziness,restlessness, sedation,or seizures.SevereCNS depressioncan lead to cardiovascularand respiratory collapse. d. Local anestheticscan produce hlpersensitivity reactions.In general,if patients are allergic to ester-tFpeagents,they are not allergic to amide-type agents,and vice versa. Patientsare more commonly allergic to the ester-t)?e agents.

Pharmacology: DrugsAffectingthe CNS

B. Specific agents 1. Ester-type local anesthetics a. Cocaine (1) Pharmacologic properties include vasoconstriction, slow absorption, and a half-life of t hour following oral or nasal administration. Moderate doses increaseheart rate and blood pressure. (2) Indications for use. Cocainehas been used as a topical anesthetic,especiallyin the nose and throat.

In a Nutshell Cocaine actsasa local anesthetic andalsoblocks thereuptake of catecholamines into presynaptic nerve (producing terminals vasoconstriction).

(3) Side effectsand toxicity. With increasingdoses,cocaineproducesCNS stimulation (i.e., irritabiliry psychosis,seizures)followed by respiratory depression. There is strong abusepotential. Cocainehas been associatedwith corneal ulceration when used topicaliy in the eye. b. Procaine (1) Pharmacokinetics. Procaineis rapidly absorbedfrom the injection site unlessa vasoconstrictor is used. It is hydrolyzed to para-aminobenzoic acid (PABA), which competitivelyinhibits sulfonamides. (2) Indications for use. Procaineis used for local injection, nerve blocks,and spinal anesthesia;it is ineffectiveby the topical route. (3) Side effects and toxicity. Procaine has low systemic toxicity due to short duration and rapid degradation. c. Chloroprocaine is a derivativeof procaine;it is more potent but lesstoxic than procaine.It is used for infiltration, nerve blocks,and epidural anesthesia. d. Tetracaine (1) Pharmacokinetics.Tetracaineis an esterof PABA,which is 10times more potent than procaine and has a longer duration of action. (2) Indications for use.It is used for spinal anesthesiaand as a topical anestheticin the eye and nasopharynx. (3) Side effects and toxicity. Adversereactions are similar to procaine. e. Benzocaine is an ester-typeanestheticthat is used only for topical anesthesia.It is availableover the counter. 2. Amide-tfpe local anesthetics a. Lidocaine (1) Pharmacokinetics. Lidocaine is twice as potent and toxic as procaine and is metabolizedby liver enzymes. (2) Pharmacologic properties. Lidocaine produceslocal vasodilatation. (3) Indications for use.Lidocaineis usedby topical and local injection and for spinal anesthesia.It is also administered intravenously for cardiac tachyarrhythmias. (a) Side effects and toxicity. Adverse reactions include sedation, amnesia, and convulsions. b. Bupivacaine has a prolonged duration of action. It is used for local infiltration, nerve blocks,and spinal anesthesia.Its side effectsare similar to lidocaine.

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NeruousSystem

ClinicalCorrelate

c. Mepivacaine has a pharmacologic profile similar to lidocaine, except it produces less vasodilatation.Indications include local infiltration, nerve block, and spinal anesthesia.

. Nondepolarizingblockers d. Etidocaine and prilocaine are amide-type agentssimilar to lidocaine. (e.g., tubocurarine) e. Ropivacaineis a newer amide-typelocal anesthetic. competitively blocknicotine AChreceptors intheNMJ. Patients immediately SKELETAT MUSCTE RETAXANTS paralysis. develop flaccid . Depolarizing (e.9., blockers succinylcholine) cause skeletal muscle relaxation bydepolarizing themuscle excessively, making it unresponsive. Patients have fasciculations before flaccid paralysis.

Note Acetylchol inesterase inhibitors reverse theeffects of a blocker competitive but prolong theeffects of a depolarizing blocker during phase I block. Phase ll block bysuccinylcholine isreversed byacetylcholinesterase inhibitors. ln a Nutshell Benzodiazepines actatthe CABA^ receptor. Baclofen acts attheCABA' receptor. Baclofen iscommonlv used forspasticity. In a Nutshell

A. Neuromuscular blocking drugs. Neuromuscular blockers are used to produce skeletalmuscle relaxation,as adjuncts in surgicalanesthesia,and in patientswith severerespiratoryfailure on mechanicalventilators. Theseagentsare subdivided into two groups: 1. Nondepolarizing (competitive) blockers are agents that compete with acetylcholine (ACh) for the nicotinic receptor at the neuromuscularjunction and prevent depolarization. These drugs include tubocurarine, pancuronium, atracurium, cisatracurium, mivacurium, vecuronium, pipecuronium, rocuronium, doxacurium, and rapacuronium. 2. Depolarizing blockers bind to the nicotinic receptor,initially causing depolarization. Prolongedbinding to the receptorproducespersistentdepolarization,making the membrane unresponsiveto new impulses (depolarization block); phase I block. The muscle repolarizesin phase II, but is resistant to depolarization (similar to nondepolarizing blockers).The only drug clinically availablein this classis succinylcholine. B. Spasmolytic drugs. Theseagentsare used to reduceskeletalmuscle tone and control muscle spasmsand involuntary movementsdue to such conditions asmultiple sclerosis,cerebral palsy,spinal cord injury, and stroke. 1. Diazepam. Diazepam is a benzodiazepine,which actsby enhancingthe effectsof GABA at the GABAAreceptor.It is alsoused as a sedative-hypnotic,an antianxiety agent,and an antiseizuredrug. 2. Baclofen. This is an agonist at the GABA' receptor.It may decreasethe releaseof excitatory neurotransmittersvia presynapticinhibition. Baclofenis rapidly absorbedfollowing oral administration. It is used in the treatment of spasticitydue to multiple sclerosisor other spinal cord disorders,particularly lesions due to trauma. Baclofen produces less sedationthan the benzodiazepines. It can,however,lowerseizurethreshold.Suddenwithdrawal following chronic use may causeauditory and visual hallucinations,anxiety,and tachycardia. 3. Dantrolene. Dantrolene is a direct-acting skeletalmusclerelaxant.It decreases the releaseof calcium from the sarcoplasmic reticulum, thus blocking the contractile mechanism. Dantrolene is used in the treatment of muscle spasmand malignant hyperthermia.Adverse reactionsinclude muscleweakness,sedation,and diarrhea.Prolonged usecan lead to hepatotoxicity. 4. Tizanidine. Tizanidine is a congener of clonidine that reinforces presynaptic and post-

prevents Dantrolene Car. synaptic inhibition in the spinal cord. It is usefi.rlin patients with many different types of release fromthesarcoplasmic spasticity. reticulum. lt isusedinthe C. Drugs used for acute local muscle spasm. treatment of malignant l. Cyclobenzaprine. Cyclobenzaprine is the prototype of this group. The mechanism of hyperthermia.

action is nuclear,though it appearsto act at the level of the brain stem. It has significant sedativeand antimuscarinic effects,and can causeconfusion and visual hallucinations in some patients.Cyclobenzaprineis ineffectivein muscle spasmsdue to spinal cord injury or cerebralpalsy.

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Pharmacology: DrugsAffectingthe CNS

ANDANTAGONISTS OPIOIDANATGESICS Opioid analgesicsconsistof morphine and related drugs, which reducethe perception of and the emotional responseto pain. Opiatesare drugs derivedfrom the opium poppy,Papaversomniferum. Opioids is the classof drugs, natural and synthetic,that mimic the actions of the opiates.Theseagentsare widely used clinically for analgesic,antidiarrheal,and antitussive(cough suppression)effects.Some,like heroin, are abusedfor their euphoric effects.Opioid analgesics and antagonistsare classifiedbasedon their action at opioid receptors(TableV-32-3).

Clinical Correlate Clinically, opioids areusedas analgesics, antitussives, and antidiarrheals.

Table V-32-3. Opioid analgesicsand antagonists.

ReceptorAgonists

Receptor Antagonists

Morphine Hydromorphone Heroin Codeine Oxycodone Hydrocodone Methadone r-Alpha acetylmethadol (LAAM) Propoxyphene Meperidine Fentanyl Diphenoxylate Loperamide

Naloxone Naltrexone Nalmefene

Mixed AgonistAntagonists and Partial Agonists Pentazocine Nalbuphine Butorphanol Buprenorphine

(pAe)

A. Mechanism of action. Opioid analgesicsact by stimulating the same receptors as the endogenousopioid peptides (endorphins,enkephalins,and dynorphins). 1. Receptor tn>es a. Mu (p) receptors. Stimulation of p receptorsis involved primarily in supraspinalbut also in spinal analgesia,respiratory depression,euphoria, and physicaldependence. b. Kappa (r) receptors. The K receptors are primarily involved in spinal analgesia.They

Note Endorphins bindp receptors. Enkephalins bind6 receptors. Dynorphins bindrcreceptors.

ln a Nutshell . p: Supraspinal analgesia Euphoria Respiratory depression . K: Spinal analgesia Sedation

alsoproduce sedationand some dysphoric and psychotomimeticeffect. c. Delta (6) receptors. Stimulation of 6 receptorsis involved in spinal and supraspinal analgesia. d. Subtypes of F, K, and 6 receptors exist and havebeen cloned. Identification of these may lead to the developmentof more specificdrugs with lessadversereactions. 2. Secondmessengersystems a. The F, K, and 6 receptorsrespond by inhibiting adenylatecyclasevia a G protein, resulting in alterationsin ion flux and inhibition of calcium entry into neurons. b. Potassiumchannelsare openedby p receptors. c. Calcium channelsare closedby r receptors.

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Note Fir$-pass metabolism alters theeffectiveness of some opioidanalgesia (e.g., hydromorphone).

B. Pharmacokinetics 1. Absorption. Most opioid analgesicsare well absorbedfrom the gastrointestinaltract following oral administration. However, some undergo significant first-pass metabolism (e.g.,hydromorphone, oxymorphone). 2. Distribution. Although variable degreesof plasma protein binding occur, compounds rapidly leavethe blood and accumulatein tissues.With repeatedadministration of slowly metabolizedlipophilic agents,fat accumulation becomessignificant. Most opioids crossthe placenta,producing effectsin the fetus (e.g.,respiratory depression,physicaldependence). 3. Elimination. Many of the drugs undergo hepatic metabolism, including glucuronidation. Morphine-6-glucuronide is an active metabolite of morphine with analgesicproperties. The major route of excretionis through the kidney.

ln a Nubhell OpioidEffects on CNS . Analgesia

C. Pharmacologic properties 1. Acute effects a. Central neryous system

. Euphoria

( 1) Opioids are potent analgesiaagentsthat reducethe perceptionand reactionto pain.

. Antitussive

(2) Evenat low doses,theseagentsproduce euphoria,a pleasant,cloudy mental state. Dysphoria may also occur,particularly on first administration.

- useful . Miosis fordetecting suneptitious use

In a Nutshell MajorPeripheral Effects of Opioids . Con$ipation . Hypotension . Urinary retention

(3) Opioids inhibit the brain stem respiratory centers.The degreeof depressionis dose-related.Theseagentsdecreasethe responsiveness to increasedplasma carbon dioxide levels. (4) Low dosescan produce sedativeeffects.Elderly patients are most susceptible. High dosescan further depressthe CNS to the point of sleepor narcosis. (5) Opioids depressthe cough reflex (antitussiveaction). (6) Opioids stimulate the chemoreceptortrigger zone (CTZ), resulting in nausea and vomiting, particularly in the naive and ambulatory individual. (7) Opioids (especiallyfentanyl) increasemuscular tone (truncal rigidity) and can compromiseventilation. (8) Pupillary constriction (pinpoint pupils, miosis) is characteristicof opioids except meperidine,which has antimuscarinic actions.This is useful to diagnoseopioid abuse. (9) Increasedintracranial pressuresecondaryto dilatation of cerebralvasculature resulting from CO, retention. b. Cardiovascular system. Hypotension may occur via venous dilatation, but there is minimal effect on cardiacoutput at analgesicdoses. c. Gastrointestinal system.Constipation occursbecauseopioids produce an increasein resting tone and the amplitude of contractions and motility are reduced. Biliary smooth muscleis constricted,particularly sphincters,which may exacerbatepain from biliary colic. d. Urogenital system. Opioids increase urethral and bladder sphincter tone and may causeurinary retention. e. Uterus. Relaxeduterine smooth muscle as a result of opioids may prolong labor.

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Pharmacology: DrugsAffectingthe CNS

f. Endocrine system. Opioids increase release of prolactin, antidiuretic hormone (ADH), and somatotropin, and reducethe releaseof luteinizinghormone (LH). g. Opioids stimulate the releaseof histamine. 2. Chronic effects a. Tolerance.Chronic use of theseagentsresults in toleranceto their acute pharmacologic effects.Tolerancedevelopsto a lesserdegreeto miosis and constipation than to other effects.Cross-toleranceexistsamong the drugs. b. Dependence.Psychologicaland physicaldependenceto theseagentsdevelops.Abrupt withdrawal leadsto an abstinencesvndrome. D. Indications for use

Note Tolerance develops to a greater degree to the analgesic andeuphoric effects of opiates thanto miosis or constipation.

1. Analgesia.Opioids are indicated for use in moderateto severepain. 2. Treatment of diarrhea. Opioids relieve diarrhea. Agents specific for this use are loperamide and diphenoxylate.Theseagentsdo not crossthe blood-brain barrier. 3. Pulmonary edema. Opioids are usefrrl in decreasing cardiac preload and afterload secondaryto vasodilatory effects.Morphine is now consideredsecondaryto furosemide for this use. Agentsmost used are codeineand 4. Antitussive. Opioids are useful as cough suppressants. dextromethorphan. 5. Anesthesia.Opioids are used as pre- and postoperativemedicationsbecauseof sedative, analgesic,and antianxiety effects.High dosesof morphine and fentanyl are used as anesthetics in cardiovascularsurgerybecausethey produce minimal cardiacdepression. 6. Opioid dependence.Methadoneis usedto minimize withdrawal symptomsand in maintenanceprogramsfor opioid addicts. E. Side effects and toxicity 1. Respiratory depressionis the major acute toxicity of these drugs. The drugs are contraindicated in patients with emphysema and chronic obstructive pulmonary disease

(coPD). 2. Opioid analgesicsproduce constipation,nausea,and vomiting.

Clinical €orrelate Acute overdose of opioids mayleadto respiratory depression, anddeath. coma, iswithnaloxone, Treatment anopioid antagonist.

3 . Opioids can produce dysphoria, restlessness,tremors, hyperactivity, and increased intracranial pressure. 4. Hypotension resultsfrom histamine releaseand depressionof compensatoryvasomotor reflexes. 5. Opioids can produceurinary retention.They should be usedwith caution in patientswith prostatic hypertrophy. 6. Theseagentscausepruritus due to histamine release. 7. Toleranceand physicaldependence.

Clinical Correlate leads useof opioids Chronic For to physical dependence. withdrawal or controlled replacement maintenance iswith therapy, treatment methadone.

F. Drug interactions. Use of opioids with sedative-hypnoticsincreasesCNS and respiratory depression.Opioids increasesedation,antimuscarinic effects,and alpha-blocking effectswhen combined with antipsychotic medications.Use with monamine oxidase (MAO) inhibitors is contraindicatedbecauseof the production of hypertension and hyperpyrexic coma.

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G. Specific agents 1. Opioid agonists.Thesedrugs haveprimary activity at p receptors,someat r and 5 receptors. a. Morphine is availablefor oral or parenteraladministration. It has high abusepotential. Morphine-6-glucuronide, a major metabolite,has potent analgesiceffects. b. Hydromorphone. This drug is more potent than morphine and is used for the treatment of severepain. c. Heroin is not used clinically in this country. It is metabolized to morphine. It is more lipid solublethan morphine and more readily entersthe CNS. It has high abuse potential. d. Codeine is usedorally in combination with NSAIDs to relievemoderatepain and as a cough suppressant. e. Oxycodoneand hydrocodone are analogsof codeineusedin the relief of moderatepain. f. Methadone is used for severechronic pain and in the treatment of opioid addiction. It has a longer half-life than morphine,less sedativeeffects,and lessseverewithdrawal symptoms.

ln a Nutshell Codeine andpropoxyphene areusedformild-to-moderate pain.

In a Nutshell Fentanyl andsufentanil are primarily usedin anesthesia.

ln a Nutshell Diphenoxylate and loperamide arecommonly usedantidiarrheals. Theydo notcross theblood-brain barrier well,andhavelittle euphoriant oranalgesic activity.

g. LAAM is a longer-aaingmethadoneanalogusedin maintenancetherapyof opioid addicts. h. Propoxyphene is a weak agonistusedin the relief of moderatepain. It is usedin combination with NSAIDs.Meperidine is availablefor oral and parenteraladministration. It has one-tenth the potency of morphine. It produceslessconstipation and lessurinary retention than morphine. Intravenous administration can cause tachycardia becauseof its antimuscarinicaction. CNS excitatoryeffectsare high. Normeperidine, a metabolite,can produce dysphoriaand seizures.It has high abusepotential i. Fentanyl, sufentanil, and alfentanil are congenersof meperidine and act primarily at the p receptor.They are used more frequently for anesthesiaand are short acting. Fentanylis availablein transdermalpatchesto treat cancerpain. j. Diphenoxylate. This drug is used as an antidiarrheal agent. When administered orally, it is minimally absorbed from the gastrointestinaltract. It is often given in combination with atropine to prevent potential abuse. k. Loperamide. Loperamide is an over-the-counterantidiarrheal agentwith no significant analgesiceffects. 2. Mixed agonist-antagonistsare drugs that are antagonistsat the p receptor,but agonists at the r and o receptors. a. Pentazocineis a weak antagonistat p receptorsbut a potent agonist at K receptors, which is responsiblefor its analgesicproperties. It can precipitate withdrawal in opioid-dependent patients. Addiction can develop. Pentazocine may cause psychomimeticeffectsthat are thought to result from o receptorstimulation. It is the only agonist-antagonistavailablefor oral administration. b. Nalbuphine. This is a more potent antagonistat p receptorsthan pentazocineand can precipitatewithdrawal in patientsdependenton opioid agonists. c. Butorphanol is similar to pentazocine.

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Pharmacology: DrugsAffectingthe CNS

3. Partial agonist. Buprenorphine. This drug is a partial agonist at p receptors.It is more potent as an analgesicthan morphine. 4. Opioid Antagonists. These agentsare analogs of morphine, which have affinity for, but no efficary,at opioid receptors;therefore,they block the actions of opioids. a. Naloxone (1) Pharmacologic properties. Naloxone is effective only by injection (intravenous or subcutaneous).It is rapidly metabolizedby hepaticenzymes,hasa rapid onset ( 1-5 minutes), and has a half-life of 60-100 minutes. (2) Mechanisms of action. Naloxone is a competitive antagonist at opioid receptors. (3) Indications for use. Naloxone is the drug of choice in the treatment of acute opioid overdose.Severaldosesmay be necessarydue to its short duration of action. This drug precipitateswithdrawal syndrome in individuals dependenton opioids.

Clinical Correlate Naxolone isanopiate receptor antagonist used inthetreatment of opiate overdose.

b. Naltrexone. Naltrexone has similar actions to naloxone; however,it is effective orally and has a longer duration of action. It is useful for long-term treatment of opioid and alcohol dependence. c. Nalmefene is similar to the other antagonists,but has a longer half-life. 5. Miscellaneous. Tramadol is a newer analgesic with weak mu agonist effects. It also inhibits norepinephrine and serotonin reuptake, and is only partially antagonizedby naloxone.Adverseeffectsinclude dependence,withdrawal, and seizures.

SEDATIVE.HYPNOTI CDRUGS Sedative-hypnotic and antianxiety drugs are prescribed worldwide with increasing frequenry. Many of the drugs in this classhave all three actions,with effectsbeing dose-dependent,such asmild sedation,sleep,anesthesia, respiratoryand cardiovasculardepression,coma,and death. The drugs are divided into three subclasses: barbiturates,and miscellaneous benzodiazepines, agents. A. Benzodiazepines. Benzodiazepinesare the most commonly prescribed antianxiety and sedative-hypnoticagents.Thesedrugs are saferthan the barbiturates. 1. Mechanism of action. Benzodiazepinesact by potentiating the effects of GABA, an inhibitory neurotransmitter.

Note potentiate Benzodiazepines CABAs activityattheCABA^ receptor.

a. GABA binds to the GABAA receptor, which is a chloride channel, thus causing chloride influx and hlperpolarization of the cell, making it more difficult to depolarize. b. Benzodiazepinesbind to an allosteric site on the GABA receptor and enhancethe effectsof GABA. They require the releaseof GABA to produce their effect. increasethe frequencyof opening of the chloride channel,increasing c. Benzodiazepines the amplitude of the inhibitory postsynapticpotential (IPSP). 2. Pharmacologic properties have anxiolytic effectsand sedative-hypnoticproperties. a. Benzodiazepines b. They produce skeletalmuscle relaxation and have anticonvulsant properties.

ln a Nutshell Benzodiazepines areusedas anxiolytics, sedative-hypn otics, skeletal muscle relaxants, and anticonvulsants.

c. Their effect on respiration is slight with hypnotic doseshaving no effect.

621

Nervous System

3. Pharmacokinetics. Most of the benzodiazepinesare readily absorbed from the gastrointestinal tract and crossthe blood-brain barrier. Benzodiazepinesare metabolizedin the liver, many initially to active products. 4. Indications for use a. Anxiety and insomnia b. Alcohol withdrawal symptoms (usually chlordiazepoxide,diazepam) c. Spasticityand skeletalmusclespasm(diazepam) d. Statusepilepticus(diazepamIV lorazepamIV) e. Epilepsy(clonazepsrrr,clorazepate) f. Anesthesia(midazolam,diazepam,lorazepam) 5 . Side effects and toxicity

In a Nutshell Theeffects of benzodiazepines areall additive withotherCNS depressants. Thecombination ispotentially lethal

a. Benzodiazepines can produce drowsiness,ataxia,confusion (especiallyin the elderly), increasedreaction time, impaired short-term memory, and impaired performanceof complex tasks(e.g.,driving), blurred vision, vertigo, and headache. b. Dependencymay occur.Temporaryenhancementof the symptomsthat prompted the use of thesedrugs (e.g.,anxiety,insomnia) can occur upon withdrawal. Seizuresand psychosismay occur with suddenwithdrawal after prolonged use at high doses. c. Benzodiazepinesproduce little respiratory depressionfrom oral administration. In combination with alcohol or other CNS depressants, they can produce significant respiratory depression. d. Tolerance(pharmacodynamictolerance)occurs at a cellular level. 6 . Drug interactions a. Drugs that increasebenzodiazepinelevelsinclude: (1) Acetaminophen(by decreasingdiazepamexcretion) (2) Cimetidine, disulfiram, ethanol, isoniazid, and valproic acid (by decreasing metabolism) (3) Valproic acid (by displacingthem from binding sites) b. Drugs that decreasebenzodiazepinelevelsinclude: (1) Antacids(by decreasingabsorption) (2) Oral contraceptives(by increasingmetabolism) c. Benzodiazepines enhancethe CNS depressanteffectsof alcohol and other depressants. d. There is cross-tolerancebetweenbenzodiazepinesand other CNS depressants. 7 . Specific agents. Most benzodiazepinescan be used interchangeably.The therapeutic uses are often dependent on the half-life of the drug rather than for what they are marketed. a. Oxazepam is used for the treatment of anxiety. b. Triazolam is used for the treatment of insomnia. c. Npraznlam is used for the treatment of panic disorders. d. Lorazepam is used for the treatment of anxiety,preanestheticmedication, and status epilepticus.

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Pharmacology: DrugsAffectingthe CNS

e. Temazepamis used for the treatment of insomnia. f. Midazolam is usedfor anesthesiaand medical procedures.It is administeredonly parenterally. g. Clorazepate is used for the treatment of epilepsy and anxiety. h. Diazepam is the most commonly used benzodiazepine.It is used for anxiety, skeletal muscle relaxation,preanestheticmedication, and statusepilepticus. i. Flurazepam is used for the treatment of insomnia.

Note Flumazenil isa benzodiazepi neantagonist usedto reverse theCNS depressant effects of benzodiazepines andto hasten recovery after procedures. medical

j. Chlordiazepoxide is used for ethanol withdrawal symptoms, anxiety, and preanesthetic medication.

B. Barbiturates 1. Structure-function relationship a. The CNS depressantaction of barbituratesis relatedto their lipid solubility.Increased lipid solubility is associatedwith shorter latencyto onsetof action, decreasedduration of action, increasedmetabolic degradation,and often greaterhypnotic effect. b. Thiobarbiturates such as thiopental have increasedlipid solubility and ultra-short duration of action. c. Phenobarbital, having a phenyl group at C5, has relatively selectiveanticonvulsant activity. 2. Pharmacokinetics a. The barbiturates are well absorbedafter oral administration. Thiopental is administered intravenously. b. There are three mechanismsby which the action of barbituratesare terminated: ( 1) Physicalredistribution for very short-actingbarbituratesto adiposetissue(most important with short-acting agents,e.g.,thiopental) (2) Hepatic metabolism (3) Urinary excretion c. Barbiturates induce hepatic microsomal enzymes and, to a lesserextent, cytoplasmic and mitochondrial enzymes. d. Tolerancemay result from decreasedeffect at the target site (pharmacodynamictolerance) and increasedmetabolism (pharmacokinetic tolerance). Anticonvulsant and lethal effectsshow little tolerance. 3. Mechanism of action. Barbiturates depressneuronal activity by enhancing the effects of GABA, an inhibitory neurotransmitter. Barbiturates bind to the GABAAreceptor,increasing the duration of the GABA-mediated opening of the chloride channel. 4. Specific agents include a. Phenobarbital (longest-acting) b. Mephobarbital c. Pentobarbital (short-acting) d. Secobarbital (short-acting) e. Amobarbital (short-acting)

ln a Nutshell Barbiturates induce hepatic (P*o), microsomal enzymes leading increased to metabolism ofthemselves andother drugs. ln a Nutshell Barbiturates enhance CABAtr receptor activity byincreasing theduration oftheClchannel opening. In a Nutshell Phenobarbitol isused asan anticonvulsant. Thiopental is anexcellent inducing agent forgeneral anesthetics.

62t

Neruous System

f. Thiopental (ultra-short-acting) g. Methohexital (ultra-short-acting) 5. Indications for use

ln a ftuBhell Acute toxicity of barbiturates canleadto respiratory depression, coma, anddeath. Chronic usecancause tolerance andphysical dependence.

a. Barbiturateshavebeen used as sedative-hypnoticagents.The benzodiazepinesare now most commonly used becauseof their relative safetyand minimal adversereactions. b. Phenobarbitalis used as an antiepileptic agent. c. Thiopental and methohexital are used intravenously in anesthesiafor induction or maintenanceof anesthesiafor short procedures. d. Phenobarbital has been used for treatment of kernicterus and hyperbilirubinemia in neonates.It works by increasing the elimination of bilirubin. 6. Side effects and toxicity a. CNS effectsinclude sedation,confusion,ataxia,respiratory depression,coma, and death. b. Barbiturates can produce tolerance and psychological and physical dependence. Abrupt discontinuation may produce life-threatening withdrawal symptoms, which include anxiety, tremors, nausea,and vomiting, orthostatic hypotension, convulsions, and cardiovascularcollapse. c. Mild overdose casesare similar to ethanol intoxication. Severeoverdose may cause coma, shock, and hypothermia. Osmotic diuresis with alkalinization of the urine enhancesexcretionof phenobarbital. d. Barbiturates may produce rash, angioedema,and rarely, exfoliative dermatitis. e. Barbiturates may rarely produce folate-responsivemegaloblastic anemia and osteomalacia. f. Effects on porphyrin metabolism may precipitate acute intermittent porphyria. 7. Drug interactions a. Barbiturates increase the metabolism of other drugs by induction of microsomal enzfmes. Thesedrugs include phenytoin, steroid hormones, triryclic antidepressants, oral anticoagulants,digitoxin, quinidine, theophylline, and p-adrenergic blockers. b. Barbituratesmay displacedrugs (e.g.,thyroxine) from albumin-binding sites.

ln a Nubhell

c. There is cross-tolerancebetweenbarbituatesand other CNS depressants. C. Other sedative-hlpnotic drugs

Buspirone isa anxiolytic. serotonergic

1. Buspirone is a nonbenzodiazepineanxiolytic agent,which appearsto work by binding to specificserotonin S-hydrory-tryptamine 1A (5-HT,^) receptors,acting as a partial agonist. It can alsobind to some dopaminergic receptors.Unlike the benzodiazepines, buspirone has no muscle relaxant or anticonvulsant activity and does not increasethe CNS depressant effect of ethanol.Adversereactionsof buspirone include dizzinessand headaches. 2. Zolpidem tartrate is a nonbenzodiazepinehypnotic agent. The proposed mechanism is modulation of the GABAAreceptor.It is usedfor short-term treatment of insomnia.It has minimal anxiolytic, anticonvulsant, and muscle relaxant properties when compared to benzodiazepines. This is likely becausezopidem is BZ, selective,whereas,traditional benzodiazepinesinteract with both BZrandBZ, receptors. 3. Meprobamate is an older sedative-hypnotic and antianxiety agent. Its use has generally been replacedby the benzodiazepines.

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Pharmacology: DrugsAffectingthe CNS

a. Pharmacokinetics. Meprobamate is well absorbed after oral administration. It is metabolizedin the liver, where it can induce some of the microsomal enzymes. b. Side effects and toxicity. Adversereactions include sedation and ataxia, hypotension, abusepotential, and rash.It is contraindicatedin pregnancy. 4. Chloral hydrate is a chlorinated derivative of acetaldehyde,which is used as a hypnotic, inducing sleepin about 30 minutes. a. Pharmacokinetics. Following oral administration, chloral hydrate is rapidly converted to trichloroethanol, which is largely responsiblefor its hlpnotic action. b. Mechanism of action is unknown. c. Side effects and toxicity. Adverse reactions include epigastric distress,nausea,vomiting, and flatulencedue to irritation of mucous membranes.Chloral hydrate potentiatesthe effectsof ethanol; it inhibits ethanol metabolism,while ethanol increasesthe generation of trichloroethanol. Chronic use may lead to tolerance,physical dependence,and addiction. 5. Glutethimide is a sedative-hypnoticwith pharmacologicproperties similar to the barbiturates. a. Pharmacologic properties. Glutethimide is a CNS depressant.It has pronounced anticholinergicactiviry and it inducesliver microsomal enzymes. b. Side effects and toxicity. Adversereactionsinclude constipation,mydriasis,xerostomia, sedation,ataxia,epigastricpain, rash, and blood dyscrasias.

ALCOHOT ANDRETATED COMPOUNDS Ethanol (ethyl alcohol) is a drug with sedative,hypnotic, and antianxiety actions.Its useis not regulated,and abuse(alcoholism) representsa complex sociomedicaldisorder with devastating effects(dysfunctional families,violent crimes, child and spousalabuse,work-related and automobile accidents,and medical disorders).Methanol (methyl alcohol) is consumed accidentally or as a substitute for ethanol and has significant toxicity. Ethylene glycol is sometimes consumedby children becauseof its sweettasteor is inhaled or absorbedthrough the skin and has considerabletoxicity. A. Ethanol. The structure of ethanol is CH.CH"OH. 1. Pharmacokinetics

ln a Nubhell Ethanol ismetabolized to acetaldehyde byalcohol dehydrogenase; acetaldehyde ismetabolized to acetic acid byaldehyde dehydrogenase.

a. Ethanol is water soluble.It is rapidly and completelyabsorbedfollowing oral administration; approximately30o/ois absorbedfrom the stomach and 70o/ofrom the small intestine.Absorption is delayedwith food intake. b. The rate of metabolism is independentof serum concentration (zero-orderkinetics). Over 90olois oxidized in the liver. (1) Alcohol dehydrogenaseis a cytosolic zinc-containing enzyme,which is largely responsiblefor hepatic metabolism and probably the only systemactive at low serum ethanol concentrations. It catalyzesthe following reaction: CH.CH2OH + NAD* + CHTCHO (acetaldehyde)+ NADH (2) Acetaldehyde (CH.CHO) is further oxidized by the mitochondrial enzyme, acetaldehyde dehydrogenase,to acetic acid, which can be metabolized to carbon dioxide and water. Acetaldehydedehydrogenaseis inhibited by disulfiram.

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Neruous System

(3) Microsomal enzymescontribute to ethanol metabolism at high serum concentrations. This system is called the microsomal ethanol oxidizing system (MEOS).Induction of theseenzymesaccountsfor enhancedethanol metabolism with chronic use and in drug interactions. c. TWopercent of ethanol is excretedunchangedthrough the lungs; this is the basisfor the Breathalyzertest for intoxication. Eight percent is excretedunchangedin the urine. 2. Pharmacologic properties a. Moderate use is associatedwith a decreasedincidenceof coronary artery disease.

Note There isa strong relationship withBACandlevelof intoxication. A BACof 25 mg/dlproduces impaired fine motorcontrol anddelayed reaction time;a BACof toO mg/dlisthelegallimitfor driving under theinfluence in moststates, Somestates have lowered thislimitto 80mg/dl.

ln a Nutshell Withdrawal following chronic produces useof alcohol symptoms similar to other CNSdepressants: anxiety, anorexia, insomnia, confusion, delirium, tremor, lifethreatening seizures, agitation, andhyperthermia. Seizures canbecontrolled with diazepam.

Bridgeto Gastrointestinal Thehepatic and gastrointestinal effects of ethanol arediscussed in greater detail inthe ntestinal Pathol Castroi ogy chapter of Organ Systems Bookz ft/olume lV).

626

b. The exactmechanismof action of ethanol is not known; it has been shown to affect many cellularcomponentsincluding neurotransmitterreceptors,various enzymes,the electron transport chain, and ion channels.TWo of the better studied mechanisms include the potentiation of GABA at GABA^ receptorsand inhibition of the NMDA glutamate receptor. 3. Indications for use a. Ethanol is used for the treatment of poisoning by methanol and ethyleneglycol. b. Dehydratedethanol hasbeen injected closeto nervesin patientswith trigeminal neuralgia, inoperablecancer,and other conditions for the relief of pain. It is not the first line of therapy. c. Topical ethanol, which has a vasodilatoryeffect,has been used to reducefever and as a skin disinfectant. 4. Side effects and toxicity a. CNS effects (1) Acute effects. Low dosesof ethanol can impair judgment and performance of fine motor tasks and delay reaction time. Acute intoxication is associatedwith cold clammy skin, tachycardia,hypothermia, stupor, or coma.Initial "stimulant" efifectsobservedwith ethanol use are due to depressionof inhibitory neurons. High dosesmay causeataxia,vertigo, diplopia, respiratorydepression,coma,and death.A blood alcohol concentration (BAC) of greater than 400 mg/dl can be lethal. (2) Chronic effects include psychiatric disorders; sleep disorders; Wernicke encephalopathy(a clinical triad of encephalopathSopthalmoplegia,and ataxia), resulting from thiamine deficiency; Korsakoff psychosis with memory loss; cerebellardegenerationsyndrome; lowering of the seizurethreshold; tolerance; and physicaldependence. b. Cardiovascular effects (1) Ethanol can depressthe myocardium with moderateor large consumption.This may be precededby transient hypertension and tachycardia. (2) Ethanol causesvasodilatation,resulting in loss of body heat. (3) Ethanol can produce atrial fibrillation and supraventriculartachycardia. (4) Chronic use can produce cardiomyopathy,which may be related to nutritional deficiencyoften seenin alcoholics. c. Hepatic effects include fatty liver changes,aicoholic hepatitis (often seen in binge drinkers),and cirrhosis(in chronic users).

Pharmacology: DrugsAffecting he CNS

d. G.strointestinal €ffects include irritation of the gastrointestinalmucosa,gastritis, pq>tic ulcer disease,esophageal varices,and acuteand chronic pancreatitis.Fatalgastrointestinal hemorrhagemay occur.Ethanol exacerbates aspirin-inducedprolonged bleedingtime. e. Musculoskeletaleffects (1) Ethanol usehasbeen relatedto skeletalmusclemyopathy. (2) Chronic useof ethanol may lead to peripheral neuropathy. f. Hemstopoietic€ff€cts ( I ) Inhibition of leukocfte migration to inflammatory foci may contribute to infections in alcoholics. (2) Anemia occursftom bone marrow depression,nutritional deficiences,and gastrointestinalblood loss. (3) Thrombocytopeniais associatedwith ethanolabuse. g. Body temp€rature.Vasodilatationmay produce a transient feeling of warmth, but togetherwith increasedsweating,body heat is lost. Largeamountsof ethanoldepress : CNStemperatureregulatorycenters,which producea markedd€crease in body temPerature' h. Endocrine effects include inhibition of ADH, causingdiuresisand increasedreleas of adrenocorticotropichormone (ACTH), cortisol,and circulating catecholamines. i. Carcinogenesis.Chronic alcoholuseis associated with an increasedincidenceof carcinomasofthe head,neck,lung,esophagus(especiallywhencombinedwith tobacco), and stomach. j. Teratogericeff€ctsinclude t}le fetal alcohol syndrome (FAS).This syndromeis associatedwith dronic ethanolabuseduring pregnancy.Clinical featuresinclude growth retardation, developmentaldelay,low IQ, microcephaly,poor coordination, facial anomalies(short palpebralfissuies,short nose),joi"t *J;;;"od "no-ai"r, septaldefects.Hypertelorism(wide-spacedeyes)is also seen. 5. Drug interaction" a. Chronic useinduceshepaticmicrosomalenzymesand may enhancemetabolismof other drugs (e.g.,phenytoin,oral hypoglycemics) b. Acute ingestion may inhibit metabolismof other drugs competing for microsomal " enz).mes. c. Ethanol potentiatesthe activity of other CNS depressants(e.g.,sedative-hypnotics, anticonvulsants,antidepresants,anxiolytics,opioid analgesics). 5. Disulfiram (antabuse).Disulfuam is usedasa deterrentto ethanoluse.It is an adjunct in the treatmentof alcoholism. a. Mechanisn of action Disulfiram inhibits aldebde dehydrogenase,the second enzymein the metabolismof ethanol. Thus, patientson disulfiram who consume ethanolwill haveelevatedserumacetaldehyde levels,whidl resultsin the acetatdeh'yde . syndrome.The levelsof acetaldehyde in blood are5-I0 timesthat found in untreated individuals.

h a trubherl FetalAlcoholSyndrome ' GroMhretardation . Hypertelorism ' LowlQ . Developmental delay ' Grdiacmalformations

U* Ethanol induceshepatic microsomal enrymes. lt also $e effu{B acutelypotentiates of otherCNSdepressants.

Noh

'*-'-

Manvantibiotics have disulfimmlike effecSe.g., metronidazole, moxalactam, cefoperazone, etc.

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Neruous System

b. Side effects and toxicity (1) Symptoms of the acetaldehydesyndromebegin within 5-10 minutes of ethanol consumption and last between30 minutes and severalhours. Symptomsinclude systemicvasodilatation,pulsating headache,hypotension, orthostatic syncope, weakness,vertigo, blurred vision, nausea,vomiting, sweating,and respiratory difficulties. Fatalitieshavebeen reported.

ln a Nutshell Methanol toxicityresults from anaccumulation of its meta bolites, forma ldehyde, andformic acid. Treatment is withethanol.

(2) Adverse reactions of disulfiram (alone) include acneform eruption, urticaria, headache,dizziness,garlic-like and dermatitis;lassitude,fatigue,and restlessness; taste, and mild gastrointestinal disturbances; hepatotoxicity, enhanced by ethanol consumption; enhancedabsorption of lead;and teratogenicity(not to be used in pregnant women). B. Methanol (methyl alcohol) 1. Pharmacokinetics a. Absorption from the gastrointestinaltract and distribution are similar to ethanol. b. Methanol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase to formaldehyde and formic acid, respectively. 2. Indications for use.There is no clinical usage. 3. Toxicity a. Ingestion of methanol may be accidentalor for inebriation in those who consume methanol or denaturedethanol (to which methanol is as adulterant).A latency period of 8-40 hours may precedesymptoms. b. Metabolitesof methanol are responsiblefor most of the toxicity. (1) Metabolic acidosis is causedby formic acid. (2) Blindness is causedby formaldehyde damageof retinal cells. (3) Other symptoms include headache,nausea,vomiting, agitation, vertigo, and dyspnea.

Note Ethanol isalsousedto treat glycol poisoning. ethylene Note Fomepizole, analcohol dehydrogenase inhibitor, is alsousedasanantidote for gylcol methanol andethylene poisoning.

c. Acute methanol toxicity is often treatedwith ethanol, which has a higher affinity than methanol for alcohol dehydrogenase,thus reducing the production of the toxic metabolites. C. Ethylene glycol 1. Pharmacokinetics. Exposureis usuallyby inhalation, skin absorption, or ingestion (e.g., by drinking antifreeze).Ethylene glycol is metabolized by alcohol and aldehydedehydrogenaseto glycolic acid. Metabolic products are responsiblefor renal damage. 2. Toxicity a. Ethyleneglycol is a CNS depressantwith large quantities leading to narcosis,coma, and death. The chemical causessevereacidosisand renal damage,resulting in acute renal failure. b. Acute ethylene glycol poisoning is similar to methanol; ethanol is used as a substrate for alcohol dehydrogenase, thus decreasingthe rate of formation of toxic metabolites.

628

Pharmacology: DrugsAffectingthe CNS

DRUG DEPENDENCE, TOTERANCE, ANDABUSE A. Characteristics 1. Dependence a. Drug dependenceis a state in which an individual either psychologicallyor physically requiresa drug to feel well in the absenceof medical indications. (For a scheduleof controlled substances,seeTableV-32-$. ?able V - 32-4. Abbreviated schedule of controlled substances.* Schedule

Description

Examples

I

High abusepotential; no medical use High abusepotential; medical use Moderate abusepotential; medical use Low abusepotential; medical use Lowest abusepotential; medical use

Heroin, LSD, and methaqualone marijuana Morphine, cocaine,and amphetamines Codeine,thiopental, tetrahydrocannibinol Benzodiazepines

II III ry V

Diphenoxylatewith atropine

*A controlled substanceis a drug that has been determined to have abusepotential. LSD - lysergic acid diethylamide.

b. Psychologicaldependenceis defined as compulsivedrug-using behavior or craving. c. Physical dependence is a state in which withdrawal of the drug from chronic use or administration of an antagonistleadsto physicalsymptoms,usually oppositethose of acuteadministration of the drug.

Note Withdrawal symptoms areusually opposite ofthe effects ofthedrug.

d. Abstinence syndrome is the description of the symptoms observed after withdrawal of a drug to which an individual is physically dependent. 2. Tolerance a. Drug tolerance is the phenomenon in which individuals progressivelyrequire larger dosesof a drug to achievethe sameeffect. b. Three tfpes of pharmacologic tolerance are: (1) Dispositional (pharmacokinetic) tolerance develops when changesin pharmacokineticscauselessdrug to be presentat the site of action. The major mechanism is an increaseddrug metabolism with continued administration. (2) Pharmacodynamic tolerance developswhen adaptive changesin the target tissue occur, causingdecreasedresponsesto a given drug concentration.This may involve modification of neurotransmitter systems,such as changesin neurotransmitter release,or alterationsin the number or sensitiviryof receptors.

Tolerance Tolerance maybecaused by changes inthemetabolism of a drug(pharmacokinetic tolerance) orinthecellular response to thedrug (pharmacodynam ictolera nce).

(3) Behavioral tolerance developswhen there is adaptation to behavior-altering effectsof a drug. c. Thchyphylaxis is a rapidly developing tolerance to the effects of a drug, even after a few doses.An exampleis tachyphylaxisto amphetamineas a result of the depletion of catecholaminestores.

629

Neruous System

3. Measurement of a drug of abuse or its metabolite in the urine is an indication that the drug was used,but it does not indicate when the drug was used, or if there is a current performancedecrement.Plasmalevelsare a much better indication. B. Opioids 1. Dependence

In a Nutshell OpiateWithdrawal . Chills . Mydriasis

a. Patientswithdrawing from opioids experiencethe opiate withdrawal syndrome (especially with heroin and morphine), which begins 6-10 hours after the last dose; the time courseof effectsvarieswith the individual agent. b. Symptoms,which are most severe36_48hours after the last dose,include rhinorrhea, chills, piloerection, mydriasis, hyperventilation, hyperthermia, myalgias, diarrhea, vomiting, and irritability. Thesesymptoms subsidewithin I to 2 weeks,dependingon the drug.

. Diarrhea

c. Methadone withdrawal is not as severe;the onset of symptoms is delayed and more gradual and may last up to 2 weeks.

. Vomiting

d. Treatment

. Piloerection "going (hence, coldturkey") . Hyperventilation . Dysphoria . Anxiety . Muscle aches

(1) Methadone is used for controlled withdrawal or maintenance.This therapy is effectiveas a result of good oral availabiliry longer duration, and lesssedation and euphoria produced by methadonethan by heroin or morphine. (2) LAAM is a longer acting methadone-likecompound. (3) Naltrexone,a pure opioid receptor antagonist,is useful as an adjunct to therapy to block the effectsof any opioid agonist (e.g.,heroin) that may be taken. 2. Tolerance a. Tolerance develops rapidly when large doses are given frequently. Tolerance is minimized by giving small dosesat lengthy intervals. b. Patients and opioid addicts can experienceup to a 30-fold increasein the dose required to produce a given effect. c. Tolerance develops to all effects but to different degrees.Tolerance to the euphoria, analgesia,respiratory depression,hlryotension,emesisand urinary retention develops rapidly; toleranceto the miotic and constipatingactions developsmore slowly. C. Sedative-hypnotics: barbiturates, benzodiazepines, and alcohol 1. Dependence

Clinical Correlate Diazepam isusedto treat withdrawal fromCNS depressants to prevent or reduce seizure activity.

a. Acute effects of these drugs are due to CNS depressionand may include respiratory depression,coma, and death.Benzodiazepines are the safestof thesedrugs and rarely, if ever,causecoma when taken alone. b. Short-acting barbiturates causea severeand rapid withdrawal syndrome, similar to alcohol,whereasagentswith longer half-livescausesa more prolonged,lessseveresyndrome (symptoms may not appearfor 2-3 days). c. With short-acting agents (duration of action of 8-24 hours), symptoms include tremors, twitches, nausea,and vomiting. Seizurescan occur 1il8 hours into withdrawal. If severe,hallucinations and delirium may occur. d. Tieatment of withdrawal includes replacementwith a long-acting sedative-hlpnotic (diazepam).Clonidine and propranolol are used as adjuncts.

650

Pharmacology: DrugsAffectingthe CNS

2. Tolerance a. Both metabolicand pharmacodynamicmechanismsare involvedin tle development produceonly pharmacodyof toleranc€to barbituratesand alcohol.Benzodiaznpines namic tolerance. b. Thoughpatientsrequireprogressivelylargerdosesover time to achievea giveneffect, the level ofwhat constitutesa lethal doseofbarbiturates and alcoholrisesonlv modestly.This is in contrastto the dramaticrise seenwith opioids. D. CNSstinulants: amphetanines rnd cocaine

1.Dq'€nd€trcc

' !!:J!Si:!!

Amphetamines stimulate $e a. Anphetamines and cocaineare CNS stimulants that increasemental alertnessand of catecholamines and self-confidenceandproduceeuphoria"This is becauseofincreaseddopaminelevelsin : release the brain. Sympathomimeticeffectsinclude tachycardiaand hnrrtension asa result cocaine blodstheirreuptake. of their effecton peripheralnorepinephrinereleaseor reuptake,respectively.Seizure : with its local anestheticeffect. activity with cocaineis associated I h a l{Ubhell (1) Amphetaminederivativ€swith potent CNS effectsare dextroamphetamineand : : ThecentralefeG of methamphetamine(alsoknown asspeedor ice). : stimulanbarelargelydueto (2) crack is the ftee baseform of cocaine;it is smoked. i increases The in dopamine. b. Chronic use or excessivedosescan produce a psychoticstate witl delusionsand : ordiovascular efecbof Paranoia. stimulanb aredueh in norepinephrine. c. Psychologicaland phpical dependencecan oc{ur. Abstinenceproduceslethargy, : increases sleqriness,increasedappaite, prolongeddeep,and mentaldepression. Sfimulant withdrawal: 2. Tolerance . tncreased sleeping a. Toleranceoccursto the euphoria,anorexia,and the lethal dosewith regularuse. . lnceasedappetlte b. Litde or no toleranceoccursto the CNStoxicity. . DeDression E. Nicotine 1. Dcpendence a. Chronic nicotine use,asin cigarettesmoking,producesboth psychologicaland phpwith cardiovascular and respiratorydisical dependence. Smokinghasbeenassociated and deaths, ease cancer

:

b. Withdrawalryndromevariesin intensityamongindividuals.Symptoms,which usually beginwithin 24 hours becauseof nicotinet short biologichdf-life, indude irritability, : anxiety,headaches, increasedappetite,insomnia,and difficulty irnpatience,resdessness, in heart rate,blood pressure,and circulating in concentrating.Thereis alsoa decrease andskin temperatureincreases. epinephrine.Blood flow to the skin increases, 2. Tolerance a. With repeateduse,tolerancedevelopsto the dizziness,nausea,andvomiting associat- i ed with nicotineb. l:ss tolerancedevelopsto the increasein blood pressureand hand tremor and to the in skin temperatur€. decrease c. Chronic useleadsto an increascin nicotine metabolismbv the liver.

i

6rl

Neruous System

3. Trcatment of d?€ndence. Nicotine is availablein gum and transdermalpatchesto aid individualstrying to quit smoking. '

F. Caffeine 1..Dqrcndence a. Caffeineproducesboth prychologicaland physicaldependence.Symptomsof withdrawalappearwithin 12-24hours. b. The most common symptom of withdrawal is headache.Other symptomsinclude fatigue,lethargy,anxiety,and irritability. c. Chronic ingesion of more than 250 mg of caffeinedaily can be associatedwith nervousness, resdessness, insomnia,muscletwitching, and cardiacand gastrointestinal disturbanc€s. 2. Tolerancedwelops to the dysphoriaand anxiety. G. Cannabinoids 1. Generalclaracteristics

Cli{!a! ,C9m-Fte GnnibinoidshaveDotential theraDeutic usesas

a. Tetrahydrocannabinol is the activeingredientofnarijuana. Hashishis partially purified and more potent.

o||UE|||EUL), O> OPPEUTE

b' cannabinolsact by binding to specificreceptorsin the cNS to producetheir effects'

stimulants, andin thetherapy of giaucoma. Dronabinol, or oralTHC,hasbeenapproved forusein nausea and vommn8 a550oale0 wm chemotherapy andf'r AIDS wasting syndrome.

c. Acuteeffectsinclude euphoria,distortionsin perceptionof time and space,disinhibition, increasedappetite,and reddeningof the conjunctiva. d. Cannabinoidsreduceintraocularpresure (usefirlin somepatientswith glaucoma)and havean antiemeticeffect(usefi.rlin somecancerpatientsundergoingchemotherapy). e. The increasein app€titeis the basisfor their usein the AIDS wastingsyndrome. 2. Dqrendence

llS

a. Withdrawal symptoms,following chronic heavyuse,begin within a few hours.

A putative endo8enous liSand forthe cannabinoid receptor, anandamide, haSbeen identified.

b. Symptomsof with&awal include restlessness, irritability, insomnia, neryousness, decreasedappetiteand weight loss,rebound increasein REM sle€p,increasedbody temperature,chills, and tremors. 3. Tolerance a. Tolerancedevelopsto changesin mood and in impairment of performanceof psychomotor skills. b. Tolerancealsodevelopsto the tachycardia,increasein body temperature,and decrease in skin temperature. H. Inhalants. Only a few of the many compoundsusedasinhalantshavebeensystematically studied.Abuseis due largd to ready availability,low cost, quick intoxicating effect, and short duration of action (Fl5 minutes).Toxicityvarieswith the individual agents. .

1. Chlorinated solventsdecrease cardiaccontractility,leadingto a reflexincreasein sympathetic activity. 2. Fluorinat€d hydrocarbonsfound in aerosolpropellantsmayleadto cardiacarrhythmias.

6t2

Pharmacology: DrugsAffectingthe CNS

3. Ketones havebeen reported to causepulmonary hlpertension. 4. Lacquer thinner may causefatal neurologic deterioration and peripheral neuropathy. 5. Toluene has been associatedwith renal damageand diffuse CNS atrophy. 6. A-yl nitrite may result in profound vasodilatationand a suppressionof immune function.

ANTIEPITEPTIC AGENTS Seizuresare due to abnormal electrical dischargesof cerebralneurons. Epilepsy is the state of recurrent seizures.Seizuremanifestationsvary with the site of the focus and pathwayof discharge spread;they include changesin motor activiry loss of consciousnessor confusion with subsequent amnesia,hallucinations and illusions in any sensorymodaliry and behavioral changes. A. Overview. Types of epilepsy are classifiedaccording to the clinical features of the seizures, many of which have characteristicabnormalitieson the electroencephalogram(EEG). l. Generalized seizures are bilateral symmetrical manifestations. a. Petit mal (absence)seizures (1) Clinical features include brief (5-20-second) episodes of loss of awareness. Occasionally,the seizuresare associatedwith minor motor activity (e.g.,blinking), an onset usually between ages4-8, and a usually favorable prognosis with spontaneousresolution in most cases;however,in some cases,another seizure type develops. (2) The EEG showsgeneralized3-secondspike and a slow wavepattern. (3) Ethosuximide is the drug of choice for treatment; valproic acid is equally effective but has greater toxiciry (especially hepatic). Clonazepam is available, but causessedationand tolerance.Lamotrigine is a newer agentused in children. b. Tonic-clonic (gt*d

In a Nutshell . Seizures: abnormal electric discharge of cerebral cortex . Epilepsy: recurrent spontaneous seizures ClinicalCorrelate Petitmalseizures seenin children arecharacterized by briefepisodes of lossof awareness. Ethosuximide is thedrugof choice. Valproic acidisuseful forpetitmaland allotherseizure types.

mal) seizures

( 1) Clinical featuresinclude loss of consciousness associatedwith the tonic phaseof extensorrigidiry followed by clonic movements; incontinence of urine and feces or tongue biting may occur during the clonic phase.Seizuresare intermittent, though repetitive tonic-clonic seizureswithout recovery of a normal attentive state may occur. (2) The EEG shows symmetrical electrical dischargesduring the seizure;between seizures,the EEG may or may not be normal. (3) Intermittent seizures are principally treated with carbamazepine and phenytoin. Valproic acid is also useful. Phenobarbital (in children) and primidone are lesslikely to provide complete control of seizureswhen used alone as initial treatment. More than one drug may be required. Status epilepticus is usually treated with intravenous diazepam or lorazepam.Intravenous phenytoin or phenobarbital is given for longer control. Continuous infusion with diazepamor lidocaine,or generalanestheticswith neuromuscular-blockingagentsmaybe required.

ClinicalCorrelate Tonic-clonic seizures arethe characteristic seizures of severe epilepsy. Carbamazepine andphenytoin are thedrugs ofchoice. ClinicalCorrelate Diazepam isthedrugof choice forstatus epilepticus.

c. Myoclonic epilepsy. TWo forms of symmetric myoclonus are associatedwith EEG abnormalities: infantile spasmsand childhood myoclonic epilepsy.Myoclonus refers to a group of involuntary movements characterizedby jerking movements, many of which are not epileptic. ( 1) Infantile spasmsaretreatedwith adrenocorticosteroidsor corticotropin. Valproic acid or clonazepammay alsobe used.Prognosisis poor.

6tT

NeruousSystem

(2) Childhood myoclonus epilepsyis treated with valproic acid, diazepam,and clonazepam.Lamotrigine is effectivein children with myoclonus status.Phenytoin is not used due to lack of efficacy,and it may produce hlperactivity in children. d. Febrile seizures (1) Theseare brief generalizedseizuresassociatedwith fever in the absenceof CNS infection, and usually occur between the agesof 6 months and 5 years. (2) Tieatment includes antipyretics.A single dose of phenobarbital may be required; prophylactic phenobarbital is administered when seizuresare recurrent.

Note Focal seizures beginata "focus" andmayspread (become secondarily generalized). In a Nutshell . Complex partial seizures alterconsciousness. . Simple partial seizures do notalterconsciousness.

2. Focal (partial) seizures are characterized by abnormal dischargesarising from a focal area of the brain; these dischargesmay remain localized,spreadto adjacentregions,or become generalized. a. Simple focal seizures involve no loss or alteration of consciousness. b. Complex seizuresare associatedwith impairment of consciousness, motor automatisms (lip smacking),confusion,and amnesia. c. Tieatment includes carbamazepine,phenytoin, primidone, and phenobarbital, listed in order of effectiveness. Valproic acid may be used.Felbamate,gabapentin,lamotrigine, and vigabatrin are effective in the treatment of partial seizures.Many patients require more than one anticonvulsant. 3. Neonatal seizures occur during the first 30 daysof life. a. Neonatal seizuresare characterizedby: ( 1) Tonic deviation of the eyes,repetitive blinking, or rapid eye movements (2) Clonic movementsof posturing of one or more extremities (3) Grimacing (4) Apnea (5) Generalizedtonic-clonic seizures(rare) b. The causesof these seizuresmay include perinatal hypoxia or trauma, metabolic abnormalities,drug withdrawal from addicted mothers, aminoacidurias,CNS infection, or developmentalanomalies. c. Tieatment includes correction of any metabolic abnormality, phenobarbital (the drug of choice),and phenytoin.

B. Antiepileptic drugs. There are two principal mechanisms of anticonvulsant action: inhibi-

ln a Nutshell Antiepilectis actto either: . Inhibit a focus . Inhibit spread ofa discharge

tion of seizure focus (i.e., the neurons generating the abnormal discharge) and inhibition of spread of the discharge. Most of the drugs act by reducing the excessivedischarge of neurons.ThbleV-32-5lists the drugs used in eachseizuretype. 1. Phenytoin (diphenylhydantoin) a. Mechanism of action. Phenytoin acts by inhibiting voltage-gated sodium channels, thus suppressingepisodesof repetitive neuronal firing. b. Pharmacokinetics (1) Phenytoin is slowly absorbedfollowing oral administration. (2) Ninety percent of the drug is bound to plasmaproteins.

6t4

DrugsAffectingthe CNS Pharmacology:

(3) The concentration reaching the cerebrospinalfluid is equal to that of the free drug level in the blood. ( ) The drug is metabolizedby hepatic microsomal enzymes;the major metabolite is inactive. (5) Plasmahalf-life is 6-24 hours. c. Indications for use. Phenytoin is effective in many forms of epilepsy except absence seizures.It is also usefrrl in the treatment of trigeminal neuralgia and has limited use as an antiarrhythmic agent.

Clinical Correlate forall iseffective Phenytoin absence. typesexcept seizure

Thble V-32-5.Antiepileptic drugs. Seizure Type Generalized Absence (petit mal) Tonic-clonic (grand mal) Myoclonic Febrile Partial

Status epilepticus*

Preferred Drugs

Alternatives

Ethosuximide and valproate Carbamazepineand phenytoin Valproate Antipyretics and phenobarbital Carbamazepine, phenytoin, and valproate

Clonazepam

Diazepamand lorazepam

Phenobarbital Clonazepam

Gabapentin,lamotrigine, phenobarbital,primidone, and felbamate Phenobarbital and phenytoin

*Status epilepticus is a seriesof rapidly repeated convulsions that can be life-threatening if untreated.

d. Side effects and toxicity ( 1) Phenytoin exertsits therapeuticeffectwithout causinggeneraldepressionof the CNS as do the other drugs. (2) CNS symptoms may include irritabiliry nausea,depression,nystagmus,ataxia, diplopia, confusion, and coma.

In a Nubhell sideeffemof Unique phenytoin includegingival andhirsutism. hyperplasia

(3) Gastrointestinalsymptoms include nauseaand vomiting. (a) Phenytoin causesgrngival hyperplasia. (5) Hirsutism is a common effect. (6) Other adversereactions include osteomalacia,folate-responsivemegaloblastic anemia, hypersensitivity reactions, blood dyscrasias(aplastic anemia), and peripheral neuropathy. e. Drug interactions (1) Drugs that increaseserum phenytoin levelsvia interferencewith its metabolism include warfarin, chloramphenicol, cimetidine, disulfiram, doxycycline, isoniazid, and sulfonamides. (2) Drugs that reduce serum phenytoin levelsinclude ethanol, carbamazepine,pyridoxine, theophylline, and folate.

Note phenytoin Atlowbloodlevels, metabolism. first-order exhibits levels, Atmoderateto-high phenytoi n exhibitszero-order kinetia.

655

Neruous System

(3) Phenytoin-induced decreasedserum levels of other drugs via increased metabolism include warfarin, carbamazepine, chloramphenicol,corticosteroids, haloperidol, and oral contraceptives. 2. Phenobarbital a. Mechanism of action. Phenobarbital enhancesthe effects of GABA by increasingthe duration of opening of the chloride channel of the GABAAreceptor.It may also reduce the calcium-dependentreleaseof neurotransmitters.

In a Nutshell Phenobarbita I potentiates CABA-ergic transmission at theCABA^ receptors. lt is effective withallseizure types except absence.

b. Pharmacokinetics. Phenobarbital is 50olobound to plasma proteins. Seventy-five percentis metabolizedby hepatic microsomal enzymesand conjugated;2|o/ois excreted unchangedin the urine. The plasmahalf-life is 50-120 hours. c. Indications for use ( I ) Phenobarbitalis effectivein tonic-clonic and partial seizures. (2) It is the drug of choicein febrile seizureswhen an anticonvulsantis necessary. (3) It is useful in statusepilepticus,especiallyin children. d. Side effects and toxicity (1) CNS symptoms include sedation,irritabiliry confusion, respiratory depression, nystagmus,ataxia,and coma. (2) Other adversereactions include rash, folate-responsivemegaloblasticanemia, and osteomalacia. (3) Abrupt withdrawal may precipitatestatusepilepticus.

Note Phenobarbital increases its ownmetabolism aswellas themetabolism of manyother drugs byinducing P450.

e. Drug interactions (1) Drugs that increase phenobarbital levels via interference with metabolism include ethanol (short-term), chloramphenicol,and valproic acid. (2) Drugs that reduce phenobarbital levels by increasing its metabolism include ethanol (chronic use) and pyridoxine. (3) Barbiturates decreaseserum levels of a variety of drugs via increasedhepatic microsomal metabolism. 3. Primidone a. Mechanism of action is similar to phenobarbital. b. Pharmacokinetics. Primidone is rapidly and completely absorbed following oral administration. It is metabolized to phenobarbital and phenylethylmalonamide, both active products. The half-life of primidone is 5-15 hours; the half-life of phenylethylmalonamideis 16 hours. c. Indications for use. Primidone is generallya second-linedrug effectiveagainstgeneralizedtonic-clonicseizuresand simple and complex partial seizures.It is usedin combination with phenytoin or carbamazepine.It is sometimes used to treat myoclonic seizuresin young children. d. Side effects and toxicity. Adverse reactions occur from the parent drug and its metabolites.Sideeffectsinclude sedation,respiratorydepression,vertigo,ataxia,dizziness, nystagmus, diplopia, nausea, and rarely, a lupus-like syndrome and blood dyscrasias.

656

DrugsAffectingthe CNS Pharmacology:

e. Drug interactions (1) Carbamazepineand phenytoin alter its metabolism, reducing plasma levels of primidone but increasinglevelsof phenobarbital. (2) Primidone causesincreasedmetabolism of oral contraceptivesand quinidine. 4. Carbamaznpine a. Mechanism of action. Carbamazepine inhibits voltage-gated sodium channels, resulting in decreasingepisodesof repetitive neuronal firing. b. Pharmacokinetics. Carbamazepineis slowly and erratically absorbed following oral administration. The drug is metabolized to an active product, which reaches50o/oof levelsof the parent compound in plasmaand brain. Half-life is 10-20 hours. The drug inducesits own metabolism. c. Indications for use. Carbamazepineis effectivein generalizedtonic-clonic seizuresand in simple and complex partial seizures.It is usefi.rlin the treatment of trigeminal neuralgia.

In a NuBhell canbeused Carbamazepine typesexcept forallseizure absence. lt isalsousedfor neuralgia. trigeminal

d. Side effects and toxicity (1) CNS symptoms include ataxia,sedation,nystagmus,diplopia, and convulsions. (2) Other adverseeffectsinclude nauseaand vomiting, oliguria, hepatocellularand cholestaticjaundice, bradycardia and cardiovascularcollapse,water retention and hyponatremia,and hypersensitivityreactions. e. Drug interactions (l) Drugs that increase carbamazepinelevels via interference with metabolism include cimetidine, erythromycin, and isoniazid. (2) Drugs that reduce carbamazepinelevels by increasing metabolism include phenytoin and valproate. (3) Lithium enhancescarbamazepinetoxicity. 5. Valproic acid a. Mechanism of action. Various mechanismsof action havebeen proposedfor valproic acid, including the inhibition of GABA transaminase(reducing GABA metabolism) and enhancingpotassiumconductance(causinghyperpolarization).

Clinical Conelate Lithium enhances ne'ssideeffects; carbamazepi areusedin bipolar bothdrugs has lithium although disorder, noantiepileptic effects.

b. Pharmacokinetics. Valproic acid is rapidly and completely absorbed following oral administration. It is metabolized to two active metabolites. The drug is 90oloprotein bound. It appearsto be transported into the cerebrospinalfluid (CSF)by a carrier. c. Indications for use. Valproic acid is one of the preferred drugs in the treatment of absenceseizures.It is usefi.rlin myoclonic, akinetic, and atonic seizuresin young children. It has been shown to be effective in a variety of partial and generalizedseizures. d. Side effects and toxicity (1) CNS symptoms include sedation,tremor, and ataxia.

In a Nubhell

(2) The most serious side effectsare hepatotoxicity and hemorrhagic pancreatitis.

Valproic acidisuniquely types, in allseizure effective absence. including

(3) Other adverseeffectsinclude nauseaand vomiting, mild alopecia,and weight gain. e. Drug interactions (1) Carbamazepinereducesplasmalevelsby increasingmetabolism.

6t7

l{ervousSystem

(2) Antacids increaseabsorption, and salidates displacevalproic acid from binding sites,thereby increasing free drug levels. (3) Valproic acid reducesthe metabolism of phenobarbital. 6. Ethosuximide a. Mechanism of action. The exact mechanism is not known. Ethosuximide may inhibit cdcium channels.It does not alter sodium channels,nor GABA-mediated effects.

ln a Nutshell Ethosuximide canbeused onlyforabsence seizures.

b. Pharmacokinetics. The drug is completely absorbedfrom the gastrointestinal tract. It is well-distributed with little protein binding. Ethosuximide is metabolized by hepatic microsomal enzfmes to inactive products. Plasmahalf-life is 40-50 hours in adults, less(30 hours) in children. c. Indications for use. It is the drug of choice in absenceseizures. d. Side effects and toxicity (1) CNS symptoms include sedation and headache.It may exacerbatetonic-clonic seizures. (2) Other adverseeffects include nausea,vomiting, anorexia, rash, blood dyscrasias (leukopeniaand aplasticanemia),lupus-like syndrome,and Stevens-Johnson syndrome. 7. Benzodiazepines

ln a Nutshell Benzodiazepines areusedfor status-epilepticus anddruginduced seizures.

a. Mechanism of action. Benzodiazepinesact by enhancing the inhibitory effects of GABA at the GABAA receptor to increasechloride influx, thus causing hyperp olarization of neural cells. b. Pharmacokinetics. The drugs are well absorbed from the gastrointestinal tract. Eighty-five to ninety-nine percent are bound to plasma proteins. Some are metabolized to active products, which account for their prolonged duration. c. Indications for use (1) Diazepam and lorazepam are given intravenously in the treatment of status epilepticus. They are also useful in the treatment of drug-induced seizures.

ClinicalCorrelate Flumazenil, a benzodiazepine antagonist, isusedfor benzodiazepine overdose.

(2) Clonazepam is a long-acting analog, effective in the therapy of absenceseizures and myoclonic seizuresin children. (3) Clorazepate,which is hydrolyzed in the stomach to desmethyldiazepam,is effective in combination with other drugs in the treatment of partial seizures. d. Side effects and toxicity, Intravenous diazepam may causerespiratory depressionand hypotension. Other less severeeffects are sedation, irritabiliry ataxia, diplopia, and dysarthria. Sedation is the most common effect with clonazepam and clorazepate. 8. Newer agents

ln a Nutshell Newer Antiepileptics . Cabapentin . Lamotrigine . Felbamate . Topiramate

658

a. Gabapentin is a GABA analog useful in the treatment of partial seizures.Adversereactions include dizziness,fatigue, somnolence,and ataxia. It is usually well-tolerated. b. Lamotrigine is useful as an adjunct in partial seizures.It prolongs inactivation of neuronal sodium channels.Adverse reactions include a potentially life-threatening rash, dizziness,headache,and minimal sedation. c. Felbamate is an agent found usefrrl in the treatment of partial seizuresand LennoxGastautsyndrome in children.In late l994,use of felbamatewas associatedwith aplastic anemia; accordingly,the drug use was suspended.Later it was recommended only

Pharmacology: DrugsAffectingthe CNS

asa second-lineagentin patientsthat do not respondto other antiepileptics.The drug may act through NMDA receptors. d. Topiramate is effective against partial and tonic-clonic seizures.Adverse reactions include sedation,renal stones,and weight loss.

DRUGS ANTIPARKINSONIAN Parkinson'sdiseaseis an idiopathic movement disorder characterizedbybradykinesia,resting tremor, rigidity, and postural instability. The diseaseusually appears after the age of 50 and afflicts lo/o of the population over the age of 65. People exposed to the toxin N-methyl-4-phenyl-1,2,3,6-retrahydropyridine(MPTP) develop Parkinson-like symptoms. Other causes of parkinsonism include drug toxicity (antipsychotics, reserpine), carbon monoxide, manganesepoisoning, viral encephalitis,head trauma, and stroke. Pathologically, degeneration of the substantia trigt" and the dopaminergic nigrostriatal pathway (from substantianigra to caudateand putamen) is found. Dopamine depletion in the striatum causes a relative cholinergic overactiviry which may contribute to the symptoms (especially tremor). Therapy for parkinsonism includes dopaminergic agonistsand muscarinic cholinergic blocking drugs.A list of effectivedrugs is presentedin TableV-32-6. A. Dopaminergic agonists

ln a NuBhell

1. kvodopa (r-dopa) a. Mechanism of action. Levodopa is a precursor of dopamine. It is converted to dopamine by aromatic r-amino acid decarboxylase(dopa decarboxylase)to restore dopamine levels. b. Pharmacokinetics. Levodopa is absorbed from the gastrointestinal tract. More than 95olois metabolized to dopamine by peripheral dopa decarborylase; less than 2o/o reachesthe brain. Therefore,when used alone,largedosesare required,and peripheral side effectsare common.

L-dopa replaces lost lt is endogenous dopamine. with coadministered (which carbidopa doesnot barrier) cross theblood-brain peripheral to inhibit metabolism of L-dopa.

TableV-32-6.Agentsusedin the treatmentof Parkinsonism. TherapeuticAgent

MechanismofAction

Note

Levodopa Carbidopa

Precursorto dopamine Inhibitor of peripheral dopa decarboxylase; of levodopa enhanceseffectiveness Dopaminergic receptoragonist Dopaminergic receptoragonist Stimulator of dopamine release Inhibitor of monoamine oxidasetfpe B Muscarinic receptor antagonist Muscarinic receptorantagonist Muscarinic receptorantagonist Muscarinic receptorantagonist

Pramipexole isa recently approved drugfor Parkinson lt isa dopamine disease. agonist andanantioxidant.

Bromocriptine Pergolide Amantadine Selegiline Benztropine Tiihexyphenidyl Proryclidine Biperiden

Indications for use. Levodopa is usually given with carbidopa, a peripheral dopa decarborylaseinhibitor for the treatment of Parkinson disease.It may be given alone to patients who are sensitiveto the development of involuntary movements causedby the combined preparation.

659

Nervous System

Clinical Correlate L-dopa administration can resultin toxicside-effects related to excessive dopamine levels, suchaspsychotic behavior andhyperkinetic movement disorders,

d. Side effects and toxicity (1) CNS effects include dyskinesiasand other involuntary movements and behavioral changessuch as paranoia and hallucinations. (2) Nauseaand vomiting may occur due to direct stimulation of the chemoreceptor trigger zone. (3) Cardiovascular effectsinclude postural hypotension and, rarely, tachycardia and other arrhythmias. (4) Levodopa may elevateliver function tests. (5) Most patientsexperiencesome adversereactions,which are dose-dependent.An on-off syndrome may occur in which the drug suddenly loses its effectiveness. Peripheral sympathomimetic effects are reduced by use of carbidopa. e. Drug interactions

Bridgeto Biochemistry (vitamin Pyridoxine Bu)isa cofactor forall decarboxylation reactions.

(1) Pyridoxine increasesperipheral metabolism of levodopa,thus reducing its effectiveness. (2) Reserpine,which depletesdopamine stores, and antipsychotics,which block dopamine receptors,exacerbateparkinsonism. (3) Combination with MAO inhibitors may causehypertensivecrises. (a) Anticholinergicsmay reducegastrointestinalabsorption.

2 . Carbidopa a. Mechanism of action. Carbidopa is an inhibitor of dopa decarboxylase, which does not crossthe blood-brain barrier. Therefore,it inhibits the peripheral metabolism of levodopa,increasingthe percentageof the drug that reachesthe brain. b. Indications for use. Carbidopa is given in combination with levodopa in the treatment of parkinsonism.It reducesthe amount of levodopa neededby the patient and minimizes peripheral side effectsof levodopa. c. Side effects and toxicity (1) When administeredalone,this agentis without toxic effectsat therapeuticdoses. (2) When administeredwith levodopa,it enhancesthe CNS effectsand toxicities of levodopa.

3 . Bromocriptine

Note Bromocriptine isa dopamine agonist usedin end-stage Parkinson disease, whenLdopalosesitseffectiveness because of progressive degeneration of nigrostriatal neur0ns.

a. Mechanism of action. Bromocriptine is an ergot derivative, which is an agonist at dopaminergic receptors. b. Pharmacokinetics. The drug has a half-life of 8-12 hours. It is 30oloabsorbedfrom the gastrointestinaltract and undergoesextensivefirst-passmetabolism. c. Indications for use (1) Bromocriptine is usually usedin combination with levodopain the treatment of parkinsonism to allow a reduced dosageof levodopa.It is also used when levodopa is associatedwith the on-off phenomena. (2) Bromocriptine is used in the treatment of hyperprolactinemia endocrine abnormalities.

640

and other

Pharmacology: DrugsAffectingthe CNS

d. Sideeffectsand toxicity (1) CNS symptomsinclude involuntary movement(lesscommon than levodopa), behavioralchanges,hallucinations,delirium, and conf.rsion. (2) Other side effects include nauseaand vomiting, arrhythmias, and postural hn>otension. (3) The drug is contraindicatedin patientswith recentmyocardialinfarction or prydriatric illness. (4) It maygiverise to a first-doseph€nomenacharacterizedby suddencardiovascular collapse. 4. Pergolide.Pergolideis a dopaminergic(Dl and D2) r€ceptoragonisLIts therapeuticuse with longand pharmacologyare similar to bromocriptine.It tendsto lose effectiveness t€rm use.

s.Amantadine a. Mechanismof action. Amantadinestimulates the releaseof dopamine from presynaptic vesicles.It may alsodelayreuptake. b. Pharrnacokinetics.Amantadineis well-absorbedfollowing oral administration.It is excretedunchangedin the urine and hasa plasmahalf-life of24 hours. c. Indications for use (1) Amantadineis usedin t}te treatm€nt of Parkinsondisease-Effcacy is reduced after 2 months of therapy;it is thereforeoften usedintermittently asan adjunct. (2) Amantadineis alsousedin prophylaxisand treatmentof influenzaA infections.

!ti!-s9!9!l-q-9-li9l9.!y Amantadine wasdeveloped as ananti-viral agentandwas discovered to havea beneficial effecin Parkinson diseaselt stimulates dopamine release. lts usein A is thetreatment of influenza discusedin theAntimicrobial Agenb,chapter of ceneral PrinciDles BookI 0olumel).

d. Sideeffectsand toxicity (1) Amantadineis r€lativd fue of sideeffecrc;most are reversible.Mverse reactions aremostcommonin patientswith impairedrenalfunction. (2) CNSeffectsinclude insomnia,arxiety, andbehavioralchanges. (3) Amantadinemay induce congestiveheart failure (CHF) in patientswith preexistingcardiacinsufficiency. 6' selegiline (r-deprenyl) a. Mechanisn of action. Selegilineis a selectiveinhibitor of MAO tylte B (MAO-B), which metabolizesdopamine. b. Indications for use. Selegilineis used as an adjunct in the treatm€nt of Parkinson diseasein patients who are being managedwith levodopa-carbidopaand exhibit reducedresponseto therapy.The addition of this drug reducesthe requireddoseof levodopa,and the interval betweendosescanbe increased.The drug appearsto have limited valuein patientswith advanceddisease.

!r! 9..!-rtF..!-e!! seregirine is a I!iAO-B inhibitor,andisanadjundin thetreatment of parkinson disease

c. Sideeffecrsand toxicity (1) The drug increaseslevodopa-associated adversereactions;thus, the dose of levodopamay haveto be reduced. (2) At higher doses,the drug becomeslessselectivefor MAO-B and may potentiate when tyramine-likesubstances arepresent. the effectsof catecholamines (3) Other adversereactionsincludenausea,dizziness,lightheadedness, and fainting.

641

Neruous System

In a Nubhell (-)

(+)

striatum

B. Anticholinergic drugs. Normally, dopaminergic neurons have an inhibitory effect on cholinergic neurons in the striatum. Due to a decreasein dopaminergic activiry there is a decreaseof this inhibitory control of the excitatory cholinergic neurons. Anticholinergic agentsare sometimesgiven as adjuncts to reduce the relative increasein cholinergic activity. 1. Mechanism of action. These drugs compete with acetylcholine for the muscarinic receptors. They have affinity but no efficacy and, thus, block the effectsof acetylcholine.

v

2. Pharmacokinetics. Thesedrugs are given by the oral route. They are well-absorbed from the gastrointestinal tract and distribute to the CNS.

(to substantia Substantia niora pars . "6^pi""t"

ntgra pars reticulata and intemalglobal pallidus)

. ToolittleDAleads to excessive striatal ACh. . So,anticholinergia area useful adjunct.

3. Indications for use. These drugs are used as adjuncts with dopaminergic agents in the treatment of parkinsonism. They appear to improve tremor and rigidity but have little effect on bradykinesia. a. Benztropine has an antimuscarinic potency 25o/othat of atropine and has antihistaminic properties. b. Trihoqrphenidyl has weak antimuscarinic and antispasmodicproperties. c. Procyclidine is mostly used as a substitute for trihexyphenidyl. d. Biperiden is a congener of trihexyphenidyl.

l{o{e

4. Side effects and toxicity

Anticholinergics suchas benztropine and trihexyphenidyl helpto restore theDA/ACh balance inthestriatum.

a. These drugs produce classic antimuscarinic side effects including: (1) Sedation,confusion,hallucinations (2) Dry mouth, constipation,and urinary retention (3) Blurred vision and precipitation of acuteclosed-angleglaucoma (4) Tachyarrhythmias b. Antimuscarinic drugs should be avoided in patients with closed-angleglaucoma,prostatic hypertrophy, or obstructive gastrointestinal disease.

In a Nutshell Disease

Drug

Essential tremor

Propanolol

Huntingon disease

Neuroleptia

Tourette syndrome

Neuroleptia

5. Drug interactions include tricyclic antidepressantsor antihistamines since these drugs have antimuscarinic properties and, thus, may be additive.

DRUG THERAPY FOROTHER MOVEMENT DISORDERS A. Tremor. Propranolol has proven usefi,rlin the treatment of physiologic and essentialtremor. B. Huntington disease.Huntington diseaseis an inherited disorder causedby a degeneration of striatal GABA-ergic and cholinergic neurons and a deficiency of cholinergic function. Haloperidol and the phenothiazines,both of which block dopaminergic receptors,are useful in therapy. Therapy to enhanceGABA or acetylcholine brain aaivity is not currently successful. C. Tourette syndrome. This disorder is currently treated with dopaminergic (Dr-receptor) blockers (e.g.,haloperidol).

ilz

Psychoactive Drugs

physiology, Pathologic changes in theanatomy, of thebraincontribute andbiochemistry substantially to mental illness. ln addition to psychological useof drugs isa major therapies, patients. component in thetreatment However, forpharmacotherapy it is of mental to succeed, crucial to makethecorrect to choose theappropriate drugs, andto befamiliar withthe diagnosis, pharmacology of theseagents. Thischapter reviews thedrugsusedinthetreatment of depression andpsychosis.

ANTIDEPRESSANTS Depresion,a mood disorder,is manifestedby feelingsofterrible sadness andhopelesness;mental slowness;agitation;insomnia;psychoses; lossof energy,sexdrive,and hunger;and a signifi(bipolar) disordersaremanifestedby mood swingsbetween cantrisk ofsuicide.Manic-depressive mania(manifestedby euphoria,elation,restlessnes, hyperactivity,urd insomnia)anddepression.

ilote ---''

Depresionisthoughtto be ousedbya deficiency of norepinephrine and/or is believedto be causedprimarilyby a defciencyofthe ,{ Ilicyclicsandheterogrclic.s.Depression Antidepressant drug catecholamines andindoleamines: norepinephrine,serotonin,and,to a less€rodent,dopamin€ . serotonin. therapyinffeases (i.e.,the biogenicaminedeficiencytheory).This deficiencyis hypothesized thesynaptic to secondarilylead to up-regulationof the correspondingreceptors,causingthe clinicalmanifestations descibed. larelsof oneor bothof these The irnmediateeffectsof these drugs include a bloclade of the cateclolamine and/or : neurotransmitters anda indoleaminere-uptakesystemsat pre.synapticnerre terminels.However,therapeuticeffects I receptor down+egulation of thesedrugs do not app€arwrtil after 2-4 weels. The inhibition of the re-uptakeis now (delayed action). thought to increasethe levelsof synapticneuotransmittersand to producea compe ntory down+egulationof correspondingreceptorsto the normal status(FigureV-33-1).Convers€ly, maniamight be associated with an excess of theseamines.

645

Nervous System

Postsynaptic terminal

Presynaptic terminal

,-

NT )

3-/

Normalstatus

ro

@ .--'@ @ J

R

NT

R

R I,l R\\

s/

Rff

\='ry

(NT) (e.9.,NE, s-HT) levelslead Reducedneurotransmitter eventuallyto up-regulationand an increasein receptors(R) with clinicalmanifestations of depression.

.--

R R DNT F R R

n(

ft -\

Rll \-ff

Drug (D) inhibitsthe uptakeof NT, immediately leadingto increasedsynapticlevels,which,over the next few weeks,down-regulatesreceptorsto "normal"levelsand restoreshealth. Figure V-33-1.Status of "normal" neurons, of "abnormal" neurons leading to depression, and action of drugs to correct the "abnormality."

1. Pharmacologic properties a. Except those with strong anticholinergic properties, tricyclics are usually well absorbed after oral administration, and they show good central nervous system(CNS) penetration. b. They are mostly oxidized by hepatic microsomal enzymes and conjugated with glucuronic acid. c. Oxidation and demethylationof some parent drugs resultsin the production of active metabolites,some of which are also available as separatedrugs. d. Most tricyclics are strongly bound to plasmaproteins. 2. Specific agents a. Tricyclic antidepressants. Tertiary amines include amitriptyline, imipramine, doxepin, and trimipramine. Secondaryamines include desipramine, nortriptyline, and protriptyline.

644

Pharmacology: Psychoactive Drugs

Thble V-33-f . Side effects of some antidepressant drugs. Drug

AntiOrthostatic Cholinergic Sedation Hnrotension

Amitripryline Imipramine Doxepin Desipramine Fluoxetine Trazodone

+++ ++ ++ + 0 0

+++ ++ +++ + + +++

+++ +++ +++ ++ 0 ++

Insomnia

Sexual Dysfunction

0 0 0 0 +++ 0

++ ++ ++ + +++ ++

(+) Indicates extent of side effects

b. Heterocyclics include amoxapine, maprotiline, trazodone, and bupropion (secondgeneration antidepressants)and mirtazapine, nefazodone, and venlafaxine (thirdgeneration antidepressants).Tiazodone, nefazodone,and mirtazapine block 5-HT? receptors. 3. Choice of agent. Theseagentsare therapeutically similar. The choice of drug dependson the previous experienceof the patient, side effects,and the intended duration of action. A comparison of the side effectsof some of the major antidepressantsis provided in Thble

v-33-1. 4. Indications for use include depression(unipolar, bipolar), certain pain syndromes (neuralgias),prophylaxis of migraine, enuresis(bed wetting) in children (imipramine is usedin children over 6 yearsas a last resort), bulimia, diabetic neuropathy, and phobias. 5. Side effects and toxicity a. Blockade of muscarinic receptors by some drugs leads to anticholinergic effects (more common with tertiary amines),including constipation,urinary retention, dry mouth, and blurred vision. b. Blockade of cr-adrenergic receptors by some drugs leads to postural hypotension, especiallyin the elderly. c. CNS effects include sedation (especiallytertiary amines,trazodone, ofld mirtazapine), lowering of the seizurethreshold, dizziness,manic episodes,and psychosis.Maprotiline lowers the seizurethreshold significantly. d. Cardiotoxicity of some drugs includes first-degree heart block and other cardiac arrhythmias.

In a Nubhell lmportantSideEffects of Tricyclic Antidepressanb . Anticholinergic sideeffects . Postural hypotension . Sedation . Cardiac (especially toxicities uponoverdose)

e. Other side effectsinclude weight gain, obstructive jaundice, and tremor. f. Overdose is a common problem in depressedpatients and may result in convulsions, severearrhythmias, and respiratory depression.Treatment consists of gastric lavage, Noc HCO' lidocaine,and/or diazepam.With acutedepression,only small amounts of medication (e.g.,1-weeksupply) should be dispensed. g. Amoxapine is also a dopamine receptor antagonist and can causeside effects similar to antipsychotics.

645

Neruous System

6. Drug interactions

Note Tricyclis blockre-uptake, and interfere withother therefore drugs thatusethere-uptake carrier fortheirmechanism of (e.9., guanethidine). action

a. These drugs can be displaced from their binding on plasma proteins by aspirin, aminopyrine, phenothiazines,phenylbutazone,and scopolamine.This enhancesthe effectsof antidepressantsby increasingthe amount of free drug in the plasma. b. The metabolism of these agents can be decreasedby oral contraceptives, antipsychotics, and methylphenidate, thus enhancing the effectsof the antidepressants. c. The metabolism of antidepressantscan be increasedby barbiturates,some sedatives, and cigarettesmoking, thus leading to a reduction in their therapeutic effects. d. The CNS effectsof alcohol are potentiated by tricyclics. e. Becausethe tricyclics can have notable antimuscarinic activity, their effects should be monitored when used with other agentspossessingantimuscarinic activity. f. Agents that block the uptake of neurotransmitters can have a potentially dangerous interaction with biogenic amines. g. Concomitant use of MAO-inhibitors causessigns of atropine poisoning. h. Nefazodone inhibits CYP3A4, and therefore should not be used in combination with drugs such as cisaprideor astemizole. 7. Pharmacokinetics. Becauseapproximately 40o/oof patients receiving psychotherapeutic medications are noncompliant, it is important to determine plasma drug levelsto distingurshbetweenpatients who are noncompliant and those who exhibit individual differences in pharmacokinetics.Monitoring these levels also potentiully reducesthe toxic effects of antidepressantsand lithium becausetheir therapeutic indices are low. However,evenwhen an antidepressantis within its therapeutic range,not all patients respond favorably. B. Buproprion (second generation) 1. Pharmacologicproperties blockade of norepinephrine and dopamine uptake mechanisms. 2. Indications include depressionand cessationof smoking. C. Selectiveserotonin re-uptake inhibitors (SSRIs)

ln a Nutshell block SSRIs selectively 5-HTreuptake.

1. Pharmacologic properties. Unlike the tricyclics that inhibit the uptake of norepinephrine and serotonin, SSRIsselectivelyinhibit serotonin uptake. These agentsshow fewer anticholinergic and antiadrenergic side effects,less cardiotoxiciry no weight gain but loss, and a lower risk of overdosethan the triryclics. Some are metabolized to active metabolites(e.g.,fluoxetine + norfluoxetine). 2. Specific agents include fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine. 3. Indications for use. SSRIs are indicated for depression,panic disorders, obsessivecompulsivedisorder,post-traumatic stresssyndrome,and bulimia. 4. Side effects can include behavioral changes,sexual dysfunction, nervousness,nausea, diarrhea,dyspepsia,insomnia, and headache. 5. Drug interactions. SSRIsinhibit cytochrome P450 isozymes, increasing the activity of other drugs (e.g.,tricyclic antidepressants, warfarin). SSRIscombined with MAOIs can cause a potentially fatal serotonin syndrome characterized by hyperthermia, muscle rigidiry myoclonus,and rapid changesin vital signsand mental status.

646

Pharmacology: Psychoactive Drugs

D. Monoamine oxidase (MAO) inhibitors. The enzymeMAO is present on the outer membrane of mitochondria in most tissues.In neurons,it degradesbiogenicamines,including catecholamines,serotonin,and relatedamines.Hepatic MAO inactivatesdietary and circulating monoamines(e.g.,tyramine,epinephrine).Therearetwo typesof MAO: MAO-A and MAO-B. Equal amounts of both types are found in the brain and liver. 1. Pharmacologic properties a. MAO inhibitors reducebiogenic amine metabolism and, in the brain, increaseintraneuronal levels.Increasedsynaptic concentrationsof these amines are thought to result in down-regulationof the pathologicallyincreasednumber of receptorsand accountfor their antidepressant action. b. They are absorbedreadilyfollowing oral administration. c. Up to 2 weeksmay be required beforeamine metabolismreturns to normal after withdrawal of the inhibitor. 2. Agents include phenelzine and tranylcypromine. These drugs inhibit the enzyme. Phenelzineis inactivated by acetylation (50oloof the population are either slow or fast metabolizers),which can lead to increasedlevels in the slow metabolizers,causing increaseddrug toxicity. 3. Indications for use include depression(when tricyclics are ineffective),phobias, narcolepsy,and panic attacks. 4. Side effects and toxicity a. Tyramine is not degradedin the presenceof a MAO inhibitor and causesthe releaseof stored norepinephrine,leading to an increasein blood pressure(hypertensivecrisis!). Newer MAO inhibitors are currentlybeing developedwith a shorterduration of action, which allowsfyramine metabolism.

In a Nutshell MAOinhibitors increase intraneuronal levels of norepinephrine andserotonin byinhibiting theirmetabolism anddecrease theirreleases. ClinicalCorrelate Patients taking MAOinhibitors mustavoid tyraminecontaining foods(e.g., cheese, redwine). Normally, tyramine undergoes first-pass elimination uponingeston. However, withMAOinhibitors, tyramine issystemically absorbed, andenters norepinephrine nerve terminals viare-uptake. Massive amounts of norepinephrine aredisplaced bemetabolized andcannot because MAOinthenerve isalsoinhibited. This terminal fatal canleadto a potentially hypertensive crisis.

b. Restlessness, insomnia,and dizzinessarerelativelycommon. c. Orthostatic hypotensionis mostly at start of therapy.

ClinicalCorrelate

d. Constipation,urinary retention (lessthan with the tricyclics),tremors, peripheral neuropathy,nausea,weight gain, and edemaoccur occasionally.

g interactions Life-threatenin withMAOinhibitors include:

e. The useof any irreversibleMAO inhibitor in patientsover 60, in patientswith cardiac disordersor hypertension,or in patients at risk for stroke is questionable.

. Drugs thatincrease synaptic (e.g., NElevels tyramine, tricyclic antidepressants, Ldopa, alpha agonists)

f. Hepatotoxicity is very rare. 5. Drug interactions a. Precursorsof biogenic amines (e.9., t--dopa), sympathomimetic drugs (e.9., amphetamine),and tricyclics should not be given with MAO inhibitors since severe hypertensionmay result. b. Detoxificationof certain drugs is impaired, and toxicity may developwith general anesthetics, alcohol,antihistamines,and sedatives. c. Patientstaking opiatesand MAO inhibitors may develop rigidity, hypertension,and irritability. d. A hypoglycemiceffectwith drugs used for diabetescan be expected.

. Drugs thatincrease 5HT, causing a serotonin (e.9., syndrome SSRI) . Opiates (e.g., meperidine)

Correlate Clinical Co-administration ofeither (e.g., or opiates demerol), tricyclic antidepressants with MAOinhibitors canbefatal andiscontraindicated.

647

NervousSystem

E. Lithium. The mechanismof action of lithium in depressionis uncertain but seemsto block development of dopamine-receptorsupersensitivity,increaseacetyicholinesynthesis,and enhanceserotonergicactivity. Lithium is thought to prevent the recyclingof phosphoinosi(PIP2),which is the tides,leadingto the depletionof phosphatidylinositol-4,5-biphosphate precursor to the second messengersinositol 1,4,5-triphosphate(IP.) and diacylglyceroi (DAG). This may diminish the effectsof excesscatecholaminesor serotonin,which are thoughtto causemania. l. Pharmacologic properties a. Given orally aslithium carbonate,lithium ions (Li*) are absorbedreadilyand almost tract. completelyfrom the gastrointestinal condithrough the blood-brain barrier is slow. Under piasma steady-state b. Passage (CSF) found 40-50o/o of that fluid is about in the cerebrospinal the level of Li* tions, plasma. in

ln a Nutshell second Lithium seems to affect messenger system, andNa.loss leads to Li.increase.

c. Lithium doesnot bind to plasmaproteins. d. Lithium is excretedsolelyby the kidneys.An inverserelationship existswith sodium if ions (Nat); that is, a Na* loss increasesLi* levels.A reduction in doseis necessary creatinineclearanceis impaired. e. Lithium hasa low therapeuticindex. initially to optimize f. Measurementof serum concentrationsof lithium are necessary effects. to minimize the toxic effects and the therapeutic 2. Indications for use include acute mild-to-moderatemania, prevention of manic and depressive episodesin patientswith bipolar illness,and asan alternativeor supplementto antidepressant treatment. 3. Side effectsand toxicity a. Acute intoxication includes nausea,vomiting, and tremors, and late toxicity includes convulsions,coma,and death. b. Lithium is contraindicatedin pregnanryand may causecardiacand other birth defects. Becauselithium is secretedin breastmi1k,it should not be usedby nursing mothers. c. Lithium is excretedby the kidneys.With impairedrenalfunction,levelsmust be monitored carefully.It rarely causeschronic interstitial nephritis. d. Other side effectsinclude thyroid enlargement,polydipsia,polyuria, and fatigue. 4. Drug interactions a. Diureticsand other conditionsthat promote Na' lossincreaselithium reabsorption. and phenytoin. b. IncreasedCNS toxicity resultswith methyldopa, carbamazepine, c. Indomethacin and phenylbutazonecan increasetubular resorption of lithium and renal lithium clearance. decrease

648

Drugs Psychoactive Pharmacology:

ANTIPSYCHOTICS Schizophreniais manifestedmainly asa thought disorderwith delusions(often paranoid),halsocialwithdrawal, and blunted affect.It is believedto lucinations,looseningof associations, result from a coexistenceof hyperdopaminergicactivity in the mesolimbic system (positive signs)and hypodopaminergicactivity in the mesocorticalsystem(negativesigns).There are severaldopaminereceptorsubtypesincluding Dl,D2,D3,D4, and D5. SubtypesD2 andD4 seemparticularly involved.In addition, serotonin receptorsin the cortical structuresplay a role Anatomic abnormalitieshavebeenfound in the temporallobe and the amygin schizophrenia. dalaof schizophrenicpatients. A. Pharmacologic properties 1. Mechanism of action a. Antipsychotic drugs are thought to be effectivebecausethey block dopamine receptors (particularly D2 and Da) in mesocorticaland mesolimbic areas.However,they alsoblock dopaminereceptors(CD2) in the following areas: (1) In the basalgangiia(nigrostriatalpathways),causingmovementdisorders (2) In the hypothalamusand pituitary gland (tuberoinfundibularpathway),leading to increasedprolactin secretion (3) In the chemoreceptortrigger zone,inhibiting emesis b. Antipsychoticsalsoblock cholinergicreceptors(leadingto anticholinergicsigns)and u-receptors(leadingto posturalhypotension).Other receptors,suchashistamineand serotonin receptors,are also blocked.Newer "atypical" antipsychoticsblock mostly 5HT2 receptors.

ln a Nutshell Allantipsychotics (neuroleptics) aredopamine Thegoalisto antagonists. in receptors block dopamine andmesocortical mesolimbic theyare areas. Unfortunately, inthebasal alsoblocked (leading ganglia to sideeffects) extrapyramidal (leading to andinthepituitary hyperprolactinemia).

2. Routesof administration include oral, intravenous,or intramuscularinjection. Depot injectionsare available(e.g.,fluphenazine,haloperidol)for psychiatricpatientswho are noncompliant.One dosemay last 2-6 weeks. mediatedby hepaticmicrosomalor other 3. Metabolism is mainly by oxidativeprocesses drug-metabolizing enzymes.These drugs are highly lipophilic and protein-bound (92-99o/o).They are sequestered in the lipid compartmentsof the body and have long durations of action, resulting in elimination half-lives of 20-40 hours. After cessationof therapy,they can be detectedfor months in body fat. 4. Efficacyis similar for all antipsychoticdrugs but they vary in their potency.They are often classifiedashigh-potency(i.e.,lowdose)or low-potency(i.e.,high dose)drugs.For example, chlorpromazineis a low-potencydrug, and haloperidol is a high-potencydrug.

ln a Nutshell Drugs Low-potency Chlorpromazine Thioridazine Drugs High-potency Fluphenazine, Haloperidol

B. Indications for use l. Antipsychotic drugs are used for psychoticsymptomatologyor schizophrenia.The onset of antipsychoticaction is delayed2-6 weeks,but sedationoccursquickly.Therapy is often necessaryfor life. 2. Thesedrugs are also usefulfor severemanic or agitatedepisodes,for certaindrug overdoses(e.g.,amphetamines). 3. Somedrugs in this classare usedto treat nauseaand vomiting (e.g.,prochlorperazine), intractablehiccups,and Tourettesyndrome(e.g.,haloperidol). C. Side effectsand toxicity. The following side effectsare common to almost all antipsychotic drugs,but they may vary in intensity.This classof drug showsa high therapeuticindex with only rare fatal overdoses.

649

NervousSystem

In a Nutshell Extrapyramidal sideeffects (EPS) arethought to result froma dopamine/ACh imbalance inthestriatum. Balance canberestored with anticholinergics.

ln a Nutshell Extrapyramidal SideEffects Acute: . Parkinsonism . Akathisia . Dystonia Late: . Tardive dyskinesia Miscellaneous SideEffects . Sedation . Anticholinergic . Postural hypotension . Hyperprolactinemia . Lowers seizure threshold

l. Extrapyramidal side effects (EPS) are causedby a disturbance of the balancebetween dopamine and acetycholine(ACh) in the basalganglia.Cholinergic overactivityis caused by dopamineblockade.Balancecanbe restoredby administeringan anticholinergicagent (e.g.,benztropin). a. Parkinsonian syndrome is observed,including rigidiry restingtremor, and bradykinesia. b. Akathisia occurswith restlessness and increasedmotor activity. c. Acute dystonic reactions are observed,including oculogyric crisis. d. Thrdive dyskinesi4 a condition characteruedby stereotypicalinvoluntary movements such aslip-smackingand grimacing,ffiny develop,especiallyin the elderlyand after longterm therapy.It is thought to be causedby dopamine receptorup-regulation asa result of long-term receptorblockade.No satisfactorytreatment for tardive dyskinesiais available. 2. Other side effectsinclude sedation,galactorrhea,postural hypotension (most severewith intramuscular injections of chlorpromazine),anticholinergicside effects,lowered seizure threshold,difficultiesin regulatingbody temperature,and menstrualchanges. 3. Neuroleptic malignant syndrome with muscular rigidity, fever,diaphoresis,myoglobinuria, and metabolic acidosisoccurs in some patients.Tieatment is with dantroleneor dopamineagonists. 4. Depot antipsychotic drugs should not be given unlessthe patient has receivedthe drug orally and respondedfavorably.Toxic results after a depot injection may be severesince the drug cannotbe removed. D. Specificagents 1. Phenothiazines

. Neuroleptic malignant syndrome

a. Aliphatic group. This group includes chlorpromazine and triflupromazine. These drugs causea high incidenceof anticholinergicand anti-o-adrenregicsideeffectsand a low incidenceof extrapyramidalsideeffects.This group is low potency.

In a Nutshell

b. Piperidine group. Thioridazine is the protofFpe of this group. Thioridazine causesa high incidenceof anticholinergicand anti-o-adrenergicside effects,a low incidenceof extrapyramidalside effects,and pigmentary retinopathy at high doses.This group is moderatepotenry.

Thioridazine isa particularly goodanticholinergic, leading to fewerextrapyramidal side peripheral effects, butgreater sideeffects.

c. Piperazine group. This group includesfluphenazine, trifluoperazine, and prochlorperazine. Side effectsinclude a high incidence of extrapyramidal side effects,fewer autonomicsideeffects,and lenticulardeposits.This group is high potency. 2. Thioxanthenes. This class includes thiothixene and chlorprothixene, which causes lenticulardeposits. 3. Butyrophenones. The prototype of this classis haloperidol. Haloperidol causesa high incidence of extrapyramidal toxicity and impotence. Drug interactions include increased metabolism by phenytoin and barbiturates. When used with lithium, it may cause encephalopathyand fever.This group is high potenry.

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Pharmacology: Psychoactive Drugs

4. Atypical antipsychotics. These drugs have advantagesbecausethey are efficaciousin treatingboth positiveand negativesymptomsof schizophrenia.(The other drug ciasses are successfulprimarily with the positivesymptomsonly). In addition, they havefar f-ewer extrapyramidal side effects.Thesedrugs typically have a high affinity for 5-HT2A receptors and alsoblock other receptorssuchas D, and alpha, receptors. a. Clozapine (dibenzodiazepineclass)has a high affinity for 5HT2 and D4 receptors.It produces fewer extrapyramidal effects and is often effective in treating refractory schizophrenicpatientsor patientswith tardivedyskinesia;may improve tardivedyskinesia.Side effectsinclude agranulocytosis(in up to 3o/oof the patients).Frequent blood testsare necessaryin the beginning of therapy.Anticholinergic side effects, sedation,orthostatichypotension,and weight gain are common sideeffects. b. Risperidonehas a lower risk of extrapyramidalsideeffectsthan most typical antipsychotics,though it has a higher incidencethan clozapine.At doses>l0mg/day, the EPS profile is similarto tlpical antipsychotics. Risperidonehaslessanticholinergicsideeffects, orthostatichypotension,and weight gain than clozapine.Sedationis lesscommon. c. Olanzapinehas a very low incidenceof EPS.It hasa high incidenceof sedation,anticholinergicsideeffects,orthostatichypotension,and weight gain. d. Qeutiapine has a very low incidenceof EPS.I producesmoderatesedationand orthostatichypotension,hasa low incidenceof weightgain,and no anticholinergicsideeffects. e. Sertindolehasbeenat leasttemporarilywithdrawn from the market for further evaluation becauseof prolongation of the QT or QTc interval, increasingthe risk of arrhythmias. E. Drug interactions include potentiated effectswhen combined with other drugs that have anticholinergic,anti-alpha-adrenergic or sedativeproperties.They also decrease the effects of r-dopa and dopamineagonists.

In a Nutshell Highandlow-potency drugs produce a different spectrum ofsideeffects: LowPotency . Fewer extrapyramidal sideeffects . Creater anticholinergic, antiadrenergic, andsedative effects HighPotency . Greater extrapyramidal sideeffects . Fewer anticholinergic, antiadrenergic, and sedative effects

Clinical Correlate Clozapine isconsidered atypical because it generally doesnotcause extrapyramidal sideeffects ortardive dyskinesia. However, it can cause agranulocytosis. Patients musthave frequent blood tests if taking clozapine.

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