KEY POINT:
A
The largest obstacle to designing a functional headache classification is the lack of reliable diagnostic tests for even such thoroughly studied illnesses as migraine and cluster headache.
CLASSIFICATION OF PRIMARY HEADACHES: CONCEPTS AND CONTROVERSIES Morris Levin
ABSTRACT Designing a comprehensive and practical classification schema for headache disorders has been an elusive goal for many reasons. The International Classification of Headache Disorders, 2nd Edition (ICHD-II) is the best attempt to date, but it, like its predecessor the ICHD-I, is plagued with a number of limitations. It was designed as both a research and clinical tool but can be frustrating for practitioners in either area. Primary headaches, such as migraine, chronic daily headache, and ‘‘other’’ headaches, such as new daily persistent headache, are particularly problematic sections of the classification. In addition, classification of a number of more complex (ie, where pathophysiology is poorly understood) secondary headaches, such as medication overuse and posttraumatic headaches, is also vexing. This chapter is an attempt to summarize the ICHD-II, focusing on primary headache types, and suggest best practices for usage of it.
INTRODUCTION
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Why Headache Classification? To properly study and effectively treat the various headache disorders, they must somehow be sorted. Arguably, the largest obstacle to designing a functional headache classification is the lack of reliable diagnostic tests for even such thoroughly studied illnesses as migraine and cluster headache. Any diagnostic system will therefore have to rely on subjective data, hence the descriptive approach to all headache classifications to date. In a rather circular type of logic, the only way to improve upon the methods of dividing various headache types is to subject the classification system itself to systematic study. To learn more about headaches, they must first be separated into more or less discrete categories,
then examined with the best tools available, next rearranged into more accurate categories based on evidence accumulated in this way, then reexamined, and so on. A number of pitfalls are easily encountered. First, there is the risk of making the classification too specific— the tendency of ‘‘splitters.’’ The ‘‘lumper’’ approach is equally fraught with risks. When categories are too broad, the results of analysis can be all but unusable since conclusions may be so general as to apply to virtually no individuals. Another large problem is to decide where to establish demarcations between diagnostic categories in the absence of evidence (ie, most of the time). Here, the opinions of experts are taken into account. But which experts? And the experts do often disagree. Another problem is
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the reasonable assumption that most headache patients generally have one illness. This, however, may not be the result when applying a diagnostic schema based on morphological features that can occur with several headache types, leading to multiple diagnoses. On these grounds and others, the ICHD classifications (Headache Classification Subcommittee of the International Headache Society, 2004; Headache Classification Subcommittee of the International Headache Society, 1988) have been criticized (Bigal et al, 2004; Leone et al, 1998; Manzoni and Torelli, 2004; Olesen and Rasmussen, 1996; Pearce, 1996; Silberstein et al, 1995; Silberstein et al, 1994; Winner et al, 1997). Still, without a headache classification, research on pathophysiology, genetics, and treatment of headache disorders is essentially impossible. In addition, patients expect a diagnosis and prior to ICHD might well have received a different one from each physician they saw. Fields such as headache, where attempts at classification are evidence based, are those where the most efficient scientific progress is occurring. This chapter will focus on key areas of the ICHD classification of primary headaches rather than an exhaustive exploration of the 45 diagnostic entities contained therein. Tables for reference will be highlighted, and clinical examples of important diagnostic entities will be presented. Controversial areas as well as suggested revisions to the ICHD-II will be discussed. History of Classification Systems in Headache Headache classification began (as far as we know) with Aretaeus of Cappadocia in the first century, who divided headaches into cephalea (chronic, frequent, severe, long-lasting headaches) and cephalalgia (infrequent milder head-
aches). Thomas Willis, a founder of modern neurological thought, described in De Cephalalgia in 1672 headaches as ‘‘within or without the skull; universal or particular; short, continuous or intermittent; wandering or uncertain; before, behind or the side; and occasional or habitual.’’ Christian Baur in 1787 divided headaches into primary headaches (‘‘idiopathic’’) and secondary headaches (‘‘symptomatic’’), with a total of 84 categories, most of which have not withstood the test of time (Gladstone and Dodick, 2004; Isler, 1993; Pearce, 1986). The first significant modern attempt at classifying headache disorders was done by an ad hoc committee formed by the National Institutes of Health in 1962, which consisted of prestigious American thinkers in headache: Arnold Friedman, Knox Finley, John Graham, Charles Kunkle, Adrian Ostfeld, and Harold Wolff (Ad Hoc Committee on Classification of Headache of the National Institute of Health, 1962). This classification (Table 2-1) consisted of brief glossary-type definitions of a limited number of headache types. With its relatively vague diagnosis definitions, it required subjective interpretation and relied primarily on accepted ideas of headache diagnostic classes without much in the way of evidence to support them. This classification system, notable for strict differentiation between migraine headaches (pulsatile unilateral headaches with a vascular pathology) and tension headaches (with muscular pathophysiology) became accepted worldwide but by the 1970s began to be seen as more of an impediment than a help to advancing headache understanding. The International Headache Society (IHS), formed in 1982, embarked upon the task of classification by forming a classification committee in 1985 with Dr. Jes Olesen as the chairman. The IHS classification system was published
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" CLASSIFICATION OF PRIMARY HEADACHES
KEY POINT:
A
The effects of the International Classification of Headache Disorders were dramatic. It served to drive massive amounts of headache research, unified headache clinicians and researchers worldwide, and made a major first step in providing much-needed credibility and scientific rigor for the field of headache.
TABLE 2-1 Ad Hoc Committee on Classification of Headache of the National Institute of Health: Classification of Headache 1. Vascular headache A. Classic migraine B. Common migraine C. Cluster D. Hemiplegic, ophthalmoplegic migraine E. Lower-half headache 2. Muscle contraction headache 3. Combined headache: vascular and muscle contraction headache 4. Headache of nasal vasomotor reaction 5. Headache of delusional, conversion, or hypochondriacal states 6. Nonmigrainous vascular headaches 7. Traction headache 8. Headache due to overt cranial inflammation 9–13. Headache due to diseases of ear, nose, sinus, teeth 14. Cranial neuritides
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15. Cranial neuralgias Reprinted with permission from Ad Hoc Committee on Classification of Headache of the National Institute of Health. Classification of headache. JAMA; 1992;179:717–718. Copyright # 1992, American Medical Association. All rights reserved.
in 1988 (Headache Classification Committee of the International Headache Society, 1988). It was 96 pages long and consisted of 165 diagnoses. The effects of the ICHD were dramatic. It served to drive massive amounts of headache research, unified headache clinicians and researchers worldwide (it was trans-
lated into all major languages), and made a major first step in providing much-needed credibility and scientific rigor for the field of headache. In addition, a correspondence to the International Classification of Diseases of the World Health Organization further enabled uniformity and accuracy in diagnosis. The revision of the IHS classification was begun in 1999 (it had actually been planned for revision in 1993). After attempts were made to obtain input from headache and other specialists and a limited number of prepublication presentations occurred, the ICHD-II was published in Cephalalgia in January 2004 (Headache Classification Subcommittee of the International Headache Society, 2004). The ICHD-II is 160 pages long and contains approximately 200 diagnoses.
ICHD-II—BASIC ORGANIZATION Format The ICHD-II, like its predecessor, consists of several parts (Table 2-2). This edition includes the following: Part 1: primary headaches; Part 2: secondary headaches; Part 3: cranial neuralgias, central and primary facial pain and other headache; and the Appendix. Part 1, primary headaches, consists of 45 diagnostic categories in chapters 1 through 4 and includes migraine, tension-type headache, cluster headache and its relatives, and a group of ‘‘other primary headaches.’’ The first four groups are considered to have ‘‘no other causative disorder.’’ Part 2, secondary headaches, consists of 120 diagnostic categories in chapters 5 through 12 and includes headaches ‘‘caused by another disorder,’’ such as head trauma, vascular disease, abnormal intracranial pressure, mass lesions, hydrocephalus, and so on. These chapters also describe headaches
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TABLE 2-2
International Classification of Headache Disorders Revised
Part 1: Primary Headaches, Chapters 1 Through 4 (No Other Causative Disorder) 1. Migraine 2. Tension-type headache 3. Cluster and its relatives (trigeminal autonomic cephalalgias) 4. Other primary headaches— exertional, hemicrania continua, hypnic headache, et al
due to processes involving a number of structures in and around the head, including the eyes, nose, sinuses, teeth, and neck. In addition, a brief chapter on headaches presumably caused by psychiatric disorders is included. Part 3 consists of 29 causes of facial pain or neuralgic illnesses as well as chapter 14, ‘‘empty for now,’’ to serve as something of a placeholder for any unclassifiable headache types. The appendix (Table 2-3) is an intriguing collection of suggested criteria for possible new entities, alternative diagnostic criteria for certain existing categories, and previously accepted
Part 2: Secondary Headaches, Chapters 5 Through 12 (Caused by Another Disorder) 5. Posttraumatic 6. Vascular disease 7. Other intracranial pathology, eg, abnormal intracranial pressure, neoplasm, hydrocephalus 8. Substances 9. Central nervous system infection 10. Homeostatic disorders, eg, hypoxia, hypertension, thyroid dysfunction 11. Cervicogenic; eyes; ears, nose, and throat; sinuses, mouth, teeth, temporomandibular joint 12. Psychiatric Part 3: Cranial Neuralgias, Central and Primary Facial Pain, Other Headaches 13. Neuralgias and neuropathy 14. Other headaches (no subheadings for now) Appendix Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
International Classification of Headache Disorders, 2nd Edition, Appendix Contents
TABLE 2-3
1. Suggested criteria for possible new entities: For example, A1.1 Menstrual migraine A3.3 SUNA (short-lasting unilateral neuralgiform headache attacks with autonomic symptoms) 2. Alternative diagnostic criteria for certain categories (pending evidence): For example, A2 Two alternative tension-type headache diagnostic criteria 3. Some previously accepted disorders that have not been supported by evidence: For example, A.1.3.4 Alternating hemiplegia of childhood Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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" CLASSIFICATION OF PRIMARY HEADACHES
KEY POINTS:
A
A
36
Decisions about diagnoses and diagnostic criteria were made by International Headache Society subcommittees based on evidence, when possible, and expert opinion (consensus) when no evidence was available. In patients with more than one distinct type of headache, each headache type is coded separately.
related disorders, short descripdisorders that have not been suptions, explicit diagnostic criteria, ported by evidence. The appendix is notes and comments thus a list of fertile research topics and a vehicle for eventual incorporation of o Bibliography for the entire chapter with breakdown by subcategory new evidence into the next revision of the ICHD. For a particular diagnosis, all criteria Decisions about diagnoses and diag- must be fulfilled. Thus, to be considnostic criteria were made by the vari- ered orgasmic headache, 4.4.2, all of ous subcommittees based on evidence, the following must be true: when possible, and expert opinion A. Sudden severe (‘‘explosive’’) (consensus) when no evidence was headache available. (The choice of experts is an B. Occurs at orgasm obvious area of controversy.) C. Not attributed to another disorder A troublesome, but unavoidable In patients with more than one discomponent of the ICHD is that the tinct type of headache, each is coded definitions for headache disorders are separately, ie, a patient’s headache may symptom based for primary headaches, but etiology based for second- be coded as: ary headaches (which will presumably 1. 1.1 Migraine without aura, change when etiologies for primary 2. 2.2 Frequent episodic tension type headache, and headaches become known). 3. 8.2 Medication overuse headache Specificity in diagnosis is weighted higher than sensitivity. Precise incluIf a single headache type fulfills two sion and exclusion criteria for each different sets of explicit criteria, the use diagnosis are enumerated. The classifi- of other data is recommended, eg, hiscation is hierarchical, with a decimal tory of headache onset, family history, system for subdivision. For example, in menstrual relationship. the case of 5.2.2, chronic posttraumatic The classification of a patient’s headheadache attributed to mild head ache is based upon his or her current injury, 5 denotes posttraumatic head- phenomenology, or at least that occurache, 5.2 denotes chronic posttraumatic ring during the last year. This is a bit headache, and 5.2.2 denotes that this problematic since, for example, if the chronic posttraumatic headache was patient experienced different headache caused by mild head injury. types in the past, eg, migraine with The hierarchical format allows one to aura several years ago, the implication decide how detailed to make the may be drawn that the patient may diagnosis. The classification committee have the ‘‘trait’’ for migraine with aura. felt that in primary care settings, one to These considerations may be importwo digits of specificity would be useful tant in clinical as well as in research (eg, migraine without aura, 1.1) and that settings. for a researcher or specialist, a threeSecondary headaches (Part 2) should digit diagnosis would be more appro- begin to occur close in time to the priate (eg, typical aura with nonmigraine, causative disorder and disappear when 1.2.2). the cause is removed. The problem is Each chapter is organized with a that the cause may not be possible to standard order of information: eliminate. For these ambiguous situations, the ICHD encourages the use o General introduction of ‘‘probable’’ until further clarificao Subcategories, each including discussion of previously used terms, tion may be obtained (see below).
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Nomenclature Chronic refers to frequency for some of the primary headache disorders— eg, chronic migraine and chronic tensiontype headache occur on more than 50% of days. But in cluster headache and paroxysmal hemicrania, ‘‘chronic’’ denotes the pattern of continuous vulnerability to individual attacks, eg, chronic cluster, as opposed to the more typical recurring cluster or hemicrania cycles (episodic). Finally, as is more typical in other pain terminology, ‘‘chronic’’ denotes the duration of the problem, eg, greater than 3 months for secondary headaches such as chronic posttraumatic headache. Aura is used for the well-described brief preheadache symptoms of migraine with aura and premonitory symptoms for the 2- to 48-hour period of forewarning before a migraine. The terms prodrome and warning symptoms are not used. Probable is the term used ubiquitously to indicate that generally all but one criterion has been met for a
particular diagnosis. For example, if a patient has recurrent headaches that seem ‘‘migrainous’’ (old term used in the ICHD-I) but fail to fulfill one of the four criteria for migraine, 1.6, probable migraine is used in place of migraine without aura, 1.1. Attributed to replaces the ‘‘associated with’’ phrase used for secondary headaches in ICHD-I to imply a causal link between the underlying disorder and the headache. (The problem of proving causality will lead to frequent ‘‘probable’’ secondary headache diagnoses.) All of the primary headache criteria include the requirement that the headache not be attributed to another disorder. Thus, in patients where doubt exists, two diagnoses are likely—a probable primary headache disorder as well as a probable secondary headache (Case 2-1).
KEY POINT:
A
All of the primary headache criteria include the requirement that the headache not be attributed to another disorder. Thus, in patients where there is doubt, two diagnoses are likely—a probable primary headache disorder as well as a probable secondary headache.
GENERAL MODELS FOR PRIMARY HEADACHES The generally held concepts of migraine, tension-type headache, and
Case 2-1 Headaches Following Trauma A 28-year-old man describes a recurrent syndrome of posterior headache pain. Although it may occur spontaneously, the headache can be induced by coughing or sneezing. The pain can last between several minutes and several hours. He remembers that these began in high school after he played in a ‘‘rough’’ football game and sustained a minor head injury (without concussion). Nausea is generally absent, but he states he sometimes gets ‘‘queasy.’’ Sexual intercourse does not induce headache. Medication, including indomethacin, has failed to relieve his headaches. His examination is entirely normal. Magnetic resonance imaging (MRI) scan reveals mild to moderate cerebellar tonsillar herniation. Comment. The obvious problem is to determine whether this young man’s headaches represent a primary headache disorder or are, instead, due to an Arnold Chiari malformation. According to the ICHD-II classification, headache attributed to Chiari malformation can be assigned only if the headaches disappear following surgical correction. Until then, one could use the ‘‘probable’’ diagnosis. The history of head trauma is intriguing as well, perhaps suggesting an additional secondary headache due to head trauma. New daily persistent headache (NDPH) is another possibility but would be difficult to support in the presence of a suspected instigating factor.
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" CLASSIFICATION OF PRIMARY HEADACHES
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cluster headache have been maintained in the ICHD-II. As would be expected, however, borderlands between them have been sacrificed. Some headaches are grouped into the cluster headache chapter (ICHD-II chapter 3) without clear linkage to cluster headache (eg, short duration, unilateral, neuralgic, conjunctival injection, and tearing [SUNCT]). ICHD-II chapter 4, Other Primary Headaches, includes many headaches that are not necessarily related to one another (eg, cough headache, hypnic headache, hemicrania continua, and NDPH). Hence, boundaries can be seen as arbitrary and not implying shared or similar causation. The one unifying feature to primary headaches is their unknown link to any other disease process. However, this begs the question of how to conceive of such things as typical ‘‘migrainoid’’ or cluster headaches newly occurring in the setting of a systemic illness or postulated secondary cause. Again, classifications force distinctions that at best may not be significant or at worst may be quite misleading. Neuralgias are presented in a completely separate part of the classification, although a case can be made that some of these fulfill the spirit of the concept of primary headache disorder. And this section contains symptomatic neuralgias such as Tolosa Hunt syndrome and postherpetic neuralgia, which can properly be considered secondary headache disorders. MIGRAINE AND ITS RELATIVES Migraine diagnosis depends on a relatively complex set of criteria (Table 2-4). In practice, the diagnosis is not difficult, but a number of patients with migraine will likely receive the diagnosis of probable migraine if ICHD criteria are strictly applied. Commonly reported migraine accompaniments such as nausea and light and sound sensitivity are expected criteria, but exercise
International Classification of Headache Disorders, 2nd Edition, 1.1 Migraine Without Aura
TABLE 2-4
A. At least five attacks fulfilling criteria B through D B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
intolerance, pulsation, and unilaterality are believed by many to be much less significant clues. Moderate or severe pain intensity is rather broad, and the requirement for both photosensitivity and phonosensitivity seems rather stringent to some. The migraine with aura category, 1.2, includes the odd-sounding terms aura with migraine, aura with nonmigraine, and aura without headache (Tables 2-5 and 2-6). The rationale behind this classification was to find a consistent way to evaluate the unusual patient
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KEY POINT:
International Classification of Headache Disorders, 2nd Edition, 1.2 Migraine With Aura—Subtypes
TABLE 2-5
1.2.1 Typical aura with migraine headache 1.2.2 Typical aura with nonmigraine headache 1.2.3 Typical aura without headache 1.2.4 Familial hemiplegic migraine 1.2.5 Sporadic hemiplegic migraine 1.2.6 Basilar-type migraine Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
with typical aura but whose headache type otherwise did not meet migraine criteria. It is very conceivable to assign tension-type headache, 2.1, and aura with nonmigraine, 1.2.2, to the same patient. Most examiners would consider the aura proof of migraine pathophysiology, and hence this begs the question of whether migraine criteria are too strict. Motor auras are placed in the separate hemiplegic migraine categories with the implication that motor auras are different from other auras, a concept suggested, although certainly not proven, by genetic studies of hemiplegic migraine (Carrera et al, 2001; De Fusco et al, 2003). Still, the criteria for the migraine chapter seem useful and do distinguish significant subtypes (Eriksen et al, 2004). As stated above, migrainelike headaches that meet all criteria save one are best termed probable migraine. Ophthalmoplegic migraine, once felt to be a primary headache, is now relegated to the neuralgia section
A TABLE 2-6 International Classification of Headache Disorders, 2nd Edition, 1.2.1 Typical Aura With Migraine Headache A. At least two attacks fulfilling criteria B through D B. Aura consisting of at least one of the following, but no motor weakness:
Motor auras are placed in the separate hemiplegic migraine categories with the implication that motor auras are different from other auras.
1. Fully reversible visual symptoms including positive features (eg, flickering lights, spots, or lines) and/or negative features (eg, loss of vision) 2. Fully reversible sensory symptoms including positive features (eg, pins and needles) and/or negative features (eg, numbness) 3. Fully reversible dysphasic speech disturbance C. At least two of the following: 1. Homonymous visual symptoms and/or unilateral sensory symptoms 2. At least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 3. Each symptom lasts 5 and 60 minutes D. Headache fulfilling criteria B through D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes E. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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" CLASSIFICATION OF PRIMARY HEADACHES
KEY POINT:
A
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There is no diagnostic category that applies to the oftenencountered patient with previous intermittent migraine who evolves to a condition with frequent headaches, many of which have minimal migraine features.
(13.17) based on suggestive evidence that the entity is more closely related to neuralgic syndromes. Basilar (type) migraine and retinal migraine are listed in the migraine chapter, however. Basilar migraine should have symptoms and or signs suggestive of the posterior cerebral circulation, such as bilateral visual symptoms, dysarthria, vertigo, hearing loss, diplopia, or ataxia (Table 2-7). Retinal migraine, of course, requires symptoms referable to one eye. Primary chronic daily headache, defined as headaches on 15 or more days per month (not due to underlying systemic or cranial pathology), is clearly an important public health problem with a surprisingly high prevalence— probably 4% worldwide. This category consists of a mixture of several disorders, including a chronic form of migraine, chronic tension-type headache, hemicrania continua, and NDPH. Chronic migraine, 1.5.1, requires that all headaches meet criteria for migraine (Table 2-8). Many objections have been made to this requirement for chronic migraine since there is thus no diagnostic category that applies to the often-encountered patient with previous intermittent migraine who evolves to a condition with frequent headaches, many of which have minimal migraine features (Case 2-2). This condition was initially termed transformed migraine by Mathew in 1982 and was included by Silberstein and Lipton in their commonly accepted classification of chronic daily migraine (Mathew et al, 1982; Silberstein et al, 1994) (Table 2-9). So where do these patients fit in the ICHD-II? Most, by virtue of the fact that migrainous features are sparse, will receive the ICHD diagnosis of chronic tension-type headache. Those who have been using frequent antiheadache medication will also, or instead, be diagnosed as probable
International Classification of Headache Disorders, 2nd Edition, 1.2.6 Basilar-type Migraine
TABLE 2-7
A. At least two attacks fulfilling criteria B through D B. Aura consisting of at least two of the following fully reversible symptoms, but no motor weakness: 1. Dysarthria 2. Vertigo 3. Tinnitus 4. Hypacusia 5. Diplopia 6. Visual symptoms simultaneously in both temporal and nasal fields of both eyes 7. Ataxia 8. Decreased level of consciousness 9. Simultaneously bilateral paraesthesias C. At least one of the following: 1. At least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 2. Each aura symptom lasts 5 and 60 minutes D. Headache fulfilling criteria B through D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes E. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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TABLE 2-8 International Classification of Headache Disorders, 2nd Edition, 1.5.1 Chronic Migraine A. Headache fulfilling criteria C and D for 1.1 Migraine without aura on 15 days/ month for >3 months B. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
medication overuse headache pending resolution of the headache after discontinuation of analgesic medication. (Interestingly, in one study of 50 consecutive chronic daily headaches seen
in a tertiary headache clinic, all those felt to represent transformed migraine could actually be made to fit the chronic migraine category of ICHD-II if histories were taken very carefully [Levin et al, 2005]). The American Headache Society proposed a revised category of chronic migraine in an attempt to include these patients, with the softened requirement of only the majority of headaches meeting strict migraine criteria or responding to migraine-specific medication. The IHS Classification Committee agreed to include this set of criteria as an appendix diagnosis (Headache Classification Committee et al, 2006) (Table 2-10). Status migrainosus, 1.5.2, which refers to the uncommon condition of persistent migraine without abatement for 72 hours, also requires that migraine criteria be met. Here the requirement
Case 2-2 Chronic Daily Headache A 32-year-old woman with a 20-year history of severe throbbing headaches associated with nausea, photophobia, phonophobia, and exercise intolerance is referred to a tertiary headache treatment clinic because of increasing frequency of headaches to a near-daily occurrence. Many of her headaches are now nonnauseating, and phonophobia is less common. She notes that stress seems to intensify the headache, but she has identified no other triggers. Headaches have led her to take several over-the-counter medications (‘‘sometimes every day’’), which fortunately are allowing her to continue to function at her job as a receptionist. She states that she sometimes uses no medication because she gets ‘‘sick of it’’ for several weeks on end. She is on no other medication other than an oral contraceptive and has no other medical illnesses of which she is aware. Examination is unremarkable. Comment. The apparently frequent use of over-the-counter medications is very suggestive of medication overuse headache, but the persistence of headache when she abstains is problematic. The headache morphology is more typical of tension headache, but the history of migraine (as well as family history) suggests an underlying migraine pathophysiology. This patient’s most appropriate ICHD-II diagnoses would be (1) probable medication overuse headache, 8.2; (2) probable chronic tension type headache, 2.3; and (3) a history of migraine headache without aura, 1.1. It may be difficult to ascertain whether the headaches have improved sufficiently after analgesics are removed to permit a diagnosis of chronic tension-type headache. Furthermore, the migraine history and features are so suggestive here that use of proposed new criteria for chronic migraine (Table 2-10) is a compelling alternative.
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" CLASSIFICATION OF PRIMARY HEADACHES
TABLE 2-9
"
Silberstein-Lipton Chronic Daily Headache Classification
Transformed Migraine With medication overuse Without overuse
"
Chronic Tension-type Headache With overuse Without overuse
"
New Daily Persistent Headache With overuse Without overuse
"
children), 1.3.2; and benign paroxysmal vertigo, 1.3.3 (Case 2-3). Finally, the worrisome migraineinduced stroke, migrainous infarction, 1.5.4, is included in the complications of migraine portion of the chapter. This diagnosis now requires both the persistence of aura symptoms for more than 60 minutes and MRI changes consistent with stroke in the appropriate brain region. TENSION-TYPE HEADACHE Not only is the pathophysiology of tensiontype headache not well understood, but even the epidemiology is somewhat unclear. In most studies tensiontype headache is much more prevalent that migraine, with an apparent
Hemicrania Continua With overuse Without overuse
From Silberstein SD, Lipton RB, Goadsby PJ. Headache in clinical practice. 2nd ed. London: Martin Dunitz, 2002. Reproduced by permission of Routledge/Taylor & Francis Group, LCC.
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seems sensible, but the longer the migraine persists unabated, the more likely migrainous features will fade with primarily pain remaining, so here too there may be unnecessary stringency in applying migraine criteria. Pure menstrual migraine and menstrually related migraine are in the appendix (A1.1.1, A1.1.2). Some have recommended inclusion of these subtypes of triggered migraine in the migraine chapter proper. Three childhood ‘‘migraine’’ syndromes exist in the ICHD-II migraine chapter, ostensibly because they are felt to be precursors of migraine. These include cyclical vomiting (spells of nausea and vomiting up to 5 days in duration), 1.3.1; abdominal migraine (recurrent abdominal pain with varying degrees of nausea in school age
Proposed International Headache Society Appendix Criteria for a Revised Chronic Migraine Category
TABLE 2-10
A. Headache on 15 or more days each month B. Diagnosis of migraine without aura 1.1 C. Eight or more headaches per month meeting criteria for 1.1 migraine without aura or 1.2 migraine with aura, or responsive to migraine-specific medication before complete migraine symptomatology develops D. No medication overuse headache, no chronic tension-type headache, no cluster headache, no new daily persistent headache E. No underlying pathology Headache Classification Committee, Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26:742–746. Copyright # 2006. Reprinted with permission from Blackwell Publishing.
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KEY POINTS:
A
Case 2-3 Childhood Pain A 12-year-old boy has a 5-year history of recurrent bouts of abdominal pain and nausea. He has also had consistent motion sickness. He recently began having unilateral temporal headaches with nausea, blurred vision, and photophobia, responsive to oral triptan medication. Extensive diagnostic evaluation has been negative, including MRI of the head and electroencephalogram. Comment. This patient seems to fit the 1.3 childhood periodic syndromes that are commonly precursors of migraine category, in particular, abdominal migraine, 1.3.2. Interestingly, he is also beginning to develop migraine. Key points here, however, are to avoid the trap of assuming the gastrointestinal symptoms are benign and to maintain vigilance in the event that new data surface to suggest possible systemic illness.
lifetime prevalence approaching 80%. Thus, tension-type headache is an important pressing public health problem. Despite this, a paucity of research on tension-type headache has been done, which probably derives in large part from the underrepresentation of tension-type headache in specialty and academic settings. The ICHD criteria for tension-type headache are notable for their vagueness and requirements for nonexistence of certain features (Table 2-11). ICHD divides tensiontype headache into three broad categories based on frequency: 2.1 Infrequent episodic tension-type headache—headache episodes on less than 1 day per month on average 2.2 Frequent episodic tension-type headache—headache episodes on 1 to 14 days per month on average 2.3 Chronic tension-type headache—headache episodes on 15 or more days per month on average Because of their arbitrariness these frequency-based categories have been controversial. Chronic tension-type headache classification, like chronic migraine, requires that tension-type headache occurs on 15 days per month or more
(Table 2-12). The prevalence of this diagnosis is really unknown, but it is likely that when patients with chronic daily headache who meet revised chronic migraine criteria are excluded (as well as those with medication overuse), the occurrence of chronic tensiontype headache is uncommon. Also controversial are the subcategories of each of the three tensiontype headache types: tension-type headache with pericranial muscle contraction and tension-type headache without pericranial muscle contraction. No consistent evidence (despite concerted efforts) documents that tension-type headache is more prone to muscle contraction than any other headache type, so the presence or absence of it may not be meaningful (Jensen, 1999; Sandrini et al, 1994).
A
The ICHD criteria for tension-type headache are notable for their vagueness and requirements for nonexistence of certain features. The term trigeminal autonomic cephalalgia was coined to include three headache types that are felt to be somehow related: cluster headache, paroxysmal hemicrania, and SUNCT.
CLUSTER HEADACHE AND TRIGEMINAL AUTONOMIC CEPHALALGIA The term trigeminal autonomic cephalalgia was coined to include three headache types that are felt to be somehow related: cluster headache, paroxysmal hemicrania, and SUNCT. All have headache brevity in common
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" CLASSIFICATION OF PRIMARY HEADACHES
TABLE 2-11 International Classification of Headache Disorders, 2nd Edition, 2.1 Infrequent Episodic Tension-type Headache A. At least 10 episodes occurring on <1 day per month on average (<12 days per year) and fulfilling criteria B through D
chronic form (3.2.2—no remissions). PH is manifested by brief attacks of 2 to 30 minutes (shorter than those of cluster headache), which generally occur more than 5 times daily. PH is nearly unique in the ICHD-II (apart from hemicrania continua, see below) in that response to indomethacin is required for diagnosis. This creates the potential that patients with episodes similar to those of PH who fail to respond to indomethacin will defy diagnostic classification.
B. Headache lasting from 30 minutes to 7 days C. Headache has at least two of the following characteristics: 1. Bilateral location 2. Pressing/tightening (nonpulsating) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. No nausea or vomiting (anorexia may occur) 2. No more than one of photophobia or phonophobia E. Not attributed to another disorder
44
Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
International Classification of Headache Disorders, 2nd Edition, 2.3 Chronic Tension-type Headache
TABLE 2-12
A. Headache occurring on 15 days per month on average for >3 months (180 days per year) and fulfilling criteria B through D B. Headache lasts hours or may be continuous C. Headache has at least two of the following characteristics: 1. Bilateral location 2. Pressing/tightening (nonpulsating) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following:
and may include autonomic abnormalities in the head. Cluster headache with its intense, brief (15 to 180 minutes) periorbital pain occurring in cycles is generally straightforward in diagnosis and treatment (Table 2-13), but the chronic form, 3.1.2, can be a treatment nightmare. Paroxysmal hemicrania (PH) also has an episodic form (3.2.1, with flurries of attacks separated in time) and a
1. No more than one of photophobia, phonophobia, or mild nausea 2. Neither moderate or severe nausea nor vomiting E. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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International Classification of Headache Disorders, 2nd Edition, 3.1 Cluster Headache
TABLE 2-13
A. At least five attacks fulfilling criteria B through D B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 to 180 minutes if untreated C. Headache is accompanied by at least one of the following: 1. Ipsilateral conjunctival injection and/or lacrimation 2. Ipsilateral nasal congestion and/or rhinorrhea 3. Ipsilateral eyelid edema 4. Ipsilateral forehead and facial sweating 5. Ipsilateral miosis and/or ptosis 6. A sense of restlessness or agitation D. Attacks have a frequency from one every other day to eight per day E. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
SUNCT 3.3 is a rare condition manifested by yet briefer attacks (5 to 240 seconds) occurring up to 200 times daily. They are notoriously treatment resistant. The fact that some patients may not experience tearing led to the appendix diagnosis of SUNA (shortlasting unilateral neuralgiform headache attacks with autonomic symptoms), A3.3. The resemblance of some patients with SUNCT headaches to trigeminal neuralgia has been noted
by several authors and highlights the diagnostic dilemma when choosing between two headache disorders that lack diagnostic markers (Sesso, 2001). OTHER PRIMARY HEADACHES This group of miscellaneous unrelated headaches includes the exercise-related headaches and a number of new headache types, many of which mimic more serious secondary headaches. Primary stabbing headache, 4.1, is known as ‘‘jabs and jolts’’ and presents with sharp pains in areas innervated by the first two divisions of the trigeminal nerve. Pain is brief, similar to the pain of PH, but no associated autonomic abnormalities are present. Primary cough headache, 4.2, consists of brief head pain brought on by any Valsalva maneuver and thus may closely mimic the headache secondary to Chiari malformation. Primary exertional headache, 4.3, is migrainelike, lasting longer than cough headache, and can be induced by any exercise. Primary headache associated with sexual activity (4.4) has two forms: the so-called preorgasmic headache (formerly known as dull headache), 4.4.1, characterized by posterior moderately severe aching pain during intercourse; and the severe orgasmic headache, 4.4.2, which mimics subarachnoid or intracerebral hemorrhage as well as arterial dissection. The postural form of coital headache was sent to the secondary category of 7.2 (low cerebrospinal fluid pressure) based on a number of case reports suggesting this cause. Hypnic headache, 4.5, newly included in this version of the ICHD, occurs during sleep in elderly persons. While its pathophysiology is unclear, it shares some features with cluster headache (nocturnal occurrence and response to lithium). Primary thunderclap headache is a mysterious entity that mimics subarachnoid hemorrhage. Diagnosis requires
KEY POINT:
A
Primary headache associated with sexual activity (4.4) has two forms: the so-called preorgasmic headache (formerly known as dull headache), 4.4.1, characterized by posterior moderately severe aching pain during intercourse; and the severe orgasmic headache, 4.4.2, which mimics subarachnoid or intracerebral hemorrhage.
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" CLASSIFICATION OF PRIMARY HEADACHES
that it cannot meet criteria for any of the above exertion-related headaches and, of course, it must be shown not to be due to more serious disease (Case 2-4). Hemicrania continua, 4.7, manifests as unilateral continuous pain, often with autonomic features and, like PH, it is completely responsive to indomethacin (Table 2-14). (The resemblance to the trigeminal autonomic cephalalgias would seem to indicate placement in chapter 3 rather than in Other Headaches). NDPH, 4.8, consists of continuous headache, essentially meeting chronic tension-type headache diagnostic criteria, which begin acutely. (Goadsby and Boes, 2002; Li and Rozen, 2002; Vanast, 1986). This diagnosis points out the difficulty of assigning diagnosis based on history alone, since it is clear that some patients simply do not remember the precise details of their headache onset. The fact that a new onset of persistent non–tension-type headache is currently not diagnosable as NDPH
by the ICHD-II has been another area of controversy. CONCLUSIONS The ideal headache classification would have the following characteristics: o Hierarchical, with groups nested within one another o Each entity with its own unique classification o Intuitive rules o Easy to use o Practical for all the purposes for which it is designed The ICHD-II as yet does not fulfill all of the above criteria. It is hierarchical with nesting of diagnostic groups, thereby pleasing splitters and lumpers. Unfortunately, entities can coexist, eg, different subtypes of migraine or migraine and tension-type headache, which is not intellectually satisfying. The ICHD-II primary headache portion is really a classification of current headache features rather than
Case 2-4 Sudden Severe Headache
46
A 48-year-old man develops an extremely severe headache during sexual intercourse and is brought to the emergency department. He has no history of headaches other than ‘‘regular headaches every so often’’ and no family history of migraine or subarachnoid hemorrhage. He denies weakness, sensory changes, vision abnormality, or difficulty with cognition. His neck is supple, and his examination, including vital signs, is normal. A head computerized tomographic scan of the brain and lumbar puncture are entirely normal. His pain abates over the next several hours. The next morning a cerebral angiogram is performed and a 4-mm basilar artery berry aneurysm is detected. Comment. This worrisome situation is not uncommon. The multiple possibilities here include headache due to undetected aneurysmal rupture (6.2.2), headache due to unruptured aneurysm (6.3), thunderclap headache (4.6), orgasmic headache (4.4.2), or perhaps simply exertional headache (4.2), or even migraine. The fact that there is an aneurysm does not mean that it caused the headache. The false-negative rate with computerized tomography and lumbar puncture for ruptured aneurysms should be quite low, but is not zero. ICHD-II diagnosis is not clear here but perhaps is not so crucial because the most important issue now revolves around the decision concerning aneurysm resection.
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International Classification of Headache Disorders, 2nd Edition, 4.7 Hemicrania Continua
TABLE 2-14
A. Headache for >3 months fulfilling criteria B through D B. All of the following characteristics: 1. Unilateral pain without side-shift 2. Daily and continuous, without pain-free periods 3. Moderate intensity, but with exacerbations of severe pain C. At least one of the following autonomic features occurs during exacerbations and ipsilateral to the side of pain: 1. Conjunctival injection and/or lacrimation 2. Nasal congestion and/or rhinorrhea 3. Ptosis and/or miosis D. Complete response to therapeutic doses of indomethacin E. Not attributed to another disorder Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
of syndromes over time, which is also not entirely satisfactory for certain purposes. Rules are for the most part
logical but not always intuitive. This, as well as the sheer size of the ICHD, makes ease of use a goal rather than a reality. Practicality is the ICHD’s easiest target for criticism, particularly the primary headache portion. The number of possible diagnoses and rigorous criteria make use in clinical settings often too time-consuming for most practices unless single-digit diagnoses are acceptable. As for research purposes, inconsistencies and arbitrary criteria have led to controversies that make conclusions drawn from headache studies debatable. This, of course, ironically includes those studies designed to add refinement to the ICHD. However, the ICHD-II must still be considered one of the most important publications in clinical neurology of the last several years. As noted before, it has led to far deeper understanding and authentication of the many entities productive of head and facial pain. Moreover, the ICHD-II provides a vehicle for much-needed further study of headaches. This is particularly true for the primary headaches, many of which remain more or less mysterious in terms of etiology, pathophysiology, and treatment. The appendix, with its proposed alternative or new diagnoses, is designed to spur such research. The linking of the ICHD to the International Classification of Diseases (ICD-10) helps to advance the goal of diagnostic consistency. Future editions will presumably be more and more based upon evidence as it becomes available, resulting in a more internally consistent and practical tool.
KEY POINT:
A
Future editions of the ICHD will presumably be more and more based upon evidence as it becomes available, resulting in a more internally consistent and practical tool.
REFERENCES AND RECOMMENDED READING
"
Ad Hoc Committee on Classification of Headache of the National Institutes of Health. Classification of headache. JAMA 1962;179:717–718. The first modern attempt at headache classification, used widely until the International Classification of Headache Disorders, 1st Edition (ICHD-I ).
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" CLASSIFICATION OF PRIMARY HEADACHES
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Bigal ME, Tepper SJ, Sheftell FD, et al. Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria. Headache 2004;44:684–691. The authors made a systematic study of a large number of patients with chronic daily headache seen at a tertiary headache center, comparing ICHD diagnoses with Silberstein-Lipton classification diagnoses for chronic daily headache subtypes. They found that patients satisfying the chronic migraine criteria in ICHD-II were very rare and that the proposed patients with ‘‘transformed migraine’’ were not properly identified by the ICHD, a problem pointed out by a number of authors.
"
Carrera P, Stenirri S, Ferrari M, et al. Familial hemiplegic migraine: a ion channel disorder. Brain Res Bull 2001;56:239–241. Review of the mutations within the chromosome 19 CACNA1A gene (which encodes the brain-specific P/Q type calcium channel -subunit) associated with familial hemiplegic migraine.
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De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003;33:192–196. This article reports the discovery of the locus of the genetic mutation responsible for familial hemiplegic migraine type 2.
"
Eriksen MK, Thomsen LL, Olesen J. New international classification of migraine with aura (ICHD-2) applied to 362 migraine patients. Eur J Neurol 2004;11:583–591. ICHD-11 was used to assess 362 patients with migraine with aura to see how patients were distributed among the various subtypes. The authors concluded that these subtypes (including typical aura with migraine headache, typical aura with nonmigraine headache, typical aura without headache, and basilar-type migraine) were distinguished by specific features and therefore the classification was less arbitrary than that in the ICHD-I.
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Gladstone JP, Dodick DW. From hemicrania lunaris to hemicrania continua: an overview of the revised International Classification of Headache Disorders. Headache 2004;44:692–705. The authors review the (at the time) recently revealed ICHD-II and put it into historical perspective, beginning with a history of headache classifications.
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Goadsby PJ, Boes C. New daily persistent headache. J Neurol Neurosurg Psychiatry 2002;72(suppl 2):ii6–ii9. A review of the clinically distinct syndrome of new daily persistent headache (NDPH), including primary and secondary forms.
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Headache Classification Committee: Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26:742–746. This article attempts to properly address the category of transformed migraine.
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Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160. First appearing at scientific meetings in 2003, this second edition is known as the ICHD-II.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8:1–96. The first headache classification produced by the International Headache Society, also known now as ICHD-I.
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Isler H. Headache classification prior to the Ad Hoc criteria. Cephalalgia 1993;13(suppl 12):9–10. A brief history of attempts at headache classification from the time of Aretaeus of Cappadocia in the first century AD to the 1962 Ad Hoc Committee classification.
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Jensen R. Pathophysiological mechanisms of tension-type headache: a review of epidemiological and experimental studies. Cephalalgia 1999;19:602–621. This is an exhaustive review of the data concerning the pathophysiology of tension-type headache.
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Leone M, D’Amico D, Grazzi L, et al. Cervicogenic headache: a critical review of the current diagnostic criteria. Pain 1998;78:1–5. The authors critically reviewed the strict diagnostic criteria of Sjaastad and colleagues for cervicogenic headache in the light of clinical studies, finding many drawbacks to these criteria and concluding that the ‘‘neck-headache relationship has still not been adequately defined.’’
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Levin M, Peterlin BL, Ward TN. Review of International Classification of Headache Disorders (ICHD-II) diagnoses of 50 consecutive patients with chronic daily headache. Cephalalgia 2005;25:999. In this exercise to determine the inclusiveness of the ICHD-II, the authors were able to diagnose ICHD chronic migraine in all transformed migraine patients in this group of 50 patients with consecutive chronic daily headache seen in consultation at a tertiary headache clinic.
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Li D, Rozen TD. The clinical characteristics of new daily persistent headache. Cephalalgia 2002;22;66–69. This review of 56 cases of NDPH reveals some interesting phenomena, including the fact that 82% of patients with this syndrome were able to pinpoint the exact date their headache started and that approximately one third developed NDPH after a flulike illness.
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Manzoni GC, Torelli P. Headache classification: criticism and suggestions. Neurol Sci 2004;25:S67–S69. This review of the ICHD-II focused on several drawbacks and shortcomings, including sections on transformed migraine, trigeminal autonomic cephalalgias, NDPH, medication overuse headache, and headache attributed to psychiatric disorder.
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Mathew NT, Stubits E, Nigam MP. Transformation of episodic migraine into daily headache: analysis of factors. Headache 1982;22:66–68. Of 80 patients with daily headache, 61 (76%) were found to have had episodic migraine in the past. These patients, for whom Mathew coined the term transformed migraine, were compared with 82 patients with episodic migraine, and some interesting differences were found.
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Olesen J, Rasmussen BK. The International Headache Society classification of chronic daily and near-daily headaches: a critique of the criticism. Cephalalgia 1996;16:407– 411. Olesen and Rasmussen review the criticisms of the ICHD-I and point out strengths (particularly its comprehensiveness) and methods for its improvement.
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Pearce JM. Are the International Headache Society criteria for headache useful? Cephalalgia 1996;16:289–293. A review of the author’s perceived defects in the ICHD from a clinical as well as research perspective. Examples are cited and recommendations made.
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Pearce JM. Historical aspects of migraine. J Neurol Neurosurg Psychiatry 1986;49:1097–1103. An excellent and thorough review of the history of medical thinking about migraine from Hippocrates to the present.
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Sandrini G, Antonaci F, Pucci E, et al. Comparative study with EMG, pressure algometry and manual palpation in tension-type headache and migraine. Cephalalgia 1994;14:451–457. The authors used different methods of measuring muscle tension in patients with episodic tension-type headache, chronic tension-type headache, and migraine. They found that electromyography-measured muscle tension was no higher in tension-type headache sufferers than in migraineurs.
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Sesso RM. SUNCT syndrome or trigeminal neuralgia with lacrimation and conjunctival injection? Cephalalgia 2001;21:151–153. A case report suggestive of the theory that short duration, unilateral, neuralgic, conjunctival injection and tearing headache (SUNCT) is most closely related to trigeminal neuralgia.
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Silberstein SD, Lipton RB, Goadsby PJ. Headache in clinical practice. 2nd ed. London: Martin Dunitz, 2002.
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Silberstein SD, Lipton RB, Sliwinski M. Assessment for revised criteria of chronic daily headache. Neurology 1995;35:A394. Diagnoses of 150 patients with chronic daily headache were evaluated using International Headache Society criteria; 55% were found to have chronic tension-type headache and 43% were unclassifiable by criteria. Using their proposed revision of the ICHD, which included a transformed migraine category, most patients could be classified with transformed migraine (78%) and chronic tension-type headache (15%), and only 7% unclassified.
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Silberstein SD, Lipton RB, Solomon S, et al. Classification of daily and near-daily headaches: proposed revision to the IHS criteria. Headache 1994;34:1–7. The authors proposed specific criteria for the subtypes of primary chronic daily headache, including transformed migraine, NDPH, chronic tension-type headache, and hemicrania continua.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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Vanast WJ. New daily persistent headaches: definition of a benign syndrome. Headache 1986;26:317. In this report the authors described 45 patients with new onset of chronic headache for which they coined the term NDPH.
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Winner P, Wasiewski W, Gladstein J, et al. Multicenter prospective evaluation of the proposed pediatric migraine revisions to the IHS criteria. Pediatric Headache Committee of the American Association for the Study of Headache. Headache 1997;37:545–548. The authors reviewed proposed revisions in the ICHD-I classification of pediatric migraine, concluding that the revised criteria were significantly more sensitive as well as specific.
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MIGRAINE: SPECTRUM OF SYMPTOMS AND DIAGNOSIS
KEY POINT:
A
Most patients develop migraine in the first 3 decades of life, some in the fourth and even the fifth decade.
William B. Young, Stephen D. Silberstein
ABSTRACT The migraine attack can be divided into four phases. Premonitory phenomena occur hours to days before headache onset and consist of psychological, neurological, or general symptoms. The migraine aura is comprised of focal neurological phenomena that precede or accompany an attack. Visual and sensory auras are the most common. The migraine headache is typically unilateral, throbbing, and aggravated by routine physical activity. Cutaneous allodynia develops during untreated migraine in 60% to 75% of cases. Migraine attacks can be accompanied by other associated symptoms, including nausea and vomiting, gastroparesis, diarrhea, photophobia, phonophobia, osmophobia, lightheadedness and vertigo, and constitutional, mood, and mental changes. Differential diagnoses include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoenphalopathy (CADASIL), pseudomigraine with lymphocytic pleocytosis, ophthalmoplegic migraine, Tolosa-Hunt syndrome, mitochondrial disorders, encephalitis, ornithine transcarbamylase deficiency, and benign idiopathic thunderclap headache.
Migraine is a common episodic headache disorder with a 1-year prevalence of approximately 18% in women, 6% in men, and 4% in children. Attacks consist of various combinations of headache and neurological, gastrointestinal, and autonomic symptoms. Most patients develop migraine in the first 3 decades of life, some in the fourth and even the fifth decade. The term migraine is derived from the Greek word hemicrania, introduced by Galen in approximately AD 200. DIAGNOSIS Early migraine descriptions stressed three features: the unilateral distribution of the headache, the presence of a warning (often visual), and nausea or vomiting. The Ad Hoc Committee on Classification of Headache described vascular headache of migraine type as
(Headache Classification Subcommittee, 2004): Recurrent attacks of headache, widely varied in intensity, frequency, and duration. The attacks are commonly unilateral in onset; are usually associated with anorexia and sometimes with nausea and vomiting; some are preceded by, or associated with, conspicuous sensory, motor, and mood disturbances; and are often familial. In order to increase precision, the International Headache Society (IHS) proposed and published its classification of headache disorders in 1988 and revised it in 2004 (Headache Classification Subcommittee, 2004). The IHS criteria added photophobia and phonophobia and required an untreated duration of 4 to 72 hours.
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" MIGRAINE: SYMPTOMS AND DIAGNOSIS
KEY POINTS:
A
A
At most, only 30% of migraineurs have classic aura. The same patient may have migraine headache without aura, migraine headache with aura, and migraine aura without headache. If sufficient criteria but one are present, the headache is called probable migraine.
Migraine headaches were formerly divided into two varieties: classic and common, which are now called migraine with aura and migraine without aura. The aura is the complex of focal neurological symptoms that precedes or accompanies an attack. At most, only 30% of migraineurs have ‘‘classic’’ aura. The same patient may have migraine headache without aura, migraine headache with aura, and migraine aura without headache. In addition to the symptoms described in the IHS definition, other symptoms of migraine are extremely common. A wide variety of premonitory symptoms may occur; nasal congestion and neck pain may be present; and the typical eye findings of cluster headache may occur with some regularity (Table 4-1).
TABLE 4-1
Rates of Migraine Symptoms
Symptom
Approximate %
Throbbing* Unilaterality
68
80 *
61
Moderate to severe*
97
Worse with activity*
95
Nausea*
87
Vomiting* Photophobia
56 *
Phonophobia
*
85 80
Allodynia
65
Nasal congestion
70
Neck pain
65
Stabbing pain
40
Clusterlike eye symptoms
5
*In International Headache Society criteria.
To establish a diagnosis of migraine under the IHS classification, certain clinical features must be present and organic disease must be excluded (Table 4-2). Several attacks, each lasting 4 to 72 hours (untreated), are necessary and must have two of the following four pain characteristics: unilateral location, pulsating quality, moderate to severe intensity, and aggravation by routine physical activity. In addition, the attacks must have at least one of the following associated symptoms: nausea and/or vomiting, and/or photophobia and phonophobia. Using these criteria, no single associated feature is mandatory for diagnosing migraine, although recurrent episodic attacks must be documented. Different patients or different attacks may fulfill entirely nonoverlapping criteria. If sufficient criteria but one are present, the headache is called probable migraine. Table 4-2 lists the current subtypes of migraine. A migraine attack usually lasts less than a day; when it persists for more than 3 days, the term status migrainosus is applied. Although migraine often begins in the morning, sometimes awakening the patient from sleep at dawn, it can begin at any time of the day or night. The frequency of attacks is extremely variable, from a few in a lifetime to several in a week. The median attack frequency is 1.5 attacks per month; 10% of migraineurs have one or more attacks per week (Stewart et al, 1994). The diagnosis of migraine with aura requires at least two attacks with any two of three features: (1) one or more fully reversible aura symptoms; (2) the aura developing over more than 4 minutes but lasting less than 60 minutes; and (3) the headache following the aura with a free interval of less than 60 minutes. Migraine with aura is subdivided into migraine with typical aura (homonymous visual disturbance, unilateral numbness, or aphasia); migraine
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KEY POINTS:
TABLE 4-2
International Classification of Headache Disorders. 2nd Edition, Migraine Classification
A
1. Migraine
A
1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Typical aura with migraine headache 1.2.2 Typical aura with nonmigraine headache 1.2.3 Typical aura without headache 1.2.4 Familial hemiplegic migraine 1.2.5 Sporadic hemiplegic migraine 1.2.6 Basilar-type migraine 1.3 Childhood periodic syndromes that are commonly precursors of migraine
Most migraineurs with migraine with aura also have attacks without aura. In contrast to a transient ischemic attack, the aura of migraine evolves gradually and typically consists of both positive (eg, scintillations, tingling) and negative (eg, scotoma, numbness) features.
1.3.1 Cyclical vomiting 1.3.2 Abdominal migraine 1.3.3 Benign paroxysmal vertigo of childhood 1.4 Retinal migraine 1.5 Complications of migraine 1.5.1 Chronic migraine 1.5.2 Status migrainosus 1.5.3 Persistent aura without infarction 1.5.4 Migrainous infarction 1.5.5 Migraine-triggered seizures 1.6 Probable migraine 1.6.1 Probable migraine without aura 1.6.2 Probable migraine with aura 1.6.5 Probable chronic migraine Data from Headache Classification Subcommittee. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
aura with nonmigraine headache or without headache; familial and sporadic hemiplegic migraine; and basilar migraine. Other varieties of migraine include retinal migraine and childhood periodic syndromes. Most patients with migraine with aura also have attacks without aura. The aura usually lasts 20 to 30 minutes and typically precedes
the headache, but occasionally it occurs with the headache or only during the headache. In contrast to a transient ischemic attack (TIA), the aura of migraine evolves gradually and typically consists of both positive (eg, scintillations, tingling) and negative (eg, scotoma, numbness) features. If the aura is stereotypical, the diagnosis of migraine
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" MIGRAINE: SYMPTOMS AND DIAGNOSIS
KEY POINTS:
A
A
A
70
Almost any symptom or sign of brain dysfunction may be a feature of the migraine aura, but commonly the aura is visual. Particularly in mid or late life, the migraine aura may not be followed by the headache (migraine equivalent or late-life migraine accompaniment). Associated symptoms of migraine, such as nausea, photophobia, or phonophobia, may occur before headache as part of the premonitory phase.
with aura is warranted, even if the subsequent headache does not have typical migrainous features. Almost any symptom or sign of brain dysfunction may be a feature of the aura, but commonly the aura is visual. Focal symptoms and signs of the aura may persist beyond the headache phase. Formerly termed complicated migraine, the IHS classification has introduced two more-specific labels. If the aura lasts for more than 1 hour but less than 1 week, the term migraine with prolonged aura was formerly applied, but now the episode is called migraine with aura and an atypical feature. If the signs persist for more than 2 weeks without radiographic evidence of infarction, it is called a persistent aura without infarction. If a neuroimaging procedure demonstrates a stroke, a migrainous infarction has occurred. Particularly in mid or late life, the aura may not be followed by the headache (migraine equivalent or latelife migraine accompaniment). CLINICAL FEATURES OF MIGRAINE The migraine attack can be divided into four phases: (1) premonitory, which occurs hours or days before the headache; (2) the aura, which immediately precedes the headache; (3) the headache itself; and (4) the postdrome (Table 4-3). Migraine without aura consists of at least the headache and possibly the postdrome. Migraine with aura consists of at least the aura and
TABLE 4-3
" " " "
Migraine Attack
Phase 1 Premonitory phase Phase 2 Aura Phase 3 Headache Phase 4 Postdrome
the headache. If the headache is absent, it is migraine aura without headache. Both may be associated with premonitory symptoms. (Premonitory symptoms often extend into the headache or may begin in the headache phase). Premonitory Phase Premonitory phenomena occur hours to days before headache onset in about 60% of migraineurs and can consist of psychological, neurological, or general (constitutional, autonomic) symptoms (Table 4-4). Psychological symptoms include depression, euphoria, irritability, restlessness, mental slowness, hyperactivity, fatigue, and drowsiness. Neurological phenomena include photophobia, phonophobia, and hyperosmia, among others. General symptoms include a stiff neck, a cold feeling, sluggishness, increased thirst, increased urination, anorexia, diarrhea, constipation, fluid retention, and food cravings. Premonitory symptoms are present in approximately 60% of migraineurs with equal frequency in migraine with or without aura (Blau, 1980). Two types of migraine premonitory phases are described: nonevolutive, which precede the attack by up to 48 hours, and evolutive, which start approximately 6 hours before the attack, gradually increase in intensity, and culminate in the attack. A dopaminergic mechanism has been suggested. More recent data suggest that many features of the premonitory phase may develop during headache. Furthermore, associated symptoms of migraine, such as nausea, photophobia, or phonophobia, may occur before headache as part of the premonitory phase (Giffin et al, 2003). Although these findings belie the idea of a unique set of symptoms that apply specifically to the premonitory phase of headache, the concept of the premonitory phase with an identifiable set of symptoms before the pain of
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KEY POINTS:
TABLE 4-4
Premonitory Phenomena (Prodrome)
Psychological
Neurological
General
Depressed
Photophobia
Stiff neck
Hyperactive
Difficulty concentrating
Food cravings
Euphoric
Phonophobia
Cold feeling
Talkative
Dysphasia
Anorexia
Irritable
Hyperosmia
Sluggish
Drowsy
Yawning
Diarrhea or constipation
Restless
A
Thirst Urination Fluid retention
migraine remains important. It indicates that (1) the pain is but one feature of a complex neurological process and (2) symptomatic treatments may be possible even before pain develops. Aura The migraine aura is composed of focal neurological phenomena that precede or accompany an attack. Most aura symptoms develop over 5 to 20 minutes and usually last less than 60 minutes (Headache Classification Subcommittee, 2004). The aura can be characterized by visual, sensory, or motor phenomena and may also involve language or brain stem disturbances (Table 4-5). If it occurs, the headache usually begins within 60 minutes of the end of the aura. In one prospective study, headache followed the aura only 80% of the time (Jensen et al, 1986). If the headache is delayed, most patients fail to return to a normal sense between the end of the aura and the onset of the headache. Fears, somatic complaints, alterations in mood, disturbances of speech or thought, or detachment from the environment or from other people may
occur during this ‘‘gap.’’ The headache may begin before or simultaneously with the aura, or the aura may occur in isolation. Rarely, auras may occur repeatedly. This may be many times an hour for as long as several months. These have been termed migraine aura status, but other organic causes must be considered (Silberstein and Young, 1995). Sacks described two variations: scotomata occurring repeatedly, even alternating sides; and closely repeating cycles of migrating sensory auras occurring for hours on end (Sacks, 1985). Patients may experience more than one type of aura, with a progression from one symptom to another. Most patients with a sensory aura also have a visual aura (Figure 4-1) (Airy, 1871). Visual aura is the most common of the neurological events; it occurs in up to 99% of patients who have an aura and often has a hemianopic distribution. The aura may consist of photopsia (the sensation of unformed flashes of light before the eyes), scotoma (partial loss of sight) (Lance and Anthony, 1966), or the most diagnostic aura of migraine, the fortification spectrum (Airy, 1871). Auras vary in
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In migraine, the headache may begin before or simultaneously with the aura, or the aura may occur in isolation. Rarely, auras may occur repeatedly. This may be many times an hour for as long as several months. These have been termed migraine aura status, but other organic causes must be considered. Visual aura is the most common of the neurological events in migraine. It occurs in up to 99% of patients who have an aura and often has a hemianopic distribution.
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TABLE 4-5
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Aura
Visual Scotoma; photopsia or phosphenes, geometric forms, fortification spectra Objects may rotate, oscillate, or shimmer; brightness often appears very bright.
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Visual Hallucinations or Distortions Metamorphopsia, macropsia, zoom or mosaic vision
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Sensory Paresthesias, often migrating, often lasting for minutes (cheiro-oral) Can become bilateral
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Olfactory Hallucinations
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Motor
cated auras include teichopsia (Greek teichos, [town] wall, + opsis, vision) or fortification spectrum, the most characteristic visual aura of migraine. An arc of scintillating lights, usually but not always beginning near the point of fixation, may form into a herringbonelike pattern that expands to encompass an increasing portion of a visual hemifield. It migrates across the visual field with a scintillating edge of often zigzag, flashing, or occasionally colored phenomena. The visions of Hildegard of Bingen, an 11th century abbess, have been attributed in part to her migrainous auras, as have the visions of prophets, including Ezekiel, who experienced positive and negative visual phenomena, sparkling, boiling, or fermenting lights, that march across the visual field. Visual distortions and hallucinations, speculated to represent Lewis Carroll’s descriptions in Alice in Wonderland, can occur. These phenomena are more
Weakness or ataxia
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Language Dysarthria or aphasia
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Delusions and Disturbed Consciousness De´ja` vu, multiple conscious trancelike states
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their complexity. Elementary visual disturbances include scotomata, simple flashes (phosphenes), specks, or geometric forms. They may move across the visual field, sometimes crossing the midline. Shimmering or undulations in the visual field may also occur and may be described by patients as ‘‘heat waves.’’ These ‘‘minor visual disorders’’ are more likely to occur during than before the headache (Selby and Lance, 1960) and often do not meet the full criteria for migraine aura. Because they are bilateral they are believed to arise from the occipital cortex. More compli-
FIGURE 4-1
Migraine aura. It grows with the passage of time.
Airy H. On a distinct form of transient hemianopsia. Philos Trans R Soc Lond 1871;160:247–270. Reprinted with permission from the Royal Society.
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common in children, are usually followed by a headache, and are characterized by a complex disorder of visual perception that may include metamorphopsia, micropsia, macropsia, zoom, or mosaic vision. Nonvisual symptoms can occur and include complex difficulties in the perception and use of the body (apraxia and agnosia); speech and language disturbances; states of double or multiple consciousness associated with de ´ja` vu or jamais vu; and elaborate dreamy, nightmarish, trancelike, or delirious states. Olfactory hallucinations may also occur. Paresthesias characterize the second most common aura and occur in about one third of migraineurs with aura (Case 4-1). They are typically cheirooral with numbness starting in the hand, migrating up the arm, and then jumping to involve the face, lips, and tongue. The leg is occasionally involved. As with visual auras (with positive, followed by negative, symptoms), paresthesias may be followed by numbness and, in a few cases, loss of position
sense. Paresthesias begin bilaterally or become bilateral in half of patients. Sensory auras rarely occur in isolation and usually follow a visual aura. Olfactory auras may also occur and may be confused with epilepsy. Motor symptoms may occur in more than 10% of patients, often in association with sensory symptoms; however, true weakness is rare and is always unilateral. Genetically proven familial hemiplegic migraine is characterized by true weakness and is described below. Sensory ataxia is often reported as weakness. Hyperkinetic movement disorders, including chorea, have been reported. Aphasic auras have been reported in 17% to 20% of patients ( Jensen et al, 1986). However, since patients are rarely examined during an aura, many of the reported cases may be dysarthria and not aphasia.
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Periodic neurological phenomena, which may be the aura of migraine, can occur in isolation without the headache. These phenomena (scintillating scotoma, recurrent sensory, motor, and mental phenomena) must be differentiated from transient ischemic attacks and focal seizures and are diagnosed as migraine only after full investigation and reasonable follow-up.
Migraine Aura Without Headache Periodic neurological phenomena, which may be the aura of migraine, can occur
Case 4-1 A 28-year-old, right-handed woman is being treated for episodic migraine without aura. She calls one morning because she notes difficulty seeing on the right side, noting ‘‘things are missing,’’ but with no scintillations or other positive visual phenomena. This spell is similar to several that she had 15 years before in childhood. After 1/2 hour she notes paresthesias in her right hand that migrate up her arm, also skipping to her right face, then progressing to her right leg. On arrival at the office 1 hour later she has a severe, holoacranial headache and an expressive aphasia. Her visual and sensory symptoms have resolved. On examination there is no hemiplegia, hemisensory loss, or hemianopsia. The aphasia resolves within 5 minutes of arrival in the office, with a total duration of less than 1 hour. The severe headache resolves after intravenous prochlorperazine and ketorolac. Comment. The above case illustrates the spread of fairly typical visual aura (no positive visual phenomena and no clear evidence of spread within the visual domain) to the sensory and language cortex, consistent with spreading regional depression. If motor weakness had occurred, it would be typical of hemiplegic migraine. Each component resolved within 1 hour, which is typical of migraine aura, and, according to many experts, reflects a low risk of either secondary causes of migraine or evolving into a migraine stroke.
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Transient neurological phenomena not associated with headache can occur, often in patients over the age of 40 (late-life migrainous accompaniments or transient migrainous accompaniments); 57% of patients had a history of recurrent headache. Transient migrainous accompaniments (scintillating scotomata, numbness, aphasia, dysarthria, and motor weakness) that occur for the first time after the age of 45 can be easily confused with TIAs of cerebrovascular origin. Diagnosis in all but the most classical cases is still by exclusion. The headache of migraine can occur at any time of day or night but occurs most frequently on arising in the morning.
in isolation without the headache. These phenomena (scintillating scotoma, recurrent sensory, motor, and mental phenomena) must be differentiated from TIAs and focal seizures and are diagnosed as migraine only after full investigation and reasonable follow-up. Transient visual disturbances with flickering or scintillating phenomena also occur with numerous other conditions, including blood cell diseases, retinal detachment, cluster headaches, trauma, and syncope, but are not generally associated with cerebrovascular embolic or thrombotic disease. Headache occurring in association with the symptoms of aura will help confirm the diagnosis but does not include slightly less than half of the patients who had headache with aura and aura without headache at some time. Transient neurological phenomena not associated with headache can occur, often in patients over the age of 40 (late-life migrainous accompaniments or transient migrainous accompaniments); 57% of patients had a history of recurrent headache (Fisher, 1980). The attacks of episodic neurological dysfunction last from 1 minute to 72 hours and have variable recurrence rates (one attack, 27%; two to 10 attacks, 45%; more than 10 attacks, 28%). Isolated neurological spells attributed to migraine are a diagnosis of exclusion unless typical scintillating scotoma occurs. Thirty-two percent of Cornell neurologists had a history of transient neurological symptoms, most commonly visual (field cuts, obscurations, scotomata) and less commonly nonvisual symptoms (hemiparesis, clumsiness, paresthesias, dysarthria) (Levy, 1988). Migraine was reported in 29%, occurring in 44% of those reporting and 22% of those not reporting transient central nervous system dysfunction. None developed any residual deficit or
chronic neurological disorder at 5-year follow-up, suggesting that these are benign migrainous accompaniments. Migraine-related visual symptoms were investigated in the Framingham study (Wijman et al, 1998). Visual symptoms that could be interpreted as migraine related occurred in slightly more than 1% of patients but met the IHS definition of migraine in only 19% of these cases. The episodes, which often recurred (10 or more times), usually failed to develop slowly over 4 minutes. They were often not accompanied by headache and often occurred without a headache history. Migraineurs have approximately 3 times the risk of developing transient visual disturbances than nonmigraineurs. Gradual onset occurred in slightly less than half of subjects. If headache follows transient visual disturbance, it is more likely migraine in persons with a history of migraine headache. The stroke rate among subjects with migrainous visual symptoms is less than in subjects with TIAs and similar to that in subjects without TIAs or migrainous phenomena. Transient migrainous accompaniments (scintillating scotomata, numbness, aphasia, dysarthria, and motor weakness) that occur for the first time after the age of 45 can be easily confused with TIAs of cerebrovascular origin. Diagnosis in all but the most classical cases is still by exclusion (Table 4-6). Headache A migraine headache is typically unilateral, throbbing, moderate to marked in severity, and aggravated by routine physical activity. The IHS does not require all of these features: pain may be bilateral and throbbing or unilateral and achy. The headache of migraine can occur at any time of day or night but occurs most frequently on arising in the morning (Selby and Lance, 1960). The onset is usually gradual; the pain
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TABLE 4-6
Migraine Equivalents
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Scintillating scotoma
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Ophthalmoplegia
Paresthesias Aphasia Dysarthria Hemiplegia Blindness Blurring of vision Hemianopia Transient monocular blindness
Oculosympathetic palsy Mydriasis Confusion/stupor Cyclical vomiting Seizures Diplopia Deafness Recurrence of stroke deficit Chorea
peaks and then subsides and usually lasts less than 24 hours, with a range of 4 to 72 hours in adults and 2 to 48 hours in children. The headache is bilateral in 40% and unilateral in 60% of cases; it consistently occurs on the same side in 20% of patients (Selby and Lance, 1960). Migraineurs whose headaches alternate sides do not develop more consistently lateralized headache with the passage of time. The pain varies greatly in intensity, ranging from annoying to incapacitating, although most migraineurs report at least moderate pain (Stewart et al, 1994). The pain has a throbbing quality, particularly when it is severe, but it can be tight or bandlike (Selby and
Lance, 1960). During an attack, pain may move from one part of the head to another and may radiate down the neck into the shoulder. Physical activity or simple head movement commonly aggravate the pain. Patients prefer to lie down in a dark, quiet room. Many migraineurs have headache profiles that do not meet the IHS criteria for migraine. Some are probable migraine, missing one criterion; others will be shorter and less severe and often meet the IHS criteria for episodic tension-type headache (TTH). Many patients note that their headache begins as a TTH and builds into a ‘‘migraine.’’ The authors of this chapter believe these phenomenological TTHs are all migrainous in nature. They have more migraine features than TTH features and, unlike typical TTH occurring in nonmigraineurs, respond to specific migraine drugs (Lipton et al, 2000). Migraineurs may also experience shortlived jabs of pain, lasting for seconds, occurring between more characteristic migraine attacks (so-called idiopathic stabbing headache). The pain is described as an ‘‘icepick,’’ ‘‘needle,’’ ‘‘nail,’’ ‘‘jabs and jolts,’’ or ‘‘pinprick’’ headache, and occurs in about 40% of migraineurs. Scalp tenderness and other forms of cutaneous allodynia develop during untreated migraine in 60% to 75% of cases. This tenderness may involve the head and neck and prevent the patient from lying on the affected side. Allodynia typically begins in the trigeminal distribution and spreads to involve the arms. Characteristically it develops approximately 1 hour after the throbbing headache. Typical symptoms of allodynia are listed in Table 4-7. After the migraine headache ends, allodynia may persist for several hours.
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Migraine headache is bilateral in 40% and unilateral in 60% of cases; it consistently occurs on the same side in 20% of patients. The pain of migraine headache varies greatly in intensity, ranging from annoying to incapacitating, although most migraineurs report at least moderate pain. Many migraineurs have headache profiles that do not meet the International Headache Society criteria for migraine. Scalp tenderness and other forms of cutaneous allodynia develop during untreated migraine in 60% to 75% of cases.
Associated Phenomena Migraine attacks are accompanied by other associated symptoms that often
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Gastric emptying can be delayed and oral drug absorption impaired during an attack of migraine, and vomiting may result in drug loss, thereby compromising the therapeutic effectiveness of orally administered drugs. A recent study has demonstrated that gastric emptying may be delayed interictally compared with controls. Neck pain is common in patients with migraine, occurring in 60% to 90% of migraines studied: 20% in the premonitory phase, 60% during the headache phase, and 20% during the postdrome phase.
TABLE 4-7
Typical Questions to Evaluate Allodynia in Migraineurs
Do you experience pain or unpleasant sensation on your skin during migraine attack when you engage in any of the following activities (Yes, No, N/A)? Combing your hair Pulling your hair back (eg, ponytail) Shaving your face Wearing eyeglasses Wearing contact lenses Wearing earrings Wearing necklaces Wearing tight clothes Taking a shower (when shower water hits your face) Resting your face on the pillow on the side of pain Heat exposure (eg, cooking, placing heating pads on your face) Cold exposure (eg, breathing through your nose on a cold day, placing ice packs on your face) N/A = not applicable.
contribute to migraine-related disability. Gastrointestinal disturbances are often the most distressing symptoms. Anorexia is common, but food cravings can occur; nausea occurs in 90% of patients and vomiting in about one third. Gastroparesis may contribute to gastrointestinal distress and poor absorption of oral medication. Diarrhea occurs in about 16% of patients. Many migraineurs have enhanced sensory perception or sensitivity manifested by photophobia, phonophobia, and osmophobia, and they seek a dark, quiet
room. Others will have lightheadedness and vertigo. Premonitory symptoms, such as exhilaration, agitation, fatigue, lethargy, disorientation, hypomania, anger, rage, or depression, can continue into the headache. Constitutional, mood, and mental changes are almost universal. Blurry vision, nasal stuffiness, pallor or redness, and sensations of heat, cold, or sweating may occur. Fluid retention can develop hours to days before the headache. Frank edema may precede, accompany, or follow the headache, with resolution of the fluid retention after the headache resolves. The prevalence of associated symptoms is higher in clinic-based than population-based studies, probably because more effective interviewing techniques and more definitive criteria are used in the clinic. A selection bias toward patients with more severe headache may result in more symptoms being reported. Studies that graded the severity of nausea, photophobia, and phonophobia improved the differentiation of migraine from TTH; by definition, these symptoms were more prevalent and more severe in migraineurs. The prevalence of migraine-associated symptoms, particularly nausea and vomiting, has also been estimated by placebocontrolled drug studies. Forty-five percent to 100% of patients had nausea prior to treatment, which was similar to prevalence rates observed in other studies of adult migraineurs. The prevalence of vomiting was much lower and varied dramatically from study to study. Photophobia occurred in more than 85% of patients, while phonophobia was slightly less common. Nausea and vomiting also interfere with medication ingestion and were among the principal reasons for a patient’s discontinuing a specific migraine medication. Gastric emptying can be delayed and oral drug absorption impaired during an attack of migraine,
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and vomiting may result in drug loss, thereby compromising the therapeutic effectiveness of orally administered drugs. A recent study has demonstrated that gastric emptying may be delayed interictally compared with controls (Aurora et al, 2006). Nasal congestion is common in migraine. Most patients with migraine endorse nasal stuffiness during an attack. Among persons who believe they have sinus headache, a large preponderance actually have migraine or ‘‘probable migraine.’’ Nasal congestion may be prominent in persons with migraine and clusterlike ocular symptoms. Neck pain is common in patients with migraine, occurring in 60% to 90% of migraines studied: 20% in the premonitory phase, 60% during the headache phase, and 20% during the postdrome phase. In a more recent study, neck pain preceded the headache in 61% of patients, occurred during the headache in 92%, and followed the headache in 41% (Kaniecki, 2002). In an animal model, increased sensitivity in the trigeminal distribution occurred after stimulation of the greater occipital nerve, and increased responses of the cervical nociceptors occurred after noxious dural stimulation. Postdrome Following the headache, the patient may have impaired concentration or feel tired, washed out, irritable, and listless. Rarely people feel unusually refreshed or euphoric after an attack. Muscle weakness, aching, and anorexia or food cravings can occur. MIGRAINE VARIANTS Hemiplegic Migraine The IHS has subdivided hemiplegic migraine into sporadic and familial forms, both of which typically begin in childhood and cease with adulthood. This separation may not be
justified. In patients with motor weakness, 47% had a family history of migraine; 18% had a family history of hemiplegic migraine. The average age of onset of hemiplegic migraine may be earlier than that of migraine without aura, while the attacks themselves are frequently precipitated by minor head injury. Changes in consciousness ranging from confusion to coma are a feature, especially in childhood, and occurred in 23% of the series of Bradshaw and Parsons (1965). The prevalence of both familial and sporadic hemiplegic migraine has been estimated at 0.01% (Lykke Thomsen et al, 2002). The differential diagnosis of hemiplegic migraine includes focal seizures; stroke; homocystinuria; and myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome (Hosking, 1988). Familial hemiplegic migraine (FHM) is an autosomal dominant, genetically heterogenous form of migraine with aura, with variable penetration. Three genes are associated with this disorder. Type 1 is due to a mutation of CACNIA, a subunit of neuronal voltage gated P/Q type channels, on chromosome 19; type 2 is due to a mutation of ATP1A2, the Na+, K# ATPase pump gene, on chromosome 1; and type 3 is due to a mutation of SCN21A, a neuronal voltage-gated sodium channel, on chromosome 2. In approximately 50% of cases, type 1 FHM is associated with cerebellar degeneration. Type 3 FHM is occasionally associated with epilepsy during infancy (Dichgans et al, 2005; Ducros et al, 1997). The aura is characterized by motor weakness of variable intensity. The syndrome includes attacks of migraine without aura, migraine with typical aura, and severe episodes with prolonged aura (up to several days or weeks), fever, meningismus, and impaired consciousness ranging from confusion to profound coma. Headache
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Following the headache, the patient may have impaired concentration or feel tired, washed out, irritable, and listless. The differential diagnosis of hemiplegic migraine includes focal seizures, stroke, homocystinuria, and MELAS syndrome. Familial hemiplegic migraine type 1 has the best-characterized phenotype; patients have associated paresthesias; 88% had visual auras, and 44% had speech disturbances. Weakness lasted less than 1 hour in 58% of patients; however, it lasted 1 to 3 hours in 14%, 3 to 24 hours in 12%, and between 1 day and 1 week in 16% of patients.
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In 20% of unselected families with familial hemiplegic migraine, patients have fixed cerebellar symptoms and signs such as nystagmus and progressive ataxia. Retinal migraine, sometimes called ocular migraine, is a rare condition in which monocular scotoma or blindness accompanies migraine headache. The bilateral nature of many of the neurological events associated with basilar migraine helps differentiate it from more typical migraine. Thirty-eight percent of persons in a dizziness clinic have migraine, while 50% of migraineurs have vestibular symptoms and 9% have vertigo. Confusional migraine is characterized by a typical aura, a headache (which may be insignificant), and confusion, which may precede, occur with, or follow the headache.
may precede the hemiparesis or be absent. The onset of the hemiparesis may be abrupt and simulate a stroke. FHM type 1 has the best characterized phenotype. Patients have associated paresthesias; 88% had visual auras, and 44% had speech disturbances. Weakness lasted less than 1 hour in 58% of patients; however, it lasted 1 to 3 hours in 14%, 3 to 24 hours in 12%, and between 1 day and 1 week in 16% of patients. The syndrome can change in an affected individual over his or her lifetime (Stewart et al, 1994). A person who has FHM in adolescence may develop migraine with aura as an adult and migraine without aura later in life. The headache can be generalized, contralateral (almost half), or ipsilateral to the hemiparesis. One sixth of subjects may have a single attack; one third had between two and six episodes; and less than 50% had more than seven attacks. The longer-lasting episodes were associated with more profound weakness and tended to be less frequent in their recurrence. In 20% of unselected families with FHM, patients have fixed cerebellar symptoms and signs such as nystagmus and progressive ataxia. Cerebellar ataxia may occur before the first hemiplegic migraine attack and progress independently of the frequency or severity of hemiplegic migraine attacks. All of these families have been shown to be linked to chromosome 19 (Tournier-Lasserve, 1999). Retinal migraine, sometimes called ocular migraine, is a rare condition in which monocular scotoma or blindness accompanies migraine headache. Most persons reporting monocular symptoms are probably unaware of symptoms generated by the occipital lobe. When retinal migraine does occur, it is monocular, occurring most commonly in young adults. Visual symptoms may persist for days or weeks or be per-
manent. Retinal migraine is most likely caused by spasm of the ophthalmic artery. Alternatively, spreading depression of retinal neurons could explain some cases. Basilar migraine was originally called basilar artery migraine or Bickerstaff’’s syndrome. Although originally believed to be mainly a disorder of adolescent girls, it affects all age groups and both sexes, with the usual migraine female predominance. The aura generally lasts less than 1 hour and is usually followed by a headache that may be occipital. The headache can be associated with nausea and even projectile vomiting. A typical hemianopic field disturbance can rapidly expand to involve all visual fields, leading at times to temporary blindness. The bilateral nature of many of the neurological events associated with basilar migraine helps differentiate it from more typical migraine. The visual aura is usually followed by one or more of the following symptoms: dysarthria, vertigo, tinnitus, decreased hearing, diplopia, ataxia, bilateral paresthesia, bilateral paresis, and impaired cognition, which, when marked, define confusional migraine. The IHS criteria for basilar migraine require the presence of one or more of the preceding aura symptoms. Vestibular migraine is a diagnostic entity that attempts to describe the overlap of dizziness and migraine, which is not well described by IHS basilar migraine. Thirty-eight percent of persons in a dizziness clinic have migraine, while 50% of migraineurs have vestibular symptoms and 9% have vertigo (Neuhauser et al, 2001). Conversely, one study found vertigo in up to 25% of migraineurs (Kayan and Hood, 1984). Typically, headache precedes vertigo by 10 years. Vestibular symptoms can last minutes to 1 day and are loosely timed to the occurrence of headache (may occur separately or together). Some symptoms can last days to weeks
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and include chronic motion sensitivity (mal de debarquement). Nonvestibular symptoms may include ear pressure, pain, and tinnitus, as well as panic anxiety and phobic behavior (Neuhauser et al, 2001). Confusional migraine occurs more commonly in boys than girls, with an incidence of about 5% (Hosking, 1988). It is characterized by a typical aura, a headache (which may be insignificant), and confusion, which may precede, occur with, or follow the headache. The confusion is characterized by inattention, distractibility, and difficulty maintaining speech and other motor activities. Agitation, memory disturbances, obscene utterances, violent behavior, and sedation or a drugged feeling can occur. The electroencephalogram may be abnormal during the attack. Single attacks are most common, multiple attacks are rare, and attacks can be triggered by mild head trauma. If the level of consciousness is more profoundly disturbed, migraine stupor lasting 2 to 5 days can occur. The differential diagnosis includes drug ingestion, metabolic encephalopathies (Reye’s syndrome, ornithine transcarbamylase deficiency, hypoglycemia), viral encephalitis, the postictal state, and acute psychosis. Confusional migraine is also part of the syndrome of migraine with white matter abnormality linked to chromosome 19 (Chabriat et al, 1995). Abdominal migraine occurs in approximately 5% of recurrent abdominal pain in children. It may also occur in adults. The pain is typically midline, lasts 1 to 72 hours and is associated with anorexia, nausea, vomiting, and/or pallor. It is a diagnosis of exclusion, and other gastrointestinal disorders must be considered. Seventy percent of children with abdominal migraine have or will develop migraine within 10 years. In contrast, cyclic vomiting, another childhood migraine variant, is not ac-
companied by pain. These recurrent attacks of severe vomiting last 1 to 5 days.
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DIFFERENTIAL DIAGNOSIS Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain that was mapped to chromosome 19 and has since been reported in more than 200 families worldwide. The main clinical feature of CADASIL is recurrent subcortical events, either transient or permanent, that occur at a mean age of 45 years. Migraine with aura occurs earlier in life. The vascular presentation is not constant, and other symptoms, such as dementia or migraine with aura and depression, can occur. Although these symptoms are usually associated with a history of recurrent strokes, they may be a prominent or the only manifestation of the disease. Subcortical dementia associated with pseudobulbar palsy is the second most common manifestation of CADASIL, occurring in one third of the overall affected family members and in 90% of subjects before death. It is characterized by frontal-like symptoms, memory impairment, gait disturbances, pyramidal signs, pseudobulbar palsy, and sphincter incontinence. Attacks of migraine with aura occur in 30% and mood disorders in 20% of patients (Chabriat et al, 1995; Ducros et al, 1997). Most of the strokes are classic lacunar infarcts. All individuals with symptoms have abnormal magnetic resonance images (MRIs) with extensive symmetrical areas of increased T2 signals in the white matter and well-delineated hypointense
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If the level of consciousness is more profoundly disturbed in patients with confusional migraine, migraine stupor lasting 2 to 5 days can occur. CADASIL is an inherited arterial disease of the brain that was mapped to chromosome 19 and has since been reported in more than 200 families worldwide. All individuals with symptoms of CADASIL have abnormal MRIs with extensive symmetrical areas of increased T2 signals in the white matter and well-delineated hypointense lesions on T1-weighted images suggestive of small infarcts in the deep white matter and basal ganglia. Familial hemiplegic migraine is distinguished from CADASIL by its earlier-onset type, more benign prognosis, and normal MRI findings.
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Ophthalmoplegic migraine is no longer classified by the International Headache Society as a type of migraine and is now listed under the neuralgias. Using modern MRI, most patients with typical clinical features of ophthalmoplegic migraine have enhancement of the cisternal segment of the oculomotor nerve during the acute phase. Contrast-enhanced MRI and MR angiography are the procedures of choice in evaluating patients with oculomotor palsy. If MR shows enhancement of the cisternal portion of the oculomotor nerve and lumbar puncture is negative, a presumptive diagnosis of ophthalmoplegic migraine can be made. Tolosa-Hunt syndrome is a rare, painful ophthalmoplegia due to a granulomatous inflammation of the cavernous sinus.
lesions on T1-weighted images suggestive of small infarcts in the deep white matter and basal ganglia ( Joutel et al, 1996). FHM is distinguished from CADASIL by its earlier-onset type, more benign prognosis, and normal MRI findings. The arteriopathy underlying the disorder is neither atherosclerotic nor amyloid and involves the media of small cerebral arteries. However, lesions may be observed to a lesser extent in extracerebral arteries, including skin arterioles. Ultrastructural examination reveals abnormal patches of agranular osmiophilic material within the basal membranes of vascular smooth-muscle cells. Alternatively, a skin biopsy can be diagnostic, although most diagnoses are currently made by genetic testing. Ophthalmoplegic migraine is no longer classified by the IHS as a type of migraine and is now listed under the neuralgias. It characterized by at least two attacks associated with ocular cranial nerve palsy (usually the third cranial nerve with a dilated pupil) and unilateral migrainous eye pain. Rarely the fourth and sixth cranial nerves are involved. The duration of ophthalmoplegia is variable, from hours to months. Parasellar, retro-orbital cavernous sinus, or midcranial fossa lesion must be ruled out. The differential diagnosis includes berry aneurysm, acute sphenoid sinusitis, or sphenoid mucocele. Some cases of ophthalmoplegic migraine fit the criteria for the TolosaHunt syndrome of painful ophthalmoplegia (Hansen et al, 1990): spontaneous remission, with recurrent attacks occurring after months or years, and abnormal computed tomography (CT) or MRI. Using modern MRI, most patients with typical clinical features of ophthalmoplegic migraine have enhancement of the cisternal segment of the oculomotor nerve during the acute phase. Similar findings have been described for the fourth and sixth cranial
nerves. The enhancement resolves over several weeks as the symptoms abate. Enhancement can occur in a variety of infectious (Lyme disease, syphilis, coccidioidomycosis, human immunodeficiency virus) and noninfectious inflammatory conditions (lymphoma, leukemia, sarcoid, Tolosa-Hunt, Fisher syndrome). A lumbar puncture is needed to rule out infections and neoplastic causes. This disorder may be due to a viral infection of the oculomotor nerve similar to Bell’s palsy. Contrast-enhanced MRI and MR angiography are the procedures of choice in evaluating patients with oculomotor palsy. If MR shows enhancement of the cisternal portion of the oculomotor nerve and lumbar puncture is negative, a presumptive diagnosis of ophthalmoplegic migraine can be made, but follow-up is necessary to be sure the symptoms resolve. If the MR and lumbar puncture are negative, angiogram may still be necessary to rule out an aneurysm. Tolosa-Hunt syndrome is a rare, painful ophthalmoplegia due to a granulomatous inflammation of the cavernous sinus. Diagnosis is based on the combination of one or more episodes of painful ophthalmoplegia with paralysis of the third, fourth, and/or sixth cranial nerves, lasting an average of 8 weeks untreated, pain relief with corticosteroids within 72 hours, and exclusion of other causes, including aneurysm, diabetes mellitus, paranasal mucocele, parasellar neoplasm, carotid cavernous fistula, sphenoid sinusitis, and other disorders of the cavernous sinus. CT scan, with and without contrast enhancement, may show an enlarged cavernous sinus in only one of five patients. MRI is more likely to be abnormal, showing a convex enlargement of the symptomatic cavernous sinus by an abnormal tissue isointense with gray matter on short TR/TE images and iso-hypointense on long TR/TE scans, which enhances
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after contrast injection. In some cases it may extend into the orbital apex and subtemporal fossa. The MRI findings disappear slowly over approximately 6 months with corticosteroid treatment. Three months after successful treatment with corticosteroids, the abnormal tissue, although diminished in size, is still visible on MRI. Pseudomigraine With Lymphocytic Pleocytosis Pseudomigraine with lymphocytic pleocytosis, also known as headache with neurological deficit and lymphocytosis, is a rare condition with one to 12 episodes of migrainelike headache, weakness, sensory and visual symptoms, aphasia or confusion lasting minutes to hours (average 5 hours) (Pascual and Valle, 2003), lymphocytic pleocytosis with 10 cells/mm3 to 760 cells/mm3, negative workup, and normal brain imaging. Single-photon emission CT may reveal decreased uptake consistent with the focal symptoms. Sensory symptoms occur in 78% of patients, followed by aphasic and motor symptoms. Visual symptoms are relatively uncommon, occurring in 12%. Recurrent cases have been described (Pascual and Valle, 2003). Alternating Hemiplegia of Childhood Alternating hemiplegia (AH) is a rare, progressive disorder that produces a fixed motor deficit, retardation, and dyskinesias. It begins in infancy (before 18 months of age). The disorder is characterized by sudden, repeated attacks of hemiplegia involving each side alternately, lasting hours to days and associated with dystonic features. During an attack, the child is acutely uncomfortable and has signs of autonomic disturbance. Other paroxysmal phenomena, such as tonic spells, dystonic posturing, choreoathetosis, and nystagmus, can occur with the hemiplegia or independently. Fifty percent
of patients with AH have a family history of migraine. Flunarizine is effective in AH. Benign Idiopathic Thunderclap Headache Benign thunderclap headache is a sudden-onset headache (maximum intensity in less than 30 seconds). It usually lasts up to several hours with a less severe headache lasting weeks. In a significant minority it may recur. Attacks may be precipitated by exercise or sexual intercourse. They may be accompanied by nausea and vomiting, a variant that has been called ‘‘crash migraine.’’ Dodick (2002) has suggested that this term be abandoned until the pathogenesis of idiopathic thunderclap headache can be elucidated and in order to avoid diagnostic complacency. Thunderclap headache may be accompanied by diffuse focal vasospasm in very large arteries at the circle of Willis and second- and third-order segments. If focal symptoms or stroke accompany the vasospasm, Call-Fleming syndrome is present. The differential diagnosis of thunderclap headache is listed in Table 4-8 (Dodick, 2002). Diagnostic evaluation includes early CT, lumbar puncture, MRI with MR or CT angiography, and venography. Mitochondrial Disorders Most patients with MELAS have migraine. Migraine also appears to be common in Leber hereditary optic neuropathy and myoclonic epilepsy with ragged red fibers. Testing for mitochondrial abnormalities in persons with otherwise typical migraine has not been fruitful.
KEY POINTS:
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In patients with Tolosa-Hunt syndrome, MRI is likely to be abnormal, showing a convex enlargement of the symptomatic cavernous sinus by an abnormal tissue isointense with gray matter on short TR/TE images and iso-hypointense on long TR/TE scans, which enhances after contrast injection. Alternating hemiplegia is characterized by sudden, repeated attacks of hemiplegia involving each side alternately, lasting hours to days and associated with dystonic features. Benign thunderclap headache is a sudden-onset headache (maximum intensity in less than 30 seconds). It usually lasts up to several hours with a less severe headache lasting weeks.
Migraine in Children Children frequently have migraine or TTH. Headache prevalence in 1993 showed increases from about 40% at age 6 to more than 70% by age 15.
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Thunderclap headache may be accompanied by diffuse focal vasospasm in very large arteries at the circle of Willis and second- and third-order segments. Most patients with MELAS syndrome have migraine. Pure menstrual migraine is menstrual migraine without attacks at other times of the cycle. Menstrually related migraine allows additional attacks. Migraine attacks occur around the menses in 60% of women and exclusively during this period (true menstrual migraine) in 14%. Women with a history of menstrual migraine typically have an improvement of all their migraine types with pregnancy, perhaps due to sustained high estrogen levels.
TABLE 4-8
Differential Diagnosis of Thunderclap Headache
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Acute hypertensive crisis
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Idiopathic thunderclap headache
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Pituitary apoplexy
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Spontaneous retroclival hematoma
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Subarachnoid hemorrhage
Carotid artery dissection Cerebral venous sinus thrombosis
Spontaneous intracranial hypotension
include depression, mania, anxiety, and panic (Table 4-9). Co-occurring (any other disorder present) and comorbid disease and the presence of nonheadache symptoms present both therapeutic opportunities and limitations. HORMONAL FACTORS AND MIGRAINE Menstrual Migraine Menstrual migraine is defined as an attack occurring 1 day before and up to 4 days after the onset of menses. Pure menstrual migraine is menstrual migraine without attacks at other times of the cycle. Menstrually related migraine allows additional attacks (Headache Classification Subcommittee, 2004). Premenstrual migraine occurs 7 days to
Unruptured intracranial aneurysm
Adapted from Dodick DW. Thunderclap headache. Headache 2002;42:309–315. Copyright # 2002. Reprinted with permission from Blackwell Publishing.
TABLE 4-9
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Migraine Comorbid Disease
Cardiovascular Hypertension or hypotension
Migraine prevalence (probably underestimated by overstrict criteria), equal in boys and girls, was 3.9%. After puberty, the expected female predominance was observed. Migraine is different in children; it is typically bilateral and often briefer. The IHS now allows children to have attacks as short as 1 hour (Headache Classification Subcommittee, 2004). The location of the pain is usually frontal, and an occipital headache may be an ominous sign in children, in contrast to adults.
Raynaud’s syndrome Mitral valve prolapse Angina/myocardial infarction Stroke
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Psychiatric Depression Mania Panic disorder Anxiety disorder
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Neurological Epilepsy
Migraine Comorbidities Comorbidity is the presence of two or more disorders, the association of which is more likely than by chance. Conditions that occur in migraineurs with a higher prevalence than expected include stroke, epilepsy, mitral valve prolapse, Raynaud’s syndrome, and certain psychological disorders, which
Positional vertigo
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Gastrointestinal Functional bowel disorders
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Other Asthma Allergies
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1 day before the onset of menses. Migraine attacks occur around the menses in 60% of women and exclusively during this period (true menstrual migraine) in 14%. Premenstrually the headache may be accompanied by other features of premenstrual dysphoric disorders, including mood changes, backache, nausea, and breast tenderness and swelling. During menstruation, migraine is often associated with dysmenorrhea. Menstrual migraine is most likely due to estrogen withdrawal, which may trigger migraine attacks in susceptible women. Migraine and Pregnancy Migraine may worsen in the first trimester of pregnancy but may significantly improve during later pregnancy. Twenty-five percent of women have no change. Women with a history of menstrual migraine typically have an improvement of all their migraine types with pregnancy, perhaps due to sustained high estrogen levels. Migraine and Menopause Migraine prevalence decreases with advancing age. Menopause may bring regression, worsening, or no change in migraine. Estrogen replacement therapy can exacerbate migraine or prevent natural improvement. Women with natural menopause often show an improvement in their migraines while women with surgical menopause often worsen. Chemical menopause with a gonadotropin-releasing hormone analog did not alter the headache index (product of headache frequency and intensity) compared with the period before treatment; however, adding
back low-dose transdermal estradiol (known to produce steady levels of estrogen) led to a substantial improvement (Martin et al, 2003). Migraine and Hormonal Contraception The oral contraceptives (OCs) that are most commonly used in the United States contain combinations of estrogen and progestin and are taken 21 days each month. The older highestrogen OCs had an increased risk of stroke, but this risk has been significantly reduced with the new lowestrogen formulations. Progestin-only OCs are also available, as are implantable and injection progestins. Combination OCs can induce, change, or alleviate headache. OCs can provoke the first migraine attack, most often in women with a family history of migraine. Existing migraine may be exacerbated, and headaches may predictably occur on the days off the OC. The headache pattern may become more severe and/or frequent and may be associated with neurological symptoms. The headaches may become refractory to standard treatment. Generally, data from neurological or migraine clinics show an increased incidence, severity, and refractoriness of migraine in OC users; however, studies from contraceptive clinics and general practitioners are more favorable. Women with cardiovascular or cerebrovascular risk factors or moderate to severe neurological events in migraine, especially those who smoke, should avoid OCs. Progestin-only hormonal contraception may be safer but probably aggravates headache.
KEY POINTS:
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Menopause may bring regression, worsening, or no change in migraine. Combination oral contraceptives can induce, change, or alleviate headache. The headache pattern may become more severe and/ or frequent and may be associated with neurological symptoms. Women with cardiovascular or cerebrovascular risk factors or moderate to severe neurological events in migraine, especially those who smoke, should avoid oral contraceptives.
REFERENCES
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Airy H. On a distinct form of transient hemianopsia. Philos Trans R Soc Lond 1871;160:247–264. Classic description of ‘‘classical’’ migraine.
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Aurora SK, Kori SH, Barrodale P, et al. Gastric stasis in migraine: more than just a paroxysmal abnormality during a migraine attack. Headache 2006; 46:57–63.
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Blau JN. Migraine prodromes separated from the aura: complete migraine. Br Med J 1980;281:658–660. Important conceptual paper establishes the phases of migraine.
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Bradshaw P, Parsons M. Hemiplegic migraine, a clinical study. Q J Med 1965;34:65–85.
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Chabriat H, Tournier-Lasserve E, Vahedi K, et al. Autosomal dominant migraine with MRI white-matter abnormalities mapping to the CADASIL locus. Neurology 1995;45:1086–1091. Outlines cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) phenotype.
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Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371–377. Discovery of the third familial hemiplegic migraine gene but little phenomenological characterization.
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Dodick DW. Thunderclap headache. Headache 2002;42:309–315. Excellent review of thunderclap headache, giving diagnostic approach and management strategy for this fairly common complaint with many pitfalls.
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Ducros A, Joutel A, Vahedi K. Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity. Ann Neurol 1997;42:885–890. Discovery of the second familial hemiplegic migraine gene.
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Fisher CM. Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci 1980;7:9–17. First and most complete description of this condition. An absolute classic.
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Giffin NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 2003;60:935–940. Modern scientific look at the phenomenology of prodrome and the predictive value of symptoms for the development of headache.
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Hansen SL, Borelli-Moller L, Strange P, et al. Ophthalmoplegic migraine: diagnostic criteria, incidence of hospitalization and possible etiology. Acta Neurol Scand 1990;81:54–60. Good description of ophthalmoplegic migraine.
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Headache Classification Subcommittee. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160. The new International Headache Society (IHS) classification revised after the 1988 version. In addition to consensus definitions, the brief discussion of some of the rarer forms of migraine and its mimics are very useful.
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Hosking G. Special forms: variants of migraine in childhood. In: Hockaday JM, ed. Migraine in childhood: and other non-epileptic paroxysmal disorders. Boston: Butterworth-Heinemann, 1988:35–53.
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Jensen K, Tfelt-Hansen P, Lauritzen M, Olesen J. Classic migraine. A prospective recording of symptoms. Acta Neurol Scand 1986;73:359–362. Important prospective study of aura symptom.
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Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–710. Paper outlining this important entity.
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Kaniecki RG. Migraine and tension-type headache: an assessment of challenges in diagnosis. Neurology 2002;58:S15–S20. Challenges previous assumptions about neck pain and tension-type and cervicogenic headache.
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Kayan A, Hood JD. Neuro-otological manifestations of migraine. Brain 1984;107:1123–1142. Classic description of relationship between migraine and vertigo in this sparsely studied area.
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Lance JW, Anthony M. Some clinical aspects of migraine. A prospective survey of 500 patients. Arch Neurol 1966;15:356–361.
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Levy DE. Transient CNS deficits: a common, benign syndrome in young adults. Neurology 1988;38:831–836. Sobering explanation of the rate of unusual or hard to explain ‘‘spells.’’
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Lipton RB, Stewart WF, Cady R, et al. 2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the spectrum study. Headache 2000;40:783–791. Important paper correlating phenomena with treatment intervention.
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Lykke Thomsen L, Kirchmann Eriksen M, Faerch Romer S, et al. An epidemiological survey of hemiplegic migraine. Cephalalgia 2002;22:361–375. Important study.
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Martin V, Wernke S, Mandell K, et al. Medical oophorectomy with and without estrogen add-back therapy in the prevention of migraine headache. Headache 2003;43:309–321. Prospective (uncontrolled) headache study describing effects of oophorectomy with and without estrogen replacement provides solid information that physicians can give to patients.
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Neuhauser H, Leopold M, von Brevern M, et al. The interrelations of migraine, vertigo, and migrainous vertigo. Neurology 2001;56:436–441. Recent study of migraine and vertigo. Looks at migraine in dizziness clinic and vertigo in an outpatient setting.
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Pascual J, Valle N. Pseudomigraine with lymphocytic pleocytosis. Curr Pain Headache Rep 2003;7:224–228. Useful review of this uncommon but important disorder.
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Sacks O. Migraine: understanding a common disorder. Berkeley: University of California Press, 1985. Extraordinary descriptions of the phenomenology of migraine. Sack’s unique perspective is both entertaining and challenging.
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Selby G, Lance JW. Observation on 500 cases of migraine and allied vascular headache. J Neurol Neurosurg Psychiatry 1960;23:23–32. The classic paper describing the symptoms of migraine.
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Silberstein SD, Young WB. Migraine aura and prodrome. Seminars Neurol 1995;15:175–182. Review of the symptoms of aura and prodrome. In the case of aura, it remains essentially up-to-date.
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Stewart WF, Schechter A, Lipton RB. Migraine heterogeneity. Disability, pain intensity, attack frequency and duration. Neurology 1994;44:S24–S39. Epidemiological description of episodic migraine.
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Tournier-Lasserve E. CACNA1A mutations: hemiplegic migraine, episodic ataxia type 2, and the others. Neurology 1999;53:3–4. Important review article on familial hemiplegic migraine.
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Wijman C, Wolf PA, Kase CS, et al. Migrainous visual accompaniments are not rare in late life: the Framingham Study. Stroke 1998;29:1539–1543. Phenomenological and epidemiological descriptions.
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ACUTE TREATMENT OF MIGRAINE Stewart J. Tepper
ABSTRACT The goals of acute treatment in migraine should be sustained pain-free response, which will reduce disability and optimally restore function with minimal adverse events and cost. A validated four-item tool, Migraine-ACT, can measure adequacy of acute treatment. The strategy for picking the right acute treatment initially should be one of stratified care, matching patient need to migraine characteristics. Disability is a surrogate marker for disease severity, allowing for the decision as to when to use migraine-specific treatment versus nonspecific treatment in the absence of vascular disease. The evidence for efficacy of nonspecific treatments in migraine is mixed, due to variabilities in study designs, but they can be effective for moderate level migraine with low disability. Most studies for acute treatment with oral opioids have been poorly designed or negative. No randomized controlled trials have shown benefit for butalbital mixtures in the acute treatment of migraine. Migraine-specific treatments include triptans and ergots. Triptans are divided into groups by speed of onset and formulation. When possible, patients should be instructed to take these medications early in the migraine attack to make a sustained pain-free response more likely. Ergot use is limited by poor oral absorption and adverse events.
HISTORICAL VIEW Initially, the acute treatment of migraine involved alleviation of pain with nonspecific treatment, opioids, aspirin, or mixed analgesics. Opioids reduced pain, but often with the burden of sedation and nausea, both of which prevented return to function. Aspirin was unhelpful for severe, disabling headache. Wolff’s pathophysiological model of migraine envisaged migraine pain as caused by vasodilation, and aura by vasoconstriction. The acute treatment of migraine would thus involve use of a vasoconstrictive agent, such as an ergot, to reverse the vascular cause of the headache (Wolff, 1963). Other vasoconstrictive agents include isometheptene mucate (one of the active ingredients in Midrin/Duradrin), caffeine, triptans, and serotonin itself.
Intravenous serotonin (5-hydroxytryptamine [HT]) relieves migraine but causes significant adverse effects, including blood pressure change, nausea, and diaphoresis (Kimball et al, 1960). Both ergots and triptans are 5-HT1 agonists, and their action in migraine may be due to both their serotonergic activity and vasoconstriction. The serotonin-agonist effect may inhibit neurogenic inflammation peripherally around extracerebral intracranial vessels and most likely also inhibits nociceptive afferent input centrally. The vasoconstriction reverses peripheral meningeal vasodilation. It is by no means certain which mechanism is most important in acute migraine pain and its treatment, but it is clear that these medications are migraine specific.
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The International Headache Society has suggested a rigorous end point, pain free, which means moving from 2 or 3 to 0 after treatment. The three attributes most important to patients in an acute migraine medication are, in order: (1) complete pain relief (pain free), (2) no recurrence of headache, and (3) rapid onset of pain relief.
The clinical questions that have evolved and are critical in acute treatment for migraine are: Which patients should receive specific treatment for migraine? When in the attack should patients be instructed to take specific treatment? GOALS OF ACUTE TREATMENT The US Headache Consortium published a list of goals for acute migraine treatment in 2000 in Neurology (Silberstein, 2000). The goals are: o Treat attacks rapidly and consistently without recurrence. o Restore the patient’s ability to function. o Minimize the use of back-up and rescue medications. o Optimize self-care and reduce subsequent use of resources. o Be cost effective for overall management. o Have minimal or no adverse events. These goals are clearly what physicians set out to accomplish in the acute treatment of migraine. But are they what patients want from acute treatment? Over the last 15 years, a number of clinical end points have been used in the evaluation of acute migraine medications. The International Headache Society (IHS) has utilized a 4-point scale from 0 to 3, where 1 is mild pain, 2 is moderate pain, and 3 is severe pain. The end point in a roundtable discussion underwritten by pharmaceutical researchers in conjunction with headache specialists was ‘‘headache response,’’ also referred to as ‘‘headache relief’’ or ‘‘pain relief,’’ depending on the study, and meaning that a patient moves from moderate to severe pain (2, 3) to mild pain or no pain (1, 0) at a particular point in time after treatment. The IHS has suggested a more rigorous end point, pain free, which means moving from 2 or 3 to 0 after
treatment. The advantage of this end point is a lower placebo rate, but the disadvantage is that it raises the bar for treatment and may discourage patients and doctors alike when they find that treatment of a moderate to severe headache results in only a 30% to 40% or lower likelihood of pain freedom at 2 hours. All of the triptan regulatory trials used an artificial model in which patients were told to wait until they had at least moderate to severe–level pain before treating. This was to assure that they really had a migraine, which by one of the IHS criteria requires moderate to severe pain for diagnosis. However, this does not mean that this approach is the correct clinical technique to maximize benefit from an acute medication. By allowing the migraine to reach a moderate to severe level, the diagnosis becomes clearer, but the treatment may be more difficult. This will be discussed further below. Several studies have asked patients what is most important to them in an acute migraine medication. While this is not the same as asking what goals a physician should set in acute treatment, it is important to bear in mind the patient’s perspective when providing acute treatment. Lipton and Stewart (1999) found that the three attributes most important to patients in an acute migraine medication are, in order: (1) complete pain relief (pain free), (2) no recurrence of headache, and (3) rapid onset of pain relief. The IHS has suggested incorporation of these three features into an even more rigorous single clinical end point with which to evaluate acute migraine medications called sustained pain free, which consists of a patient with a migraine reaching a pain-free state within a specific time after taking acute medication and then having no recurrent migraine or use of rescue medication for the next 24 hours.
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Thus, to optimize acute treatment, clinicians should correctly select patients for specific acute migraine treatment and then use these specific medications in such a way as to reach the sustained pain-free state, the patient’s first goal and the new standard of the IHS. Dowson and colleagues (2004) tested 27 items in four domains to evaluate patient satisfaction and adequacy of acute treatment. The domains were headache impact, global assessment of relief, consistency of response, and emotional response. The four most sensitive and specific questions to ask patients for adequacy of acute treatment constitute the Migraine Assessment of Current Therapy (MigraineACT) and are as follows: o Consistency of response: Does your migraine medication work consistently, in the majority of your attacks? o Global assessment of relief: Does the headache pain disappear within 2 hours? o Impact: Are you able to function normally within 2 hours? o Emotional response: Are you comfortable enough with your medication to be able to plan your daily activities? Scoring the questionnaire is by adding the number of ‘‘yes’’ scores (range: 0 to 4). A score of 2 or less indicates that a change in the acute medication is
warranted, and a score of 1 or less may indicate a change is mandated. Evaluation of the effectiveness of acute treatment for reaching treatment goals can be as simple as asking if the patient has a sustained painfree response or using Migraine-ACT (Dowson et al, 2004) (Tepper et al, 2005) (Case 5-1). STRATEGIES FOR SELECTING ACUTE MIGRAINE MEDICATION The significant clinical question facing the neurologist after diagnosing migraine in the office is whether to initially select a nonspecific treatment or a migraine-specific treatment for acute management. Lipton and colleagues (2000b), after surveying various approaches to acute migraine treatment, described three strategies for treating diagnosed acute migraine, which they called step care across attacks, step care within attacks (also called staged care), and stratified care. Lipton and colleagues’ prospective study in 2000 showed that the stratified care approach yields optimal clinical outcome (Lipton et al, 2000b), and post hoc analysis suggested lower costs with stratified care when compared with the other approaches (Sculpher et al, 2002).
KEY POINTS:
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The four most sensitive and specific questions to ask patients for adequacy of acute treatment were incorporated into the tool Migraine-ACT. A Migraine-ACT score of 2 or less suggests a need to switch acute medications, and a score of 1 or less may indicate a change is mandated.
Step Care Across Attacks In this approach after a diagnosis of migraine, the least expensive nonspecific
Case 5-1 Patient A takes a triptan early in three migraine attacks and is not pain free at 2 hours in two of the three attacks. She cannot go back to work during any of the three attacks even though she gets headache relief, and she is very anxious about her next menstrual attack since she gets menstrually related migraine. She takes the Migraine-ACT and scores 0. Comment. It is mandatory to switch acute medications in this patient. Her description of only partial relief and her very low Migraine-ACT score should compel the clinician to make a change.
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In the step-careacross-attacks approach to acute migraine treatment, the least expensive nonspecific medication is selected by the physician for the patient to use first. If this medication fails, the physician will then ‘‘step up‘‘ to the next drug, until finally reaching a specific, more effective medication.
medication is selected by the phy- o Presence of associated symptoms, sician for the patient to use first. If eg, nausea, vomiting, phonophobia, this medication fails, the physician will and photophobia then ‘‘step up’’ to the next drug, until o Time to associated symptoms finally reaching a specific, more effecThe second type of stratified care is tive medication. that which is based on disability or impact of the migraine on the patient over Step Care Within Attacks time, rather than evaluation of the (Staged Care) character of multiple attacks. In this This approach involves starting with a form of stratified care, a disability or imnonspecific, less expensive medication pact assessment tool is used, usually the first and then if it fails, having the Migraine Disability Assessment Scale patient take the specific medication (MIDAS), developed by Lipton and at that point. The specific drug would colleagues (2000a), or the Headache be used during an attack only if the Impact Test (HIT)-6 (Ware et al, 2000). lower-level medicine had failed. The MIDAS uses five questions to assess specific medication would in fact be disability, which can be condensed into used as a rescue. Patients often take a single question (not validated as the staged-care approach themselves. such): ‘‘How many days in the last 3 Patients reason that since insurance months were you at least 50% disabled companies will pay for only a limited at work, home, school, or recreational number of triptan tablets each month, activities?’’ Each day of at least 50% they should only use the triptan when disability is given one point, and a score ‘‘things are really bad.’’ They will start of greater than 10 suggests moderate to with nonsteroidal anti-inflammatory severe level of disability (Table 5-1). drugs (NSAIDs) and over-the-counter HIT-6 uses six questions in six domains medication or prescribed nonspecific to assess headache impact and disabilmedication and step up to the triptan ity, and scores greater than 60 suggest during the attack only if the lower-level severe impact (Ware et al, 2000). medication fails. They will hoard their The Disability in Strategies of Care expensive, specific medication. (DISC) study is the only randomized prospective comparison of step care Stratified Care within attacks, step care across atThe third strategy is stratified care, tacks (staged care), and stratified care defined as matching treatment to a pa- (Lipton et al, 2000b). Patients with tient’s characteristics or the character- episodic migraine were treated with istics of the disease. Two types of either 900-mg aspirin (ASA) and 10-mg stratified care have been described. metoclopramide (MCP) as nonspecific The first would be to evaluate the medication, or zolmitriptan as the specharacteristics of the attack itself. cific triptan. This would involve establishing the The patients were randomly assigned following: by the strategy with which to treat them. In Group I, the step-care-across-attacks o The severity of the peak intensity group, subjects received ASA/MCP to of the attack o The time to peak intensity, ie, the abort migraine for three attacks, and if rate at which the attack proceeds this was not successful, the patients were allowed to ‘‘step up’’ to zolHow much time is available to achieve adequate treatment before mitriptan for the fourth attack and thereafter. the patient is disabled?
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TABLE 5-1
MIDAS Questionnaire
1. On how many days in the last 3 months did you miss work or school because of your headaches? _____ days 2. How many days in the last 3 months was your productivity at work or school reduced by half or more because of your headaches? (Do not include days you counted in question 1 where you missed work or school.) _____ days 3. On how many days in the last 3 months did you not do household work because of your headaches? _____ days 4. How many days in the last 3 months was your productivity in household work reduced by half or more because of your headaches? (Do not include days you counted in question 3 where you did not do household work.) _____ days 5. On how many days in the last 3 months did you miss family, social, or leisure activities because of your headaches? _____ days Your rating: TOTAL: _____ days A. On how many days in the last 3 months did you have a headache? (If a headache lasted more than 1 day, count each day.) _____ days B. On a scale of 0–10, on average how painful were these headaches? (Where 0 = no pain at all, and 10 = pain as bad as it can be.) Grade
Definition
Score
I
Minimal or infrequent disability
0–5
II
Mild or infrequent disability
6–10
III
Moderate disability
11–20
IV
Severe disability
21+
Reprinted with permission from Stewart WF, Lipton RB, Whyte MS, et al. An international study to assess reliability of the Migraine Disability Assessment (MIDAS) score. Neurology 1999;53:988–994. Copyright # 1999, AAN Enterprises, Inc.
In Group II, step care within attacks, subjects were given ASA/MCP for three attacks, and if it was not successful within each attack, they were given zolmitriptan to use at 2 hours. In Group III, the stratified-care group, subjects were stratified to a low treatment–need group (MIDAS score less than 11, or fewer than 11 days of at least 50% disability in the previous 3 months), to receive ASA/MCP, or to a moderate to high treatment–need group (MIDAS score greater than 10) to receive zolmitriptan from the beginning. If after six attacks, the subjects receiving ASA/MCP wished to switch to zolmitriptan, they were then allowed to do so.
The primary end points were the 2-hour headache response rate over six attacks and the disability time per attack. Note that the study was not meant to see which worked better, low-level, nonspecific treatment or specific treatment with triptans. Rather this was a study to determine which strategy for selecting an acute-care medication would work better for patients. The idea was to find out when to use which treatment in which patient (ie, how to get to the right treatment the first time). All primary end points were superior for stratified care as the strategy for treatment, as opposed to the step-care strategies. Even in the patients who
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91
" ACUTE TREATMENT OF MIGRAINE
KEY POINTS:
A
A
A
92 A
Even in a low treatment– need group, patients feel a need for stronger or specific medication more often than not. A stratified care strategy is likely to provide greater pharmacoeconomic benefit than other treatment strategies. Patients with episodic migraine with more than 10 days of at least 50% disability in the last 3 months by MIDAS score and no medical contraindication should be given triptan therapy at the outset as their first medication for acute treatment. The evidence for effectiveness of nonspecific treatments for migraine is mixed.
were stratified to ASA/MCP in the stratified-care group because of low disability scores, 56% chose to move up to zolmitriptan after six attacks treated with ASA/MCP. This suggests that even in the low treatment–need group, patients felt a need for stronger or specific medication more often than not. Disability time was also consistently less for stratified care, suggesting pharmacoeconomic benefit for choosing a stratified-care strategy for patients. Three post-hoc analyses have been conducted since the primary end points were calculated. All found lower costs with the stratified-care model (Rapoport et al, 2000a; Rapoport et al, 2000b; Sculpher et al, 2002; Tepper and Meddis, 2000). Thus, the DISC study has yielded clear, prospective evidence in favor of matching disability to treatment. Patients with episodic migraine with more than 10 days of at least 50% disability in the last 3 months by MIDAS score and no medical contraindication should be given triptan therapy at the outset as their first medication for acute treatment, and not be given a lower-level medication and stepped-up care across attacks or in the same attack. NONSPECIFIC TREATMENT Nonspecific treatments for migraine include NSAIDs; ASA; acetaminophen (APAP); combinations of ASA, APAP, and aspirin/amphetamine/caffeine(AAC); neuroleptics; antiepilepsy drugs (AEDs);
-aminobutyric (GABA) agonists, such as baclofen; antihistamines; mild vasoconstrictor/sedative/APAP mixtures (isometheptene/dichloralphenazone/APAP); barbiturate mixtures (butalbital/caffeine with either ASA or APAP); and opioids. Some of these are available over-thecounter and some require prescriptions, but all are used for cost reasons and to avoid significant vasoconstrictive effects of migraine-specific treatment.
The evidence for effectiveness of these medications is mixed. There is evidence that 1000 mg of ASA is as effective as 1000 mg of APAP in treatment of migraine (Tfelt-Hansen and Olesen, 1980). In a placebo-controlled study of AAC, 172 subjects with IHS migraine but no vomiting for more than 20% of their attacks and no incapacitating disability (requiring bed rest for more than 50% of their attacks) on presentation were included. Thus they were preselected in a nonrandomized way. Eighty-nine subjects were randomly assigned to AAC and 83 to placebo. The end points of pain intensity, functional disability, nausea, vomiting, photophobia, and phonophobia were rated at baseline and after 30 minutes, 1, 2, 3, 4, and 6 hours postdose. From 1 hour and continuing through 6 hours postdose, the proportion of responders was significantly greater (P.01) for AAC than placebo. These patients took two tablets of AAC, each containing 250-mg APAP, 250-mg ASA, and 65-mg caffeine. Other studies have confirmed AAC effectiveness in preselected patient groups with lowerlevel migraines (Goldstein et al, 1999; Lipton et al, 1998). A subsequent factorial analysis found that two tablets of a German AAC combination of ASA 250 mg, APAP 400 mg, and caffeine 50 mg was more effective than its individual single and dual combinations (Diener et al, 2005), suggesting that caffeine can be a useful adjuvant in nonspecific medications. For the acute treatment of migraine attacks with NSAIDs, most of the anthranilic class (eg, tolfenamic acid) and propionic acid class (eg, naproxen) have been proven effective in randomized controlled studies (Limmroth and Przywara et al, 2000). Diclofenac, an NSAID derivative of acetic acid, was tested in migraine attacks and shown to be superior to placebo and APAP
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(Dahlof and Bjorkman, 1993; Massiou et al, 1991). Solubilized ibuprofen is also effective in migraine compared with placebo (Kellstein et al, 2000). The US Headache Consortium guidelines have suggested that NSAIDs or AAC can be effective for moderate-level migraine (Silberstein, 2000). However, as noted above, the studies on ibuprofen and AAC over-the-counter medications for acute migraine treatment are not as strong methodologically as those suggesting effectiveness for triptans because in the US over-the-counter studies, patients were selected who had reduced frequency of vomiting or bedrest with their migraine, ie, less severe attacks, while in the triptan studies, all patients with episodic migraine of any intensity were included (Lipton et al, 2000b; Sculpher et al, 2002). Therefore, the evidence for effectiveness in the acute treatment of migraine is not equivalent for the nonspecific medications and the triptans. Most studies for acute treatment with oral opioids have been poorly designed or negative (Boureau et al, 1994; Carasso and Yehuda, 1984; Gawel et al, 1990; General Practitioner Research Group, 1973; Silberstein and McCrory, 2000; Snow et al, 2002; Uzogara et al, 1986). After considering the data on oral and nonoral opioids, the following recommendations were made by the US Headache Consortium (Silberstein, 2000; Snow et al, 2002): Nasal butorphanol is a treatment option when other medications can’t be used or as a rescue medication when severe sedation is not a critical issue for the patient. Oral opioid combinations may be considered when sedation will not put the patient at risk and/or the risk for abuse has been addressed. Parenteral opioids may be considered a choice only in a supervised setting and again when sedation
will not put the patient at risk and/ or the risk for abuse has been addressed. One prospective study suggests that after migraine progresses to a state manifested by allodynia, sumatriptan subcutaneous plus parenteral NSAIDs such as ketorolac may make patients pain free. However, those patients previously exposed to opioids did not benefit from the intravenous ketorolac, suggesting that (1) NSAIDs may reverse central sensitization in migraine, but (2) opioids may worsen central sensitization and should be avoided for acute treatment ( Jakubowski et al, 2005). No randomized controlled trials have shown benefit for butalbital mixtures in the acute treatment of migraine. Most countries, including the entire European Union, have elected to remove butalbital from the market because of the lack of evidence for efficacy and the high rates of habituation and dependence with its use. Butalbital is also not available in Latin America or Asia, leaving the United States as one of the only countries left in the world with this pernicious medication available for prescription (Case 5-2). SPECIFIC MEDICATIONS: TRIPTANS Oral triptans can be divided into two clinical groups. Group I consists of those triptans with fast onset, relatively high headache response, and pain-free rates at 2 hours (Tables 5-2, 5-4, 5-5, and 5-6). Group II triptans have slower onset and lower efficacy rates. Their efficacy numbers at 4 hours are similar to the Group I triptans at 2 hours (see Tables 5-3, 5-4, 5-5, and 5-6). The similarities among the Group I oral triptans are greater than the differences, and the population differences are less important than individual patient preferences. Robert Kaniecki,
KEY POINTS:
A
A
A
A
For the acute treatment of migraine attacks with NSAIDs, most of the anthranilic class (eg, tolfenamic acid) and propionic acid class (eg, naproxen) have been proven effective in randomized controlled studies. The US Headache Consortium guidelines have suggested that NSAIDs or aspirin/amphetamine/caffeine can be effective for moderatelevel migraine. The evidence for effectiveness in the acute treatment of migraine is not equivalent for the nonspecific medications and the triptans. Data suggest that after migraine progresses to a state manifested by allodynia, sumatriptan subcutaneous plus parenteral NSAIDs such as ketorolac may make patients pain free.
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93
" ACUTE TREATMENT OF MIGRAINE
KEY POINTS:
A
A
94
Once the group of triptans is selected and the need for formulation is established, a triptan can be selected based on formulary tier status. In patients who develop allodynia, treatment with a triptan before allodynia develops is far more likely to result in a pain-free response.
Case 5-2 Patient B goes to her physician, who diagnoses migraine and prescribes 600 mg of ibuprofen. This does not work. Upon return, the physician gives the patient MIDAS to fill out and finds that this healthy 25-year-old woman has had 21 days of at least 50% disability at work, home, school, and recreational activity. What is the proper course of action? Comment. A patient presenting with migraine should always have a disability assessment, either with MIDAS or another validated impact test, such as the HIT-6. The MIDAS score belatedly given this patient without vascular risk factors is in the severely disabled range and suggests the need to prescribe a migraine-specific medication from the beginning, stratifying the patient by disability. The lack of success with ibuprofen is linked to the severity of the disability and is an example of the failure of step care across attacks.
in public lectures, has described the decision as to which triptan to choose as picking among the three F’s: fast versus slow, formulation, and formulary availability. Two brief cases of young patients without vascular risk factors will illustrate this decision process (Cases 5-3 and 5-4). The orally dissolvable tablets available with rizatriptan (Maxalt MLT) and zolmitriptan (Zomig ZMT) do not have buccal or sublingual absorption. Rather, they are oral tablets that taste better than conventional tablets and so do not represent truly different formulations that would meet patient need in the setting of vomiting, such as in patient C in Case 5-3. Finally, once the group of triptans is selected and the need for formulation is established, a triptan can be selected based on formulary tier status. In the United States, triptans are either Tier 2 or Tier 3, with average copays of $25 and $50 respectively. Patients greatly appreciate a preferred formulary status in Tier 2 for cost reasons. Having decided which patients in whom to use triptans, the next question is how to use the triptans to best achieve a sustained pain-free response. Burstein and colleagues published evidence that as migraine progresses, cu-
taneous allodynia is manifested, and they have suggested that earlier treatment might avoid this process. They have shown that in patients who develop allodynia, treatment with sumatriptan before allodynia develops is far more likely to result in a pain-free response (Burstein et al, 2004; Burstein et al, 2000; Burstein and Jakubowski, 2004). If the migraine is allowed to proceed, multiple non-nociceptive stimuli—sensitivity to light, noise, smell, movement, and possibly to the effects of medication—become painful. Treating early would abort this. Reviewing the naratriptan database for evidence that early treatment would be associated with lower recurrence, Sheftell and colleagues (1994)
TABLE 5-2
Group I Triptans: Fast Onset
Generic Name Brand Name Sumatriptan
Imitrex, Imigran
Zolmitriptan
Zomig, AscoTop, Zomigon
Rizatriptan
Maxalt
Almotriptan
Axert, Almogran
Eletriptan
Relpax
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TABLE 5-3
Group II Triptans: Slower Onset
Generic Name
Brand Name
Naratriptan
Amerge, Naramig
Frovatriptan
Frova
found that patients who were treated in the first 90 minutes of an attack were less likely to experience recurrence than those who were treated after 2 hours. They speculated that achieving a pain-free response might be tied to reduced recurrence rate. Early intervention resulting in greater likelihood of a sustained painfree effect appears to be a triptan class effect. The preponderance of evidence suggests that early intervention is the best way to use triptans to achieve TABLE 5-4
optimal results in terms of both patient outcome and pharmacoeconomics, since a sustained pain-free result means fewer tablets per attack because there is no recurrence. To summarize, selection of patients for specific migraine treatment involves stratifying the patient according to disability or characteristics of the migraine attack. In the absence of medical contraindications, if an episodic migraineur has had greater than 10 days of at least 50% disability in the last 3 months, initial acute treatment should be with a triptan (although more than half of the patients stratified to nonspecific treatment in the DISC study requested a triptan later). Furthermore, if the patient has been stratified to use a triptan, the patient should be instructed not to step up medication in an attack or delay treatment, but rather to treat with the triptan at the mild level of
KEY POINTS:
A
A
Patients who are treated in the first 90 minutes of an attack are less likely to experience recurrence than those who are treated after 2 hours. The preponderance of evidence suggests that early intervention is the best way to use triptans to achieve optimal results in terms of both patient outcome and pharmacoeconomics, since a sustained pain-free result means fewer tablets per attack because there is no recurrence.
Triptan Medications
Generic
Brand
Formulations
Doses
Maximum Daily Dose
Sumatriptan
Imitrex
Tablets
25 mg, 50 mg, 100 mg
200 mg (US)
Nasal spray
5 mg, 20 mg
40 mg
Subcutaneous injection
4 mg, 6 mg
12 mg
Suppositories (EU)
25 mg
50 mg
Zomig
Tablets
2.5 mg, 5.0 mg
10 mg
Zomig-ZMT
Orally disintegrating
2.5 mg, 5.0 mg
10 mg (US)
Zomig
Nasal spray
5.0 mg
10 mg (US)
Maxalt
Tablets
5 mg, 10 mg
30 mg (US)
Maxalt-MLT
Orally disintegrating tablet
5 mg, 10 mg
30 mg (15 mg if on concomitant propranolol)
Naratriptan
Amerge
Tablets
1.0 mg, 2.5 mg
5 mg
Almotriptan
Axert
Tablets
12.5 mg
25 mg
Frovatriptan
Frova
Tablets
12.5 mg
25 mg
Eletriptan
Relpax
Tablets
20 mg, 40 mg
80 mg
Zolmitriptan
Rizatriptan
US = United States; EU = European Union.
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" ACUTE TREATMENT OF MIGRAINE
TABLE 5-5
Pharmacokinetics of the Triptans
Drug
Tmax (h)
Sumatriptan
2
Elimination Route/ T1/2 (h) Bioavailability (%) Metabolism Hepatic; MAO-A; 60% renal
50-mg tablet
2.5
2
14
20-mg spray
1
17
6-mg subcutaneous
0,2
97
Zolmitriptan
Hepatic (1 active and 2 inactive metabolites; CYP/MAO-A
2.5-mg tablet
2
2.5–3.0
40–48
2.5-mg ZMT
3.3
2.5–3.0
40–48
1.2 (Tablet)
2.0–3.0
45
Hepatic MAO-A; 30% excreted renally unchanged
1.6–2.5 (MLT)
2.0–3.0
Naratriptan
2.0–3.0
5.0–6.3
63 (men), 74 (women)
70% excreted renally unchanged; CYP; not MAO-A
Almotriptan
1.4–3.8
3.2–3.7
80
Hepatic; CYP/MAO-A; 15% active N-demethyl metabolite 26%–35% excreted renally unchanged
Eletriptan
1.0–2,0
3.6–5.5
50
Hepatic CyP3A4; 15% active N-demethyl metabolite; not MAO-A
Frovatriptan
2.0–4.0
24–30
Hepatic; CYP/MAO-A; 26%–35% excreted renally unchanged
2.5-mg nasal Rizatriptan
25
Tmax = time to peak plasma concentration.; T1/2 = half-life; MAO-A = monoamine oxidase-A; CYP = cytochrome P450.
96
Modified from Tepper SJ, Rapoport AM. The triptans: a summary. CNS Drugs 1999;12:403–417, with permission from Adis International.
pain to avoid incomplete response, recurrence, and disability. ERGOTS—THE OTHER MIGRAINESPECIFIC TREATMENTS The ergot alkaloids were the first specific antimigraine therapy available. Their use in the treatment of migraines has declined, and their role is less clear now in the triptan era. The ergot alkaloids interact with multiple receptors. The two used for
acute treatment of migraine, dihydroergotamine (DHE) and ergotamine (ET), can cause vasoconstriction by stimulating -adrenergic and 5-HT receptors, although ET is a more potent vasoconstrictor (Tables 5-7 and 5-8). Both can inhibit the actions of norepinephrine (NE) and 5-HT and are venoconstrictors (Mu ¨ller-Schweinitzer, 1984; Silberstein, 1997). ET and DHE bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A (D), 5-HT2C, and 5-HT3 (M) receptor sub-types (Mu ¨ller-Schweinitzer
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TABLE 5-6
Clinical End Points for the Triptans From Selected Clinical Trials
Drug
Dose and Route
Therapeutic Gain at 2 Hours (%)
Recurrence Rate (%)
Sumatriptan
6-mg subcutaneous
51
34–38
50-mg oral RT
25
26–28
100-mg oral RT
30
28–30
34
30
20-mg nasal spray Zolmitriptan
2.5-mg oral 2.5-mg ODT
41
2.5-mg nasal spray
26
5.0-mg nasal spray
40
Naratriptan
2.5-mg oral
22
17–28
Rizatriptan
10-mg oral
27–40
30–47
10-mg ODT
19–46
Almotriptan
12.5-mg oral
26–32
18
Eletriptan
40-mg oral
22–41
19–23
Frovatriptan
2.5-mg oral
16–19
7–25
RT = Formulated with RT Technology ODT = orally disintegrating tablet. Data from Rapoport AM, Tepper SJ, Bigal ME, Sheftell FD.The triptan formulations: how to match patients and products. CNS Drugs 2003;17:431–447. Sheftell FD, Dahlof CG, Brandes JL, et al. Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets. Clin Ther 2005;27:407–417.
and Weidmann, 1978). Triptans bind only to 5-HT1B, 5-HTD, and 5-HTF receptors. Clinically, ergots are difficult to use. The oral bioavailability of ET is less than 1% (Little et al, 1982). Because most of the drug is metabolized during the first pass through the liver (Iversen et al, 1990), use of ET suppositories is more likely to give clinical benefit than the oral formulation. Oral ET is appropriate for patients with slowly evolving migraine without early-onset nausea. The patient should take one 1-mg tablet at the start of an attack, with a maximum total dose of 6 mg per attack. Even this 1-mg dose, the smallest available in the United States, is often nauseating.
Nausea may indicate that the dose is too high, but the ET currently available in the United States is neither scored nor breakable into smaller doses, further limiting clinical usefulness. Taking the ET early, before migraine nausea has begun with its associated
Case 5-3 Patient C with no vascular risk factors has episodic migraines with severe peak intensity, a short time to vomiting, and a short time to peak intensity. Comment. A nonoral triptan will be necessary. The only two triptans with multiple formulations are sumatriptan with oral, nasal, and subcutaneous (SC) formulations, and zolmitriptan with oral and nasal formulations. With severe vomiting and prostration, injectable sumatriptan will be necessary.
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" ACUTE TREATMENT OF MIGRAINE
Case 5-4 Patient D without vascular risk factors has episodic migraines with severe peak intensity and a short time to peak intensity, but never vomits. Comment. An oral triptan might be appropriate if the patient prefers tablets. Patient D requires a fast-onset, oral triptan from Group I. It is hard to go wrong with any Group I triptan for patient D; the question is how best to use it. A patient with a more indolent onset of attacks over 4 to 6 hours could use a Group II triptan.
gastric stasis, is critical for using the oral formulation. Even more important than limiting total dosage is restricting ET use to no more than 2 days per week with an interval of at least 4 days in between usage days to prevent drug-induced headache (Saper, 1987; Silberstein and Young, 1995), which is extremely common with frequent ET usage. The suppository, which is useful in patients with severe nausea and vomiting, yields higher plasma levels of ET and has greater efficacy than oral tablets. According to Raskin (1988) and Mathew (1997), the likelihood of drug-associated nausea, a frequent side effect of ET, can be reduced through determination of a subnauseating dose of ET suppository. The patients are instructed to cut the sup-
98
TABLE 5-7
positories, and subnauseating doses may range from one-half suppository (1.0 mg) down to as little as oneeighth suppository (0.25 mg) (Mathew, 1991). When an attack develops, the patient should administer the subnauseating dose at the start of the attack. Once again, limiting to no more than 1 to 2 days of usage per week is critical to avoiding habituation, rebound, and daily headache. There is no doubt that DHE represents an advance over ET in treating migraine with or without aura, status migrainosus, and chronic daily headache (transformed or chronic migraine). Side effects are fewer, and habituation is rare. Oral DHE has even lower bioavailability than ET, due to incomplete drug passage across the gastrointestinal
Ergotamine and Dihydroergotamine Receptor Profile
Adrenergic Receptors*
Dopaminergic y Receptors
Serotoninergic Receptors
Alpha1
DA1
5-HT1A
Alpha2
DA2
5-HT1B
Beta
5-HT1F 5-HT2A 5-HT2C
*Alpha 1 >Alpha2 >Beta. y DA2 >DA1. Mathew NT. The abortive treatment of migraine. In: Gallagher RM, ed. Drug therapy for headache. New York: Marcel Dekker, 1991:95–114. Reprinted with permission from Taylor and Francis.
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TABLE 5-8
Dihydroergotamine Mesylate Versus Ergotamine Tartrate: Clinical Comparisons
Safety/Efficacy Measure
Dihydroergotamine Mesylate
Ergotamine Tartrate
5-hydroxytryptamine 1 (5-HT1) activity
++
++
Arterial vasoconstriction
+
+++
Venoconstriction
++
++
-Adrenergic antagonist activity
++
+
Nausea/vomiting
+
+++
Uterotonic effects
+
++
Pain relief
+++
+++
Headache recurrence
+
++
Rebound headache
0
++
0 indicates none; + mild; ++ moderate; +++ prominent. Adapted from Lipton RB. Ergotamine tartrate and dihydroergotamine mesylate: safety profiles. Headache 1997;37:S33–S41. Copyright # 1997. Reprinted with permission from Blackwell Publishing.
mucosa and a high first-pass metabolism, in contrast to the absolute bioavailability of intramuscular (IM) DHE (100%) (Little et al, 1982). The absolute bioavailability of DHE following intranasal (IN) administration is approximately 40% (Bigal and Tepper, 2003). Peak plasma levels occur approximately 1 to 2 minutes after intravenous (IV) administration, 24 minutes after IM administration, and 30 to 60 minutes after IN administration. IN administration of DHE avoids firstpass hepatic metabolism (Ziegler et al, 1994). Both IN and parenteral administration of DHE are reasonable. Studies published in the 1990s have shown comparable efficacy between SC and IM administrations (Winner et al, 1993). Anecdotally, clinicians advise patients to mix DHE with 0.25 mL to 0.50 mL of 1% to 2% lidocaine in the same syringe (they are miscible) to reduce injection-site burning. The patient will need training to selfadminister DHE by IM or SC injection, starting with a single injection of
DHE 1 mg, which may be repeated, if needed, after 60 minutes. Once again, titration to a subnauseating dose is important. Maximum dosing is 3 mg/d, 21 mg per week. Dosing of IN DHE is one spray (0.5 mg) into each nostril (without sniffing) at the first sign of migraine, followed 15 minutes later by an additional spray into each nostril. Thus, the total dose administered is 2 mg in four sprays. The maximum recommended dose is 4 mg per attack (Raskin, 1988). The utility of DHE nasal spray is limited clinically by relatively low efficacy and high frequency of prolonged nasal stuffiness. The advantage of ergots is that once headache relief is established, recurrence of migraine is low. In randomized clinical trials, oral ET was found superior to placebo but inferior to oral sumatriptan 100 mg (Tfelt-Hansen, 2001; Tfelt-Hansen et al, 2000). IN DHE was found superior to placebo but less effective than SC and IN sumatriptan, at least for initial response. Recurrence was lower
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" ACUTE TREATMENT OF MIGRAINE
Case 5-5 Patient E wakes up with a vomiting migraine, takes a 100-mg sumatriptan tablet, and only partially holds it down. She calls and says she needs a rescue medication. What options does she have to avoid a trip to the emergency department? Comment. The easiest rescue would be sumatriptan SC, since forms of sumatriptan can be mixed. This can be supplemented with a neuroleptic suppository, since she is vomiting. If she comes to the office, parenteral ketorolac, steroids, or valproate can also be used.
with IN DHE than with sumatriptan (Winner et al, 1996). In summary, the issues for use of ergots are as follows: (1) They cannot TABLE 5-9
be mixed with each other or triptans. (2) They are difficult to use, requiring titration of dose. (3) ET is highly associated with medication overuse
Parenteral Acute Treatments for Migraine for Use in Clinic or Emergency Department
Medication
Dose
Route
Other Facts
Dihydroergotamine 1-mg or maximum SC, IM, IV May be mixed with subnauseating dose lidocaine in SC or IM dosing; recurrence is low; nonsedating; contraindicated with vascular disease
100
Sumatriptan
6 mg
SC
Nonsedating; contraindicated with vascular disease
Metoclopramide
10 mg
IV
Risk of extrapyramidal effects and mild sedation
Promethazine
25 mg to 50 mg
IM, IV
Risk of extrapyramidal effects and sedation
Prochlorperazine
10 mg
IV
Risk of extrapyramidal effects and sedation
Droperidol
2.5 mg to 5.0 mg
IV
Risk of QT prolongation, extrapyramidal effects and sedation
Ondansetron
4 mg to 8 mg
IV
Nonsedating antinauseant
Ketorolac
30-mg IV, 60-mg IM IM, IV
Nonsedating
Dexamethasone
4 mg to 10 mg
Nonsedating
Valproate
500 mg to 1000 mg IV
Nonsedating
Magnesium
1g
Nonsedating; works best for patients with migraine with aura
IM, IV
IV
SC = subcutaneous; IM = intramuscular; IV = intravenous.
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headache (Saper, 1987). (4) Adverse events can be significant. (5) They are not clearly superior to the more convenient triptans, except with respect to IV DHE. Both triptans and ergots are contraindicated in the setting of vascular disease, and when vascular risk factors are present, a functional workup should be undertaken prior to administering the first dose in the office. As noted, both triptans and ergots are vasoconstrictive. Also, both triptans and ergots are contraindicated in hemiplegic and basilar-type migraine within 24 hours of each other. RESCUE AND EMERGENCY TREATMENT As noted above in the section on opioids, the use of narcotics as rescue treatment for status migrainosus should be avoided. In an outpatient setting, when a migraine appears to spiral out of control due to late or inadequate treatment, this author rec-
ommends use of SC sumatriptan, repetitive DHE nasal spray, or a brief several-day course of steroids, such as dexamethasone (Case 5-5). In the clinic or emergency department, a variety of IM or IV treatments can be used together or separately, with the only contraindication that of mixing triptans and ergots in the same day, and that of avoiding triptans and ergots in patients with vascular disease. Rescue treatments are listed with doses in Table 5-9. CONCLUSIONS Acute treatment of migraine involves stratified care and preferential use of migraine-specific medications for those with disabling migraines. Nonspecific treatment is probably less effective for severe migraine, and ergots are more difficult to use. Rescue can involve medications from multiple classes, including triptans or ergots, neuroleptics, steroids, nonsteroidal anti-inflammatories, valproate, and magnesium.
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Winner of the Wolff award for best headache research of 2005, this is a must-read study describing the effects of NSAIDs on central sensitization and of the deleterious effects of opioids in treating acute migraine.
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Rapoport A, Williams P, Sawyer J. Stratified care: cost-efficient in the management of migraine. Headache 2000b;40:426. Post-hoc pharmacoeconomic analysis of the DISC study.
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105
CHRONIC DAILY HEADACHE AND ITS SUBTYPES Marcelo E. Bigal, Fred D. Sheftell
ABSTRACT Chronic daily headache is one of the more frequently seen headache syndromes at major tertiary care centers worldwide as well as in office practices of general neurologists. One of the major classification approaches subdivides chronic daily headache into four headache types: transformed or chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. In this chapter the authors review the clinical features and classification of the chronic daily headaches, as well as the pathophysiology of chronic daily headache with a focus on chronic migraine. Effective treatment regimens will be discussed, which include the following steps: (1) education and support to the patient, establishing expectations and a follow-up plan; (2) use of nonpharmacological and behavioral therapies; (3) discontinuation of overused and potentially offending medications plus caffeine by outpatient or inpatient detoxification procedures; and (4) institution of a program of acute care and preventive pharmacological therapy.
INTRODUCTION Chronic daily headache is a clinical syndrome defined by primary headaches that occur for 4 or more hours a day on 15 or more days a month over more than 3 months (Mathew et al, 1987; Saper, 1982; Silberstein, 1993). Chronic daily headache is one of the more common presentations to headache specialty care centers and afflicts 4% to 5% of the general population (Castillo et al, 1999; Scher et al, 1998). Most patients with chronic daily headache report frequent and severe impairment of their role functioning and well-being (Spierings et al, 2000), highlighting the important impact of this group of headaches on quality of life. The burden of chronic daily headache is severe. Studies show that subjects with chronic daily headache have significantly lower health-related quality of life scores when compared with pa-
KEY POINT:
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Chronic daily headache is a clinical syndrome defined by primary headaches that occur for 4 or more hours a day on 15 or more days a month over more than 3 months.
tients with episodic headaches (Bigal et al, 2003). As a syndrome, chronic daily headache has been included in neither the first nor the second edition of the International Classification of Headache Disorders (ICHD-I and ICHD-II) (Headache Classification Subcommittee of the International Headache Society, 1988; Headache Classification Subcommittee of the International Headache Society, 2004). As a consequence, several separate proposals for their classification have emerged. The Silberstein and Lipton criteria have been most widely used (Silberstein et al, 1996). The Silberstein and Lipton criteria divided primary chronic daily headache into transformed migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua, and subclassified each of these into subtypes ‘‘with medication
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KEY POINTS:
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Chronic daily headache is usually subdivided into chronic or transformed migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. The prevalence of chronic daily headache in the population ranges from 2.4% to 4.7%.
overuse’’ or ‘‘without medication overuse’’ (Table 7-1). Of these, the ICHD-I (Headache Classification Committee of the International Headache Society, 1988) classification included only chronic tension-type headache, while the ICHD-II (Headache Classification Subcommittee of the International Headache Society, 2004) has detailed diagnostic criteria for all four types of primary chronic daily headache of long duration. Evidence, however, suggested that the ICHD-II scheme remained cumbersome and not intuitive in the classification of adults with chronic daily headache (Bigal et al, 2004a; Silberstein et al, 1996). As a consequence, revised criteria for chronic migraine was proposed (Bigal et al, 2006). Recently, a revised version of the criteria for chronic migraine, endorsed by the ICHD-II (Headache Classification Committee of
TABLE 7-1
Silberstein-Lipton Criteria for Classification of Chronic Daily Headache
Daily or Near-daily Headache Lasting > 4 Hours for >15 Days Per Month 1.8 Transformed Migraine
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1.8.1 With overuse 1.8.2 Without overuse 2.2 Chronic Tension-type Headache 2.2.1 With overuse 2.2.2 Without overuse 4.7 New Daily Persistent Headache 4.7.1 With overuse 4.7.2 Without overuse 4.8 Hemicrania Continua 4.8.1 With overuse 4.8.2 Without overuse
the International Headache Society, 2006), has been published as well and will be discussed herein. Since transformed migraine, as defined by Silberstein and Lipton, and chronic migraine, as defined by the ICHD-II, refer to analogous disorders representing the result of episodic migraine that progressed over time, and since accepted criteria for chronic migraine were just recently published, both definitions will be addressed in this chapter. Clinical features of the other chronic daily headaches will be discussed as well as strategies for the treatment of chronic daily headache. Potential prospects for avoiding the development of chronic daily headache will be emphasized. Since medication overuse is a strong risk factor for the development of chronic daily headache, this chapter is complemented by the chapter Medication Overuse Headache. EPIDEMIOLOGY OF CHRONIC DAILY HEADACHES The prevalence of chronic daily headache is remarkably consistent among studies, ranging from 2.4% (Hagen et al, 2000) to 4.7% (Castillo et al, 1999). In the United States, the prevalence is 4.1%. In the population, transformed migraine and chronic tension-type headache are equally prevalent (both around 2%) (Scher et al, 1998). The prevalence of new daily persistent headache and hemicrania continua is unknown. Clinic-based studies show that chronic daily headache accounts for about 10% to 20% of the patients in European headache clinics although, according to Dowson and colleagues (2005), this is likely an underestimation. In the United States, studies show that from 50% to 80% of all patients presenting to a headache clinic have chronic daily headache (Bigal et al, 2004a; Mathew, 1993). In this setting, transformed migraine/chronic migraine (transformed migraine and
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chronic migraine refer to the same condition; the terms will be used synonymously in this chapter) is by far the most common type of chronic daily headache. In a study by Mathew (1993), 77% of the patients with chronic daily headache had transformed migraine. In a large study conducted at the New England Center for Headache, transformed migraine represented 87.4% of the cases of chronic daily headache seen in a headache specialty center (Bigal et al, 2004a). The relative frequency of the different headache subtypes presenting to a headache clinic is different in adults and in adolescents. Chronic tensiontype headache and new daily persistent headache are more common in adolescents than in adults (respectively, 10.0% versus 0.9% and 20.0% versus 10.0%), transformed migraine is more common in adults, and hemicrania continua is equally rare (Bigal et al, 2005a). Furthermore, the clinical presentation, as discussed below, of transformed migraine is different in adolescents than in adults. Adolescents with transformed migraine have a higher frequency of migraine attacks than adults (Bigal et al, 2005b). CLINICAL CHARACTERIZATION OF CHRONIC DAILY HEADACHES Transformed Migraine/ Chronic Migraine Patients with transformed migraine/ chronic migraine typically have a history of migraine. It is more frequent in women with a history of migraine without aura. Subjects usually report a process of transformation over months or years, and as headache increases in frequency, associated symptoms become less severe and frequent. The process of transformation frequently ends in a pattern of daily or nearly daily headache that resembles chronic tension-type headache, with some attacks of full-migraine superimposed
(Mathew et al, 1987; Rapoport et al, 1996; Saper, 1982; Scher et al, 1998; Silberstein, 1993). In the clinical setting, migraine transformation most often is related to acute medication overuse, but transformation may occur without overuse. In the more general population, most cases of transformed migraine are not related to medication overuse (Scher et al, 1998). Multiple risk factors may be involved in these cases (see section on risk factors for the development of chronic daily headache). The Silberstein and Lipton criteria basically define transformed migraine as those cases that satisfy two situations (Table 7-2) as follows: (1) The headache is not a chronic daily headache and develops de novo in a previously headache-free subject (if a chronic daily headache develops de novo, the diagnosis is new daily persistent headache). (2) The headache has one of the three following links with migraine: (A) a history of International Headache Society–defined migraine; (B) a period of escalating headache frequency; and (C) concurrent superimposed attacks of migraine that fulfill the International Headache Society criteria. Recent proposed modifications for these criteria, which will most likely be endorsed by the International Headache Society, are listed in Table 7-2. The ICHD-II included criteria for chronic migraine that required 15 or more days of migraine per month (Headache Classification Subcommittee of the International Headache Society, 2004), but these criteria were restrictive in clinical practice and research (Bigal et al, 2006; Bigal et al, 2004a). As a consequence of the many research studies showing that ICHD-II criteria for chronic migraine were cumbersome, the International Headache Society has recently revised the criteria for chronic migraine. The new criteria will be moved to the appendix, awaiting evidence to support their
KEY POINTS:
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In the United States, the prevalence of chronic daily headache is 4.1%. In the population, chronic or transformed migraine and chronic tension-type headache are equally prevalent; new daily persistent headache and hemicrania continua are rare. In specialty care, chronic/ transformed migraine is by far the most common chronic daily headache subtype. Chronic/ transformed migraine is a chronic daily headache that does not develop abruptly. Subjects with chronic/ transformed migraine usually report a process of transformation over months or years.
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KEY POINT:
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As headache increases in frequency, associated symptoms become less severe and frequent.
TABLE 7-2
International Classification of Headache Disorders (2006) Revised and Silberstein-Lipton Diagnostic Criteria for Primary Chronic Daily Headache
Silberstein-Lipton From 1996 Transformed Migraine
ICHD-II Revised Chronic Migraine
Daily or almost daily (>15 days per month) head pain for >1 month
Diagnostic criteria: Headache on 15 days per month for >3 months
Average headache duration of > 4 hours per day (if untreated) At least one of the following: (1) History of episodic migraine meeting any IHS criteria 1.1 to 1.6 (2) History of increasing headache frequency with decreasing severity of migrainous features over at least 3 months (3) Headache at some time meets IHS criteria for migraine 1.1 to 1.6 other than duration
Does not meet criteria for new daily persistent headache (4.7) or hemicrania continua (4.8)
Occurring in a patient with at least five prior migraine attacks On 8 days per month, for at least 3 months, headache fills criteria for migraine (C1 and/or C2) (1) Unilateral Throbbing Moderate or severe Aggravated by physical activity Nausea and/or vomiting Photophobia and phonophobia (2) Treated or relieved with triptans or ergotamine compounds No medication overuse and not attributable to other causative disorder
IHS = International Headache Society.
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utility (Table 7-2). Basically, chronic migraine is classified as 15 days or more of headache per month and 8 or more days of migraine or use of acute migraine medications. If patients are overusing acute medication, they should be classified as having medication overuse headache (Case 7-1). Phenotype of chronic/transformed migraine. Differences exist regarding the clinical presentation of transformed migraine in adolescents and adults. Most adults with transformed migraine have fewer than 15 days of full-blown migraine per month and more days of headache resembling tension-type headache than of migraine. In contrast, transformed migraine in adolescents is replete with
migraine attacks. Also, most adults with transformed migraine overuse acute medication (84.0%), while most adolescents (58.9%) do not (Bigal et al, 2004b). Phenotype of chronic/transformed migraine changes over time. In a recent study of 402 subjects with transformed migraine, the proportion of migraine attacks decreased with age (with a proportional increase of tension-type headache attacks), from 71% below the age of 30 years to 22% at age 60 or above. It was higher in those with shorter interval from the onset of migraine to the onset of chronic daily headache (less than 5 years, P=.003), and in those with a more recent onset of chronic daily headache (less than
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KEY POINTS:
A
Case 7-1 A 42-year-old woman started to have attacks of headache when she was in her teens. At that time, attacks were related to menstruation and were bilateral, severe, and throbbing. Nausea, as well as photophobia, was always present. Phonophobia was sometimes also present. She remembers that, when she was 20, she started to have attacks unrelated to menstruation as well. She used no medication to prevent her headaches and used ibuprofen as her acute therapy. When she was in her 30s, she realized that her headaches were becoming more frequent. At that time, the headaches were moderate or severe most of the days, and she started to use ibuprofen almost daily. Her primary care doctor prescribed propranolol at a dose of 40 mg 2 times a day to prevent her headaches. Since then she has also used amitriptyline and verapamil, with no success. She now has headache every day. About 5 times per month (and always during her menstrual cycle) the headaches are severe and associated with nausea, photophobia, and phonophobia. On most of the other days the headache is mild and without associated symptoms. She uses ibuprofen only to treat the severe headaches. She is married, obese (body mass index of 32), and without symptoms of depression. She has also been investigated for arthritis. Because of her obesity, verapamil was switched to topiramate 100 mg/d. With this treatment she remitted to episodic migraine and now has eight headache days per month. Comment. This case illustrates the process of transformation from episodic to chronic migraine and, as discussed in the text, includes some points that deserve to be emphasized: (1) The phenotype of migraine/ chronic migraine changes over time. Just after transformation, most attacks resemble migraine. As time evolves, the attacks become less typical and resemble tension-type headache. (2) Of the risk factors for transformation, this patient is obese and has arthritis.
6 years, P<.0001). These findings suggest that chronic migraine (15 or more days of migraine per month) is the first stage of migraine chronicity in most patients. Subsequently, the frequency of clearcut migraine attacks diminishes. Thus, chronic migraine may be viewed as the earlier stage of transformed migraine, and both are different evolutive stages of a chronic migrainous process (Figure 7-1) (Bigal et al, 2005c). These findings have implications for the classification of chronic daily headache and for understanding the natural history of migraine and the biology of the transformation process. The findings of this study support what is seen in clinical practice and has been taught by some headache specialists for many years.
A
Adolescents with chronic/ transformed migraine have a higher frequency of full-blown migraine attacks per month. In adults, a higher proportion of attacks early in the process of transformation fulfill criteria for migraine. Later in the process, most meet criteria for tension-type headache.
The concept that early in the process of transformation most headache days fill criteria for migraine, and, as disease evolves, the headache attacks become less typical has also been supported by an adolescent study, where those with recent-onset chronic daily headache were much more likely to have 15 or more migraine days per month (74.5% versus 25.8%, P<.001) (Bigal et al, 2005b). Chronic Tension-type Headache Chronic tension-type headache represents half of the chronic daily headache cases found in population studies but just a small fraction of those found in specialty clinics (Rasmussen and Olesen, 1994). It is the only chronic daily headache that the ICHD-I considered as a
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Proportion of subjects with transformed migraine and less than 15 days and with 15 or more days of migraine per month as a function of time elapsed between the onset of episodic headache and the onset of transformed migraine.
FIGURE 7-1
&
= less than 15 migraine days
x = 15 or more migraine days
single diagnosis. The criteria remained little changed in the ICHD-II (Table 7-3). Despite the fact that ICHD-I and ICHD-II criteria distinguish between episodic and chronic tension-type headache, the latter headache type remains surpris-
TABLE 7-3
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ingly poorly studied. This can be partially explained by the confusion between chronic tension-type headache and transformed migraine with a low frequency of superimposed migraine attacks.
International Classification of Headache Disorders, 2nd Edition, Criteria for Chronic Tension-type Headache
A. At least 10 episodes fulfilling criteria B through E. Number of days with such headache 15 days per month for at least 3-month period (180 days per year); continuous B. Headache lasts hours or may be continuous. At least two of the following pain characteristics: 1. Pressing/tightening (nonpulsating) quality 2. Mild or moderate intensity (may inhibit, but does not prohibit activities) 3. Bilateral location 4. No aggravation by walking stairs or similar routine physical activity C. Both of the following: 1. No more than one of the following: photophobia, phonophobia, or mild nausea. 2. No moderate or severe nausea and no vomiting D. Use of analgesics or other acute medication on 10 days per month. E. Not attributed to another disorder
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The prevalence of chronic tensiontype headache is markedly lower than that of episodic tension-type headache, the most prevalent primary headache disorder. Its 1-year prevalence estimates range from 1.7% to 2.2% (Lavados and Tenhamm, 1998; Rasmussen and Olesen, 1994). The female preponderance of chronic tension-type headache is greater than that of episodic tensiontype headache but lower than that of migraine. In the United States, the prevalence of chronic tension-type headache was reported to be 2.8 in women and 1.4 in men, with an overall gender prevalence ratio of 2.0. The prevalence of chronic tension-type headache increases with age (Schwartz et al, 1998). The distinguishing pain features of chronic tension-type headache are bilateral location, nonpulsating quality, mild to moderate intensity, and lack of
KEY POINTS:
aggravation by routine physical activity. The pain is unaccompanied by nausea, although just one of the symptoms of photophobia or phonophobia does not exclude the diagnosis (Case 7-2). In other words, chronic tension-type headache is defined by what it is not (ie, migraine). The Silberstein and Lipton criteria reserve the diagnosis of chronic tensiontype headache if the chronic daily headache develops abruptly (de novo). It is inferred that this is also true in the ICHD-II criteria, although this feature of evolution is described in the notes but is not part of the formal criteria.
A
New Daily Persistent Headache Chronic daily headache may begin without a history of evolution from episodic headache. New daily persistent headache is characterized by the
A
Case 7-2 A 32-year-old man presents with complaints of daily headaches. The headaches are mild, not usually impairing his usual activities. He also complains that he has pain in his neck. The headaches are bilateral, dull, and not associated with nausea or phonophobia. Occasionally, the headaches become more severe, and he then complains about intolerance to bright lights. When he has a headache, physical activities do not make him worse. Indeed, if he is occupied, he reports that his headaches disappear. He started to have headaches of this nature when he was in his middle 20s. At that time, the headaches did not occur daily. He does not remember if the headaches gradually increased in frequency, but he said that the onset of the daily pattern was not abrupt. He uses medications (over-the-counter medications, usually acetaminophen plus aspirin [Excedrin]) only occasionally, when the headaches become more severe. He is consulting because of the daily occurrence of his headaches. He wants to know the diagnosis and what can be done to provide relief. The diagnosis is chronic tension-type headache, and the proposed treatment is amitriptyline 50 mg/d and biofeedback. His headaches improved by 70%. Comment. As discussed in the text, CTTH is usually defined by what it is not (a headache without migraine features). Sometimes it is difficult to differentiate CTTH from chronic/transformed migraine, since, as mentioned in the comment for Case 7-1, the phenotype of transformed migraine changes over time, and attacks become less typical. It is important, therefore, to obtain information on the episodic headaches that preceded the CDH. CTTH evolves from episodic tension-type headache, while chronic or transformed migraine evolves from episodic migraine.
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The typical pain features of chronic tension-type headache are bilateral location, nonpulsating quality, mild to moderate intensity, and lack of aggravation by routine physical activity, although none is mandatory. The pain of chronic tension-type headache is not accompanied by nausea, although just one of the symptoms of photophobia or phonophobia does not exclude the diagnosis. Chronic tension-type headache is defined by what it is not. New daily persistent headache is characterized by the relatively abrupt onset of an unremitting primary chronic daily headache.
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The diagnosis of new daily persistent headache requires absence of history of evolution from migraine or episodic tension-type headache. Although the ICHD-II basically considers new daily persistent headache a new-onset form of tension-type headache, it has been suggested that the clinical features of the pain should not be considered in making the diagnosis, since many patients have migraine features. Hemicrania continua is characterized by strictly unilateral headache with absolute response to indomethacin.
TABLE 7-4
International Classification of Headache Disorders, 2nd Edition, Criteria for New Daily Persistent Headache
A. Headache that, within 3 days of onset, fulfills criteria B through D B. Headache is present daily and unremitting for >3 months C. At least two of the following pain characteristics: 1. Bilateral location 2. Pressing/tightening (nonpulsating) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity such as walking or climbing D. Both of the following: 1. No more than one of photophobia, phonophobia, or mild nausea 2. Neither moderate or severe nausea nor vomiting E. Not attributed to another disorder
relatively abrupt onset of an unremitting primary chronic daily headache; ie, a patient without a previous headache syndrome develops a chronic daily headache that does not remit. The patient’s remembering the circumstances, place, and date that the headache began is a pathognomonic feature. It is the new onset of this primary daily headache that is the most important feature (Rozen, 2003). The clinical features of the pain are not considered in making the diagnosis, which simply requires absence of history of evolution from migraine or episodic tension-type headache (Table 7-4) (Silberstein et al, 1996). The ICHD-II addresses new daily persistent headache as a single diagnosis in those with a new-onset chronic daily headache that resembles chronic tension-type headache. A new-onset chronic daily headache with migrainous features cannot be classified as new daily persistent headache according to the ICHD-II criteria, whereas the Silberstein and Lipton classification allows this diagnosis in patients with headache features of migraine or epi-
sodic tension-type headache if the disorder arises abruptly (Case 7-3). Hemicrania Continua Hemicrania continua is an uncommon primary headache disorder first described as a syndrome by Sjaastad and Spierings (1984). This daily and continuous strictly unilateral headache is defined by its absolute response to therapeutic doses of indomethacin. Pain is moderate with exacerbations of increased severity, and autonomic symptoms accompany these exacerbations although less prominently than in cluster headache and chronic paroxysmal hemicrania. Some bilateral or alternating side cases have been reported (Case 7-4). PATHOPHYSIOLOGY OF CHRONIC DAILY HEADACHES Although the source of pain in primary chronic daily headache is unknown and may be dependent on the subtype, recent studies suggest that the following mechanisms, alone or in
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KEY POINT:
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Case 7-3 A 19-year-old college student presents to a headache clinic stating that exactly 6 months ago he started to have daily headaches. The onset was abrupt. He only had occasional headaches before this. He can precisely remember the day of onset. At that time he reports that he was under a great deal of stress because of examinations. He denies head trauma, fever, and systemic symptoms currently and at onset. He is a poor historian and provides no other relevant information. Because he had a new-onset headache, his neurologist ordered extensive investigation, including brain neuroimaging (magnetic resonance imaging), chest computed tomographic scan, serological tests, screenings for infectious diseases, including Lyme disease, and thyroid hormones. Since he is overweight, a spinal tap was performed as well. All tests were normal. The headache calendar shows that in the past month the patient has had 15 headaches that were mild and sounded like tension-type headache, 12 headaches that reached moderate severity and usually met criteria for probable migraine, and three severe migraine headaches. He has already used amitriptyline, propranolol, topiramate, and levetiracetam, all prescribed by his neurologists, with no success. He uses no acute medications. He says that nothing helps. He is frustrated and anxious. He is being treated with topiramate and propranolol but continues to have daily headaches. Comment. Primary CDHs may start de novo without evolving from episodic forms. In such cases, the diagnosis should be NDPH. Although the ICDH-II states that NDPH attacks resemble tension-type headaches most of the time, not infrequently patients with NDPH will report plenty of migraine symptoms. NDPH is often a refractory headache subtype.
combination, contribute to the process (Welch and Goadsby, 2002): (1) abnormal excitation of peripheral nociceptive afferent fibers in the meninges; (2) enhanced responsiveness of trigeminal nucleus caudalis neurons; (3) decreased pain modulation from higher centers, such as the periaqueductal gray matter; (4) spontaneous central pain generated by activation of the ‘‘on cells’’ in the medulla; (5) decreased serotonin levels; and (6) central sensitization. Since transformed migraine is the most important chronic daily headache in the clinical setting, the following discussion will review possible mechanisms involved in the transformation. Chronic Migraine as the Result of Progression of Disease Recent evidence suggests that a subgroup of migraine sufferers may have
The pathophysiology of chronic daily headache is poorly known.
a clinically progressive disorder (Scher et al, 2003). An imaging study has shown that iron deposition occurs in the periaqueductal gray area in subjects with chronic headaches (Welch et al, 2001). The periaqueductal gray area is related to a descending analgesic network and is important in controlling pain by providing endogenous analgesia. It is closely related to the trigeminal nucleus caudalis. In this study, the iron levels were increased in migraine sufferers, compared with controls, and in chronic daily headache sufferers compared with migraineurs. These findings may be directly attributable to iron-catalyzed, free-radical cell damage. Iron deposition may reflect progressive neuronal damage related to recurrent migraine attacks. It can be hypothesized that repetitive central sensitization of the trigeminal neurons
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For chronic/ transformed migraine, repetitive central sensitization of the trigeminal neurons may be associated with neuronal damage, predisposing to disease progression.
Case 7-4 A 52-year-old divorced woman presents to the clinic with a history of unilateral daily headaches for the past 4 years. Her headaches are always on the right side and are most severe around the eye. She says that most of the time the headache is mild, but once or twice a day it reaches moderate intensity and she needs to use analgesics. She says that the headache is dull, not throbbing, and sometimes is sharp and knifelike. She has been to several physicians, and she has used topiramate, gabapentin, carbamazepine, lamotrigine, and several antidepressants without improvement. When the pain is severe, she uses aspirin plus butalbital plus caffeine (Fiorinal) with no more than mild relief (she does not know if the medication helps or if the headache decreases in severity naturally). The headache is always present, and she gets relief only when she sleeps. All investigations are normal. She reports no other symptoms, including ptosis, red eye, or lacrimation. However, examination during an exacerbation reveals a red eye on the side of the pain. She responds completely and almost immediately to indomethacin, 75 mg twice daily. However, she cannot continue the medication because of gastrointestinal intolerance. Rofecoxib has provided good but not total response, but after the drug is withdrawn from the market, she resumes a lower dose of indomethacin. Comment. The fourth CDH subtype is HC. HC is a strictly unilateral CDH. Although the headache is not very severe, during exacerbations, ipsilateral autonomic symptoms may be seen. This headache is usually absolutely responsive to indomethacin, and this drug should be tried in any primary CDH that is side-locked.
correlates with iron deposition in the periaqueductal gray area, and therefore, migraine attacks predispose to disease progression. Evidence of migraine progression also comes from a recent neuroimaging study. Kruit and colleagues (2004) used a cross-sectional design to study Dutch adults aged 30 to 60 years. They showed that male subjects with migraine with aura were at an increased risk of posterior circulation infarct. Additionally, women with migraine, with or without aura, were at a higher risk of deep white matter lesions than controls. The white matter lesions increased with attack frequency, possibly demonstrating progression of the disease. Finally, in a longitudinal epidemiological study, Scher and colleagues (Scher et al, 2003; Scher et al, 2004) showed that over the course of 1 year, 3% of individuals with episodic headache (headache frequency
2 to 104 days per year) progressed to chronic daily headache. Burstein and colleagues showed that approximately 75% of migraine sufferers develop central sensitization (sensitization of the second order trigeminal neuron, which is clinically manifested by the development of cutaneous allodynia) during the course of a migraine attack (Burstein et al, 2000; Burstein and Jakubowski, 2004). Central sensitization appears to be associated with triptan refractoriness. Central sensitization explains the progression of attacks but also may play a role in the progression of the disease itself. It has been suggested that repeated central sensitization episodes are associated with permanent neuronal damage at the level of, or close to, the periaqueductal gray, with poor modulation of pain, refractoriness to preventive treatment, and disease progression.
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Risk Factors for the Development of Chronic/Transformed Migraine Limited evidence exists about risk factors for migraine progression. A study found that the prevalence of chronic daily headache decreased slightly with age and was higher in women (odds ratio [OR]=1.65 [1.3–2.0]) and in divorced, separated, or widowed individuals (OR=1.50 [1.2–1.9]) (Saper et al, 1994; Saper et al, 2001). Chronic daily headache prevalence was inversely associated with educational level. Having less than a high-school education was associated with more than a threefold risk of chronic daily headache compared with those with a graduate school–level education (OR=3.56 [2.3– 5.6]). Chronic daily headache was also associated with a self-reported physician diagnosis of arthritis (OR=2.50 [1.9– 3.3]) or diabetes (OR=1.51 [1.01–2.3]), with previous head trauma, and with medication overuse (Scher et al, 2003). Importantly, the risk of new-onset chronic daily headache increased nonlinearly with baseline headache frequency; elevated risk was primarily limited to controls with more than about two headaches per month. Finally, the strongest risk factor for the development of chronic daily headache was obesity (OR=5.53, [1.4–21.8]). In most clinical studies of chronic daily headache, overuse of analgesics or other acute care medication figures prominently (Katsarava et al, 2001; Katsarava et al, 2004). This issue is discussed in detail under a separate review . in this issue of TREATMENT OF CHRONIC DAILY HEADACHE Principles of Treatment As with other lifelong illness, several fundamental management considerations are important for treatment success in patients with chronic daily headache.
Patients suffering from long-duration chronic daily headache often present not only with acute medication overuse, but also with psychiatric and somatic comorbidity, low frustration tolerance, and both physical and emotional dependence (Holroyd and Andrasik, 1982; Holroyd et al, 2001). In patients with primary chronic daily headache, it is important to identify the subtype of chronic daily headache and evaluate for the presence of analgesic overuse and comorbidities (including depression and anxiety). A combination of pharmacological, nonpharmacological, behavioral, and sometimes physical interventions is usually necessary for a favorable outcome. The essential features of an effective treatment regimen include a combination of the following steps (Penzien et al, 2002; Weeks, 1995; Weeks and Baskin, 1999):
KEY POINTS:
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(1) Educating the patient, establishing expectations and a follow-up plan (This must include telling patients that they will worsen before improving.) (2) Using nonpharmacological therapies when appropriate: o Biofeedback and relaxation therapy o Cognitive behavioral therapy o Individual/family counseling as necessary o Dietary instructions, chronobiological therapy, and sleep hygiene o Daily exercise program (3) Identifying, addressing, and treating psychiatric and somatic comorbidities (4) Discontinuing all potentially offending medications and caffeine by outpatient or inpatient detoxification procedures (5) Instituting a program of acute care and preventive pharmacological therapy
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Risk factors for migraine progression include high frequency of attacks, depression, snoring, other pain syndromes, and medication overuse. Obesity is a strong independent risk factor for migraine progression. For patients with chronic daily headache, a combination of pharmacological, nonpharmacological, behavioral, and sometimes physical interventions is usually necessary for a favorable outcome. Addressing risk factors for transformation, as well as aggressively treating those with risk factors, may be a rational preventive measure.
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Detoxification of those overusing medication is an essential step of treatment.
Discussion of the nonpharmacological treatment of chronic daily headache, as well as the treatment of comorbid disorders, is beyond the scope of this chapter. Addressing Risk Factors for Chronic/Transformed Migraine As discussed above, risk factors for developing chronic migraine have been identified. Some of them are not modifiable (gender, age, etc), but others (obesity, other pain syndromes, depression, caffeine and medication overuse, snoring) should be addressed even though it is not yet known whether this will translate into better outcomes once chronic migraine is already established (Table 7-5).
TABLE 7-5
Treatment of Medication Overuse Most studies suggest the benefit and necessity of detoxifying the patient from the overused medication (when present), followed by an intensive, longterm treatment plan. If patients discontinue their overused medications, they frequently improve considerably, and, if they do not, they are usually difficult to treat effectively (Bigal et al, 2004c; Diener et al, 1991; Grazzi et al, 2002). Basically, three outpatient approaches have been used for detoxification. The authors prefer the term ‘‘bridge’’ therapy, implying ‘‘bridging’’ from daily to intermittent use of as-needed medications. One approach is to taper the overused medication gradually while
Risk Factors for Chronic Daily Headache Development and Strategies to Address Them
Not Readily Modifiable
Modifiable
Strategies to Address Modifiable Risk Factors
Sex: female
Attack frequency
Preventive treatment
Low education/ socioeconomic status
Central sensitization
Early acute migraine interventions
Head injury
Obesity
Diet Using preventive medications that do not increase the weight
144 Medication overuse
Limiting the consumption of acute medications Preventive treatment Detoxification protocols
Stressful life events
Relaxation techniques Biofeedback Addressing depression when present
Snoring
Assessing sleep disturbances Treating sleep apnea when present
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Selected Preventive Therapies for Migraine That May Be Used in the Treatment of Chronic Daily Headache
TABLE 7-6
Preventive Therapies Generic Treatment
Doses
Beta-blockers Atenolol*
25 mg to 100 mg
Metoprolol
50 mg to 200 mg
Nadolol
20 mg to 240 mg
Propranolol*
60 mg to 240 mg
Timolol Alpha2-agonists Clonidine
0.05 mg/d to 0.3 mg/d
Guanfacine
1 mg
Gabapentin
*
Levetiracetam Topiramate
*
Zonisamide
500 mg/d to 1500 mg/d
40 mg 3 times a day
Diltiazem
300 mg to 3000 mg
30 mg to 60 mg 3 times a day
Nisoldipine
1500 mg to 4500 mg
10 mg to 40 mg every day
Amlodipine
2.5 mg to 10 mg every day
50 mg to 200 mg 100 mg to 400 mg
Serotonergic agents Methylsergide* 2 mg to 12 mg Cyproheptadine 2 mg to 16 mg Pizotifen*
30 mg/d to 90 mg/d
Tricyclic antidepressants Amitriptyline* 20 mg to 150 mg 20 mg to 100 mg
Selective serotonin reuptake inhibitors Fluoxetine
10 mg to 40 mg
Sertraline
50 mg to 100 mg
Paroxetine
10 mg to 30 mg
Venlafaxine
37.5 mg to 225.0 mg
Mirtazapine
Calcium channel antagonists
Nimodipine
Monoamine oxidase inhibitors
Nortriptyline
10 mg to 30 mg
240 mg to 960 mg
Antidepressants
Phenelzine
*
Verapamil*
Anticonvulsants Divalproex sodium*
Continued
TABLE 7-6
15 mg to 45 mg
1.5 mg to 3 mg
Miscellaneous Montelukast sodium
10 mg to 20 mg
Lisinopril
10 mg to 40 mg
Botulinum 25 units to 150 units toxin A injection (intramuscular) Feverfew
50 mg/d to 82 mg/d
Chelated magnesium glycinate
400 mg/d to 600 mg/d
Riboflavin
100 mg/d
Petasites 75 mg*
75 mg bid or 50 tid
bid = 2 times a day. *Evidence for moderate efficacy from at least two well-designed placebocontrolled trials.
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Preventive treatment, associated with early acute treatment (no more than 3 times a week) and detoxification of overused medications may be the most effective treatment regimen.
an effective preventive therapy is established. The second strategy is to abruptly discontinue the overused drug, institute a transitional medication (bridge therapy) to break the cycle of headache, and subsequently taper the transitional medication. The third approach is to combine the two strategies by eliminating the rebound medication rapidly, adding a preventive medication rapidly, but also supplying a temporary bridge, to give the patient the maximum chance to improve without drastically worsening first. No matter what medication is being tapered, it is very useful to use a 3- to 7day taper of oral corticosteroids, either prednisone starting at 60 mg/d or dexamethasone starting at 4 mg/d to 12 mg/d. Alternatively, triptans or dihydroergotamines are frequently used as bridge therapies (Bonuccelli et al, 1996; Drucker and Tepper, 1998; Krymchantowski, 2003; Mathew et al, 1997; Raskin, 1986; Sheftell et al, 1999). Details on strategies for the treatment of medication overuse are discussed in the chapter Medication Overuse issue. Headache in this Establishing an Effective Preventive Treatment Most of the commonly used preventive agents for primary chronic daily headache have not been evaluated in welldesigned, double-blind studies. They are usually the same medications that are tried for migraine prevention. Table 7-6 summarizes the medications commonly used in chronic daily headache. The choice of a preventive drug is based on its proven efficacy, the
patient’s preferences and headache profile, the drug’s side effects, and the presence or absence of coexisting or comorbid disease. The clinician should select the drug with the best risk-tobenefit ratio for the individual patient and minimize the side effects that are most concerning to the patient. The reader is referred to the chapter Behavior Medicine for Chronic Headache: Overview and Practical Tools for the Practicing Physician, which covers refractory headache, and the chapter Diagnostic Testing and Secondary Causes of Headache, which covers behavioral approaches, for further discussion on the treatment of chronic daily headache, medication overuse, and behavioral and psychological factors related to these disorders. CONCLUSION Based on recent data, some episodic headaches (migraine, episodic tensiontype headaches) are now conceptualized not solely as episodic disorders, but as chronic-episodic and sometimes chronic-progressive disorders. Ongoing research and new emerging therapeutic strategies should consider this change in the conceptual model of migraine and chronic daily headaches. Preventing disease progression in migraine has already been added to the traditional goals of relieving pain and restoring patients’ ability to function. Emerging treatment strategies to prevent disease progression include risk factor modification, use of preventive therapies, and possibly the use of triptans as early as possible in the course of a migraine attack.
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Lavados PM, Tenhamm E. Epidemiology of tension-type headache in Santiago, Chile: a prevalence study. Cephalalgia 1998;18:552–558. The epidemiology of chronic tension-type headache was not different than other studies in different countries.
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Saper JR. The mixed headache syndrome: a new perspective. Headache 1982;22:284–286. Describes the clinical features of migraine transformation.
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Saper JR, Lake AE, Tepper SJ. Nefazodone for chronic daily headache prophylaxis: an open-label study. Headache 2001;41:465–474. Since many patients with chronic daily headache are refractory, several pilot studies tested new drugs for this syndrome.
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Saper JR, Silberstein SD, Lake AE 3rd, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 1994;34:497–502. Discusses the efficacy of fluoxetine in the treatment of migraine and chronic daily headaches.
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Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache 1998;38:497–506. Epidemiological study on the prevalence of chronic daily headache in the United States.
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Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology 2004;63:2022–2027.
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Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003;106:81–89. Currently the only population-based study describing risk factors for chronic daily headache.
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Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998;279:381–383. Describes the epidemiology of tension-type headache in the United States.
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Sheftell FD, Rapoport AM, Coddon DR. Naratriptan in the prophylaxis of transformed migraine. Headache 1999;39:506–510. First pilot study assessing naratriptan in the prevention of chronic daily headache.
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Silberstein SD. Tension-type and chronic daily headache. Neurology 1993;43:1644–1649. This study suggests that chronic daily headache and tension-type headache are not the same syndrome.
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Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology 1996;47:871–875. Study presenting proposed criteria for the chronic daily headache subtypes, now used worldwide.
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Sjaastad O, Spierings EL. ‘‘Hemicrania continua’’: another headache absolutely responsive to indomethacin. Cephalalgia 1984;4:65–70. First paper describing hemicrania continua.
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Spierings EL, Ranke AH, Schroevers M, Honkoop PC. Chronic daily headache: a time perspective. Headache 2000;40:306–310. The authors present their personal experience in following subjects with chronic daily headache over several years.
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Weeks R. The difficult headache patient calls for a multifaceted approach. Neurol Rev 1995;3:15–16. This paper reviews the multidisciplinary approach required in the management of refractory headache syndromes, including chronic daily headache.
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Weeks R, Baskin SM. The patient who refused pharmacotherapy. In: Rapoport AM, Sheftell FD, Purdy RA, eds. Advanced therapy of headache. Saint Louis: Decker, 1999:119–124. Case-based chapter that describes the principles of the nonpharmacological treatment of migraine.
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Welch KM, Goadsby PJ. Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 2002;15:287–295. Excellent review of the pathophysiology of chronic daily headache, correlating with implications on nosology.
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Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001;41:629–637. Shows that migraine attacks are associated with iron deposition in the brain stem, providing a rationale for migraine progression.
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The intracranial vasculature and its innervation are essential components in the current understanding of the pathophysiology of headache.
HEADACHES AND THEIR RELATIONSHIP TO CEREBROVASCULAR AND CARDIOVASCULAR DISEASE Todd J. Schwedt, David W. Dodick
ABSTRACT The relationship between the cerebrovascular system and headache is multifaceted and incompletely understood. However, several important observations have been made. Head pain can be generated by stimulation of the intracranial vasculature. This is evident on an experimental level as well as with common vascular conditions. Headaches occur in association with ischemic strokes, cervical artery dissections, intracranial aneurysms, and following cervical or cranial vascular procedures. In addition, migraine has been identified as a risk factor for the development of vascular diseases such as ischemic stroke and cervical artery dissection. Patent foramen ovale, a structural cardiovascular disorder, is more common in patients with migraine with aura. In addition, certain rare migraine syndromes (aura without headache, hemiplegic migraine, retinal migraine, ophthalmoplegic migraine, and basilar-type migraine) may mimic stroke. Study of each of these entities will lead to a better understanding of the pathophysiology of headache and its relationship to the vascular system.
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INTRODUCTION The intricate relationship between head pain and the cerebrovascular system has long been recognized. Initially, migraine pathophysiology was explained by a ‘‘vascular theory’’ of alterations of vasomotor tone. Migraine aura was thought to result from cerebral vasoconstriction leading to cerebral ischemia and neurological deficits. The head pain that followed was explained by reactive vasodilation. This theory persisted for many decades until the trigeminovascular system was described and recognition of the processes of neurogenic inflammation and sensitization of nociceptive trigeminal pathways
were understood. However, the intracranial vasculature and its innervation remain as essential components in our current understanding of the pathophysiology of headache. Several lines of evidence support the complex relationship between headache and the vasculature. Multiple headache types can be classified as primary vascular headaches, which are initiated by stimulation of the intracranial vasculature (Table 10-1). In addition, migraine is a risk factor for the development of vascular diseases, such as stroke and cervical artery dissection. Certain cardiovascular structural abnormalities, such as patent
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TABLE 10-1
Vascular Headaches
" " " " "
Ischemic stroke
" " "
Postcarotid angioplasty
" " "
Cerebral arteritis
"
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes)
"
Pituitary apoplexy
Arterial dissection Postcerebral angiography Postcarotid endarterectomy Postcoiling/postclipping of intracranial aneurysm
Intracranial hemorrhage Ruptured/unruptured vascular malformations
Cerebral venous thrombosis CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)
Vestergaard et al, 1993). The majority of sensory nerves innervating the anterior circulation terminate in the trigeminal nucleus caudalis. Most of these sensory afferents project via the ophthalmic division of the trigeminal nerve (Mayberg et al, 1981). The posterior circulation sensory nerves terminate in the superior cervical ganglia and dorsal vagal ganglia with a smaller contribution from the trigeminal nucleus caudalis (Keller et al, 1985; Saito and Moskowitz, 1989). In animal models, stimulation of the intracranial arteries and dural venous sinuses results in activation of the trigeminovascular system. Superior sagittal sinus stimulation in the cat has been shown to cause measurable increases in metabolic activity and blood flow in the trigeminal nucleus caudalis, upper cervical dorsal horn,
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The intracranial vasculature is innervated by the parasympathetic, sympathetic, and sensory nervous systems. The majority of sensory nerves innervating the anterior circulation terminate in the trigeminal nucleus caudalis.
foramen ovale, occur with a higher prevalence in patients with migraine with aura. In fact, the distinction between primary cerebrovascular diseases and headache syndromes can be clouded at times with rare headache types that may mimic stroke. VASCULAR INNERVATION The intracranial vasculature is innervated by the parasympathetic, sympathetic, and sensory nervous systems (Figure 10-1). The sensory nervous system plays the predominant role in the generation of head pain. The density of sensory afferents is greatest in the proximal segments of the major intracranial arteries and in the posterior circulation (Kumral et al, 1995; O’Connor and van der Kooy, 1986;
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FIGURE 10-1
Perivascular nerve fibers.
NA = nonadrenaline; NPY = neuropeptide Y; Ach = acetylcholine; CGRP = calcitonin gene-related peptide; NKA = neurokinin A; VIP = vasoactive intestinal polypeptide; PHI = peptide histidine isoleucine; NOS = nitric oxide synthase; V1 = first division of the trigeminal nerve; V2 = second division of the trigeminal nerve; V3 = third division of the trigeminal nerve; SPG = sphenopalatine ganglion; SCG = superior cervical ganglion; TNC = trigeminal nucleus caudalis; VII = seventh cranial nerve; SSN = superior salivatory nucleus; T2–T3 = second and third thoracic segments of the spinal cord.
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The posterior circulation sensory nerves terminate in the superior cervical ganglia and dorsal vagal ganglia with a smaller contribution from the trigeminal nucleus caudalis. Approximately 25% of stroke patients experience headache around the onset of stroke symptoms. Headaches more frequently occur with strokes that are large, in the posterior circulation, and hemorrhagic, and in patients with a history of a primary headache disorder. Headache is the most frequent presenting symptom of cervical artery dissection.
and the ventral posterior medial thalamus (VPM) (Goadsby et al, 1991). Furthermore, studies by Davis and Dostrovsky (1988) have identified thalamic neurons with orofacial inputs. These neurons are activated by stimulation of excitatory receptive fields on the face. The majority of these receptive fields are located in the distribution of the ophthalmic division of the trigeminal nerve. These same thalamic neurons are also excited by electrical stimulation of the middle meningeal artery and/or the superior saggital sinus. These data, in conjunction with a large body of experimental evidence, have led to the conclusion that nociceptive input at any portion of the trigeminovascular system, which of course includes the intracranial vasculature, may result in referred pain to the head, face, and neck. VASCULAR HEADACHES Ischemic Stroke Approximately 25% of stroke patients experience headache around the onset of stroke symptoms. (Ferro et al, 1995). In the clinical setting such headaches are commonly overlooked, often occurring in conjunction with more worrisome focal neurological symptoms. Approximately 50% of patients who develop headache with stroke have headache onset prior to the manifestation of other neurological deficits. Others develop headache coincident with or after onset of stroke symptoms. In patients with a preexisting primary headache disorder, the headache associated with stroke often resembles the patient’s preexisting headaches. For example, migraineurs may develop a migraine headache in the setting of their stroke. Other patients have onset of a new headache. These headaches are most often described as pressing or throbbing in quality, and, if unilateral, pain is usually ipsilateral to the
side of the stroke (Vestergaard et al, 1993). It has been suggested that frontal pain is more common with anterior circulation strokes and occipital pain is more common with posterior circulation strokes. Headaches more frequently occur with strokes that are large, in the posterior circulation, and hemorrhagic, and in patients with a history of a primary headache disorder (Kumral et al, 1995). Cervical Artery Dissection Headache is the most frequent presenting symptom of cervical artery dissection. Headache occurs with 60% to 95% of carotid artery dissections and about 70% of vertebral artery dissections (Silbert et al, 1995). Most commonly, headaches have a slow and gradual onset. However, about 20% of patients have a sudden and severe onset of pain consistent with a thunderclap headache (Mitsias and Ramadan, 1992). Headaches are typically located ipsilateral to the dissected artery. According to the International Headache Society (IHS), ipsilateral pain is a requirement for headache to be considered as secondary to cervical artery dissection (Headache Classification Subcommittee of the International Headache Society, 2004). Neck pain occurs in 50% of patients with vertebral artery and 25% of patients with carotid artery dissections. The median duration of headaches in both groups is 3 days. The vast majority of headaches associated with carotid dissection resolve within 1 week, while those of vertebral dissection may last up to 5 weeks. The occasional patient will develop chronic headaches. It is uncommon for patients with cervical artery dissection to present solely with headache and/ or neck pain. The majority of patients have additional neurological symptoms and signs, including amaurosis fugax, Horner’s syndrome, pulsatile tinnitus,
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Case 10-1 A 38-year-old man with a history of migraine without aura presents after 1 day of left temporal, ear, and jaw pain. The pain started suddenly and has remained quite severe. It is described as constant, steady, and aching in quality. No associated photophobia, phonophobia, nausea, vomiting, or visual phenomena are present. However, a family member noticed that the patient’s left eyelid appeared to ‘‘droop.’’ On examination, the patient is noted to have mild ptosis of the left eyelid and pupillary asymmetry (right = 5 mm; left = 3 mm). No other neurological abnormalities are found. Magnetic resonance imaging (MRI) with diffusion images of the brain is normal. Magnetic resonance angiography of the cervical vessels reveals a long segment of tapering of the left internal carotid artery. MRI with fat saturation of the neck shows a double lumen in the left internal carotid artery that is semilunar shaped and hyperintense on T1- and T2-weighted images. Comment. Headaches are the most common presenting symptom of cervical artery dissection. No specific characteristics of dissection headaches differentiate them from other headache types. However, any new headache, especially if associated with neurological symptoms and/or signs, must prompt evaluation for underlying pathology. The majority of patients with cervical carotid artery dissections will have neurological features in addition to unilateral head, neck, or facial pain. Most commonly, these include Horner’s syndrome, amaurosis fugax, pulsatile tinnitus, dysgeusia, diplopia, or other focal neurological manifestations of stroke.
dysgeusia, diplopia, or other stroke manifestations (Case 10-1). Intracranial Aneurysms Headaches are common in patients with cerebral aneurysms prior to the diagnosis, at the time of diagnosis, at the time of treatment, and following treatment. Headache is the presenting symptom of unruptured cerebral aneurysm in approximately 33% of patients (International Study of Unruptured Intracranial Aneurysms Investigators, 1998). However, given the prevalence of headache and unruptured intracranial aneurysms in the general population and the frequency with which brain imaging is performed in patients with headache, it is not at all clear the percentage of patients in whom the aneurysm represents an incidental finding and is unrelated to the headache. Also, no specific head-
Patients with thunderclap headache must be evaluated for subarachnoid hemorrhage.
ache characteristics are associated with a high likelihood of discovering an unruptured aneurysm. Therefore, it is imperative to evaluate for associated neurological features, such as cranial nerve palsies, which provide evidence for an underlying lesion. Headache is more common in patients with aneurysm rupture, occurring in association with nausea and vomiting in 75% of patients (Fontanarosa, 1989). Headaches of subarachnoid hemorrhage are often sudden in onset and of severe intensity. Although thunderclap headaches have numerous causes, every patient presenting with such a headache should be evaluated for subarachnoid hemorrhage (Table 10-2, Figure 10-2). Headaches of subarachnoid hemorrhage are most often bilateral, and may be associated with neck stiffness and elevated body temperature. Severe pain is usually short-lived, lasting
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A history of a sentinel or warning headache is reported by 10% to 43% of patients with aneurysmal subarachnoid hemorrhage. Approximately 25% to 50% of patients with subarachnoid hemorrhage are initially misdiagnosed.
TABLE 10-2
Thunderclap Headaches
" " " " " " "
Subarachnoid hemorrhage
" " "
Cerebral vasospasm
"
Primary headache associated with sexual activity
" "
Primary exertional headache
Sentinel leak Acute hypertensive crisis Cerebral venous thrombosis Cervical artery dissection Pituitary apoplexy Spontaneous intracranial hypotension
Retroclival hematoma Primary thunderclap headache
Primary cough headache
1 to 2 hours, followed by a less severe headache of longer duration. With small hemorrhages, headaches tend to resolve after 2 to 3 days, while those with larger hemorrhages last an average of 8 days. Additional neurological symptoms and signs are the rule and often include disorientation, nausea, vomiting, altered mentation, focal motor deficits, seizures, coma, cranial nerve palsies, papilledema, ocular hemorrhages, visual field deficits, and paresthesias. A history of a sentinel or warning headache is reported by 10% to 43% of patients with aneurysmal subarachnoid hemorrhage (Polmear, 2003). A sentinel headache is an episode of headache similar to that of subarachnoid hemorrhage that occurs prior to aneurysm rupture. Such headaches develop over a few seconds, reach maximal intensity within minutes, and endure for hours to days. Certain features of subarachnoid hemorrhage headaches, such as stiff neck, focal
neurological symptoms and signs, and alteration in consciousness, are usually absent. Warning headaches tend to occur days to weeks before aneurysm rupture. They are likely caused by small aneurysmal leaks or stretching of the aneurysm wall without seepage of blood into the subarachnoid space. In many cases, recognition of these headaches as early features of subarachnoid hemorrhage would allow for surgical or endovascular intervention and avoidance of a catastrophic event. However, sentinel headaches are often ignored by the patient or physician or misdiagnosed. Approximately 25% to 50% of patients with subarachnoid hemorrhage are initially misdiagnosed (Edlow and Caplan, 2000). According to a review by Edlow and Caplan (2000), misdiagnosis occurs because of failure to recognize the spectrum of possible presentations of subarachnoid hemorrhage, lack of knowledge regarding the limitations of computed tomography (CT), failure to perform lumbar puncture, or misinterpretation of cerebrospinal fluid (CSF) tests (Case 10-2). Postcarotid Endarterectomy, Postcerebral Angiography, and Postcoiling and Postclipping of Intracranial Aneurysm New headaches are a frequent complication following cerebral artery procedures such as carotid endarterectomy, cerebral angiography, and coiling/clipping of aneurysms (Ramadan et al, 1995; Schwedt et al, 2005; Tehindrazanarivelo et al, 1992). The characteristics of each headache type differ (Table 10-3). However, headaches must have onset in close temporal relationship to the procedure and usually are located ipsilateral to the site of intervention. The presence of a primary headache disorder prior to intervention has often been recognized as a risk factor for postprocedure headaches. In fact, stimulation of the cranial vasculature can result
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KEY POINT:
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FIGURE 10-2
Migraine has been identified as a risk factor for stroke.
Evaluation of suspected subarachnoid hemorrhage. SAH = subarachnoid hemorrhage; CSF = cerebrospinal fluid.
in initiation of a patient’s usual headache type. At other times, onset of a new type of headache occurs. Following carotid endarterectomy, severe unilateral headaches, sometimes in association with seizures and contralateral focal deficits, may be manifestations of a hyperperfusion syndrome. MIGRAINE AS A RISK FACTOR FOR CEREBROVASCULAR DISEASE Cerebral Infarction Migraine has been identified as a risk factor for stroke in multiple studies.
However, study conclusions have often been contradictory, and certain subpopulations of patients with migraine are at greater risk. Epidemiological studies have shown stroke to be more common in migraineurs with and without aura. This is especially true in women younger than 45 years of age who smoke and use oral contraceptives. In this patient group, the risk of stroke is increased 3 times in migraine without aura and 6 times in migraine with aura (Chang et al, 1999; Tzourio et al, 1995). A meta-analysis of observational studies between 1966 and June 2004 concluded that the
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The relative risk for ischemic stroke among patients with any type of migraine headache is 2.16.
Case 10-2 A 55-year-old man presents to the emergency department 36 hours after onset of a severe headache. He reports that he was in his usual state of health and suddenly had the sensation that he ‘‘got hit with a frying pan on the back of the head.’’ Initially, his headache was 10/10 in intensity, although it decreased in severity to 8/10 after the first few hours. His headache is diffuse, pressurelike, and associated with neck pain, nausea, vomiting, and photophobia. He reports that he has had headaches intermittently in the past but nothing like his current headache. He decided to come to the emergency department because he ‘‘just can’t take it anymore.’’ On examination, his blood pressure is 170/100 mm Hg and heart rate is 120 beats per minute. He has decreased range of motion at the neck, and such movements worsen his head pain. Otherwise, no abnormalities are visible on neurological examination. CT of the brain without contrast is normal. Lumbar puncture is performed. CSF reveals 3 white blood cells/uL, 120 red blood cells in tube 1 and 122 in tube 4, a protein of 85 mg/dL, and glucose of 32 mg/dL. Visual inspection is positive for xanthochromia, and spectrophotometry reveals a bilirubin peak. Comment. The classical headache associated with subarachnoid hemorrhage is sudden and severe. Headache may be associated with nausea, vomiting, photophobia, altered level of consciousness, seizures, motor or sensory deficits, cranial nerve palsies, and ocular hemorrhages. Initial evaluation should include an unenhanced brain CT, which has its highest sensitivity in detecting subarachnoid hemorrhage in the first 24 hours (approximately 98%) and then decreases over time (50% or less at 1 week). Patients clinically suspected to have subarachnoid hemorrhage with a normal CT must undergo a lumbar puncture with CSF analysis for the presence of red blood cells and xanthochromia. When lumbar puncture is inconclusive, spectrophotometry, if available, for detection of bilirubin is highly sensitive (greater than 95%).
relative risk for ischemic stroke among patients with any type of migraine headache is 2.16 (95% confidence interval [CI] 1.89 to 2.48) (Etminan et al, 2005). The relative risk for subjects with miTABLE 10-3 Procedure
graine with aura is 2.27 (1.61 to 3.19) while it is 1.83 (1.06 to 3.15) in patients without aura. This risk does not differ when corrected for age, but the use of oral contraception increases the risk of
Postvascular Intervention Headaches Frequency Onset
Severity Duration
Carotid 60% endarterectomy
1 week
Angiography
During procedure Severe to 2 hours
33%
Aneurysm 20% coiling/clipping
Immediately postoperative to 3 days
Mild
Average 3 days; maximum 1 month 72 hours
Moderate Chronic to severe
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stroke eightfold. A cross-sectional, prevalence study of Dutch adults aged 30 to 60 years suggests that this increased risk of stroke is confined to the cerebellar region of the posterior circulation (Kruit et al, 2004). In this study, the highest risk was among migraine with aura patients with one or more attacks per month (odds ratio [OR] 15.8, 95% CI 1.8 to 140.0). Despite the presence of these imaging lesions, none of the patients in this study reported a history of stroke or transient ischemic attack, and none had relevant abnormalities on neurological examination. Contradictory to these results, a recent prospective cohort study of patients aged 45 years or older participating in the Women’s Health Study concluded that migraine (with and without aura) was not associated with total, ischemic, or hemorrhagic stroke (Kurth et al, 2005). However, subgroup analyses showed a minimal increase in risk of total and ischemic stroke for migraineurs with aura (3.8 additional cases per year per 10,000 women). True migrainous infarction defines stroke that results when deficits associated with a patient’s usual migraine aura become permanent. This classification must not be used to define the patient who has their usual migraine either before or at the time of a stroke. As discussed previously, headache with stroke, which may resemble a patient’s usual migraines, occurs in approximately 25% of all stroke patients. The IHS criteria for migrainous cerebral infarction are highlighted in Table 10-4. Although the evidence is reasonably clear that migraine is a risk factor for ischemic stroke, both during and remote from the ictus, and particularly in women during their childbearing years, the mechanism(s) remains unclear. It is likely that multiple mechanisms are involved, however. Evidence suggests that regional cerebral blood flow is reduced in migraineurs during
KEY POINT:
TABLE 10-4
Migrainous Infarction— International Headache Society Criteria
"
Present attack in a patient with migraine with aura is typical of previous attacks except that one or more aura symptoms persist for >60 minutes
"
Neuroimaging demonstrates ischemic infarction in a relevant area
"
Not attributed to another disorder
A
Migraine is a risk factor for the development of cervical artery dissection.
aura. Using perfusion-weighted MRI, Cutrer and colleagues (1998) demonstrated reductions in regional cerebral blood flow of up to 50%. Platelet hyperactivity and elevation in circulating von Willebrand factor (vWF) have been reported in migraineurs (D’Andrea et al, 1982). vWF is a large, endothelial glycoprotein that causes platelet aggregation by activating the platelet glycoprotein IIb-IIIa receptors for fibrinogen. It has been reported to be an independent risk factor for stroke (Folsom et al, 1999). Migraineurs with prior stroke had significantly higher vWF antigen and activity than controls. vWF antigen (126%) and activity (130%) were also significantly higher in migraineurs without stroke (Tietjen et al, 2001). It is conceivable, therefore, that these procoagulant abnormalities may increase the risk of stroke in migraine sufferers, especially during periods of hemodynamic stress (aura) or when other risk factors are present (cigarette smoking, hypertension, oral contraceptive pill use). Cervical Artery Dissection Migraine is a risk factor for the development of cervical artery dissection. A history of migraine is reported in
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An increased prevalence of patent foramen ovale occurs in patients with migraine with aura. PFOs are found in approximately 20% to 25% of the general population and in about 50% of patients with migraine with aura.
34% to 49% of patients with cervical artery dissection (d’Anglejan Chatillion et al, 1990; Tzourio et al, 2002). Even after adjusting for age, sex, and body mass index, a history of migraine is associated with an OR of cervical artery dissection of 3.6 (Tzourio et al, 2002). A meta-analysis of risk factors for cervical artery dissection lists migraine as one of the top four risk factors (Rubinstein et al, 2005). Others include aortic root diameter greater than 34 mm (OR 14.2), relative diameter change (greater than 11.8%) during the cardiac cycle of the common carotid artery (OR 10.0), and trivial neck trauma (OR 3.8). Patients with multiple dissections have a higher OR for migraine (OR 6.7) than patients with a single artery dissection (OR 2.9) (Tzourio et al, 2002). It is unclear why migraine is a risk factor for cervical artery dissection. One suggestion is that patients with migraine have abnormalities of the extracellular matrix. Increased levels of serum elastase activity, an enzyme involved in matrix degradation, have been measured in patients with migraine (Tzourio et al, 2000). Higher levels of extracellular matrix degradation and loss of vessel wall stability may certainly be associated with the risk of cervical artery dissection. However, there have been no additional studies supporting the role of matrix degradation in patients with migraine. PATENT FORAMEN OVALE AND MIGRAINE An increased prevalence of patent foramen ovale (PFO) occurs in patients with migraine with aura. PFO is the result of incomplete fusion of the atrial septum that normally occurs shortly after birth. It acts as a persistent connection between the right and left atria, allowing for right to left shunt. Shunting may occur at rest or with elevations in right atrial pressure during Valsalva. PFO
may be detected by transesophageal echocardiography, transthoracic echocardiography, or transcranial Doppler of the middle cerebral artery with peripheral injection of agitated saline. Transesophageal echocardiography is the most sensitive, albeit the most invasive, method. PFOs are found in approximately 20% to 25% of the general population and in about 50% of patients with migraine with aura. A prevalence study using transcranial Doppler sonography with agitated saline injection evaluated for PFO in 113 patients with migraine with aura, 53 patients with migraine without aura, and 25 age-matched nonmigraine controls (Anzola et al, 1999). PFO was identified in 48% of migraine with aura patients, 23% of migraine without aura patients, and 20% of control subjects. When comparing patients with migraine with aura to patients with migraine without aura, the OR of PFO is 3.13 (CI 1.41 to 7.04). Comparison of patients with migraine with aura to controls yields an OR of 3.66 (CI 1.21 to 13.25). No significant difference in the prevalence of PFO is found between patients with migraine without aura and controls. A study focusing on decompression illness in divers and PFO also examined the frequency of migraine (Wilmshurst and Nightingale, 2001). Of 120 patients with decompression illness and right-to-left shunt detected by transthoracic contrast echocardiography, migraine with aura in daily life occurred in 42 (35%). Migraine with aura was more common in patients with large shunts present at rest (38 of 80; 47.5%) than in those with smaller shunts and those only seen after Valsalva (4 of 40; 10%) and those with no shunt (11 of 80; 13.8%). The prevalence of migraine without aura did not significantly differ between groups. The authors conclude that the size of the right-to-left shunt is related to migraine prevalence. A follow-up study from the
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same investigators examined an additional 119 patients with decompression illness and right-to-left shunt (Wilmshurst et al, 2005). Results were very similar in that patients with shunts more frequently had migraine with aura than those without shunts. Once again, this association did not exist for migraine without aura and was related to shunt size. Migraine with aura was 4.5 times more prevalent in those with large shunts as compared with those with no shunt (52.9% versus 11.8%). The prevalence of migraine with aura in patients with small shunts was similar to those without shunts. The prevalence with medium-sized shunts at rest and those that are large only with Valsalva was intermediate. In the Migraine Intervention with STARFlex1 Technology (MIST) trial currently underway in the United Kingdom, 60% of 147 patients enrolled have a right-to-left shunt, the majority of which were PFOs. In addition, more than 40% of the migraine patients studied had a large shunt, 6 times greater than what would be expected in the general population. Again, PFO was the most prevalent shunt seen in these patients with migraine, accounting for more than 85% of all large shunts detected. These data confirm previous studies and indicate a strong correlation between PFO and migraine headaches (Dowson et al, 2005). Several analyses of the effects of PFO closure on migraine have reported resolution or a decrease in the frequency of headaches in patients with migraine without and with aura. However, these studies are retrospective, uncontrolled, and may include subjects undergoing PFO closure for paradoxical cerebral embolism. Although results are promising, prospective, controlled analyses of PFO closure in patients with migraine need to be completed prior to drawing conclusions about such interventions.
Thus far, the exact relationship between migraine and PFO is not clear. The two conditions, both relatively common, may be co-inherited, or PFO may be a risk factor for the development of migraine. PFO acts as a conduit for paradoxical cerebral embolism, which may potentially trigger the migraine attack and could account for the increased incidence of cerebral MRI lesions in migraine patients. HEADACHE SYNDROMES THAT MIMIC STROKE Occasionally, the clinical features of migraine may mimic stroke. This may occur during attacks of migraine with aura, aura without headache, hemiplegic migraine, retinal migraine, ophthalmoplegic migraine, and basilar migraine.
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Occasionally, the clinical features of migraine may mimic stroke. Visual symptoms, followed by sensory, aphasic, and motor symptoms, are the most frequent migraine aura manifestations.
Migraine With Aura and Aura Without Headache The manifestations of migraine aura may mimic transient ischemic attacks or stroke. An analysis of 163 patients with migraine with aura by Russell and Olesen (1996) found that visual symptoms were the most frequent aura manifestations occurring in 99% of patients. This was followed by sensory symptoms in 31%, aphasic symptoms in 18%, and motor symptoms in 16%. Patients with several different aura symptoms had visual aura with almost all attacks. The typical visual aura consists of positive phenomena (scintillations) compared with the negative symptoms (scotoma) most commonly seen with stroke. In addition, visual changes of aura may have a slow progression corresponding to cortical spreading depression and may suggest involvement of more than one arterial territory. The typical sensory aura of migraine begins in the hand and then progresses to the arm, face, and tongue (cheiro-oral distribution). Tongue involvement is rare with ischemic stroke. In addition, the sensory symptoms in
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Hemiplegic migraine must meet criteria for migraine with aura and in addition, must meet some degree of paresis.
migraine are usually positive (paresthesias) as opposed to the negative sensory symptom (numbness) of stroke. Further differentiating the two entities, sensory deficits of slow onset that are progressive in distribution are uncommon with stroke. The typical motor aura is unilateral and involves the arm and hand. Paresis may start focally and then spread to involve additional muscles, a characteristic uncommon with ischemic stroke. Although visual and sensory auras usually resolve in less than 1 hour, motor phenomena may persist for hours or days. Table 10-5 summarizes features that help distinguish migraine aura from symptoms of cerebral ischemia. The distinction between migraine aura and cerebral ischemia can be even more challenging in patients who have aura without headache. Several names have been given to this condition, including acephalgic migraine, migraine equivalent, late-life migraine accompaniment, and, most recently, according to the IHS, typical aura without headache. According to IHS criteria, manifestations should include visual and/or sensory symptoms with or without speech involvement (Table 10-6). Symptoms should have a gradual onset, be completely reversible within 1 hour,
TABLE 10-5
and have no associated headache. Patients with aura without headache often are afflicted by migraine with aura or aura with nonmigraine headaches as well. Aura without headache is most commonly seen in patients with a history of migraine with aura. Hemiplegic Migraine Hemiplegic migraine may mimic stroke. Hemiplegic migraine must meet criteria for migraine with aura and in addition must involve some degree of paresis (Table 10-7). At least one aura symptom in addition to motor weakness is present. This may include sensory symptoms, speech disturbance, visual symptoms, imbalance, diplopia, or altered mental status. If the patient has a first- or second-degree relative with hemiplegic migraine, the diagnosis is familial hemiplegic migraine. In the absence of such a family history, the diagnosis is sporadic hemiplegic migraine. Approximately 50% of cases are familial, and the other 50% are considered sporadic. The weakness of hemiplegic migraine may be mild or consistent with complete hemiplegia. Although the aura usually lasts 1 to 2 hours, it may range from 10 minutes to several days or even weeks. Generally, this is
Migraine Aura Versus Cerebral Ischemia
Feature
Migraine Aura
Cerebral Ischemia
Onset
Slow progression
Sudden
Duration
15 to 60 minutes
Often shorter
Distribution
Spreads during attack
No spread
Visual symptoms
Positive—scotoma
Negative—visual loss
Sequential symptoms
Present (eg, visual, then sensory)
Absent
History of similar attacks
Present
Often absent
History of migraine
Present
Present or absent
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TABLE 10-6
International Headache Society Criteria for Typical Aura Without Headache
A. At least two attacks fulfilling criteria B through D B. Aura consisting of at least one of the following, with or without speech disturbance but no motor weakness: 1. Fully reversible visual symptoms including positive features (flickering lights, spots, or lines) and/or negative features (loss of vision) 2. Fully reversible sensory symptoms including positive features (pins and needles) and/or negative features (numbness) C. At least two of the following: 1. Homonymous visual symptoms and/or unilateral sensory symptoms 2. At least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 3. Each symptom lasts 5 and 60 minutes D. Headache does not occur during aura or follow aura within 60 minutes Data from Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
followed by migrainelike head pain. Onset of hemiplegic migraine is usually between 10 and 15 years of age with a reduction in frequency commonly seen in the third decade (Ducros et al, 2001). Familial hemiplegic migraine (FHM) is inherited in an autosomal domi-
nant pattern although with incomplete penetrance. Three genes have been identified as playing a role in this disease. Type 1 (FHM1) has been linked to CACNA1A located on chromosome 19p13 (Ophoff et al, 1996). CACNA1A codes for a pore-forming subunit of the neuronal P/Q type voltage-gated TABLE 10-7
International Headache Society Criteria for Hemiplegic Migraine
A. At least two attacks fulfilling criteria B and C B. Aura consisting of fully reversible motor weakness and at least one of the following: 1. Fully reversible visual symptoms including positive features (flickering lights, spots, or lines) and/or negative features (loss of vision) 2. Fully reversible sensory symptoms including positive features (pins and needles) and/or negative features (numbness) 3. Fully reversible dysphasic speech disturbance C. At least two of the following: 1. At least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 2. Each aura symptom lasts 5 minutes and <24 hours 3. Headache fulfilling criteria B through D for 1.1 migraine without aura begins during the aura or follows onset of aura within 60 minutes Data from Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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205
" CEREBROVASCULAR/CARDIOVASCULAR DISEASE
KEY POINTS:
A
A
206
Retinal migraine attacks consist of monocular scotoma or visual loss lasting less than 1 hour followed by headache. Ophthalmoplegic migraine is a condition in which a migrainelike headache is associated with paresis of one or more of cranial nerves III, IV, and VI.
calcium ion channel. Type 2 (FHM2) is linked to ATP1A2, found on chromosome 1 (De Fusco et al, 2003). ATP1A2, expressed mainly in glial cells, encodes for a sodium-potassium pump adenosine triphosphatase. The most recently discovered gene, SCN1A, located on chromosome 2q24, is linked to type 3 (FHM3) (Dichgans et al, 2005). SCN1A codes for a voltage-gated sodium channel. Genotype-to-phenotype correlations have thus far proven difficult. Retinal Migraine Retinal migraine, in which monocular visual changes are the main feature, may mimic the stroke symptoms of retinal artery embolism. IHS diagnostic criteria are illustrated in Table 10-8. Retinal migraine tends to affect young adults. Attacks consist of monocular scotoma or visual loss lasting less than 1 hour followed by headache. Visual loss tends to affect the entire visual field, although any of the visual changes that have been described in migraine with aura may manifest in a monocular pattern (Tomsak and Jergens, 1987). A retrospective analysis of 24 patients with retinal migraine by Tomsak and Jergens (1987) found that 92% of patients had recurrent visual disturbances in the same eye and never the other. Attack characteristics were stereotyped in the majority of patients and occurred with a frequency ranging from twice per week to once every 6 months. In 92% of patients in this study, visual changes were fully reversible. The symptoms of retinal migraine are likely due to retinal or optic nerve hypoperfusion from vasospasm of the central retinal or ophthalmic arteries respectively. Appropriate investigations must be performed to rule out other causes of transient monocular visual loss. Ophthalmoplegic Migraine Ophthalmoplegic migraine is a condition in which a migrainelike head-
ache is associated with paresis of one or more of cranial nerves III, IV, and VI. It is an exceedingly rare condition, occurring with an annual incidence of approximately 0.7 per 1 million people (Hansen et al, 1990). Diagnostic criteria are illustrated in Table 10-9. It is unclear whether this condition is truly a migraine subtype or if it represents a recurrent demyelinating neuropathy. Patients tend to have onset before the age of 10 and are most often male. Headache precedes ophthalmoplegia in the majority of cases, usually by 3 to 4 days. Pupillomotor fibers are often affected, resulting in a poorly responsive, mydriatic pupil. Usually, head pain resolves with persistence of ophthalmoplegia for the following 1 week to 1 month. Full recovery over several
TABLE 10-8
International Headache Society Criteria for Retinal Migraine
A. At least two attacks fulfilling criteria B and C B. Fully reversible monocular positive and/or negative visual phenomena (scintillations, scotoma, or blindness) confirmed by examination during an attack or (after proper instruction) by the patient’s drawing of a monocular field defect during an attack C. Headache fulfilling criteria B through D for migraine without aura begins during the visual symptoms or follows them within 60 minutes D. Normal ophthalmologic examination between attacks Data from Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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TABLE 10-9
International Headache Society Criteria for Ophthalmoplegic Migraine
A. At least two attacks fulfilling criterion B B. Migrainelike headache accompanied or followed within 4 days of its onset by paresis of one or more of the third, fourth, and/or sixth cranial nerves C. Parasellar, orbital fissure, and posterior fossa lesions ruled out by appropriate investigations Data from Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004; 24(suppl 1):9–160.
weeks is expected. However, recurrent attacks may result in permanent and progressive functional limitation of extraocular muscles. Abnormal enhance-
TABLE 10-10
ment of the oculomotor nerve on MRI with gadolinium has been documented in several patients meeting IHS criteria for ophthalmoplegic migraine.
International Headache Society Criteria for Basilar-type Migraine
A. At least two attacks fulfilling criteria B through D B. Aura consisting of at least two of the following fully reversible symptoms, but no motor weakness: 1. Dysarthria 2. Vertigo 3. Tinnitus 4. Hypacusia 5. Diplopia 6. Visual symptoms simultaneously in both temporal and nasal fields of both eyes 7. Ataxia 8. Decreased level of consciousness 9. Simultaneously bilateral paresthesias C. At least one of the following: 1. At least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 2. Each aura symptom lasts 5 minutes and 60 minutes D. Headache fulfilling criteria B through D for migraine without aura begins during the aura or follows aura within 60 minutes Data from Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
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KEY POINT:
A
Basilar-type migraine refers to the occurrence of migrainelike headache and neurological signs or symptoms that localize to the brain stem, cerebellum, or occipital lobes.
Basilar-type Migraine Basilar-type migraine refers to the occurrence of migrainelike headache and neurological signs or symptoms that localize to the brain stem, cerebellum, or occipital lobes. The aura of basilar-type migraine may mimic posterior circulation stroke. Manifestations may include binocular visual symptoms, dysarthria, vertigo, tinnitus, diplopia, hearing impairment, ataxia, bilateral motor or sensory deficit, and alteration in level of consciousness. IHS criteria for basilar-type migraine are illustrated in Table 10-10. Basilar migraine is an uncommon condition that tends to affect patients aged younger than 35 years (Sturzenegger and Meienberg, 1985). In Sturzenegger’s and Meienberg’s review of 49 patients
with basilar migraine, 65% had onset in the second or third decade of life, although there was a wide range of ages from 10 to 63 years. Forty-percent of patients had attacks of basilar migraine only, while 60% also experienced more common forms of migraine. In most cases, the aura of basilar migraine lasts between 5 and 60 minutes, but it can be prolonged, lasting up to 3 days. In the great majority of patients, a migrainelike headache develops and aura symptoms and signs resolve. Most patients have a decrease in basilar migraine frequency with age. As with all of the rare headache types that may mimic stroke, other etiologies for the patients’ headaches and neurological deficits must be entertained and investigated.
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APPROACH TO THE INTRACTABLE HEADACHE CASE: IDENTIFYING TREATABLE BARRIERS TO IMPROVEMENT
KEY POINT:
A
It is not a treatmentrefractory primary headache until all possible (reasonably) organic causes have been considered or ruled out.
Joel R. Saper
ABSTRACT The diagnosis of a primary headache disorder requires applying symptom profiles to existing diagnostic criteria and ruling out organic disease that can mimic the primary headache disorders. Many physicians encounter patients whose headaches appear consistent with a primary condition but whose response to treatment is insufficient or absent altogether. This chapter provides a strategic approach to the patient with intractable headaches, emphasizing the possible reasons for intractability and ways to address these variables. The most important factors to consider include medication overuse headache (formerly rebound ), the presence of an incorrect diagnosis, improper medication selection or dosing, psychological barriers, the need for a more intense and aggressive treatment environment (hospitalization), use of opioids, and the need for interventional therapy. Each of these variables will be considered in detail with recommendations and approach strategies provided.
INTRODUCTION Patients suffer illnesses long before physicians understand the pathology or develop treatments to address them. Such is certainly the case with headache. The understanding of disease and its treatment predictably lags by years, if not centuries, the need to find effective therapies. Such is the case with headache. Physicians frequently encounter patients with headaches who do not respond to what appears to be appropriately administered interventions. The patient reports persisting or recurring pain, despite the most aggressive and creative therapeutic efforts.
Standard diagnostic tests only rarely provide a likely cause or therapeutically relevant information. This chapter will set forth an approach strategy for patients with refractory headache. The principal burden is to rule out organic disease. If none is present, the clinician must address intractable headache of a primary origin, perhaps confounded by secondary headache or confounding neuropsychological factors. It is not a treatment-refractory primary headache until all possible (reasonably) organic causes have been considered or ruled out.
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KEY POINTS:
A
A
260
Intractable cases of migraine and related headaches are frequently associated with medication overuse and ‘‘rebound.’’ It is increasingly clear that rebound or medication overuse headache represents a receptor disturbance.
REVIEW OF PRIMARY HEADACHES The primary headaches have been previously discussed in this issue of . They include those in which intrinsic dysfunction of the nervous system, which can be genetic in some instances, such as migraine, predispose an individual to increasing vulnerability to headache attacks. This chapter will focus principally on the treatment of persistent daily or almost daily intractable headaches, which, if not due to organic disease, are usually, but not always, associated with chronic migraine, transformed migraine, or new daily persistent headache, as described earlier in this issue of . As noted in the chapter ‘‘Classification of Primary Headaches: Concepts and Controversies’’ earlier in this issue, the classification of chronic migraine remains controversial. Nonetheless, despite confusing terminology and classification disagreement, a pernicious form of migraine does indeed exist, with attacks usually increasing in frequency over time and often occurring on a previous background of episodic migraine without aura. This form of migraine is frequently accompanied by comorbid neuropsychiatric phenomena. Comorbid conditions associated with the pernicious form of migraine include depression, anxiety and panic disorders, bipolar disorder, obsessivecompulsive disorder, character disorders, and perhaps even fibromyalgia. Intractable cases of migraine and related headaches are frequently associated with medication overuse and ‘‘rebound’’ (see ‘‘Medication Overuse Headache’’ chapter). The diagnosis of chronic migraine or new daily persistent headache cannot be established until medication overuse headache and organic disease have been ruled out (see chapters ‘‘Classification of Primary Headaches: Concepts and Controversies,’’ ‘‘Medication Overuse Headache,’’
and ‘‘Diagnostic Testing and Secondary Causes of Headache’’). Selected Causes for Primary Headache (Principally migraine) intractability. Table 13-1 lists the broad categories that are considered important in intractability. MEDICATION OVERUSE HEADACHE, ALSO KNOWN AS MEDICATION REBOUND This discussion supplements the ‘‘Medication Overuse Headache’’ chapter. It is increasingly clear that rebound or medication overuse headache represents a receptor disturbance. Rebound or medication overuse headache should be distinguished from medication toxicity, which reflects the acute, direct provocation of headache from a toxic exposure to a drug or
TABLE 13-1
Possible Reasons for Intractability
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‘‘Rebound’’ (medication overuse headache) or excessivemedicationoveruse, toxicity, etc
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Wrong diagnosis (wrong primary or undetected secondary causes) or nondiagnosis
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Medication selection not proper/dosages not adequate
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Psychological barriers
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Current or previous use of opioids
"
Requires interventional therapy
"
Beyond current physiological understanding
More aggressive treatment required: hospitalization
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substance (Olesen et al, 2006). By contrast, medication overuse headache reflects a receptor disturbance, generally developing over time from chronic exposure. Srikiatkhachorn and colleagues (1998) have shown changes in serotonin receptors with paracetamol therapy during medication rebound. More recently Mao (2002) has shown alterations in opioid receptor function. Meng and Porreca (2004) reviewed the literature that considers sensitization of neuronal receptors, possibly related to the effects of calcitonin gene-related peptide as a result of opioid induction. Even an initial exposure to opioids appears to have long-lasting, if not permanent, receptor effects (Lim et al, 2005). Recently, Burstein and colleagues ( Jakubowski et al, 2005) have shown that previous intermittent exposure to opioids prevented an otherwise expected therapeutic response to agents that consistently controlled the headache in patients never having used opioids. Rebound headache (or medication overuse headache) is a self-sustaining
TABLE 13-2
headache condition characterized by persisting and recurring headache (usually migraine forms) against a background of chronic, regular use of centrally acting analgesics, ergotamine tartrate, or triptans. Although it is considered unlikely that other primary headaches are influenced by medication overuse, Hering-Hanit (2000) has described a case of likely rebound in a patient with cluster headache who overuses triptans. The key features of this condition are noted in Table 13-2. Recently the International Headache Society has classified medication-induced headaches and renamed this phenomenon medication overuse headache.
KEY POINT:
A
A recent study has shown that previous intermittent exposure to opioids prevented an otherwise expected therapeutic response to agents that consistently controlled the headache in patients never having used opioids.
Treatment of Medication Overuse (Rebound) Headache Rebound headache (also known as medication overuse headache) requires aggressive treatment, since continued use renders patients refractory to effective treatment. Outpatient and inpatient strategies are available, depending upon the intensity of medication usage
Key Clinical Features of Rebound Headache*
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Weeks to months of excessive use of abortive agents, with usage exceeding 2 to 3 days per week
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Insidious increase of headache frequency
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Evidence of psychological and/or physiological dependency
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Reliable onset of headache within hours to days following the last dose of symptomatic treatment
Dependable and predictable headache, corresponding to an irresistible escalating use of offending agents at regular, predictable intervals
Failure of alternate acute or preventive medications to control headache attacks
*See ‘‘Classification of Primary Headaches: Concepts and Controversies’’ and ‘‘Medication Overuse Headache’’ chapters for current International Headache Society criteria for medication overuse headache. Modified from Saper JR, Silberstein SD, Gordon CD, et al. Handbook of headache management: a practical guide to diagnosis and treatment of head, neck, and facial pain. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999b.
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KEY POINTS:
A
A
A
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Rebound headache (medication overuse headache) requires aggressive treatment, since continued use renders patients refractory to effective treatment. Among the most valuable adages in clinical medicine is, ‘‘When all else fails, take more history.’’ Very little can substitute for a careful neurological examination with special attention to those factors that are particularly important in headache provocation, such as eyes, ears, neck, and jaw, including trigeminal, vagal, and glossopharyngeal distribution.
and behavioral characteristics of each case. Rebound, or medication overuse headache, must be distinguished from headaches resulting from toxic substances or acute exposure to certain drugs. These have a direct provocative influence and are not the result of chronic receptor changes. Table 13-3 identifies important principles in the approach to the treatment of rebound or medication overuse headache. Certain drugs that do not cause rebound or medication overuse headache can be used frequently and even daily for a while to control pain acutely during withdrawal. These include: o Hydroxyzine (25 mg to 50 mg oral [PO] or intramuscular [IM]) o Various neuroleptics (chlorpromazine, etc) o Low-dose nonsteroidal anti-inflammatory drugs (NSAIDs) (ketorolac PO, intravenous [IV], or IM; indomethacin, per rectum) o Steroids (Pageler et al, 2004; Smith, 2002) o Compatible and safe combinations of several agents listed above The value of buprenorphine in transitioning from opioid overuse in patients with headache remains uncertain but is currently under study (Case 13-1).
TABLE 13-3
THE WRONG DIAGNOSIS OR NONDIAGNOSIS Among the most valuable adages in clinical medicine is, ‘‘When all else fails, take more history.’’ This exhortation resounds over and again during neurology training because it recognizes that more clinical information often leads to a better diagnosis and ultimately to effective treatment. Very little can substitute for a careful neurological examination with special attention to those factors that are particularly important in headache provocation, such as eyes, ears, neck, and jaw, including trigeminal, vagal, and glossopharyngeal distribution. In addition to neurological signs or symptoms during history taking or examination, the clinician should pay special attention to the following: o Movement of the neck o The presence of occipitocervical pain on palpation and movement o The presence of submandibular pain (indicating styloid process factors, lymph nodes, carotid artery disturbances or masses) o Disc margin clarity, visual function, eye movement o Oral cavity health or pain sources o Facial sensation o Temporal artery integrity
Principles in Treating Rebound Headache
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Discontinuation of offending agent (taper if agent contains opioid or barbiturate)
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Aggressive treatment of resulting ‘‘withdrawal’’ headache
" " "
Implementation of pharmacological prophylaxis
Hydration, including intravenous fluids and support in severe cases (treat nausea, etc)
Implementation of behavioral therapies Use of outpatient infusion or hospitalization techniques for advanced and severe conditions
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Case 13-1 A 35-year-old female with menstrual migraine experiences increasingly frequent headaches that were initially treated with simple analgesics, later a barbiturate-analgesic combination, and most recently triptan medication, used 3 to 4 days per week. Medical history includes reactive airway disease, Raynaud’s phenomenon, gastroesophageal reflux disease, noninsulin-dependent diabetes, and hepatitis C. A family history of stroke in her father at age 65 and cardiac disease in her mother at age 60 is noted. Previously administered medications include gabapentin and a variety of other analgesics. On examination, blood pressure is 165/95 mm Hg. Magnetic resonance imaging (MRI) of the brain is interpreted as normal. The patient is effectively transitioned from the triptans during a 2-day taper program. Chlorpromazine suppositories 25 mg to 50 mg and hydroxyzine 50 mg to 75 mg 3 times a day (tid) given orally are used. Clonazepam 0.5 mg is administered 2 times a day (bid) to tid as needed (prn) and used for pain control and sedation. Following withdrawal and transition, preventive treatments are successful in controlling most of the headaches. These include nortriptyline 25 mg at bedtime, topiramate 75 mg bid, and tizanidine 2 mg tid. Abortive medication includes chlorpromazine and hydroxyzine. Blood pressure normalizes. A triptan is readministered for acute breakthrough headaches, but strict limits of no more than one usage day per week are established. Comment. This case posed several challenges. It was likely that this woman’s headaches increased in part as a result of overuse of analgesics and the triptans. Transition therapy was required and was effective using chlorpromazine suppositories, hydroxyzine, and clonazepam. The choice of preventive medications was limited, since reactive airway disease and Raynaud’s phenomenon prevented the use of beta-blockers; gastroesophageal reflux disease prevented the use of nonsteroidal antimedication; and noninsulin-dependent diabetes, along with her family history of vascular disease, limited the use of constricting drugs. The limited use of a triptan once blood pressure normalized was considered appropriate in light of a normal cardiogram. During the period of transition from analgesics and triptans to the current program, physician availability and support were available, and clonazepam aided in sleep control. Had contraindications to the use of vasoconstrictive agents not been present, this woman could ordinarily have been given several days of nasal dihydroergotamine to transition from the triptans. For practical reasons, the preventive treatments were started soon after withdrawal.
The following two general considerations are among the most important: (1) Make certain that the diagnosis of primary headache is accurate. For example, failure to diagnose an indomethacin-sensitive headache, such as chronic paroxysmal hemicrania, will result in failure to provide effec-
tive treatment. (2) Make certain that an organic disorder has not been overlooked. The following various categories or conditions are important to consider. Trauma. Does the patient have a traumatic history? Frequently overlooked in the standard history is a
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mild to moderate closed head injury, which can render an individual more likely to be refractory to standard headache treatments. Such a history will also explain other coexisting phenomena or findings that may accompany mild closed head and/or neck injury, including the presence of occipitocervical local pain (which might respond to interventional procedures, including facet joint and cervical nerve blockade). Also, posttraumatic headache is often associated with depression, sleep disturbance, and cognitive changes. Dissection syndromes. In addition, the clinician must consider the possibility of carotid or vertebral dissection syndromes when a history of head and neck trauma or sudden movement is followed by headache. Spontaneous, otherwise unexplained headaches, with or without neurological findings, should prompt consideration of a dissection syndrome as well. Postural or exertional features. A careful pursuit of relieving and aggravating factors that relate to posture and neck movement can provide a clue to the diagnosis and often to an effective treatment approach. Does standing up, lying down, or moving the neck relieve or aggravate the headache? Consider ‘‘low-pressure’’ headaches from spontaneous cerebrospinal fluid (CSF) leakage (postural headache) or cervical or posterior fossa disease associated with neck movement, coughing, sneezing, or Valsalva maneuvers. General health or medication use. The recent development of a medical or psychological condition or change in medicines used is important. Headacheassociated illnesses, infection, or hormonal disturbances are likewise important. Nature of the headache onset. How old is the headache history; what is the rate of attack onset? How sudden or over what time period did the headaches begin? Are they of recent onset
or previous onset? Consider sphenoid sinusitis among important new-onset disorders, as well as new daily persistent headache. Rapid, sudden, lightninglike onset could be the result of cerebral vein thrombosis, aneurysm, cervical disease, arterial dissection, or ‘‘crash migraine,’’ among other considerations (see the chapter ‘‘Diagnostic Testing and Secondary Causes of Headache’’). Exposures. Exposure to fumes, toxins, or other environments can be headache provoking. Specific consideration of carbon monoxide exposure is important, particularly in winter months when heating systems are used. Obtain a smoking history, including frequency and quantity, as well as vocational exposures to various substances and fumes. Nasal/dental conditions. The presence or absence of recent symptoms or intervention of a dental nature can be vital information. Root canals, tooth extractions, or bite disturbances may provoke or be associated with the development of an intractable headache, including migraine. Otolaryngological disturbances, such as nasal blockage, infection, drainage, pressure, or other features, should be pursued. (Consider nasopharyngeal carcinoma, which can present with headache). Dermatological conditions. The recent development of a skin rash (as in Lyme’s disease), vesicles (as in herpes zoster), or other dermatological problem might indicate the presence or absence of systemic or localized disease related to headache. Ocular symptoms. The presence of ocular pathology, such as increased intraocular pressure, or localized infection, tearing, or related disturbances must be considered. Medication review. A review of all medications, over-the-counter and prescribed, is a worthwhile undertaking. Give special consideration to caffeine usage, over-the-counter medication,
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recreational drug use, and other mediother sinus disease) and cines that individually or collectively nasopharyngeal disturbances, (toxic amounts) can produce headincluding cancer (may require ears, ache symptoms. Also inquire as to nose, and throat visualization/ which medicines have failed and at assessment) what dose. o Disorders along the course of Sleep-and-wake cycles. Consider the trigeminal nerve, including work hours, sleep/wakefulness cycles, dental, nasal, oral/aural (partially sleep apnea disturbances, etc. innervated by trigeminal nerve) Hormonal. Are hormonal disturdisease, jaw pathology, etc bances present? Consider menstrual ir- o Glaucoma and other ocular diseases regularity, amenorrhea, breast discharge, o Vasculitis/rheumatic/connective etc. Have oral contraceptives been retissue disorders cently introduced or changed, or horBecause of the relationship between monal supplements used; has there the cervical spine, descending trigembeen weight loss or weight gain? Chronic inal system (nucleus caudalis), and opioid use may alter normal endocri- headache mechanisms (cervical or trinological function. geminal cervical connection) (Bartsch and Goadsby, 2001; Bogduk, 1997) (see the chapter ‘‘Classification of Primary Selected Illnesses to Headaches: Concepts and ControverBe Considered ), sies’’ in this issue of The following list represents selected disturbances at the level of the upper conditions that ‘‘mimic’’ or aggravate/ cervical spine, its nerves, and joints activate primary headache conditions. have become important targets for o Low/high CSF pressure syndromes the evaluation and treatment of othero Infections: Lyme disease, West Nile wise pharmacologically resistant headvirus, human immunodeficiency aches. It is possible that the C2-C3 virus, encephalitis, fungal level of the cervical cord is a therameningitis, etc. peutic entry zone for pain modulatory o Carotid or vertebral artery influence, independent of whether dissection/cerebrovascular disease cervical pathology exists. Premature or o Occipital/cervical disease, including excessive use of interventional proArnold-Chiari malformation type I; cedures is unwarranted, but when upper cervical joint, root, or nerve selectively and expertly administered, (neuralgic) syndromes they clearly have a role in the overall o Hormonal disturbances/ spectrum of diagnosis and treatment endocrinological disease (estrogen of headache conditions. Weiner and factors, thyroid and parathyroid Reed (1999) and personal communidisease, pituitary abnormalities, cation from D. W. Dodick (2002) reetc) port that implantable stimulators are o Metabolic disturbances (including on the horizon, but data affirming their hepatitis, renal disease, B12 utility in chronic headache remain to deficiency, anemia, toxins, carbon be established. The clinician must obtain approprimonoxide levels) o Overuse of medications (rebound ate consultations from a variety of or toxic drug overuse conditions) specialties to identify the presence or absence of coexistent organic or barriero Otolaryngological disease, producing psychological disturbances. including acute or chronic Otolaryngological, ophthalmological, sphenoid sinusitis (or
KEY POINTS:
A
A
Because of the relationship between the cervical spine, descending trigeminal system (nucleus caudalis), and headache mechanisms (cervical or trigeminal cervical connection), disturbances at the level of the upper cervical spine, its nerves, and joints have become important targets for the evaluation and treatment of otherwise pharmacologically resistant headaches. Premature or excessive use of interventional procedures is unwarranted, but when selectively and expertly administered, they clearly have a role in the overall spectrum of diagnosis and treatment of headache conditions.
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KEY POINT:
A
Avoidance of long-acting reservoir progesterone preparations is recommended.
and dental examinations are essential in intractable cases. Dental pathology, including cracked teeth, postsurgical neuromas, temporomandibular dysfunction, or oral malignancy can all incite nociceptive activity along the trigeminal system and activate headaches. Nasal contact syndromes, disturbances within the sinus system, nasopharyngeal pathology, or throat pathology, including prolonged or painful styloid processes and ligaments, may produce headache or headache activation. Diseases of the eyes similarly must be ruled out. Endocrinological and gynecological evaluations to assess hormonal integrity, cycling, and appropriate hormonal replacement or use of oral contraceptives can be valuable. Based on personal observations, this author rec-
TABLE 13-4
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ommends that long-acting reservoir progesterone preparations be avoided. Additional Diagnostic Tests The chapter ‘‘Diagnostic Testing and Secondary Causes of Headache’’ reviews many of the diagnostic tests used in headache diagnosis. Here are some additional thoughts. Diagnostic testing must include a wide range of studies, including the investigation of metabolic, endocrinological, toxic, dental, traumatic, cervical, and infectious disorders, and spaceoccupying lesions. Table 13-4 lists diagnostic tests that are among those that should be considered in intractable or variant cases. Initial testing may provide normal results, but experience suggests that occasionally a repeat study will demonstrate
Selected Diagnostic Testing
Physical Examination Metabolic Evaluation Hematological/clotting profile Erythrocyte sedimentation rate/C-reactive protein Endocrinological Chemistry
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Toxicology (drug urine screening, etc)
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Standard X-rays Neuroimaging CT scans, including CT arteriography Magnetic resonance imaging/magnetic resonance angiography/magnetic resonance venography
" " " "
Dental, Mandibular, and Otological Examinations Lumbar Puncture (Pressure, Viral Studies, etc) ‘‘Diagnostic’’ Blockades Cardiac Doppler and Ultrasound (Patent Foramen Ovale, Atrial Aneurysm).
CT = computed tomographic.
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More extensive studies, including pathology that was neither initially evident nor present in an identifiable arteriography, are justified occasionally form. In the presence of intractable and should be considered in individuals symptoms of pain, responsible repeated when the symptoms of headache or testing and additional testing as listed pain are accompanied by factors that would otherwise be considered not below are sometimes justified. identifiable except by arteriographic o Lumbar puncture to assess the procedures. presence of inflammatory or Recently, attention has focused on infectious changes or alteration the possible relevance of patent foraof CSF pressure. An opening and men ovale and atrial aneurysms, toclosing pressure should be gether with right-to-left shunting, in measured, and the relative change intractable migraine with aura and in light of the amount of fluid embolic stroke (Anzola et al, 1999; removed should be considered. Dowson et al, 2005; Wilmshurst et al, The opening pressure in 2005; Wilmshurst and Nightingale, hypovolemic (low pressure) 2001). This author has evaluated a syndromes may be in ranges small number of patients in whom generally considered normal patent foramen ovale and atrial aneu(Mokri, 2004). Diffuse meningeal rysmal disturbances were found. In enhancement is often present a few patients, the intractable headin low-pressure syndromes. aches diminished significantly upon o Flow-sensitive MRI (rule out patent foramen ovale closure, but in cervical occipital obstruction) others they did not. In some, ino Cisternography or computed creased aura appears to develop for tomographic (CT) myelogram a while or more persistently. The reaif CSF leak is suspected o Repeat MRI and CT scanning with son for this remains unclear; studies are underway. Surgical closure of the special attention to the posterior fossa and occipitocervical junction, patent foramen ovale to control headache should be either resisted or unnasopharyngeal regions, and sphenoid sinus may prove helpful. dertaken with caution and reluctance until appropriate studies confirm its (Standard CT scanning may not utility (Cases 13-2, 13-3, and 13-4). provide adequate views of the sphenoid, and radiological attention should be focused WRONG TREATMENT, and sinus views ordered when INADEQUATE DOSAGE, OR evaluating patients with suspected COTHERAPY NEEDED sphenoid disease). Because the treatment of the primary o MRI/magnetic resonance disorders has already been reviewed angiography of the carotid/ in detail in earlier chapters, this disvertebral arteries, looking for cussion will emphasize those princidissection in patients with recent ples that are most important in the onset of headache, particularly those with neurological symptoms treatment of the intractable patient. Initially the clinician must establish o Magnetic resonance venography the true pattern of usage of previous (for ruling out cerebral vein medications that have ‘‘failed.’’ Key thrombosis, intracranial questions include: hypertension, sudden-onset headache, etc) o Were these medicines provided at a time when the patient was o Others
KEY POINTS:
A
A
A
Initial testing may provide normal results, but experience suggests that occasionally a repeat study will demonstrate pathology that was neither initially evident nor present in an identifiable form. The opening pressure in hypovolemic (low pressure) syndromes may be in ranges generally considered normal. Surgical closure of the patent foramen ovale to control headache should be either resisted or undertaken with caution and reluctance until appropriate studies confirm its utility.
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Case 13-2
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A 35-year-old man was seen in an emergency department with 2-day onset of severe vertex headaches and insomnia. The patient complained of a ‘‘tight band’’ around his head, vertex pain, and periodic jabs of severe pain in his right eye. During the previous 12 hours the right eye became blurry, but no other neurological symptoms were noted. No history of headache was reported. A neurological examination by the emergency department physician was reported to be unremarkable. An unenhanced CT scan of the brain was interpreted as ‘‘no intracranial hemorrhage or mass.’’ The patient was treated with aspirin plus butalbital plus caffeine (Fiorinal) and sent home. Two days later the patient returned with intensifying headaches and significant loss of vision in the right eye. A repeat CT scan of the brain, this time visualizing the paranasal sinuses, demonstrated acute right sphenoid sinus occlusion. The patient was hospitalized and administered IV antibiotics for 10 days. The visual impairment did not improve, but the headaches dissipated. One week later the headache intensified again, and the patient underwent surgical drainage of the right sphenoid sinus. Purulent material was extracted. The patient underwent a second course of antibiotics by IV administration. Except for persistent impairment of vision on the right, a full recovery ensued. Comment. Acute sphenoid sinusitis is a potentially serious and life-threatening condition. Routine visualization of the brain by CT imaging, as in this case, does not necessarily include views of the sphenoid sinuses, which are located inferior to the clivus and medial to the cavernous sinus. Acute, expansive infections of the sphenoid cause lateral compression of the cavernous sinus in which are located the trigeminal (V1, V2) cranial nerves III, IV, and VI, the optic nerve (CN II), FIGURE 13-1 Computed tomographic scan of as well as the carotid the sinuses. Opacification of the right sphenoid sinus is clearly artery. IV antibiotics are evident in this case of acute sphenoid sinusitis. required in most cases, and surgical drainage is necessary in up to 50% of cases. Some cases of acute sphenoid sinusitis are caused by fungal infections, particularly aspergillosis (Figure 13-1).
‘‘rebounding’’ and thus may have been of less value? o Were dosages taken to the appropriate level to provide therapeutic value?
o What was the duration of usage? o Were the medications used in combination or as monotherapy? Table 13-5 identifies the key pharmacotherapeutic principles in the
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approach to treatment of intractable headaches and related phenomena. Treatment Modalities Numerous treatment modalities are available (Table 13-6) (Silberstein et al, 2001). Nonpharmacological treatments can be very helpful and sometimes essential, particularly when combined with pharmacological therapy (Holroyd et al, 2001). Behavioral modification, biofeedback, exercise, and dietary manipulation add a dimension of help beyond the administration of medications and also provide patients a method of helping themselves. Pharmacological therapy provides the principal treatment for the majority of patients with intractable headache. However, psychological factors
and situational circumstances can serve as serious, if not profound barriers, to effective treatment and resolution of symptoms (this will be discussed later). Recently, increasing attention has focused on the important contribution that interventional treatment may provide to patients with primary headache (this will be discussed later). Occipital nerve blocks, although not reversing the primary problem, can be particularly useful for symptomatic treatment. At the author’s center, facet blockade and subsequent radiofrequency neurolysis in patients with intractable headache have been surprisingly positive, although not universally effective (Silverman, 2002). Popeney and Alo (2003) and Weiner and Reed (1999) report that recent preliminary work on
Case 13-3 A 62-year-old woman reported the acute onset of headaches 2 years earlier, at which time she awakened in the morning with a severe headache. There was no previous history of headaches. Upon standing up, her pain markedly intensified but would improve upon reclining. Within 1 week the postural component of this headache dissipated, but the headache persisted 24 hours per day. Examinations were reported as normal. A lumbar puncture revealed no evidence of blood or xanthochromia. Pressures were not recorded. A variety of analgesics and treatments were tried without benefit. Her medical history was negative, except for an uneventful removal of a Morton’s neuroma 2 weeks prior to the onset of headache. Upon referral the patient’s examination was normal. Neuroimaging with enhancement demonstrated no abnormal findings. Laboratory testing was normal. The patient was hospitalized but failed to respond to standard aggressive treatment, including IV protocols. A lumbar puncture was performed with an opening pressure of 100 mm CSF. Following removal of 10 cc of CSF, the pressure dropped to 70 mm of CSF. An abdominal binder produced minimal relief, and IV lactated caffeine infusion produced modest improvement. An autologous injection of blood (20 cc) was injected at L2-L3 with complete reduction in headache. Three months later the headaches returned, and a second administration of autologous blood administration into the L2-L3 region was undertaken. Complete relief of pain occurred, and no recurrence of headache was noted during 3 years of follow-up. Comment. Upon further questioning, the woman acknowledged that the Morton’s neuroma removal had been preceded by spinal anesthesia. It is speculated that a CSF leak occurred at this time.
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KEY POINT:
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Reduction of medication overuse and the treatment of rebound and the behavior behind it provide a fundamental and critical element to the treatments of patients with chronic headache when medication overuse exists.
Case 13-4 A 27-year-old woman experienced the subacute onset of right burning facial pain radiating to her ear and temple region 3 years earlier. At onset the pain was constant and without jabs and jolts, and no associated symptoms were present. During the subsequent 3 years, despite treatment, the pain ‘‘spread’’ to involve most of her right cranium and neck. Many treatments for headache failed to bring results, and various doctors were consulted. Neuroimaging of the cervical and cranial regions and magnetic resonance angiography of the brain are without abnormal findings, and a bone scan is negative. Medical history is unremarkable. A mandibular root canal ipsilateral to the pain had been performed 4 months before the pain onset. Dental evaluation is unremarkable. Neurological examination shows slight and questionable reduction of pinprick sensation in V3 on the right. Corneal and nasal tickle reflexes are normal. Percussion over the midmandibular area with a reflex hammer results in a painful recoil. Selective alveolar blocks to the area of the root canal bring moderate but temporary reduction of pain to the involved tooth. Carbamazepine raised to anticonvulsant therapeutic levels brings substantial benefit, and the patient is referred to an oral surgeon for diagnostic consideration of a possible post–root canal oral necrotic cavitation versus neuroma. Comment. In the pursuit of intractable head and face pain, dental structures are important considerations. It is likely that this woman experienced some sequelae from her previous root canal. A true trigeminal neuralgic picture was not present, but a persistent painful pattern emerged. Painful responses from hammer percussion along the midmandibular region suggested a localized process, perhaps an infectious cavitation or postsurgical neuroma. Carbamazepine brought substantial relief. Finally, the spread of pain long after its onset is seen in some patients with peripheral painful disorders and may result from central sensitization with extension.
neurostimulation and headache raises the possibility that neurostimulation may in the future have an important role in the treatment of patients with intractable headache. Behavioral and Other Nonpharmacological Treatments for Primary Headaches A variety of factors related to health, habits, and education can assist patients with headache. Education on headache triggers and eliminating headacheproducing behaviors can be essential.
Reduction of medication overuse and the treatment of rebound and the behavior behind it (Saper et al, 2004) provide a fundamental and critical element to the treatments of patients with chronic headache when medication overuse exists. Discontinuing smoking, establishing and maintaining regular eating and sleeping patterns, and exercising regulary are reported as very helpful by many patients with headache. Biofeedback and behavioral treatment, together with cognitive-behavioral therapy, may be of important value in many cases. Formal behavioral therapy and biofeedback as well as other
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KEY POINTS:
TABLE 13-5
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Key Principles in the Pharmacotherapy of Intractable Headache
A
Correctly Diagnosing the Specific Primary Headache Entity if Present Determining Attack Frequency and Severity Establishing the Presence or Absence of Comorbid Illnesses Identifying Confounding Factors, Including External or Internal Phenomena, Such as: Rebound
A
Psychological, comorbid illnesses, and medication factors Hormonal disturbances Use of or exposure to headache-producing toxic substances Other
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Identifying Previous Treatment Successes and Failures
therapeutic approaches are helpful in many, if not most, cases of intractable headache, since the pain itself often produces changes in mood, function, and vocational goals. At times behavioral issues are the principal problem serving as a barrier to effective treatment. The chapter ‘‘Behavioral Medicine for Chronic Headache: Overview and Practical Tools for the Practicing Physician’’ lists a series of behavioral red flags in headache patients.
Numerous agents are used for the acute treatment of migraine. Some agents, such as analgesics, are of general value for pain, whereas others, such as the ergots and triptan medications, are specific and influence receptor and transmitter systems thought relevant to migraine pathogenesis. The triptans represent narrow spectrum, receptor-specific (serotonin
TABLE 13-6
Pharmacological Treatment of Migraine Routes of treatment. There are many routes of delivery for medications that can control headache. Table 13-7 reviews these with the caveat that routes other than the oral route of delivery may prove most effective in some cases of refractory headache. Acute treatment of migraine. The chapter ‘‘Acute Treatment of Migraine’’ provides an extensive discussion of the acute therapies. This section will review important principles in the treatment of intractable cases.
" " " " "
At times behavioral issues are the principal problem serving as barriers to effective treatment. The triptans represent narrow spectrum, receptor-specific (serotonin [5-HT1]) agonists that stimulate the 5-HT1 receptors to reduce neurogenic inflammation. The ergot derivatives are broader spectrum agents, affecting the serotoninergic receptors and also -adrenergic and dopamine receptors (and others).
Therapeutic Categories of Treatment for Intractable Headache
Nonpharmacological Treatment Pharmacological Treatment (Acute and Preventive) Hospital/Rehabilitation Programs Behavioral Treatment Interventional Procedures, Including: Neuro-blockade (nerve, facet, epidural space) Radiofrequency and cryolysis procedures Implantations and neurostimulation Others
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TABLE 13-7
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Routes of Delivery of Medications
Oral Nasal Spray (Sumatriptan/Zolmitriptan/DHE) Rectal (Neuroleptics, Indomethacin) Transdermal (Lidocaine) Parenteral Subcutaneous (sumatriptan/DHE) Intramuscular (DHE, ketorolac, diphenhydramine, hydroxyzine, neuroleptics, etc) Intravenous (DHE, ketorolac, valproic acid, steroids, magnesium sulfate, neuroleptics)
DHE = dihydroergotamine.
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[5-hydroxytryptamine (HT)1]) agonists that stimulate the 5-HT1 receptors to reduce neurogenic inflammation. The ergot derivatives are broader spectrum agents, affecting the serotoninergic receptors and also -adrenergic and dopamine receptors (and others). While many patients respond well to the triptans, others appear to require the broader influence of ergot derivatives. Experienced clinicians are adept at administering several of the triptans as well as the ergots. Short-acting triptans include almotriptan, sumatriptan, rizatriptan, zolmitriptan, and eletriptan, while naratriptan and frovatriptan have longer half-lives. Several delivery formats are available in addition to tablets: injection (sumatriptan), nasal spray (sumatriptan and zolmitriptan), and rapidly dissolving forms (zolmitriptan and rizatriptan). It is increasingly apparent that the triptans, and probably the ergot derivatives as well, should be administered to patients in the early phases of an ensuing headache attack in order to bring about maximum benefit and reduce the possibility of recurrence (the return of headache within the
same 24-hour period). Previous use of opioids may render a patient refractory to otherwise appropriate acute therapy (Jakubowski et al, 2005). Acute medications are sometimes used in conjunction with antinauseants and in combination with each other for maximum efficiency (do not combine ergots and triptans). Clinicians must be familiar with important contraindications and safety warnings of each of these medication groups as well as adverse effects and influence on hepatic metabolism, particularly when these drugs are used in combination with others. Finally, for reasons that are not fully understood but perhaps related to the cervical/trigeminal connections, occipital nerve blocks may relieve acute migraine and cluster attacks in some individuals. This method has historically been used by anesthesiologists but is increasingly employed by neurologists and others treating headache. Persistent benefit is rare, but shortterm relief is frequently seen. Repeat procedures are sometimes warranted. Combination treatments for acute headache are sometimes useful. Most frequently the triptans or the ergots are combined with NSAIDs, antihistamines, neuroleptics, or -adrenergic blockers (clonidine, tizanidine) (Saper et al, 1999b). Each of these complementary agents has the potential to provide relief in its own right. The clinician must be willing to consider a variety of treatments and treatment combinations for refractory acute headache. At times parenteral treatments are necessary to address intractable headache attacks. Preventive treatment of intractable (usually migraine) headache. Many agents are available for the prevention of migraine. However, the clinician must determine when preventive pharmacotherapy should be introduced. Table 13-8 lists certain
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KEY POINTS:
Points in Determining the Need for Preventive Treatment
TABLE 13-8
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Failure to respond adequately to acute medications
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Overuse of acute medications
A
Increasing disability from migraine headaches despite treatment
Risks from increasingly frequent headaches Acute medications are contraindicated
A
Patient preference, provided it is justified
conditions that can be used to make this determination. Preventive treatments have been extensively reviewed in an earlier chapter. This section will address these in the perspective of intractability. The categories of medications useful in prevention are listed in Table 13-9. A wide range of therapies is available,
TABLE 13-9
and increasingly useful are those that appear to work on one or more neurotransmitter systems. Several of these categories do not have influence over vasculature or blood flow, suggesting again that the primary pathogenesis of migraine seems more likely to involve neuronal rather than vascular dynamics.
Categories of Preventive Medications
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Tricyclic Antidepressants (Particularly Amitriptyline, Nortriptyline, and Doxepin)
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"-Adrenergic Blockers* (Particularly Propranolol,* Nadolol, Timolol*)
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Calcium Channel Blockers (Verapamil, Flunarizine**)
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Others
Anticonvulsants (Valproic Acid,* Gabapentin, Topiramate*) Ergot Derivatives (Methylergonovine and Methysergide*) Monoamine Oxidase Inhibitors (Phenelzine, etc) (for Refractory Cases)
Selective serotonin reuptake inhibitors Neuroleptics Tizanidine Botulinum toxin? Riboflavin *Indicates a category or drug approved by the US Food and Drug Administration for migraine/headache prevention. **Not available in the United States.
A
While many patients respond well to the triptans, others appear to require the broader influence of ergot derivatives. It is increasingly apparent that the triptans, and probably the ergot derivatives as well, be administered to patients in the early phases of an ensuing headache attack in order to bring about maximum benefit and reduce the possibility of recurrence (the return of headache within the same 24-hour period). Combination treatments for acute headache are sometimes useful. Most frequently the triptans or the ergots are combined with NSAIDs, antihistamines, neuroleptics, or -adrenergic blockers (clonidine, tizanidine). Each of these complementary agents has the potential to provide relief in its own right.
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KEY POINTS:
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Drug combinations may be essential in treating refractory cases where standard treatments are not available. Careful administration is essential, since many of these drugs have overlapping mechanisms and can lower seizure threshold, affect QT intervals, and have neurocognitive impact, particularly when used in combination. The presence of behavioral and/or other psychological disturbances can serve as barriers to effective treatment, or at least be a confounding factor.
The treatment of intractable headache is directed at the treatment of the daily or almost-daily pain as well as the acute episodic events. Because of the likely presence of a progressive course, medication overuse, and neuropsychiatric comorbidities in this population, a more comprehensive approach beyond medications alone is required. This includes cognitive-behavioral therapy, other forms of psychotherapy, and family therapy. With respect to medications, the tricyclic antidepressants and betablockers are well-established, first-line medications for preventive treatment of migraine in those patients who do not have contraindications or restrictions to either medication (Silberstein, 2000). Calcium channel blockers are generally not as effective. The anticonvulsants (neuromodulators) have considerable value and are increasingly popular in the treatment of intractable headache and the frequently present neuropsychiatric comorbidities. The multiple central mechanisms of drugs such as topiramate and others have gained recent attention as important drugs with a significant potential for cases of intractable headache, but the value of other anticonvulsants, including zonisamide, levetiracetam, and lamotrigine, await published outcome results. The selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are helpful for neuropsychiatric comorbidities, such as depression and panic and anxiety disorders, but generally do not have a strong antiheadache influence. Recently, venlafaxine has been shown to have preventive value in migraine (Ozyalcin et al, 2005). Some patients with migrainerelated headaches benefit from the antidopaminergic influence of the new neuroleptics, although the potential for adverse effects limits their widespread use (Silberstein et al, 2002). Tizanidine, an -adrenergic agonist, has been
shown effective in an adjunctive, preventive role (Saper et al, 2002). Botulinum toxin is increasingly administered for the prevention of difficult migraine cases. Numerous anecdotal reports and uncontrolled studies support efficacy, but a paucity of controlled data is available at this time to support efficacy convincingly. Recently, evidence has suggested a potential value in headache in the presence of analgesic overuse. If botulinum toxin is shown to work for migraine, it is likely to work through a central mechanism and not through a primary muscular influence. Drug combinations may be essential in treating refractory cases where standard treatments are not available. Careful administration is essential, since many of these drugs have overlapping mechanisms and can lower seizure threshold, affect QT intervals, and have neurocognitive impact, particularly when used in combination. The monoamine oxidase inhibitor phenelzine and perhaps others can be particularly helpful in intractable cases. They require patient education and compliance as well as expert knowledge by the physician prescribing the medications. Nonetheless, the use of phenelzine can be an important element in the effective treatment of some cases of intractability. The use of phenelzine together with amitriptyline, nortriptyline, and doxepin can be achieved safely, but careful attention to the details and methods of this combination therapy must be understood and practiced (Saper et al, 1999b). PSYCHOLOGICAL BARRIERS The presence of behavioral and/or other psychological disturbances can serve as barriers to effective treatment, or at least be a confounding factor. They may be primary or secondary to the pain illness itself. The presence of severe Axis I disorders and particularly
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the presence of Axis II cluster B personality disorders are troubling and distracting illnesses that often complicate an otherwise straightforward treatment approach to a headache condition. The problem patient is often characterized by features identified in Table 13-10. The clinician must distinguish between a challenging headache case versus a challenging patient who also has headaches. See the chapter ‘‘Behavioral Medicine for Chronic Headache: Overview and Practical Tools for the Practicing Physician’’ for a further discussion of behavioral issues related to headache. Pain has a powerful influence in a person’s life and relationships. Pain can control those around one and instill guilt, sympathy, and lessening of expectations as well as influence financial reward, disability status, avoidance of abandonment, and loss of relationships. In intractable cases, these possibilities must be considered and addressed when identified. The Personality Disorders Among the more confounding behavioral and psychological barriers are certain personality disorders (Table 13-11). The personality disorders that
TABLE 13-10
Selected Characteristics of the Problem Patient
" "
Drug overuse
" "
Somatization features
" "
Family dysfunction, enabling
Various forms, subtle and nonsubtle, of noncompliance
Anger/anxiety/‘‘unidentifiable spells’’
Formal Axis II diagnosis
KEY POINTS:
TABLE 13-11
" " " " " " " " " " "
Specific Personality Disorders
A
Paranoid Schizoid Schizotypal Antisocial Borderline Histrionic Narcissistic Avoidant Dependent Obsessive-compulsive Personality disorder, not otherwise specified
present the most challenging dilemmas during the treatment of headache are the borderline personality disorder and others in the cluster B category (borderline, narcissistic, sociopathic) (Saper and Lake, 2002). A personality disorder is an enduring pattern of inner experience and behavior that deviates significantly from the expectations of an individual’s culture and peer group, is pervasive and inflexible, and has an onset in adolescence or early adulthood. It is generally stable over time but can be exacerbated and intensified by life stressors. It leads to distress and impairment. There are ten specific personality disorders. (Please refer to the Diagnostic and Statistical Manual of Mental Disorders-Revised for detailed descriptions). The personality disorders are categorized in the Axis classification as Axis II diagnoses, which include personality disorders and mental retardation. Axis I disorders are generally those of the major psychiatric conditions, such as major depression, psychosis, etc. The presence of an Axis II disorder,
A
Pain has a powerful influence in a person’s life and relationships. Pain can control people around one, lessen expectations, influence financial reward, and prompt disability status. These possibilities must be considered and addressed when identified. Among the more confounding behavioral and psychological barriers are certain personality disorders. Those that present the most challenging dilemmas during the treatment of headache are the borderline personality disorder and others in the cluster B category (borderline, narcissistic, sociopathic).
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KEY POINTS:
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A
A
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Many patients with intractable primary headaches are trapped in a medicationmisuse cycle or are frankly opioid dependent. Some have addictive disease. Many of these cases are neither identifiable nor treatable on an outpatient basis. Both formal and informal programming in inpatient settings can provide value when treatment is ineffective on an outpatient basis. In many patients, progression of the condition appears evident after opioids are used. Most cases are initially refractory to appropriate treatment.
particularly cluster B, which includes borderline, narcissistic, and antisocial personality disorders, in a patient with headache reliably transforms even the most straightforward headache case into a supreme clinical ‘‘challenge.’’ In this author’s experience, patients with cluster B personality disorders may benefit in terms of headache and behavior from the administration of modulators, such as topiramate, lamotrigine, valproate, or lithium, together with a neuroleptic drug, in addition to other primary headache treatments. MORE AGGRESSIVE TREATMENT REQUIRED The office visit is but a snapshot of a patient’s life with limited potential to ‘‘know the patient’’ and understand what may be important dynamics that involve eating, sleeping, relationships, and habits that may influence treatment. Moreover, many patients with intractable primary headaches are trapped in a medication-misuse cycle or are frankly opioid dependent. Some have addictive disease. Many of these cases are neither identifiable nor treatable on an outpatient basis. Also, patients with intractable headache frequently require parenteral therapy to break the pain cycle and similarly benefit from the observations afforded by an intense treatment setting. In the author’s experience, the ability to see a patient day to day; administer medicines aggressively; better understand and treat misuse patterns; monitor around the clock; and observe sleeping patterns, eating patterns, and behaviors can in many instances unlock the basis for intractable headache and provide a foundation for effective treatment. Both formal and informal programming in inpatient settings can provide value when treatment is ineffective on an outpatient basis (Freitag et al, 2004; Lake et al, 2006; Lake et al, 1993; Saper et al, 1999a; Saper et al, 1999b).
The following are the criteria justifying admission to the hospital used at the Michigan Head Pain and Neurological Institute (Saper et al, 1999a; Saper et al, 1999b): (1) Moderate to severe intractable headache, failing to respond to appropriate and aggressive outpatient or emergency department services and requiring repetitive, sustained, parenteral treatment (2) The presence of continuing nausea, vomiting, and diarrhea (3) The need to detoxify and treat toxicity, dependency, or rebound phenomena and the requirement for close monitoring for withdrawal symptoms, including seizures (4) The presence of dehydration, electrolyte imbalance, and prostration, requiring monitoring and IV fluids for the presence of unstable vital signs (5) The presence of repeated, previous emergency department treatments (6) The presence of serious concurrent disease (eg, subarachnoid hemorrhage, intracranial infection, cerebral ischemia, severe hypertension or hypotension) (7) The need to simultaneously develop an effective pharmacological prophylaxis in order to sustain improvement achieved by parenteral therapy (8) To acutely address other comorbid conditions contributing to or accompanying the headache, including medical or psychological illness (9) Concurrent medical and/or psychological illness requiring careful monitoring in high-risk situations (ie, severe hypotension, coronary artery disease, etc)
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Table 13-12 identifies the principles of inpatient care for headache. The duration of hospitalization varies, depending upon the intensity and type of medication that has been overused and requires discontinuation, the amount of pain and its duration during the weaning process, the behavioral issues that emerge, and the confounding factors that are often present in patients with these symptoms. Developing a preventive treatment during this time is difficult since medications take time to work and because, generally, patients are in a refractory period that may last up to months after discontinuation of the offending agents. A variety of parenteral agents can be used during hospitalization to control painful symptoms, particularly during rebound withdrawal. Table 13-13 lists several of these (Case 13-5). PRIOR AND CURRENT USE OF OPIOIDS The use of opioids for nonmalignant cancer pain has increased dramatically over the past decade, prompted by a variety of influences, but without, in this author’s view, substantial data to justify the extent to which administration of opioids has occurred. The author and his colleagues have received a dramatically increased number of referrals of patients who have been using high doses of opioids. In many patients whom the author has personally evaluated, it seems that headache events occurred more frequently and more intensely than prior to the use of these medications and that progression of the condition appeared evident. Most of these patients have become refractory to appropriate treatment, some perhaps as a basis for using opioids and some as a consequence of using them. The evidence supporting the use of preventive opioids (as distinct from
symptomatic, rescue use) in headache is limited. No data currently exist that support long-term use of daily opioids in patients with intractable headache. This author and his colleagues undertook a long-term observational study to review the use of opioids in their center (Saper et al, 2004). Approximately 25% of patients benefited from the use of opioids, but subsequently collateral information suggested that no more than 10% to 15% of patients were helped by such treatment. This means that 85% of patients failed chronic opioid therapy. Approximately 50% of those maintained on opioids demonstrated noncompliant drugrelated behavior. Despite reports of pain reduction, a major improvement in function was not noted in a significant percentage of patients who nonetheless reported improvement. The occasional and limited use of opioids in acute situations when other treatments are contraindicated or clearly fail seems appropriate. Recently Saper and Lake (2006) have proposed criteria for opioid use in headache patients. Nonetheless, as noted earlier, Burstein and colleagues’ recent work (Jakubowski et al, 2005), together with the experience of many
TABLE 13-12
KEY POINT:
A
In one observational study, approximately 25% of patients with intractable headache benefited from the use of opioids, but subsequently collateral information suggested that no more than 10% to 15% of patients were helped by such treatment.
Principles of Inpatient Care
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Interrupt daily/intractable headache pain with parenteral protocols (see Table 13-13)
" " " "
Discontinue offending analgesics if rebound is present
" " "
Employ interventional modalities when indicated
Implement preventive pharmacotherapy Identify effective abortive therapy Identify and treat behavioral and neuropsychiatric comorbidities
Educate the patient Establish discharge and follow-up plan
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A
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Recent work, together with the experience of many experts, raises concern that even occasional previous use of opioids may render future acute treatment ineffective or at least less effective for an uncertain period of time. Patients who do not respond to standard treatment should be referred to specialists and/or centers where more comprehensive and advanced treatment regimens can be imposed, where cryptogenic medication misuse can be identified and effectively treated, and where psychological influences on headache treatment refractoriness can be most effectively addressed.
TABLE 13-13
Parenteral Regimens to Treat Intractable Headaches
" " "
Dihydroergotamine (0.25 mg to 1.0 mg IV or IM, tid)
" " " " "
Ketorolac (10 mg IV, tid; 30 mg IM, tid)
Diphenhydramine (25 mg to 50 mg IV or IM, tid) (Swidan et al, 2005) Various neuroleptics (ie, chlorpromazine 2.5 mg to 10.0 mg IV, tid, droperidol (0.325 mg to 2.5 mg IV tid)
Valproic acid (250 mg to 750 mg IV, tid) Magnesium sulfate (1 g IV, bid) Hydrocortisone (100 mg tid for 3 days) Sumatriptan (6 mg subcutaneous, cannot use more than 2 days per week)
IV = intravenous; IM = intramuscular; tid = 3 times a day; bid = 2 times a day. From Saper JR, Silberstein SD, Gordon CD, et al. Handbook of headache management: a practical guide to diagnosis and treatment of head, neck, and facial pain. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999b. Swidan SZ, Lake AE 3rd, Saper JR. Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. Curr Pain Headache Rep 2005;9:65–70.
experts, raises concern that even occasional previous use of opioids may render future acute treatment ineffective or at least less effective for an uncertain period of time. Although the author’s experience and outcome results discourage the use of opioids in this population, if opioids are used, they should be used with significant restriction and limitation, as well as careful monitoring. Sustained daily opioid administration should be avoided and considered in only limited circumstances. It is this author’s personal belief that sustained opioid therapy for intractable headache should not be started on a primary care level. Patients who do not respond to standard treatment should be referred to specialists and/or centers where more comprehensive and advanced treatment regimens can be imposed, where cryptogenic medication misuse can be identified and effectively treated, and where psychological influences on headache treatment refractoriness can be most effectively addressed.
Except in elderly persons or during pregnancy, patients should demonstrate refractoriness to advanced, aggressive, expert-delivered treatments prior to administration of opioids. Use of opioids in the treatment of headache should be restricted and clearly and carefully monitored. Physicians who administer opioids must be prepared to monitor usage and discontinue them when clinically indicated. Unfortunately, this is not always the case. Many patients placed on opioids appear to have psychological and personality features that were influential in persuading the physician to use the medications (Saper et al, 2005). INTERVENTIONAL THERAPY Previously in this chapter the use of various forms of interventional treatment, particularly at the cervical level, has been discussed. Occipital nerve blocks and cervical interventions sometimes provide both acute relief as well as sustained benefit in patients with intractable headache. Currently,
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Case 13-5 A 25-year-old woman began experiencing headaches during her menstrual periods at age 14. Over time her headaches increased in frequency and intensity, concurrent with acquisition of increasing amounts of medications, including naproxen, isometheptene plus dichloralphenazone plus acetaminophen (Midrin), meperidine, barbiturate-containing analgesics, and eventually long-acting oxycodone. Progressive depression and social withdrawal occurred. When she is referred to a neurologist for examination, the patient is noted to be using several different opioid medications and other analgesics, having obtained these from several different physicians. The long-acting oxycodone preparation was being used to a maximum dose of 320 mg/d. Her medical history is without significant illness. A variety of previous treatments for headache have been ineffective. These include valproic acid, topiramate, beta-blockers, tricyclic antidepressants, methysergide, indomethacin, and gabapentin. Neurological examination is normal, except for her being depressed, angry, and reluctantly cooperative. MRI, magnetic resonance venography, and magnetic resonance angiography show no intracranial pathology. The patient is hospitalized. A reduction of opioid medication occurs using long-acting oxycodone, clonazepam, and clonidine over a period of 10 days. IV protocols consist of chlorpromazine, diphenhydramine, and magnesium sulfate. Behavioral defiance and disruptive, noncompliant behavior occur during detoxification and beyond. Eventually topiramate 25 mg every morning and 75 mg every afternoon, nortriptyline 50 mg at bedtime, and quetiapine 50 mg every morning and 50 mg at bedtime are administered. Indomethacin suppositories, an oral triptan, and tizanidine 4 mg 3 times a day are used as needed for pain control. Only modest benefit is achieved. The patient’s behavior improves following detoxification, but she remains angry and demanding. She is diagnosed as suffering from borderline personality disorder. Long-term therapy with frequent medical visits and psychotherapy is planned following discharge. Upon discharge, the patient reports only modest pain control, but her mood is improved, and she seems willing to maintain her written contract to avoid opioids. Outpatient treatment is continued for several months and results in slow but definite improvement in mood and pain. Then, unexpectedly, the patient cancels all visits and is lost to follow-up. Comment. This case represents an all-too-frequent encounter in headache treatment settings. Progressive headache accompanied by high-dose daily administration of opioids and other analgesics in a patient with behavioral illness poses major clinical challenges. Several qualified physicians had participated in this woman’s care, and many had administered medications before she voluntarily discontinued treatment with the physicians. Treatment strategies include detoxification and drug transition, the use of preventive treatments, some of which might address the behavioral disturbances, and symptomatic treatments for acute breakthrough headache. Many authorities believe that prolonged use of opioids renders the patient refractory to standard preventive treatments for months or longer following discontinuation. Immediate recovery is unlikely, and significant pain reduction generally requires weeks to months. A commitment by patients and their referring physicians to maintain a long period of opioid avoidance is required. Behavioral therapies focusing on Axis II issues are necessary to address what are often barriers to effective treatment and lack of cooperation. Although this woman appeared to be making some progress, she suddenly dropped out of treatment and was lost to follow-up. Patient motivation to improvement and commitment to the treatment strategy are essential elements to successful outcome.
guidelines and appropriate standards do not exist, but many headache centers often employ these treatments
as complementary to the other approaches to the patient with intractable headache (Case 13-6).
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KEY POINTS:
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A
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Use of opioids in the treatment of headache should be restricted and clearly and carefully monitored. Physicians who administer opioids must be prepared to monitor usage and discontinue them when clinically indicated. Unresponsiveness to even the most advanced and aggressive treatment is not generally the result of patients’ behavior or their psychological makeup, nor is it likely the result of obvious failure of physicians to properly diagnose or treat the condition at hand. There is much more to learn and to define than the current state of science allows.
BEYOND CURRENT SCIENTIFIC UNDERSTANDING In time, medical scientists may ascertain that some, and perhaps most, cases of refractory headache are the result of physiological events and circumstances that are beyond our current understanding and treatment. While it is easy to attribute failure to respond to treatment as the result of psychological barriers or behaviors, this is unlikely in most instances. Although psychological and behavioral issues can be very important and serve as barriers, concluding that such is the case should be restrained and only assigned when behavior is evident
and clearly obstructive. Unresponsiveness to even the most advanced and aggressive treatment is not generally the result of patients’ behavior or their psychological makeup, nor is it likely the result of obvious failure of physicians to properly diagnose or treat the condition at hand. There is much more to learn and to define than the current state of science allows.
SUMMARY Treatment of intractable headache is an important challenge. The clinician must confront all previous assumptions. Challenging and rethinking every
Case 13-6 A 25-year-old woman was involved in a motor vehicle accident 1 year earlier, during which she struck her right parietal cranium on the door frame. Momentary dizziness without loss of consciousness was reported. Subsequently the patient reported right occipitocervical pain with neck stiffness and limitation of motion. Neck movement worsened the pain. Examination shows normal cognition, head pain worsened by lateral neck movement, and cervical facet tenderness at the C2-C3 level. Hypesthesia to pinprick occurs in the posterior cranium along the C2-C3 distribution of the greater occipital nerve. MRI of the C-spine is interpreted as showing normal results. Conservative treatment with analgesics, NSAIDs, and tricyclic antidepressants is administered without benefit. Physical therapy increases the pain. Blockade of the cranial portion of the greater occipital nerve brings modest and unsustained pain relief. Trials of nortriptyline, propranolol, gabapentin, and carbamazepine are without benefit. The patient undergoes C2-C3 facet joint blockade under fluoroscopy. Pain reduction of 70% is noted for 2 days. A second blockade confirms the results. The patient then undergoes radiofrequency ganglio-rhizolysis at C2-C3 facet joint capsule on the right with significant relief for 4 to 6 months before the pain returns. A right C2-C3 facet blockade under fluoroscopic guidance is again undertaken. Complete pain relief is sustained, and pain did not return during the follow-up period. Comment. The initial injury apparently traumatized the upper facets, producing characteristic neck pain and limitation of motion. Headache is common in such a situation. Conservative therapy was only modestly beneficial. Facet joint blockade and eventually radiofrequency ganglio-rhizolysis were effective with sustained benefit for up to 4 to 6 months. A repeat, simple blockade apparently quieted the painful recurrence, since it brought sustained benefit during the many months of subsequent follow-up.
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TABLE 13-14
" " " " " " " " " "
Principles in the Approach to Patients With Refractory Headache
Take more history Do more testing; repeat previous testing when appropriate Re-establish the principal diagnoses Review the possibility of medication overuse Reconsider past and future treatment options and combinations Employ creative use of medications and combinations Identify and treat psychological barriers Consider hospitalization and more aggressive treatment Consider interventional treatment Make strategically appropriate referrals
case again and again can be helpful. Table 13-14 summarizes key considerations in the approach to patients with intractable headache. When faced with absolute refractoriness, physicians should strongly consider referring that
patient to a more advanced level of care for headache and comprehensive treatment facilities where a broader range of services and diagnostic considerations can be brought to the possible benefit of the patient.
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MEDICATION OVERUSE HEADACHE Fred D. Sheftell, Marcelo E. Bigal
ABSTRACT
KEY POINT:
A
Most of the time, medication overuse happens in the context of subjects with daily or almost-daily headaches.
Medication overuse headache is considered to be the result of an interaction between an exposure (overuse of analgesics) and a biologically vulnerable individual (migraineur). Several lines of evidence suggest that in migraineurs, but not individuals without migraine, medication overuse is a risk factor for chronic daily headaches. Therefore, medication overuse headache should be prevented. In individuals with already established daily headaches and medication overuse, treatment requires a comprehensive plan that includes education, establishment of realistic goal, detoxification, and aggressive nonpharmacological and pharmacological preventive strategies.
INTRODUCTION Medication overuse headache has been referred to in the literature as ‘‘analgesic’’ or simply ‘‘rebound’’ headache. A variety of terms commonly used have included drug-induced headache, medicationwithdrawal headache, as well as others (Mathew, 1998; Mathew, 1990; Rapoport et al, 1996; Rapoport et al, 1986; Saper, 1989; Saper, 1987). These terms refer to the well-observed and well-studied phenomenon that any type of acute antimigraine or nonspecific analgesic medications may worsen and perpetuate headaches when used excessively. Most of the time, medication overuse happens in the context of subjects with daily or almost-daily headaches. Several lines of evidence, both historically and in the recent literature as well, indicate the importance of medication overuse as a risk factor for the development of chronic daily headaches (Capobianco et al, 2001; Kudrow, 1982; Micieli et al, 1988). Furthermore, clinical observation suggests that medication overuse is associated with chronic
daily headache and that it can render headache refractory to both pharmacological and nonpharmacological prophylactic regimens and reduce the efficacy of acute migraine-specific agents (triptans). In clinical practice, causal attribution is sometimes difficult because, in addition to withdrawal, medication overuse headache is usually simultaneously treated with other pharmacological and behavioral interventions (Martignoni and Solomon, 1993; Micieli et al, 1988). However, medication withdrawal has been demonstrated to cause headache in a well-controlled trial of caffeine (Silverman et al, 1992). Kudrow showed reversion to intermittent headache in a subgroup that was simply withdrawn from the offending acute agent without other pharmacological or nonpharmacological intervention, thus making a case for causality or at least perpetuation of chronic daily headache in the face of medication overuse. His was the first prospective study to suggest that medication overuse was a driver
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According to the International Classification of Headache Disorders, Second Edition (ICHD-II), medication overuse headache happens as an interaction between a therapeutic agent used excessively and a susceptible patient. In the United States, up to 80% of the patients seen in a headache clinic have medication overuse headache.
of chronic daily headache and that the efficacy of prophylactic medication was mitigated by this phenomenon (Kudrow, 1982). Also, medication overuse is associated with chronic daily headache in the population after adjusting for confounders (Scher et al, 2003). On the other hand, it is possible that in some patients medication overuse is a consequence, not a cause, of chronic daily headache (Dodick, 2002). According to the International Classification of Headache Disorders, Second Edition (ICHD-II) (2004), medication overuse headache happens as an interaction between a therapeutic agent used excessively and a susceptible patient. This chapter discusses the importance of medication overuse headache. The clinical features of the syndrome, as well as the controversy regarding whether medication overuse headache is a cause or merely a consequence of chronic pain, will be considered. The chapter will conclude with a discussion of the basis of treatment, and the authors’ personal approaches, observations, and clinical experiences will be discussed. SETTING THE SCENE—THE IMPORTANCE OF MEDICATION OVERUSE HEADACHE Frequent use of analgesic medication is a common finding in population studies. It has been estimated that nearly 4.4% of the men and almost 7% of the women in Switzerland use analgesics at least once a week, and more than 2% use them daily (Gutzwiller et al, 1985). In Germany, about 1% of the population uses analgesics on a daily basis (Schwartz et al, 1985). Additionally, epidemiological studies have shown that approximately 4% of the individuals in the population have chronic daily headache, and around 30% of them overuse acute medication, which suggests a prevalence of medication
overuse headache of about 1% in the population (Castillo et al, 1999; Dodick, 2002; Gutzwiller et al, 1985; Headache Classification Subcommittee of the International Headache Society, 2004; Scher et al, 2003; Schwartz et al, 1985). The prevalence of medication overuse headache is, however, much higher in neurology and headache clinics. In Europe, up to 10% of the patients presenting in a headache clinic have this diagnosis, although according to Dowson and colleagues (2005) this is most likely an underestimation of the problem. In the United States, up to 80% of the patients seen in a headache clinic have medication overuse headache (Mathew et al, 1990). In the authors’ center, 84% of the subjects seen in 2001 had chronic daily headache, and 76% of them were also overusing acute medications (Bigal et al, 2004). ACUTE MEDICATION OVERUSE— CAUSE OR CONSEQUENCE OF CHRONIC DAILY HEADACHE? A number of issues regarding medication overuse headache evoke controversy. Is overuse a significant factor in transforming episodic migraine into chronic daily headache (Tepper, 2002)? Or is the frequently observed overuse merely a response to chronic pain itself (Dodick, 2002)? In a large, longitudinal, population-based study assessing the relationship between acute medication overuse and chronic daily headache, as well as with other chronic pain syndromes, Zwart and colleagues (2004) evaluated analgesic use in 32,067 adults in 1984 and 1985 and again 11 years later. Subjects who used analgesics daily or weekly at baseline had higher risk of developing chronic migraine (relative risk [RR] = 13.3), chronic nonmigrainous headache (RR = 6.2), and chronic neck pain (RR = 2.4) at follow-up. The authors concluded that overuse
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of analgesics predicted the development of chronic daily headache. In this study, information on medication overuse was collected at baseline and at follow-up. However, because the authors did not collect information on the headache status at baseline, they could not exclude the possibility that frequent analgesic use was simply a marker for frequent headache. Nor could they determine whether baseline headache type predicted the development of chronic daily headache (Lipton and Bigal, 2003). The findings, conclusions, and limitations of this study exemplify the controversy regarding medication overuse as a cause or a consequence of chronic daily headache. Because the association with medication overuse was stronger for chronic daily headache than for other pain disorders, the Zwart study suggests that the association between analgesic use and chronic daily headache is not causal. Additionally, although medication rebound (worsening of the pain pattern after discontinuation of the offending analgesic) has not been demonstrated in placebocontrolled trials, withdrawal headache has been shown to occur in a controlled trial of caffeine withdrawal (Silverman et al, 1992). Furthermore, both preventive and acute care treatment for the primary headache usually fail if the offending medication or medications are not terminated (see below). Two studies significantly helped in the current understanding of medication overuse headache. First, Wilkinson and colleagues (2001) looked for chronic daily headache in 28 patients who underwent total colectomy for ulcerative colitis. All patients with a previous history of migraine who overused opiates developed chronic daily headache (19%), whereas no patient without migraine who overused opiates did so. In a second study, Bahra and colleagues
(2003) found that when nonsteroidal anti-inflammatory drugs (NSAIDs) are used daily in large doses for medical conditions such as rheumatoid arthritis, they do not induce chronic daily headache in subjects who have no preexisting primary headache disorders. However, in those with preexisting migraine, NSAIDs were a strong risk factor for chronic daily headache. Both studies established two principles of medication overuse headache: (1) Even when the overused medication is used for reasons other than headache, it may still be associated with the development of chronic daily headache; and (2) acute medication overuse induces chronic daily headache only in those predisposed (ie, those with preexisting episodic migraine). Favoring the hypothesis that medication overuse may be a consequence rather than a cause of chronic daily headache is the observation that some patients with chronic daily headache do not improve after medication withdrawal (Relja et al, 2004). Furthermore, some subjects clearly report that the increase in headache frequency preceded the overuse of medication. Also, population and clinical studies show that high frequency of attacks is, per se, a risk factor for transformation and consequent overuse of medication (Scher et al, 2003). Finally, in the population, medication overuse is not the most important risk factor associated with migraine transformation (Scher et al, 2003). The controversy about analgesic overuse as a cause or consequence of migraine chronicity is far from over, and these viewpoints may not be mutually exclusive. It is possible and very likely that in some individuals medication overuse is the risk factor for migraine’s becoming chronic; in others it may be merely a response to an already refractory headache syndrome. In either case the clinical take-home message is that
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Patients who used analgesics daily or weekly at baseline had higher risk of developing chronic migraine, chronic nonmigrainous headache, and chronic neck pain at follow-up. Investigators concluded that overuse of analgesics predicted the development of chronic daily headache. Even when the overused medication is used for reasons other than headache, it may still be associated with the development of chronic daily headache. Acute medication overuse induces chronic daily headache only in patients predisposed (ie, those with preexisting episodic migraine).
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Favoring the hypothesis that medication overuse may be a consequence rather than a cause of chronic daily headache is the observation that some patients with chronic daily headache do not improve after medication withdrawal. It is possible and very likely that in some individuals medication overuse is the risk factor for migraine’s becoming chronic; in others it is merely a response to an already refractory headache syndrome. In either case, the clinical take-home message is that medication must be withdrawn in order for improvement to occur.
medication must be withdrawn in order for improvement to occur. CLASSIFICATION AND CLINICAL FEATURES ICHD-II Classification The ICHD-II classifies medication overuse headache under chapter 8 (headache attributed to a substance or its withdrawal), topic 8.2 (medication overuse headache). Medication overuse headache is subdivided into seven groups, plus an additional topic for probable medication overuse headache (Headache Classification Subcommittee of the International Headache Society, 2004; Silberstein et al, 2005).
TABLE 8-1
ICHD-II Code
The diagnostic criteria and the critical amount of consumption of medication are displayed in Table 8-1. According to the ICHD-II, a diagnosis of medication overuse headache is basically established when three situations are fulfilled: (1) The consumption of acute medication is beyond a critical dose. (2) Patients have headaches on more days than not. (3) Secondary disorders that may explain the headache are excluded either clinically or through subsidiary investigation. The ICHD-II does not suggest that subsidiary investigation is required in all cases but requires that, at least clinically, the provider exclude secondary disorders other than medication overuse.
Classification of the Medication Overuse Subtypes According to the International Classification of Headache Disorders, 2nd Edition
Diagnosis
Amount of Medication
8.1
Ergotamine overuse headache
Ergotamine intake on 10 days per month on a regular basis for >3 months
8.2
Triptan overuse headache
Triptan intake (any formulation) on 10 days per month on a regular basis for >3 months
8.3
Analgesic overuse headache
Intake of simple analgesics on 15 days per month on a regular basis for >3 months
8.4
Opioid overuse headache
Opioid intake on 10 days per month on a regular basis for >3 months
8.5
Combination analgesic overuse headache
Intake of combination analgesic medications on 10 days per month on a regular basis for >3 months
8.6
Medication overuse headache attributed to combination of acute medications
Intake of any combination of ergotamine, triptans, analgesics, and/or opioids on 10 days per month on a regular basis for >3 months without overuse of any single class
8.7
Headache attributed to other medication overuse
Regular overuse for >3 months of a medication other than those described above
8.8
Probable medication overuse headache
Medication overuse has ceased within the last 2 months but headache has not so far resolved or has reverted to its previous pattern
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Medications Frequently Associated With Medication Overuse Headache In a study conducted in the authors’ center, medication intake in subjects with medication overuse headache ranged from three tablets per week to 30 per day (mean = 5.2 per day). More than 10% of patients consumed more than 10 pills per day, and 4.4% of the patients took more than 15 pills per day. The majority of patients were overusing one (35.1%) or two (36.8%) substances other than caffeine, but 31.6% were overusing three or more. Investigators contrasted the medications involved in overuse, comparing patients whose first visit was more than 5 years before the study (before 1996) with those whose first visit was between 1996 and 2001. The drugs more frequently associated with acute care medication overuse, butalbital, acetaminophen, and opioids, remained the same during both periods of time. There were statistically significant reductions in NSAIDs (25.1% versus 10.1%, P<.0001), aspirin (31.7% versus 17.9%, P=.0008), ergot compounds (19.5% versus 10.5%, P=.01), and significant increase in the overuse of sumatriptan (3.0% versus 10.5%, P= .001) over time (Bigal et al, 2004). In a more recent study, Relja and colleagues (2004) found similar results. Most patients with chronic daily headache and medication overuse were overusing analgesics combined with barbiturates or other nonnarcotic substances (39.5%), simple analgesics (38.6%), triptans (11.4%), and ergotamine (10.5%). Refining the Clinical Picture: Time to the Development and Phenotype of Medication Overuse Headache Associated With Different Substances The clinical features and time to induce/ detoxify the different substances are
not the same. Diener and Katsarava (2001), using individual studies plus meta-analysis, found that the time required for the development of chronic daily headache was approximately 5 years of exposure to medication and a history of primary headache for 10 years prior to the development of chronic daily headache. A patient develops chronic daily headache, according to Diener and Katsarava, after consuming a critical dose of a single medication or a combination of medications for an extended period of time, which is shortest for triptans (1 to 2 years), longer for ergots (3 years), and longest for analgesics (5 years) (Limmroth et al, 2002). In a prospective study by Limmroth and colleagues (2002), patients overusing ergots and analgesics typically had a daily tension-type headache; patients with triptan-induced medication overuse headache were more likely to describe a (daily) migrainelike headache or an increase in migraine frequency. The authors concluded that the clinical features of medication overuse headache depend on the type of overused headache medication (Katsarava et al, 2005). The same group found a relapse rate of 38% 1 year after detoxification. The rate was similar for patients overusing triptans and ergots (19% versus 20%, [not significant]) and lower for triptans versus analgesics (19% versus 58%, P<.001) (Katsarava et al, 2004). The findings discussed above allow the following conclusions: (1) The phenotype of medication overuse headache is not uniform. It can resemble migraine, tension-type headache, or a combination of both. (2) Time to induce medication overuse headache is shorter for triptans and longer for NSAIDs. (3) The withdrawal period is shorter for triptans than for NSAIDs. (4) The relapse rate is lower for triptans than for analgesics.
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Most patients with chronic daily headache and medication overuse are overusing analgesics combined with barbiturates or other nonnarcotic substances (39.5%), simple analgesics (38.6%), triptans (11.4%), and ergotamine (10.5%). A patient develops chronic daily headache after consuming a critical dose of a single medication or a combination of medications for an extended period of time, which is shortest for triptans (1 to 2 years), longer for ergots (3 years), and longest for analgesics (5 years).
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The clinical features of medication overuse headache depend on the type of overused headache medication. The relapse rate is similar for patients overusing triptans and ergots and lower for triptans versus analgesics. The phenotype of medication overuse headache is not uniform. It can resemble migraine, tension-type headache, or a combination of both. Time to induce medication overuse headache is shorter for triptans and longer for NSAIDs.
TREATMENT A combination of pharmacological, nonpharmacological, behavioral, and sometimes physical interventions is usually necessary for a favorable outcome in medication overuse headache (Dowson et al, 2005; Limmroth et al, 2002; Mathew et al, 1990). Support programs and behavioral medicine techniques play an important role in ensuring treatment plan success (Penzien et al, 2005). However, the most essential feature of an effective treatment regimen is discontinuation of medication overuse (Case 8-1). If the offending medication is not discontinued, all other strategies usually fail. This is exemplified by a study where outcomes were compared after 1 year of followup of patients successfully detoxified at baseline (Bigal et al, 2004). Of 456 patients with medication overuse headache, 318 (69.7%) were successfully detoxified (group 1), and 138 (30.3%) were not (group 2). All subjects were seen in the same practice over the same period of time. All other steps of treatment (preventive medication, rescue medication, nonpharmacological techniques) were the same. The comparison between groups after 1 year of follow-up showed a decrease in the frequency of headache on the order of 73.7% in those who stopped the offending medication and only 17.2% in those who did not (P<.0001). Similarly, the duration of head pain was reduced by 61.2% in group 1 and only 14.8% in group 2 (P<.0001). The headache score (severity multiplied by duration) after 1 year was 18.8 in group 1 and 54 in group 2 (P<.0001) (Figure 8-1). A total of 225 (70.7%) successfully detoxified subjects returned to an episodic pattern of migraine, compared with just 21 (15.3%) who continued to overuse medication (P<.001). The other steps of the multimodal management of medication overuse
headache are essentially the same as for chronic daily headache without overuse and are covered under a separate chapter of this issue of . Therefore, the following section will focus on strategies to ‘‘bridge’’ patients with medication overuse headache from daily or frequent use of acute agents to intermittent use. Most of these strategies are based on the authors’ personal experience rather than on formal evidence and prospective data. Outpatient Setting Patients who can usually be successfully treated as outpatients include those who (Sheftell et al, 2004): o Understand the concept of medication overuse headache and its consequences in terms of prognosis o Are motivated to participate and follow the regimens prescribed o Are willing to take an active role in their treatment, including keeping headache calendars o Understand that they will initially worsen before they improve o Have no psychiatric comorbidity that will prevent outpatient participation o Have support of family or friends and their workplace Basically, three non–mutually exclusive outpatient approaches to ‘‘bridge’’ from frequent daily use to intermittent use are used. (Note: The authors prefer the term ‘‘bridge therapy’’ to ‘‘detoxification’’ because the latter connotes patterns of addiction or substance abuse, which are rarely present.) This approach involves tapering the overused medication gradually while an effective preventive therapy is established. Another approach is to abruptly discontinue the overused drug, institute a transitional medication or medication bridge to break the cycle of headache, and subsequently taper the transitional
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Case 8-1 A 31-year-old married woman, who has had two pregnancies and two live-birth deliveries and is a marketing executive, presented with a history of daily headaches that had been unresponsive to a wide variety of acute and preventive strategies. Her headaches are causing greater interference with her activities, increasing absenteeism from work, decreasing abilities to care for her family, and frequent cancellation of social engagements. She described daily mild to moderate headache that is bifrontal in location, throbbing in nature, with mild sensitivity to light and sound, and accompanied by mild nausea. Several times a week the pain increases in severity, more severe in one side than in the other (usually in either orbit), accompanied by increased intensity of associated symptoms, including severe nausea and occasional emesis, often resulting in disability and requiring retreat to a dark and quiet environment and bedrest when possible. She noted that her pain is worse around menses. Triggers include alcohol, menses, and odors (especially perfume and cigarette smoke). She is taking a combination of aspirin, acetaminophen, and caffeine at two tablets 4 to 6 times per day, which helps ‘‘to take the edge off’’ at best. Her doctor had given her samples of several triptans and advised her to find out ‘‘which worked best.’’ None was very helpful. Neurological and general examinations are normal. She reports difficulty with sleep onset and maintenance and is becoming more hopeless about her headaches. Magnetic resonance imaging with contrast is unremarkable, as is a computed tomographic scan of her sinuses. Medical history reveals that her unilateral orbital headaches had begun around puberty and would usually, but not always, occur around her menses. They began to increase in frequency toward the end of high school and again in college. She became so fearful of attacks that she often tried to preempt episodes by medicating with an over-the-counter treatment in the absence of pain. After college, this escalation continued and eventually evolved to her current frequency of headache and medication overuse. While several preventive medications had been tried, none had been tried in the absence of her acute medications. In fact, she could not recall skipping days of her over-the-counter medication use for at least the past 5 years except for both her pregnancies, when she did note a major decrease in her headaches during the second two trimesters of each. She has become increasingly concerned that she will have to live with these headaches for the rest of her life. The following diagnosis is made: (1) ICHD-II criteria: probable chronic migraine, probable medication overuse headache; (2) Silberstein-Lipton criteria: transformed migraine associated with medication overuse. The patient is educated in regard to the issues related to rebound and the necessity of discontinuing the over-the-counter medication. She is told that no improvement will occur in the face of ongoing use and that she will worsen before she improves. She is informed that the vast majority of evidence confirms improvement with discontinuation of medication overuse. She is commended for her ability to remain as functional as possible despite the daily headache. She is given calendars to record frequency, intensity, and duration of headaches along with possible trigger factors, including menses and others. Specific instructions for this transitional period include discontinuing her over-the-counter medication, substituting a 100-mg caffeine preparation for her usual caffeinated beverages, tapering by 100 mg to 150 mg every 2 to 3 days from her initial daily intake of 1200 mg. She is to take meclofenamate (NSAID) 100 mg tid with food and decrease by one tablet every 7 days and then stop. (Alternatives include long-acting triptan tapers, steroid tapers, and dihydroergotamine nasal spray tapers). She is instructed to use no medication for mild to moderate headache during this time except for menses. (Note: this is the only time during this phase when early intervention with a triptan is allowed). She is given a rapidly acting triptan tablet to take for severe episodes, especially when the headache is localizing to continued on page 160
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Continued from page 159 one orbit. (Migraine-specific nasal sprays or injections may be necessary for episodes associated with emesis.) She is given topiramate 25 mg and told to increase her daily dose by one tablet per week to 100 mg. Several supplements, such as riboflavin 50 mg, coenzyme Q10, and magnesium oxide 400 mg are also given on a daily basis. Her husband is included in the consultation and educational process. Finally, she is referred for nonpharmacological therapy in the form of cognitive behavioral therapy, including biofeedback, to help support her during this time and to address issues related to possible comorbid depression and/or anxiety often found in patients with chronic daily headache. Comment. If the patient had presented with mixed butalbital overuse, the treatment would have been similar except that the mixed butalbital agent would have been tapered slowly or phenobarbital would have been substituted for the short-acting butalbital. If opiates had been involved, again a similar taper with the opiate and possibly the addition of clonidine would have been employed. Over time, specific triggers such as menses are addressed with gradual refinement and focus on these issues and appropriate modification of strategies. This case illustrates the following key points: (1) The patient started with a history of intermittent migraine. (2) Chronic daily headache is associated with medication overuse headache in the majority of patients presenting for care. (3) Preventive strategies are mitigated by medication overuse headache. (4) Education and headache calendars are key factors. (5) The majority of patients revert to intermittent headache once the offending drug is discontinued.
medication. The third approach is to combine the two strategies by eliminating the rebound medication rapidly, adding a preventive medication rapidly,
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FIGURE 8-1
Evolution of the headache score. Comparison between group 1 (persisted without overuse medication) and group 2 (continued or restarted overused medication).
* = P<.0001 compared with the baseline period. y = P<.0001 compared with the follow-up period of group 2. z = P<.05 compared with the baseline period.
and also supplying a temporary bridge to give the patient the maximum chance to improve without drastically worsening first (Gladstone et al, 2003; Krymchantowski and Moreira, 2003; Sheftell et al, 2004). Generally, ergots, nonopioids, and triptans can be abruptly discontinued in some people. On the other hand, opioids, barbiturates, and benzodiazepines are usually withdrawn slowly, perhaps over 2 weeks or more, depending on duration of use. Serious withdrawal syndromes, due to rapid discontinuation of certain medications, must be prevented. Tapering Strategies In the following section some strategies, based on the available evidence
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and extensive clinical experience, for tapering commonly overused substances and medications will be described. The general idea is to move from the patient’s pattern of medicating continuously on a pain-contingent basis to a scheduled taper. One must avoid medicating at mild to moderate intensities during this phase and use migraine-specific medications (triptans, dihydroergotamine, ergotamine tartrate) only for severe headache and limited to 2 or fewer times a week. Tapering over-the-counter medication. Most over-the-counter medications can be stopped abruptly unless they contain caffeine, in which case they may be tapered slowly over a few weeks. Sometimes patients respond better with a gradual taper of over-thecounter medication and a temporary switch to another substance. (If someone is overusing an acetaminophen compound, he or she can be switched to an NSAID, which should be gradually tapered, eg, naproxen 275 mg 3 times a day (tid) for 7 days, 2 times a day (bid) for 7 days, every day for 7 days, and then off.) Tapering caffeine. Caffeine often relieves headaches when used acutely in patients who are not overusing it chronically. However, when it is overused on a daily basis, caffeine rebound and withdrawal can be associated with increased headache (Silverman et al, 1992). Some patients are very sensitive to caffeine and can develop withdrawal symptoms while using as little as one to two cups per day. It is important to taper caffeine slowly, over the course of several weeks. For example, a patient should decrease caffeine intake no faster than 5 ounces of coffee every 3 to 5 days. Generally patients may state that they are having two cups per day when they actually mean mugs containing 8 to 16 ounces of coffee. It is important to identify all the caffeine a patient is consuming,
whether it is in coffee, tea, soft drinks, or medication. Tapering mixed butalbital compounds. Butalbital is a short-acting barbiturate and one of the active ingredients in several headache medications in the United States and Canada, but not elsewhere. Butalbital-containing medication is still the most frequent contributor to chronic daily headache associated with prescription medication overuse in the United States (Tepper, 2002). For patients suspected of overusing butalbital compounds, it is important to calculate the average daily dose of medication they are using in order to slowly taper the dose over time. One approach is to reduce the dose by one to two tablets every 3 to 5 days. A more controlled approach is to change the overused butalbital to longer-acting phenobarbital, which is easier to withdraw. For each 100-mg butalbital, give 30-mg phenobarbital daily. Once this switch has been made, phenobarbital can be tapered by 15 mg/d to 30 mg/d, which will usually avoid withdrawal symptoms and the possibility of seizures if patients had been using more than 800-mg butalbital per day (16 tablets, since each mixed butalbital capsule or tablet contains 50-mg butalbital). Tapering opiates. One approach is to taper the opiate 10% to 15% every day over 7 to 10 days. Adding clonidine 0.05 mg or 0.1 mg bid or tid during withdrawal of an opiate usually helps. This tends to reduce withdrawal symptoms (by decreasing the release of norepinephrine from the locus coeruleus in the pons) and, if clonidine is given in high enough doses, can speed the detoxification process. Clonidine can be given either by tablet or transcutaneously (transdermal transport system patches). For many patients with opiate dependency issues, lack of ability to fall asleep and stay asleep may confound their ability to
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Generally, ergots, nonopioids, and triptans can be abruptly discontinued in some people. On the other hand, opioids, barbiturates, and benzodiazepines are usually withdrawn slowly, perhaps over 2 weeks or more, depending on duration of use. A general idea is to move away from the patient’s pattern of medicating continuously on a pain-contingent basis to a scheduled taper. One must avoid medicating at mild to moderate intensities during this phase and use migraine-specific medications (triptans, dihydroergotamine, ergotamine tartrate) only for severe headache and limited to 2 or fewer times a week. For each 100-mg butalbital, give 30-mg phenobarbital daily.
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If a patient is having increased headaches and taking triptans 3 or more days per week on an ongoing basis, taper to one tablet per day, and a short course of a steroid or an NSAID can be used concomitantly to attempt to decrease any withdrawal symptoms. No matter what medication is being tapered, a very useful technique is to use a 3- to 7-day taper of oral steroids. A second adjunctive therapy is to use a short course of daily triptan in patients who are not overusing them.
reduce their medications appropriately. Various sleep-promoting medications may help, including tricyclic antidepressants, atypical antipsychotics, tizanidine, trazodone, long-acting benzodiazepines, and zolpidem (on a short-term basis). Tapering ergotamine. Although the drug is infrequently used today, the authors’ approach to tapering ergotamine tartrate is to switch the patient to intravenous dihydroergotamine and taper it slowly over a few days. Intramuscular or intranasal dihydroergotamine can be tried if the intravenous route is not possible. Dihydroergotamine itself is a useful bridge therapy for most overuse headache syndromes, and response to ergotamine predicts response to dihydroergotamine. Tapering triptans. Many triptans have been available long enough to cause rebound as reported in open and retrospective studies (Bigal et al, 2004). If a patient is having increased headaches and taking triptans 3 or more days per week on an ongoing basis, taper to one tablet per day, and a short course of a steroid or an NSAID can be used concomitantly to attempt to decrease any withdrawal symptoms (Bonuccelli et al, 1996; Deiner et al, 1991; Drucker and Tepper, 1998). Transitional therapy. No matter what medication is being tapered, a very useful technique is to use a 3- to 7-day taper of oral steroids, either prednisone starting at 60 mg/d or dexamethasone starting at 4 mg/d to 12 mg/d (Krymchantowski and Moreira, 2003). The mechanism of action is unknown but is presumed to be related to decreasing neurogenic inflammation in the meninges. A second adjunctive therapy is to use a short course of daily triptan in patients who are not overusing them (Bonuccelli et al, 1996; Drucker and Tepper, 1998). For example, one could also use daily naratriptan (2.5 mg bid)
(Mathew et al, 1997; Rapoport et al, 2003; Sheftell et al, 1999). Patients with refractory chronic daily headache treated with daily naratriptan showed reduction in headache frequency and intensity and improvement in the quality of life, indicating that naratriptan can be an effective adjuvant in the detoxification process. Alternatively, a short course of NSAIDs in patients not overusing them can be tried, although these agents may be less effective than prednisone as a transitional therapy for medication overuse headache. A clinical trial compared 14 days of naratriptan versus prednisone versus no intervention as transitional therapies in the treatment of medication overuse headache. All subjects were instructed to stop their offending medication. The efficacy was similar in the three regimens, but the dropout rates were significantly higher in the notransitional-therapy group (indicating that subjects could not tolerate the withdrawn period without receiving bridge therapy) (Krymchantowski and Moreira, 2003). Ambulatory infusion treatment. Patients who do not need hospitallevel care but cannot be safely or adequately treated as outpatients can be considered for ambulatory infusion treatment, where the patient will, under careful medical supervision, receive intravenous medications, sometimes 2 or 3 times per day for several days, until withdrawal is complete. The authors prefer to use intravenous dihydroergotamine only in hospitalized patients. Intravenous medication protocols will be described under inpatient strategy, below. Inpatient Strategy If outpatient treatment fails or is deemed to be unsafe or unlikely to be effective, or if significant somatic and/ or psychiatric comorbidity is present, inpatient treatment may be necessary.
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For the majority of patients, the detoxification process can be enhanced and shortened and the patient’s symptoms made more tolerable by the use of repetitive intravenous dihydroergotamine preceded by an antiemetic (Raskin, 1986; Silberstein and Silberstein, 1992). A test dose of 0.25 mg of dihydroergotamine, followed by 0.5 mg of dihydroergotamine tid, with each dose preceded by an antiemetic medication, should be used. Metoclopramide and ondansetron work well and are often tried orally but are even more effective intravenously. The repetitive intravenous administration of dihydroergotamine is a safe and effective means of rapidly controlling intractable headache (Pringsheim and Howse, 1998). In a study of 214 patients suffering from daily headache with rebound, 92% became headache free, usually within 2 to 3 days, with an average hospital stay of 7.3 days (Queiroz et al, 1996). In terms of long-term outcome after repetitive intravenous dihydroergotamine, a recent study demonstrated that 46% of patients continue to have a greater than 50% decrease in headache frequency at 3 months following hospital discharge. Dihydroergotamine is usually well tolerated except for producing nausea, diarrhea, and transient increase in headache, but is contraindicated in uncontrolled hypertension, coronary, cerebral and peripheral vascular disease, and all other situations in which triptans are contraindicated. For those who are unable to tolerate dihydroergotamine or when it is contraindicated, alternative intravenous medications are available. A 2.5-mg to 12.5-mg dose of intravenous chlorpromazine diluted in saline and preceded by hydration, given every 6 hours for 2 days, is effective in some patients. Prochlorperazine 5 mg to 10 mg administered intravenously is also effective and can be repeated
every 8 hours. Other medications that have been used intravenously are magnesium sulfate, propofol, diphenhydramine, ketorolac, dipyrone (not available in the United States), and divalproex sodium. Daily use of opioids. The role of opioids in the management of chronic benign pain remains controversial. The available evidence suggests that opioids are a risk factor for medication overuse headache and transformed migraine, and patients who overuse opioids have elevated headache relapse rates after withdrawal treatment (Katsarava et al, 2005). Against this backdrop, Saper and colleagues (2004) provided long-term open-label follow-up on a large sample of carefully selected intractable headache patients treated with daily opioids as a preventive treatment. From a treated sample of 160 patients placed on daily opioids, 70 (43.7%) were still using opioids on a daily basis after 3 years. Only 41 (26.0%) of the initially enrolled patients had an improvement of at least 50% on the headache index. The study’s authors now believe, based upon follow-up and additional information, that only 10% to 15% of patients initially placed on opioids did well. Moreover, opioid misuse was detected in up to 50% of treated patients, approximately 16.5% of treated subjects annually. Although most patients had poor outcomes with daily opioids, the authors believe that a small percentage (currently estimated at 10% to 15%) had significant and impressive benefits. Given the treatmentrefractory nature of the sample, these findings suggest that careful use of daily opioids in expert hands is an important option for the treatment of selected patients with intractable headache. These findings do not mitigate concerns about opioids as causal factors in medication overuse headache and transformed migraine. For the
KEY POINT:
A
A recent study demonstrated that 46% of patients continue to have a greater than 50% decrease in headache frequency at 3 months following hospital discharge after repetitive intravenous dihydroergotamine.
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usual patient, opioids should not be taken more than 2 or at most 3 days per week to avoid the risk of medication overuse. For patients with frequent and disabling headaches that remain intractable after usual treatment approaches, daily opioids will help a small percentage, but this has to be weighed against the potential for harm (Lipton and Bigal, 2004). CONCLUSIONS Medication overuse headache is one of the controversial areas in the headache field. These authors consider that aggressive detoxification trials should be performed in all subjects with this syndrome. However, it is important also to prevent its development since medication overuse is in many cases
iatrogenic, having been fostered by well-intentioned physicians. Potential strategies include limiting the use of acute medications to no more than 10 days per month and reducing headache frequency with preventive medications and nonpharmacological strategies, such as proper diet, weight loss, exercise, cognitive behavioral therapy, and education. Central sensitization may be prevented or shortened by orienting patients to promptly use specific acute medications and endeavoring to modify other risk factors for chronic daily headache (obesity, depression, anxiety, snoring, etc). Although the benefits of this strategy must still be established from a scientifically sound perspective, they are clear in the clinical practice.
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Katsarava Z, Muessig M, Dzagnidze A, et al. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia 2005;25:12–15. After successful treatment, the majority of relapses occur within the first year after withdrawal of the offending medication.
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Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62:788–790. The incidence of chronic daily headache was 14% among migraineurs in a tertiary clinic, and medication overuse was a strong risk factor.
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Krymchantowski AV, Moreira PF. Out-patient detoxification in chronic migraine: comparison of strategies. Cephalalgia 2003;23:982–993. Patients with medication overuse headache improve just by stopping the offending medication, but prednisone and naratriptan as bridge therapies may be useful for reducing withdrawal symptoms and rescue medication consumption.
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Kudrow L. Paradoxical effects of frequent analgesic use. Adv Neurol 1982;33:335–341. Kudrow proposed in 1982 that overuse of acute migraine medications can induce chronic daily headaches.
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Limmroth V, Katsarava Z, Fritsche G, et al. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002;59:1011–1014. Study showing that overuse of triptans leads to chronic daily headache faster and with lower dosages compared with ergots and analgesics.
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Lipton RB, Bigal ME. Opioid therapy and headache: a cause and a cure. Neurology 2004;62:1662–1663. Editorial commenting on paper by Saper and colleagues (2004) (see below and text) where patients using daily opioids are followed over the long term. Saper and colleagues now believe that just a minority of the patients continue to benefit from daily opioids.
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Lipton RB, Bigal ME. Chronic daily headache: is analgesic overuse a cause or a consequence? Neurology 2003;61:154–155. Editorial discussing the issue of analgesics as a cause or consequence of chronic daily headache.
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Martignoni E, Solomon S. The complex chronic headache mixed headache and drug overuse. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The headaches. New York: Raven Press, 1993. Complete and comprehensive review on medication overuse headache using terminology before the International Classification of Headache Disorders, 2nd Edition.
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Mathew NT. Medication misuse headache. Cephalalgia 1998;18:34–36. This article reviews the clinical features of medication overuse headache.
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Mathew NT. Drug-induced headache. Neurol Clin 1990;8:903–912. Another review by Mathew on medication overuse headache.
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Mathew NT, Asgharnejad M, Peykamian M, Laurenza A. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, crossover study. The Naratriptan S2WA3003 Study Group. Neurology 1997;49:1485–1490. Clinical trial assessing naratriptan in the acute treatment of migraine.
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Mathew NT, Kurman R, Perez F. Drug induced refractory headache—clinical features and management. Headache 1990;30:634–638. Review on the treatment strategies of medication overuse headache.
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Micieli G, Manzoni GC, Granella F, et al. Clinical and epidemiological observations on drug abuse in headache patients. In: Diener HC, Wilkinson M, eds. Drug-induced headache. Berlin: Springer-Verlag, 1988:20–28. Review on the treatment strategies of medication overuse headache.
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Penzien DB, Andrasik F, Freidenberg BM, et al. Guidelines for trials of behavioral treatments for recurrent headache, first edition: American Headache Society Behavioral Clinical Trials Workgroup. Headache 2005;45:S110–S132. Pivotal paper describing the evidence beyond behavioral treatment for refractory headaches.
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Pringsheim T, Howse D. In-patient treatment of chronic daily headache using dihydroergotamine: a long-term follow-up study. Can J Neurol Sci 1998; 25:146–150. Study describing favorable long-term outcomes following detoxification with dihydroergotamine.
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Queiroz LP, Weeks RE, Rapoport AM, et al. Early and transient side effects of repetitive intravenous dihydroergotamine. Headache 1996;36:291–294. Study describing the transient side effects of dihydroergotamine.
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Rapoport A, Stang P, Gutterman DL, et al. Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996;36:14–19. The authors showed that analgesic-rebound headache (now known as medication overuse headache) was recognized as a distinct entity and a substantive component in more than 40% of the primary care practices assessed. Consistently, they conclude that general practitioners need to be able to diagnose and treat analgesic-rebound headache.
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Rapoport AM, Bigal ME, Volcy M, et al. Naratriptan in the preventive treatment of refractory chronic migraine: a review of 27 cases. Headache 2003;43:482–489. In this study, the authors showed that daily naratriptan was effective in the prevention of chronic daily headache refractory to several other regimens. Most patients had medication overuse headache.
"
Rapoport AM, Weeks RE, Sheftell FD, et al. The ‘‘analgesic washout period’’: a critical variable in the evaluation of headache treatment efficacy. Neurology 1986;36:100–101. Individuals with medication overuse headache often cannot be detoxified because they rebound to analgesic discontinuation. This problem is discussed herein.
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Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986;36:995–997. Study showing the benefits of dihydroergotamine as a bridge therapy for medication overuse headache.
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Relja G, Granato A, Maria Antonello R, Zorzon M. Headache induced by chronic substance use: analysis of medication overused and minimum dose required to induce headache. Headache 2004;44:148–153. Interesting study where the authors try to determine the critical dose to induce medication overuse headache.
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Saper JR. Chronic headache syndromes. Neurol Clin 1989;7:387–412. Review on the subtypes of chronic daily headaches.
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Saper JR. Ergotamine dependency—a review. Headache 1987;27:435–438. Review of the special features of ergotamine overuse headache.
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Saper JR, Lake AE 3rd, Hamel RL, et al. Daily scheduled opioids for intractable head pain: long-term observations of treatment program. Neurology 2004;62:1687–1694. Study suggesting that daily opioids are an option in a small group of patients with chronic daily headache who failed to everything else.
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Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003;106:81–89. This study shows that medication overuse is a risk factor for chronic daily headache in the population, although most individuals with chronic daily headache at this setting do not overuse analgesics.
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Schwarz A, Faber U, Glaeske G, et al. [Analgesics consumption and analgesic-induced nephropathies in West Germany]. Offentl Gesundheitswes 1985;47:298–300.
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Sheftell FD, Brunton SA, Coon TL, et al. Chronic daily headache: Understanding and treating a common malady. Fam Pract Recertification 2004;26:25–36. Review on chronic daily headache and medication overuse headache.
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Sheftell FD, Rapoport AM, Coddon DR. Naratriptan in the prophylaxis of transformed migraine. Headache 1999;39:506–510. Prospective study, confirming the prior results of this chapter author’s group, that naratriptan may be used in the preventive treatment of refractory chronic daily headache.
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Silberstein SD, Olesen J, Bousser MG, et al. The International Classification of Headache Disorders, 2nd Edition (ICHD-II)—revision of criteria for 8.2 Medication-overuse headache. Cephalalgia 2005;25:460–465.
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Silberstein SD, Silberstein JR. Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE. Headache 1992; 32:439–445.
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Study showing the utility of dihydroergotamine in the management of patients with chronic daily headache and medication overuse headache, with good long-term outcome.
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Silverman K, Evans SM, Strain EC, Griffiths RR. Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992; 327:1109–1114. This is the first double-blind study demonstrating that withdrawal of an offending substance associated with chronic daily headache is associated with clinical improvement.
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Tepper SJ. Debate: analgesic overuse is a cause, not consequence, of chronic daily headache. Analgesic overuse is a cause of chronic daily headache. Headache 2002;42:543–547. Review of the arguments that favor the hypothesis that analgesic overuse is a cause instead of a consequence of chronic daily headache.
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Wilkinson SM, Becker WJ, Heine JA. Opiate use to control bowel motility may induce chronic daily headache in patients with migraine. Headache 2001;41:303–309. Fundamental study showing that opioids used for control of bowel motility induce chronic daily headache only in patients with a prior history of migraine.
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Zwart JA, Dyb G, Hagen K, et al. Analgesic overuse among subjects with headache, neck, and low-back pain. Neurology 2004;62:1540–1544. Interesting study showing that medication overuse was a risk factor for headache but not neck and low-back pain.
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DIAGNOSTIC TESTING AND SECONDARY CAUSES OF HEADACHE Randolph W. Evans
ABSTRACT A complete headache history with neurological and general physical examinations, as appropriate, will usually suffice to diagnose the vast majority of headaches without the need for diagnostic testing. However, since over 300 different types and causes of headache have been identified, some of which are potentially lifethreatening, judicious use of testing is essential to distinguish primary from secondary headaches. This chapter reviews general indications and studies available for diagnostic testing in adults and then the following contexts: headaches and a normal neurological examination, migraine, and acute severe new-onset headaches.
INDICATIONS FOR DIAGNOSTIC TESTING Neurologists recommend diagnostic testing for many reasons: aiming for diagnostic certainty (Woolf and Kamerow, 1990), faulty cognitive reasoning, the medical decision rule that holds that it is better to impute disease than to risk overlooking it, busy practice conditions in which tests are ordered as shortcuts, patient and family expectations, professional peer pressure where recommendations for routine and esoteric tests are expected as a demonstration of competence, financial incentives, and medicolegal issues. Table 11-1 provides reasons to consider use of neuroimaging for headaches. In the era of managed care, equally compelling reasons for not ordering diagnostic studies include physician fears of deselection and at-risk capitation. Lack of funds and underinsurance continue to be barriers for appropriate diagnostic testing for many patients.
Computed Tomography Versus Magnetic Resonance Imaging Computed tomography (CT) will detect most abnormalities that may cause headaches that are also visualized on magnetic resonance imaging (MRI). CT is generally preferred over MRI for the evaluation of acute subarachnoid hemorrhage, acute head trauma, and bony abnormalities. However, a number of disorders may be missed on routine CT of the head, including vascular disease, neoplastic disease, cervicomedullary lesions, infections, and low cerebrospinal fluid (CSF) pressure syndrome (Table 11-2). MRI is more sensitive than CT in the detection of posterior fossa and cervicomedullary lesions, ischemia, white matter abnormalities, cerebral venous thrombosis, subdural and epidural hematomas, neoplasms (especially in the posterior fossa), meningeal disease (such as carcinomatosis, diffuse dural enhancement in low CSF pressure syndrome, and sarcoid), and cerebritis and brain
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KEY POINTS:
A
A
A number of disorders may be missed on routine CT of the head, including vascular disease, neoplastic disease, cervicomedullary lesions, infections, and low cerebrospinal fluid pressure syndrome. There is no known risk of MRI during pregnancy, but some controversy exists because the magnets induce an electric field and may slightly raise the core temperature.
TABLE 11-1
Reasons to Consider Neuroimaging for Headaches
TABLE 11-2
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Temporal and headache features The ‘‘first or worst’’ headache Subacute headaches with increasing frequency or severity
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Subarachnoid hemorrhage
Headaches always on the same side
Carotid or vertebral artery dissections
Headaches not responding to treatment
Infarcts
Demographics
Cerebral venous thrombosis
New-onset headaches in patients who have cancer or who test positive for human immunodeficiency virus infection New-onset headaches after age 50
Vasculitis (white matter abnormalities) Subdural and epidural hematomas
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Meningeal carcinomatosis
Associated symptoms and signs
Headaches other than migraine with aura associated with focal neurological symptoms or signs Headaches associated with papilledema, cognitive impairment, or personality change Reprinted with permission from Evans RW. Headaches. In: Evans RW, ed. Diagnostic testing in neurology. Philadelphia: WB Saunders, 1999;2. Copyright # 1999, with permission from Elsevier.
Neoplastic disease Neoplasms (especially in the posterior fossa)
Patients with headaches and seizures
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Vascular disease
Arteriovenous malformations (especially posterior fossa)
Chronic daily headache
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Causes of Headache That Can Be Missed on Routine CT Scan of the Head
Saccular aneurysms
A progressive or new daily persistent headache
Headaches associated with symptoms and signs such as fever, stiff neck, nausea, and vomiting
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is generally preferred over CT for the evaluation of headaches. The yield of
Pituitary tumor and hemorrhage
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Cervicomedullary lesions Arnold-Chiari malformations Foramen magnum meningioma
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Infections Paranasal sinusitis Meningoencephalitis Cerebritis and brain abscess
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Other Low cerebrospinal fluid pressure syndrome Idiopathic hypertrophic pachymeningitis
abscess. Pituitary pathology is more likely to be detected on a routine MRI of the brain than a routine CT scan. MRI
Modified with permission from Evans RW. Headaches. In: Evans RW, ed. Diagnostic testing in neurology. Philadelphia: WB Saunders, 1999;3. Copyright # 1999, with permission from Elsevier.
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MRI may vary depending on the field strength of the magnet, the use of paramagnetic contrast, the selection of acquisition sequences, and the use of magnetic resonance (MR) angiography and venography. However, MRI has contraindications, such as the presence of some aneurysm clips or a pacemaker. In addition, approximately 8% of patients are claustrophobic with about 2% to the point where they cannot tolerate the study. Neuroimaging During Pregnancy When appropriate indications are present, neuroimaging should be performed during pregnancy. With the use of lead shielding, a standard CT scan of the head exposes the uterus to less than 0.01 mGy. The radiation dose for a typical cervical or intracranial arteriogram is less than 0.01 mGy. A radiation dose of 0.15 Gy is necessary to result in deformities that might justify pregnancy termination (Silberstein et al, 2002). MRI is more sensitive for rare disorders that may occur during pregnancy, such as pituitary apoplexy, cerebral venous sinus thrombosis (with the addition of MR venography), and metastatic choriocarcinoma. There is no known risk of MRI during pregnancy, but some controversy exists because the magnets induce an electric field and may slightly raise the core temperature (less than 18C). A survey of pregnant MRI workers found no adverse fetal outcome (Kanal et al, 1993), and no adverse fetal effects from MRI have been documented to date. It is generally accepted that MRI, like all imaging techniques, should be used judiciously in pregnant patients when benefits outweigh risks (Birchard et al, 2005). Although there is no known risk of intravenous contrast for computed axial tomographic (CAT) scan or
gadolinium for MRI, contrast should be avoided if possible. The radiation dose for a typical cervical or intracranial arteriogram is less than 0.01 mGy. Electroencephalography If the purpose of the electroencephalogram (EEG) is to exclude an underlying structural lesion such as a neoplasm, CT or MRI imaging is far superior. The report of the Quality Standards Subcommittee of the American Academy of Neurology (1995) suggests the following practice parameter:
KEY POINTS:
A
A
The EEG is not useful in the routine evaluation of patients with headache. This does not exclude the use of EEG to evaluate headache patients with associated symptoms suggesting a seizure disorder such as atypical migrainous aura or episodic loss of consciousness. Assuming head-imaging capabilities are readily available, EEG is not recommended to exclude a structural cause for headache. Lumbar Puncture MRI or CT scan is performed before a lumbar puncture for the evaluation of headaches except in some cases where acute meningitis is suspected and there are no focal findings. Lumbar puncture can be diagnostic for meningitis or encephalitis, leptomeningeal metastasis, subarachnoid hemorrhage, and high (eg, pseudotumor cerebri) or low CSF pressure. In cases of blood dyscrasias, the platelet count should be 50,000 or greater for safely performing the lumbar puncture. The CSF opening and closing pressures should always be measured when investigating headaches. When measuring the opening pressure, it is important for the patient to relax and at least partially extend the head and legs to avoid the measurement of a falsely elevated pressure.
A
A
Although there is no known risk of intravenous contrast for CAT scan or gadolinium for MRI, contrast should be avoided if possible during pregnancy. The EEG is not useful in the routine evaluation of patients with headache. This does not exclude the use of EEG to evaluate headache patients with associated symptoms suggesting a seizure disorder such as atypical migrainous aura or episodic loss of consciousness. MRI or CT scan is performed before a lumbar puncture for the evaluation of headaches except in some cases where acute meningitis is suspected and there are no focal findings. Cerebrospinal fluid opening and closing pressures should always be measured when investigating headaches.
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KEY POINT:
A
Potential complications of lumbar puncture are numerous, the most common of which is low CSF pressure headache, which occurs about 30% of the time using the conventional bevel-tipped or Quincke needle. The risk of headache can be reduced to about 5% to 10% by using an atraumatic needle and replacing the stylet before withdrawing the needle.
After neuroimaging as appropriate, examples where lumbar puncture is often indicated include the following (Table 11-3): the first or worst headache; headache with fever or other symptoms or signs suggesting an infectious cause; a subacute or progressive headache (eg, in a human immunodeficiency virus [HIV]-positive patient or a person with carcinoma); and an atypical chronic headache (eg, to rule out pseudotumor cerebri in an obese woman without papilledema or to rule out low CSF pressure syndrome). Potential complications of lumbar puncture are numerous, the most common of which is low CSF pressure headache, which occurs about 30% of the time using the conventional beveltipped or Quincke needle (Evans, 2006). The risk of headache can be dramatically reduced to about 5% to 10% by using an atraumatic needle such as the Sprotte and replacing the stylet before withdrawing the needle (Armon and Evans, 2005). Blood Tests Blood tests are generally not helpful for the diagnosis of primary headache
TABLE 11-3
cases but are necessary to rule out secondary causes of headache that mimic the primary disorders. They can also be important in monitoring drug levels and the safety of treatments administered, as well as establishing a baseline for safe administration of drugs that can alter liver function or affect renal clearance or the hematological parameters. Tests are available for numerous indications (Table 11-4) such as the following: erythrocyte sedimentation rate or C-reactive protein to consider the possibility of temporal arteritis; erythrocyte sedimentation rate, rheumatoid arthritis factor, and antinuclear antibodies in patients with headaches and arthralgias to evaluate for possible collagen vascular disease such as lupus; a mononucleosis spot in teenagers with headaches, sore throat, and cervical adenopathy; a complete blood count (CBC), liver function tests, HIV test, or Lyme antibody in patients with a suspected infectious basis; an anticardiolipin antibody and lupus anticoagulant in a migraineur with extensive white matter abnormalities on MRI; a thyroidstimulating hormone (TSH) test since
Reasons to Consider Lumbar Puncture to Evaluate Headaches
216 Presentation
Possible Cerebrospinal Fluid Diagnosis
First or worst headache
Subarachnoid hemorrhage or meningitis
Headache with fever or other symptoms or signs suggesting an infectious cause
Meningitis or encephalitis
Subacute or progressive headache in a patient with risk factors
Cryptococcal meningitis in patient who is human immunodeficiency virus positive Leptomeningeal metastasis with a history of a primary cancer Pseudotumor cerebri in an obese woman without papilledema
Orthostatic headache with diffuse dural enhancement on magnetic resonance imaging
Low cerebrospinal fluid pressure syndrome
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KEY POINT:
TABLE 11-4
Reasons to Consider Blood Tests to Evaluate Headaches
Indication
Tests
Inflammatory disease (eg, temporal arteritis or lupus)
Erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid arthritis factor
Infectious disease (eg HIV, Lyme)
HIV antibody, Lyme antibody
Extensive white matter abnormalities on magnetic resonance imaging
Lupus anticoagulant, anticardiolipin antibodies
Headaches and a pituitary adenoma
Prolactin level, TSH
Anemia and thrombotic thrombocytopenic purpura
CBC with platelets
Metabolic disease
TSH, serum calcium, blood urea nitrogen, creatinine
Baseline and monitoring for drug side effects, eg, divalproex sodium, nonsteroidal anti-inflammatory drugs, and lithium
CBC, chemistry profile, TSH
A
Blood tests are generally not helpful for the diagnosis of primary headache cases but are necessary to rule out secondary causes of headache that mimic the primary disorders.
Drug screens for illicit and pharmacological agents not identified in the history HIV = human immunodeficiency virus; TSH = thyroid-stimulating hormone; CBC = complete blood count.
headache may be a symptom in 30% of cases of hypothyroidism (Moreau et al, 1998); a CBC since headache may be a symptom when the hemoglobin concentration is reduced by one half or more; blood urea nitrogen (BUN) and creatinine to exclude renal failure, which can cause headache; serum calcium because hypercalcemia can be associated with headaches; CBC and platelets because thrombotic thrombocytopenic purpura can cause headaches; and endocrine studies in a patient with headaches and a pituitary tumor. Additionally, blood tests may be indicated as a baseline and for monitoring for side effects of certain medications such as divalproex sodium for migraine prophylaxis, tricyclic antidepressants, neuroleptics, carbamazepine
for trigeminal neuralgia, nonsteroidal anti-inflammatory drugs for chronic tension type headaches, and lithium for chronic cluster headaches. HEADACHES AND A NORMAL NEUROLOGICAL EXAMINATION Neuroimaging Studies in Adults: Risk/Benefit and Findings The yield of abnormal neuroimaging in studies of patients with primary headaches as the only neurological symptom and normal neurological examinations depends on a number of factors, including the duration of the headache, study design (prospective versus retrospective), who orders the scan, and the type of scan performed (Frishberg, 1994). Table 11-5
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KEY POINTS:
A
A
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In a study of patients with headaches that had an onset at least 4 weeks previously, neuroimaging studies detected significant lesions in 22 patients (1.2%), of whom 17 had a normal neurological examination. The only variable or red flag associated with a higher probability of intracranial abnormalities was an abnormal neurological examination with a likelihood ratio of 42. Neuroimaging studies have shown a higher yield in a group with indeterminate headache (3.7%) than in the migraine (0.4%) or tension-type headache (0.8%) groups.
TABLE 11-5
Balance Sheet. CT or MRI in Patients With Headache and Normal Neurological Examinations CT With Intravenous Contrast
MRI Without Contrast
No Test
(1) Migraine*
0.3%
0.4%
0
(2) Any headache*
2.4%
2.4%
0
30%
30%
0
0
Health Outcomes Benefits Discovery of potentially treatable lesions
Relief of anxiety Risks Iodine reaction Mild
10%
Moderate
1%
Severe
0.01%
Death
0.002%
Claustrophobia Mild
5%
15%
Moderate (needs sedation)
1%
5% to 10%
Severe (unable to comply)
1% to 2%
1% to 2%
False-positive studies
No data
No data
Cost (charges)
Varies widely depending on the payor
*Indications. CT = computed tomography; MRI = magnetic resonance imaging. Modified with permission from Frishberg BM. The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations. Neurology 1994;44:1191–1197. Copyright # 1994, AAN Enterprises, Inc.
summarizes the results of numerous CT and MRI studies, which demonstrate a low yield in this circumstance, and the possible risks. Recently, Sempere and colleagues (2005) reported a study of 1876 consecutive patients (1243 females, 633 males) aged 15 years or older, with a mean age of 38 years, with headaches that had an onset at least 4 weeks previously who were referred to two
neurology clinics in Spain. One third of the headaches were new onset, and two thirds had been present for more than 1 year. Subjects had the following types: migraine (49%), tension (35.4%), cluster (1.1%), posttraumatic (3.7%), and indeterminate (10.8%). Normal neurological examinations were found in 99.2% of the patients. CT scan was performed in 1432 patients and MRI in 580; 136 patients underwent both studies.
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Neuroimaging studies detected significant lesions in 22 patients (1.2%), of whom 17 had a normal neurological examination. The only variable or red flag associated with a higher probability of intracranial abnormalities was an abnormal neurological examination with a likelihood ratio of 42. The diagnoses in these 17 patients were pituitary adenoma (n = 3), large arachnoid cyst (n = 2), meningioma (n = 2), hydrocephalus (n = 2), ArnoldChiari Type I malformation, ischemic stroke, cavernous angioma, arteriovenous malformation, low-grade astrocytoma, brain stem glioma, colloid cyst, and posterior fossa papilloma (one of each). Of these 17 patients, eight were treated surgically: hydrocephalus (n = 2), pituitary adenoma, large arachnoid cyst, meningioma, arteriovenous malformation, colloid cyst, and papilloma (one of each). The rate of significant intracranial abnormalities in patients with headache and normal neurological examination was 0.9%. Neuroimaging studies discovered incidental findings in 14 patients (75%): three pineal cysts, three intracranial lipomas, and eight arachnoid cysts. The yield of neuroimaging studies was higher in the group with indeterminate headache (3.7%) than in the migraine (0.4%) or tension-type headache (0.8%) groups. The study does not provide information on white matter abnormalities in migraineurs. MRI performed in 119 patients with normal CT revealed significant lesions in two cases: a small meningioma and an acoustic neurinoma. No saccular aneurysms were detected; MR angiography was not obtained. However, the studies do not give information about the detection of paranasal sinus disease, which may be the cause of some headaches. For example, sphenoid sinusitis may cause a severe, intractable, new-onset headache that interferes with sleep and
is not relieved by simple analgesics. The headache may increase in severity with no specific location. There may be associated pain or paraesthesias in the facial distribution of the fifth nerve and photophobia or eye tearing with or without fever or nasal drainage. The headache may mimic other causes such as migraine or meningitis (Silberstein, 2004). As noted above, CT may miss pathology seen on MRI. Complaints of headache with a normal neurological examination may be seen in patients with Arnold-Chiari Type I malformation, which is easily detected on MRI but not CT scans and can be a rare cause of headache. The headache associated with Arnold-Chiari Type I malformation is nonspecific and can be precipitated by neck flexion, coughing, or exertion; have a short or long duration; and have features of migraine, tension, or cervicogenic-type headache (Arnett, 2004). Pituitary hemorrhage can produce a migrainelike acute headache with a normal neurological examination. Pituitary infarction, with severe headache, photophobia, and CSF pleocytosis, can initially be quite similar to aseptic meningitis or meningoencephalitis. Pituitary pathology is more likely to be detected on a routine MRI than CT scan. Cerebral Venous Thrombosis Cumurciuc and colleagues (2005) described 17 patients who presented with headache as the only manifestation of cerebral venous thrombosis. The headaches were variably of the thunderclap type, acute, progressive, or continuous in a generalized or unilateral distribution of moderate to severe intensity with throbbing pain in 76% and associated nausea, vomiting, and/or phonophobia/photophobia present in 59%. The headaches resolved within 1 month. The essential CT finding was the spontaneous hyperdensity of the thrombosed sinus,
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Sphenoid sinusitis may cause a severe, intractable, new-onset headache that interferes with sleep and is not relieved by simple analgesics. The headache may increase in severity with no specific location. There may be associated pain or paraesthesias in the facial distribution of the fifth nerve and photophobia or eye tearing with or without fever or nasal drainage. The headache associated with Arnold-Chiari Type I malformation is nonspecific and can be precipitated by neck flexion, coughing, or exertion; have a short or long duration; and have features of migraine, tension, or cervicogenictype headache.
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Seventeen patients presented with headache as the only manifestation of cerebral venous thrombosis. The headaches were variably of the thunderclap type, acute, progressive, or continuous in a generalized or unilateral distribution of moderate to severe intensity with throbbing pain in 76% and associated nausea, vomiting, and/or phonophobia/ photophobia present in 59%. Spontaneous intracranial hypotension syndrome often presents with a headache that is present when a patient is upright but is relieved by lying down, or by an orthostatic headache.
present in 60% of patients. This sign, known as the dense triangle in superior sagittal sinus thrombosis, may be seen in any sinus. However it is frequently missing or difficult to recognize with certainty. False-positives occur, especially in children or in patients with hemoconcentration. MRI with MR venography is required when this sign is not absent or doubtful. Spontaneous Intracranial Hypotension Syndrome Spontaneous intracranial hypotension syndrome often presents with a headache that is present when a patient is upright but is relieved by lying down, or by an orthostatic headache. However, as spontaneous intracranial hypotension syndrome persists, a chronic daily headache may be present without orthostatic features. Spontaneous intracranial hypotension syndrome may also present with other types of headaches, including exertional without any orthostatic features, acute thunderclap onset, paradoxical orthostatic headaches (present in recumbency and relieved when upright), intermittent headaches due to intermittent leaks, and the acephalgic form with no headaches at all. Neck or interscapular pain may precede the onset of headache in some cases by days or weeks. Table 11-6 summarizes MRI abnormalities of the brain and spine, which are variably present. Spontaneous intracranial hypotension syndrome can be present with a normal MRI with contrast of the brain and spine. An MRI scan of the brain may reveal diffuse pachymeningeal (dural) enhancement with gadolinium without leptomeningeal (arachnoid and pial) involvement and, in some cases, subdural fluid collections, which return to normal with resolution of the headache (Mokri, 2004; Schievink, 2006). An interesting finding is reversible descent of the cerebellar tonsils below
the foramen magnum (acquired ArnoldChiari Type I malformation), which can be due to spontaneous intracranial hypotension syndrome and also to lumbar puncture and overdraining CSF shunts. The diffuse meningeal enhancement on MRI in spontaneous intracranial hypotension may be explained by dural vasodilation and a greater concentration of gadolinium in the dural microvasculature and in the interstitial fluid of the dura. (Before the characteristic picture of the postural headache and diffuse pachymeningeal enhancement on MRI was recognized, some patients underwent extensive testing, including meningeal biopsy, to exclude other conditions, such as meningeal carcinomatosis and neurosarcoidosis.) The pleocytosis and elevated protein in the CSF and the subdural fluid collections in spontaneous intracranial hypotension are probably due to decreased CSF volume and hydrostatic pressure changes, resulting in meningeal vasodilation and vascular leak. A lumbar puncture usually demonstrates an opening pressure from 0 cm H2O to 70 cm H2O (and can even be negative), although the pressure can be in the normal range, especially if the procedure is performed after a period of bedrest. The CSF analysis may be normal or can demonstrate a moderate, primarily lymphocytic pleocytosis (50 cells/mm3 are common and values may be as high as 220 cells/ mm3 ), the presence of red blood cells, and elevated protein levels that can rarely be as high as 1000 mg/dL. CSF glucose concentration is never low. CT myelography is more sensitive than other studies for determining the actual site of a CSF leak since most leaks occur in the spine, especially at the thoracic level (Case 11-1). Because the leaks can be high or low flow, early and delayed CT may be helpful. The study may demonstrate
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TABLE 11-6
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MRI Abnormalities in CSF Leaks
A
Head Magnetic Resonance Imaging Diffuse pachymeningeal (dural) enhancement Descent (‘‘sagging’’ or ‘‘sinking’’) of the brain Descent of cerebellar tonsils (may mimic Arnold-Chiari Type I malformation) Obliteration of some of the subarachnoid cisterns (ie, prepontine or perichiasmatic cisterns) Crowding of the posterior fossa Enlargement of the pituitary Flattening or ‘‘tenting’’ of the optic chiasm Subdural fluid collections (typically hygromas, infrequently hematomas) Engorged cerebral venous sinuses Decrease in size of the ventricles (ventricular collapse) Increase in anteroposterior diameter of the brainstem
"
Spine Magnetic Resonance Imaging Extra-arachnoid fluid collections (often extending across several levels) Extradural extravasation of fluid (extending to paraspinal soft tissues) Meningeal diverticula Identification of level of the leak (not uncommonly) Identification of the actual site of the leak (very uncommonly) Spinal pachymeningeal enhancement Engorgement of spinal epidural venous plexus
Reprinted with permission from Mokri B. Low cerebrospinal fluid pressure syndromes. Neurol Clin N Am 2004;22:55–74. Copyright # 2004, with permission from Elsevier.
extra-arachnoid fluid, meningeal diverticula, and extradural leak of contrast into the paraspinal soft tissues. Radioisotope cisternography using indium-111 may demonstrate an absence or paucity of activity over the cerebral convexities at 24 or 48 hours. Less commonly, para-thecal activity at the approximate level of the leak may be apparent. Cost/Benefit of Neuroimaging for Headache With a Normal Examination Although for many patients the scan helps to relieve anxiety, for others the scan may produce anxiety when non-
specific abnormalities are found, such as incidental anatomical variants or white matter lesions. Although the cost of finding significant pathology is quite high, the cost of neuroimaging is significantly decreasing under some managed care contracts. Cost/ benefit estimates in patients with headache and a normal examination should also include the cost to the physician of malpractice suits filed when patients with significant pathology do not have neuroimaging and the cost to the patient and society of premature death and disability of undetected treatable lesions.
A
Spontaneous intracranial hypotension syndrome may present with other types of headaches, including exertional without any orthostatic features, acute thunderclap onset, paradoxical orthostatic (present in recumbency and relieved when upright), intermittent due to intermittent leaks, and the acephalgic form with no headaches at all. The diffuse meningeal enhancement on MRI in spontaneous intracranial hypotension syndrome may be explained by dural vasodilation and a greater concentration of gadolinium in the dural microvasculature and in the interstitial fluid of the dura.
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The pleocytosis and elevated protein in the CSF and the subdural fluid collections of patients with spontaneous intracranial hypotension syndrome are probably due to decreased CSF volume and hydrostatic pressure changes, resulting in meningeal vasodilation and vascular leak. CT myelography is more sensitive than other studies for determining the actual site of a CSF leak since most leaks occur in the spine, especially at the thoracic level. Cost/benefit estimates in patients with headache and a normal examination should also include the cost to the physician of malpractice suits filed when patients with significant pathology do not have neuroimaging and the cost to the patient and society of premature death and disability of undetected treatable lesions.
Case 11-1 A 51-year-old woman without prior significant headaches presents with a 1-year history of daily headaches. She describes bitemporal, left- or right-sided headache, variably characterized as a dull feeling or pressure sensation, or throbbing. The pain has an average intensity of 7/10, but can be as intense as a 10/10 about every other day. Light and noise sensitivity and occasionally nausea can be present. For the first 6 months, the headache was more intense with standing or sitting, and she would lie down frequently with a decrease in the intensity. For the last 6 months, there has been no postural increase in intensity. The headache is not worse with coughing or sneezing. She also reports constant ringing in the ears for the last year. She had been taking two to eight tablets containing acetaminophen plus aspirin plus caffeine [Excedrin] per day with minimal help. Medical history is negative. She drinks about 8 glasses of tea per day. Neurological examination is normal. She had seen a physician initially 1 year prior, and an MRI of the brain without contrast was reported as normal. No specific treatment was recommended. An MRI of the brain with and without contrast reveals mild to moderate diffuse pachymeningeal (dural) thickening and associated diffuse meningeal enhancement. An MRI of the cervical and thoracic spine with and without contrast is consistent with a CSF leak at T2–3, confirmed by a myelogram followed by CT demonstrating contrast in the subdural or epidural space anteriorly or posteriorly. At T2–3, there is 3-mm anterolisthesis of T2 upon T3 with a partially ossified 3-mm posterocentral protrusion effacing the anterior subarachnoid space and abutting the spinal cord. Comment. The MRI of the brain with diffuse dural enhancement is consistent with spontaneous intracranial hypotension syndrome. Although an orthostatic headache is the most common clinical feature, with chronicity a chronic daily headache may be present without orthostatic exacerbation as in this case and can be associated with tinnitus. CT myelography is the most sensitive study for determining the level of a spinal leak, if present, as in this case.
American Academy of Neurology Quality Standards Subcommittee Guidelines The guidelines (Silberstein, 2000) state: The following symptoms significantly increased the odds of finding a significant abnormality on neuroimaging in patients with nonacute headache: o Rapidly increasing headache frequency o History of lack of coordination o History of localized neurologic signs or a history such as subjective numbness or tingling
o History of headache causing awakening from sleep (although this can occur with migraine and cluster headache) The absence of these symptoms did not significantly lower the odds of finding a significant abnormality on neuroimaging. Neuroimaging recommendations for nonacute headache are as follows: o Consider neuroimaging in: Patients with an unexplained abnormal finding on the neurologic examination (Grade B)
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Patients with atypical headache features or headaches that do not fulfill the strict definition of migraine or other primary headache disorder (or have some additional risk factor, such as immune deficiency), when a lower threshold for neuroimaging may be applied (Grade C) NEUROIMAGING IN MIGRAINE Incidence of Pathology Table 11-5 summarizes numerous CT and MRI studies in migraineurs demonstrating a very low yield of potentially treatable lesions. The recent study of Sempere and colleagues (2005) found a similarly low yield of 0.4%. Table 11-7 lists some reasons to consider neuroimaging in migraineurs. Frequently, MRI scans of migraineurs will reveal white matter abnormalities (Swartz and Kern, 2004). White matter TABLE 11-7
Reasons to Consider Neuroimaging in Migraineurs
"
Unusual, prolonged, or persistent aura
"
Increasing frequency, severity, or change in clinical features
" " " " "
First or worst migraine
" "
Aura without headache
" "
Posttraumatic
abnormalities are foci of hyperintensity on both proton density and T2weighted images in the deep and periventricular white matter due to either interstitial edema or perivascular demyelination. White matter abnormalities are easily detected on MRI but are not seen on CT scan. The percentages of white matter abnormalities for all types of migraine range from 12% (Osborn et al, 1991) to 46% (Soges et al, 1988). The incidence of white matter abnormality in controls ranges from 2% (Pavese et al, 1994) to 14% (Fazekas et al, 1992). While the cause of white matter abnormality in migraine is not certain, various hypotheses have been advanced, including increased platelet aggregability with microemboli, abnormal cerebrovascular regulation, and repeated attacks of hypoperfusion during the aura (Kruit et al, 2004). Antiphospholipid antibodies are not a risk factor for white matter abnormalities in migraine (Igarashi et al, 1991; Tietjen et al, 1998). American Academy of Neurology Quality Standards Subcommittee Guidelines The guidelines state, ‘‘Neuroimaging is not usually warranted in patients with migraine and a normal neurologic examination (Grade B)’’ (Silberstein, 2000).
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White matter abnormalities are foci of hyperintensity on both proton density and T2-weighted images in the deep and periventricular white matter due to either interstitial edema or perivascular demyelination. The percentages of white matter abnormalities for all types of migraine range from 12% to 46%. The incidence of white matter abnormalities in controls ranges from 2% to 14%. Neuroimaging is not usually warranted in patients with migraine and a normal neurological examination.
Basilar Confusional Hemiplegic Late-life migraine accompaniments
Headaches are always on the same side
Patient or family and friends request
ACUTE SEVERE NEW-ONSET HEADACHES Differential Diagnosis Perhaps 1% of patients presenting to the emergency department have headache, often of acute onset, as their chief complaint (Morgenstern et al, 2001). Table 11-8 presents an extensive list of possible causes of the acute severe new-onset headache (the ‘‘first or worst’’) (Davenport, 2002). About 12% to 25% of patients presenting
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About 12% to 25% of patients presenting to the emergency department with a sudden-onset severe headache described as the worst headache of their life have a subarachnoid hemorrhage. About 80% of subarachnoid hemorrhages are due to ruptured intracranial aneurysms, and 5% are due to rupture of intracranial arteriovenous malformations. In about 15% of cases, an arteriogram fails to demonstrate the cause of the bleeding.
Differential Diagnosis of the Acute Severe New-Onset Headache (‘‘First or Worst’’)
TABLE 11-8
" " "
TABLE 11-8
" "
Crash Migraine
"
Associated With Vascular Disorders
Acute sinusitis
" "
"
Temporal arteritis Internal carotid and vertebral artery dissection Cerebral venous thrombosis Acute hypertension Pressor response
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Pheochromocytoma Preeclampsia
"
Associated With Nonvascular Intracranial Disorders Intermittent hydrocephalus Benign intracranial hypertension Postlumbar puncture Related to intrathecal injections Intracranial neoplasm Pituitary apoplexy
Cervicogenic Greater occipital neuralgia Cervical myositis
Unruptured saccular aneurysm
Systemic lupus erythematosus
Disorders of Eyes
Acute glaucoma
Parenchymal hemorrhage
Subarachnoid hemorrhage
Acute Mountain Sickness
Acute optic neuritis
Acute ischemic cerebrovascular disease Subdural and epidural hematomas
Cephalic Infection Meningoencephalitis
Benign orgasmic cephalgia Posttraumatic
Associated With Noncephalic Infection
Acute pyelonephritis
Benign exertional headache
" "
Acute Intoxications
Acute febrile illness
Cluster Miscellaneous
Continued
Cervical facet and root syndromes
"
Trigeminal Neuralgia
From Evans RW. Headaches. In: Evans RW, ed. Diagnostic testing in neurology. Philadelphia: WB Saunders, 1999;7. Copyright # 1999, with permission from Elsevier.
to the emergency department with a sudden-onset severe headache described as the worst headache of their life have a subarachnoid hemorrhage (de Falco, 2004). Subarachnoid hemorrhage has many causes (Table 11-9). About 80% of subarachnoid hemorrhages are due to ruptured intracranial aneurysms, and 5% are due to rupture of intracranial arteriovenous malformations. In about 15% of cases, an arteriogram fails to demonstrate the cause of the bleeding. In about 50% of these arteriogram negative cases, the CT scan reveals blood confined to the cisterns around the midbrain, perimesencephalic hemorrhage, which may be caused by a ruptured prepontine or interpeduncular cistern dilated vein or venous malformation.
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Other causes of arteriogram-negative subarachnoid hemorrhage are listed in Table 11-9. Over 30,000 people per year in the United States have a subarachnoid hemorrhage from a ruptured saccular aneurysm, resulting in over 18,000 deaths. Based upon a meta-analysis, the prevalence of saccular aneurysms in the general population is about 2% with 93% of aneurysms 10 mm or less (Rinkel et al, 1998). Perhaps 50% of patients with subarachnoid hemorrhages will present with a Hunt and Hess grade I (no symptoms or minimal headache, slight nuchal rigidity) or II (moderate to severe headache, no neurological deficit other than cra-
TABLE 11-9
nial nerve palsy). Although most patients with headache due to subarachnoid hemorrhage will have the worst headaches of their lives with maximum intensity within 5 minutes, subarachnoid hemorrhage can be easily overlooked (Linn et al, 1998). Ten percent of patients with subarachnoid hemorrhage have no headache at onset, and 8% describe a mild, gradually increasing headache (Weir, 1994). A stiff neck is absent in 36% of patients. Ten percent to 43% of patients with subarachnoid hemorrhage have a sentinel headache (Polmear, 2003). Aware of the diverse presentations of subarachnoid hemorrhage, how should one exclude aneurysmal subarachnoid hemorrhage?
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Causes of Nontraumatic Subarachnoid Hemorrhage
Cause
Percent
Intracranial saccular aneurysm
80
Intracranial arteriovenous malformation Negative arteriogram
5 15
Benign perimesencephalic hemorrhage
50
Other causes
50
Occult aneurysm Mycotic aneurysm Vertebral or carotid artery dissection Dural arteriovenous malformation Spinal arteriovenous malformation Sickle cell anemia Coagulation disorders Drug abuse (especially cocaine) Primary or metastatic intracranial tumors Primary or metastatic cervical tumors Central nervous system infection Central nervous system vasculitides Reprinted with permission from Evans RW. Headaches. In: Evans RW, ed. Diagnostic testing in neurology. Philadelphia: WB Saunders, 1999;7. Copyright # 1999, with permission from Elsevier.
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Over 30,000 people per year in the United States have a subarachnoid hemorrhage from a ruptured saccular aneurysm, resulting in over 18,000 deaths. Perhaps 50% of patients with subarachnoid hemorrhages will present with a Hunt and Hess grade I (no symptoms or minimal headache, slight nuchal rigidity) or II (moderate to severe headache, no neurological deficit other than cranial nerve palsy). Ten percent of patients with subarachnoid hemorrhage have no headache at onset, and 8% describe a mild, gradually increasing headache. A stiff neck is absent in 36% of patients. Ten percent to 43% of patients with subarachnoid hemorrhage have a sentinel headache.
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A CT scan without contrast is the neuroimaging study of choice in the detection of acute subarachnoid hemorrhage with a high initial sensitivity. Based upon a prospective study of 100 patients, the probability of recognizing an aneurysmal hemorrhage on CT scan is 50% after 1 week, 30% after 2 weeks (mostly patients with hematomas), and almost nil after 3 weeks. Fluid-attenuated inversion recovery MRI can detect subarachnoid hemorrhage that may not be apparent on CT scans but may be revealed by lumbar puncture. Red blood cells are present in the CSF in virtually all cases of subarachnoid hemorrhage and clear in a variable period of time from about 6 to 30 days.
CT and MRI Scans and Aneurysmal Subarachnoid Hemorrhage A CT scan without contrast is the neuroimaging study of choice in the detection of acute subarachnoid hemorrhage with a high initial sensitivity (Table 11-10). In a cooperative series of 3521 patients, findings on the first CT scan after rupture of a saccular aneurysm were as follows: normal 8.3%, decreased density 1.1%, mass effect 6.1%, aneurysm 5.0%, hydrocephalus 15.2%, intraventricular hematoma 16.7%, intracerebral hematoma 17.4%, subdural hematoma 1.3%, and subarachnoid hemorrhage 85.2% (Kassell et al, 1990). CT scan detected aneurysmal subarachnoid hemorrhage in 92% of patients on day 0, decreasing to 58% on day 5. The percentage of scans that were normal on day 0 was 3.3%; day 1, 7.2%; and day 5, 27.3%. False-positives can occur from mistaking calcification (eg, in the falx cerebri) for blood or anoxic encephalopathy as diffuse subarachnoid hemorrhage. van der Wee and colleagues (1995) performed a prospective series of 175 consecutive patients with sudden headache and a normal neurological exami-
Approximate Probability of Recognizing an Aneurysmal Hemorrhage on CT Scan After the Initial Event
TABLE 11-10
Time After Ictus
Probability
Day 0
95%
Day 3
74%
1 week
50%
2 weeks
30%
3 weeks
Almost 0%
nation. CT scans performed within the first 12 hours detected subarachnoid hemorrhage in 117, for a detection rate of 98%. In the remaining 58 patients, lumbar puncture was performed 12 or more hours after the onset of the headache. Two of the 58 patients were found to have xanthochromic CSF by spectrophotometric analysis. Both of these patients were found to have aneurysms. Based upon a prospective study of 100 patients, the probability of recognizing an aneurysmal hemorrhage on CT scan is 50% after 1 week, 30% after 2 weeks (mostly patients with hematomas), and almost nil after 3 weeks (van Gijn and van Dongen, 1982). The increased attenuation values in the basal cisterns and fissures usually disappeared by days 5 to 9. Most hematomas resolved between days 14 and 22. CT scan without contrast is preferred over MRI in the acute setting for the evaluation of possible subarachnoid hemorrhage because of the wide availability of CT scans, lower expense, and faster scanning time. However, fluid-attenuated inversion recovery MRI can detect subarachnoid hemorrhage that may not be apparent on CT scans but may be revealed by lumbar puncture. In a small acute series, fluidattenuated inversion recovery MRI on a 1.5-T unit was positive in only 16.7% (2/12) of cases (Mohamed et al, 2004). False-positives for subarachnoid hemorrhage can also occur for a variety of reasons, such as patients with strokes who had previously undergone contrastenhanced perfusion studies, renal failure, active seizures, inspired oxygen, and various artifacts. MRI using a gradient echo T2 sequence is more sensitive than CT between 4 and 14 days (100% versus 75%) (Mitchell et al, 2001) and between 6 and 30 days (100% versus 45.5%) (Yuan et al, 2005) after the ictus.
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Lumbar Puncture and Subarachnoid Hemorrhage A lumbar puncture should be considered in all patients with an acute new-onset headache suspicious for subarachnoid hemorrhage who have normal CT scans. Since lumbar puncture can result in clinical deterioration and death after subarachnoid hemorrhage, a CT scan should be performed first with the exception of certain cases where acute meningitis is suspected. Cerebrospinal Fluid Examination Red blood cells (RBCs) are present in the CSF in virtually all cases of subarachnoid hemorrhage and clear in a variable period of time from about 6 to 30 days (Tourtellotte et al, 1964). However, distinguishing a traumatic lumbar puncture from a subarachnoid hemorrhage can be highly problematic. Although a decrease in RBCs from the first to the third test tube can be seen after a traumatic tap, a similar decrease can be seen after a previous bleed (Fishman, 1992). A 25% reduction between the first and third tubes can be seen in cases of ruptured aneurysms (Heasley et al, 2005). Heasley and colleagues (2005) also contrast how few RBCs may be present in subarachnoid hemorrhage, comparing two cases of aneurysmal subarachnoid hemorrhage documented on arteriogram with a negative CT that had only 69 and 80 RBCs/mm3, respectively, compared with a patient with no pathology whose CSF revealed 414,750 RBCs/ mm3. After a traumatic tap, the number of RBCs may stay constant in all three tubes. Since crenation occurs very soon after RBCs enter CSF, the presence of crenated RBCs is an unreliable sign of subarachnoid hemorrhage (Vermeulen and van Gijn, 1990). Xanthochromia may be helpful in the detection of subarachnoid hemorrhage.
When RBCs break down in CSF, they release oxyhemoglobin, which is degraded by macrophages and other cells in the leptomeninges to bilirubin by the third to fourth day. These two pigments are responsible for xanthochromia (literally ‘‘yellow color’’ but refers to a colored supernatant) after subarachnoid hemorrhage. The CSF supernatant is pink or pink-orange due to oxyhemoglobin, yellow due to bilirubin, and an intermediate color if both are present. Methemoglobin, a reduction product of hemoglobin, is found in encapsulated subdural hematomas and in old loculated intracerebral hemorrhages. Although oxyhemoglobin can be detected as early as 2 hours after entry of RBCs into CSF, xanthochromia is not present in all cases until after 12 hours. Therefore, to avoid confusing blood-stained CSF from a traumatic lumbar puncture with a subarachnoid hemorrhage, a suggestion has been made to delay lumbar puncture until 12 hours after the ictus (Vermeulen and van Gijn, 1990). However, this is not always practical since many evaluations for patients with severe headaches and a normal examination are done on an outpatient basis or in the emergency department. Unfortunately, the presence of xanthochromia assessed by spectrophotometry cannot absolutely distinguish between subarachnoid hemorrhage and a traumatic lumbar puncture. Because oxyhemoglobin can form in vivo, false-positives for subarachnoid hemorrhage can occur from traumatic taps with even a small number of RBCs (Morgenstern et al, 1998). (However, bilirubin and methemoglobin form in vitro only.) Based upon a model of adding blood to clear CSF, Graves and Sidman (2004) concluded that CSF xanthochromia assessed by spectrophotometry may be observed within 2 hours after traumatic lumbar puncture
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A 25% reduction between the first and third tubes can be seen in cases of ruptured aneurysms. Xanthochromia may be helpful in the detection of subarachnoid hemorrhage. When RBCs break down in CSF, they release oxyhemoglobin, which is degraded by macrophages and other cells in the leptomeninges to bilirubin by the third to fourth day. Although oxyhemoglobin can be detected as early as 2 hours after entry of RBCs into CSF, xanthochromia is not present in all cases until after 12 hours. The presence of xanthochromia assessed by spectrophotometry cannot absolutely distinguish between subarachnoid hemorrhage and a traumatic lumbar puncture.
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Based upon a model of adding blood to clear CSF, investigators concluded that CSF xanthochromia assessed by spectrophotometry may be observed within 2 hours after traumatic lumbar puncture and sooner in samples with greater than 10,000 RBCs/mm3. Xanthochromia is best detected by spectrophotometry since the naked eye can only detect xanthochromia about half the time.
TABLE 11-11
and sooner in samples with greater than 10,000 RBCs/mm3. Conversely, xanthochromia in traumatic lumbar puncture with less than 5000 RBCs warrants further investigation for subarachnoid hemorrhage. When the CSF RBC count is elevated above 10,000 RBCs/mm3, or the time between sample acquisition and analysis is prolonged, the clinician should not rely on xanthochromia to confirm subarachnoid hemorrhage. Xanthochromia is best detected by spectrophotometry since the naked eye can only detect xanthochromia about half the time (Vermeulen and van Gijn, 1990). Absorption spectrophotometry, which is a measurement of the light intensity in different regions of the visible spectrum (400 nm to 700 nm) after its transmission through an absorbing medium, can detect oxyhemoglobin and bilirubin by their characteristic maximum absorption bands of 415 nm and 455 nm, respectively (Weir, 1994). The probability of detecting xanthochromia by spectrophotometry at various times after subarachnoid hemorrhage is shown in Table 11-11 (Vermeulen et al, 1989). Wood and colleagues (2005), in a prospective study of 253 patients,
Probability of Detecting Xanthochromia With Spectrophotometry in the Cerebrospinal Fluid at Various Times After a Subarachnoid Hemorrhage
Time After Ictus
Probability
12 hours
100%
1 week
100%
2 weeks
100%
3 weeks
70%
4 weeks
40%
found that spectrophotometry has limited clinical utility. Although the sensitivity was 100%, the specificity was only 75.2% with a positive predictive value as an indicator of subarachnoid hemorrhage of 3.3%. Gunawardena and colleagues (2004) reported that CSF spectrophotometry resulted in the diagnosis of an intracranial aneurysm in 2% (9/463) of patients with CT-negative suspected subarachnoid hemorrhage and nonfocal neurological examinations when the lumbar puncture was performed more than 12 hours and less than 2 weeks after the ictus. Fewer than 1% of patients with oxyhemoglobin alone had aneurysms diagnosed, while 21% of patients with bilirubin had an aneurysm. Spectrophotometry has limited availability in emergency departments and is available in only perhaps 3% of hospital laboratories in the United States (Edlow et al, 2002). Other causes of xanthochromia include jaundice, usually with a total plasma bilirubin of 10 mg/dL to 15 mg/ dL; CSF protein greater than 150 mg/ dL; dietary hypercarotenemia; malignant melanomatosis; and oral intake of rifampin (Fishman, 1992). Cerebral, Magnetic Resonance, and Spiral CT Angiography After subarachnoid hemorrhage, a fourvessel cerebral digital subtraction angiogram should be performed since about 20% of patients have multiple aneurysms. Although saccular aneurysms are usually detected on the initial digital subtraction angiogram, false-negatives can occur in 6% to 16%, often missing an anterior communicating artery aneurysm (Urbach et al, 1998). Potential reasons for false-negatives include vasospasm, thrombosis of the aneurysm, observer error, and technical factors such as inadequate oblique views. A repeat digital subtraction angiogram
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should be performed after 2 weeks in the following circumstances: findings of vasospasm, an incomplete or inadequate study, an aneurysmal pattern of blood on the initial CAT scan, and when a CAT scan performed within 4 days after the subarachnoid hemorrhage shows thin or thick subarachnoid blood, particularly with a lot of blood in the basal frontal interhemispheric fissure. Occasionally, a third digital subtraction angiogram may be necessary to demonstrate an aneurysm. MR angiography is useful but not as sensitive as digital subtraction angiogram in the detection of saccular aneurysms. MR angiography with 3D time-of-flight sequences has a sensitivity of about 90% for intracranial aneurysms of 3 mm or greater as compared with digital subtraction angiogram (Okahara et al, 2002). Contrast-enhanced MR angiography may increase the yield. Okahara and colleagues (2002) found significant interobserver variability in detection of aneurysms on MR angiography studies as follows: 79% for neuroradiologists, 75% for neurosurgeons, 63%
for general radiologists, and 60% for radiology residents. Spiral (helical) CT angiography is very promising. CT angiography with a 16-detector row machine with 3D interpretation on workstations may detect intracranial saccular aneurysms with accuracy equivalent to digital subtraction angiogram (Tipper et al, 2005). However, older-generation fourslice scanners with interpretation of hard-copy films may have a lower yield of 85% to 93% and may miss smaller aneurysms of less than 3 mm in diameter. Spiral CT can be very useful instead of, or as an alternative to, MR angiography for patients with contraindications to MRI such as pacemakers, intracranial ferromagnetic clips, and severe claustrophobia. However, in addition to contrast allergy, there is additional risk of intravenous contrast in patients with renal insufficiency, dehydration, and diabetes. In practice, MR and CT angiography are both limited by the quality of the equipment, the images, and the ability of the interpreting physician.
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TRIGEMINAL AUTONOMIC CEPHALALGIAS Todd D. Rozen
ABSTRACT The trigeminal autonomic cephalalgias are a group of primary headache syndromes, all marked by headache and associated autonomic features. Cluster headache is the most common of this headache subtype, while others (SUNCT [short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing], paroxysmal hemicrania, and hemicrania continua) are rarer. These headaches typically are marked by very severe pain and if not treated correctly can produce lifelong disability. The goal of this chapter is to introduce the trigeminal autonomic cephalalgias, looking at clinical headache characteristics, recognized treatments, and interesting new developments in pathogenesis.
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The trigeminal autonomic cephalalgias are a group of primary headache syndromes, all marked by headache and associated autonomic features including lacrimation, eyelid ptosis, nasal rhinorrhea/congestion, and the presence of a Horner’s syndrome (ptosis with miotic pupil). The brain stem connection between the trigeminal system and the parasympathetic autonomic nervous system allows an understanding of how trigeminal-based pain can be associated with autonomic symptomatology. The trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, SUNCT syndrome (short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing), and hemicrania continua. This chapter will include an overview for each distinct syndrome. CLUSTER HEADACHE Introduction Cluster headache is one of the primary headache syndromes. It is very stereotyped in its presentation and fairly easy to diagnose with an in-depth headache history. There is no more severe pain
than that sustained by a cluster headache sufferer, and if not for the rather short duration of attacks, most cluster sufferers would choose death rather than continue suffering. Cluster has been nicknamed the ‘‘suicide headache’’ because cluster sufferers typically have thought about or have taken their lives during a cluster headache. Fortunately, cluster headache is easy to treat in most individuals if the correct medications are used and the correct dosages are given. Diagnosis Recently Klapper and colleagues (2000) determined that the average time it takes for a cluster headache sufferer to be diagnosed correctly by the medical profession is 6.6 years. The average number of physicians seen prior to a correct diagnosis is four, and the average number of incorrect diagnoses before a correct diagnosis of cluster headache is four. This statistic is unacceptable considering the pain and suffering cluster patients must endure when they are not treated correctly or when not being
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treated at all. In many instances cluster headache is misdiagnosed as migraine or sinus headache, so an inappropriate therapy regime is prescribed. Cluster is a stereotypical episodic headache disorder marked by frequent attacks of short-lasting, severe, unilateral head pain with associated autonomic symptoms. A cluster headache is defined as an individual attack of head pain, while a cluster period or cycle is the time during which a patient is having daily cluster headaches. Most patients with cluster headaches have episodic cluster, indicating that they will have remission periods in between cluster cycles, while a few unfortunate individuals have chronic cluster headache where cycles occur for more than 1 year without remission or with remission periods lasting less than 1 month. Typical cluster headache location is retro-orbital, periorbital, and occipitonuchal. Maximum pain is normally retro-orbital in greater than 70% of patients. Pain quality is described as boring, stabbing, burning, or squeezing. Cluster headache intensity is always severe, never mild, although headache pain intensity may be less at the beginning and end of cluster periods. Cluster headaches that awaken a patient from sleep will be more severe than those occurring during the day. The one-sided nature of cluster headaches is a trademark. Cluster sufferers will normally experience cluster headaches on the same side of the head their entire life. Only in 15% of patients will the headaches shift to the other side of the head at the next cluster period, and side shifting during the same cluster cycle will only occur in 5% of patients. The duration of individual cluster headaches is between 15 and 180 minutes with greater than 75% of attacks being less than 60 minutes. Attack frequency is between 1 and 3 attacks per day, with most patients experiencing no more than two head-
aches in a day. Peak time periods for daily cluster headache onset are 1:00 AM to 2:00 AM, 1:00 PM to 3:00 PM, and after 9:00 PM, so that most patients can complete their occupational requirements without experiencing headaches during the workday. The headaches have a predilection for the first rapid eye movement sleep phase, so the patient will awaken with a severe headache 60 to 90 minutes after falling asleep. Cluster period duration normally lasts between 2 and 12 weeks, and patients generally experience one or two cluster periods per year. Remission periods (headache-free time between cluster cycles) average 6 months to 2 years. Cluster headache is marked by its associated autonomic symptoms, which typically occur on the same side as the head pain, but can be bilateral. Lacrimation is the most common associated symptom, occurring in 73% of patients, followed by conjunctival injection in 60%, nasal congestion in 42%, rhinorrhea in 22%, and a partial Horner’s syndrome in 16% to 84%. Symptoms generally attributed to migraine can also occur during a cluster headache and include nausea, vomiting, photophobia, and phonophobia. Photophobia and phonophobia probably occur as frequently in cluster headache as in migraine. Vingen and colleagues (1998) found a self-reported frequency of photophobia in 91% of 50 studied patients with cluster headache and phonophobia in 89%. These symptoms may not be syndromespecific but just markers of trigeminalautonomic pathway activation. The occurrence of so-called migrainous symptoms in cluster has probably led to the high rate of misdiagnosis of cluster patients. During an individual cluster headache, patients are unable to sit or stand completely still. Cluster is really a state of agitation, since remaining still appears to make the pain worse. Some patients will state
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The duration of individual cluster headaches is between 15 and 180 minutes with greater than 75% of attacks being less than 60 minutes. Cluster headaches have a predilection for the first rapid eye movement sleep phase, so the patient will awaken with a severe headache 60 to 90 minutes after falling asleep. Symptoms generally attributed to migraine can also occur during a cluster headache and include nausea, vomiting, photophobia, and phonophobia.
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171
" TRIGEMINAL AUTONOMIC CEPHALALGIAS
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Only about 3% of cluster headache sufferers can lie still during an attack. Because most cluster headache patients have episodic cluster headache, medications are only utilized while a patient is in cycle and are stopped during remission periods. Abortive therapy needs to show effect usually within 20 minutes as the attacks are short in duration.
that they will lie down with a cluster headache but when questioned report that they do not lie still but roll around on the bed in agony. Many patients will develop their own routine during a cluster attack, including banging their heads against the wall, crawling on the floor, taking hot showers, or just screaming out in pain. Only about 3% can lie still during an attack (Nappi et al, 1992). Many patients will develop suicidal ideations during a headache. Cluster headaches have several distinct triggers, including alcohol, nitroglycerin, histamine, hot weather, and possibly watching television (Rozen, 2002a). The medical history of patients with cluster headache is marked by increased gastric ulcer risk, increased gastric acid secretion, and head trauma. Most patients smoke cigarettes and start to smoke prior to headache onset. A person almost has to be a smoker to develop cluster headache unless it is a secondary cluster such as from head trauma. Alcohol usage is higher in patients with cluster headache versus controls and is statistically significant if one considers heavy drinkers (greater than 1 L/d of wine or equivalent) (Levi et al, 1992). The faces of patients with cluster headache have been described as having a ‘‘leonine appearance’’ with thick, coarse facial skin, peau d’orange appearance, marked wrinkling of the forehead, and face with deep furrowed brows. In addition, Kudrow (1979) reported that two thirds of the patients in his large series had hazel-colored eyes. These features may reflect a long history of smoking and alcohol overuse rather than being specific to cluster headache patients. All patients with cluster headache require treatment. Other primary headache syndromes can sometimes be managed nonmedicinally, but in regard to cluster headache, medication, sometimes even polypharmacy, is indicated. Cluster headache treatment can be di-
vided into three classes. Abortive therapy is treatment given at the time of an attack to ameliorate that individual attack alone. Transitional therapy can be considered an intermittent or shortterm preventive treatment. An agent is started at the same time as the patient’s true maintenance preventive therapy. The transitional therapy will provide the patient attack relief while the maintenance preventive agent is being built up to a therapeutic dosage. Preventive therapy consists of daily medication, which is supposed to reduce the frequency of headache attacks, lower attack intensity, and lessen attack duration. The main goal of cluster headache preventive therapy should be to make patients cluster free on preventive agents even though they are still in a cluster cycle. As most patients with cluster headache have episodic cluster headache, medications are only utilized while a patient is in cycle and are stopped during remission periods. Abortive Therapy The goal of abortive therapy for cluster headache is fast, effective, and consistent relief. There is no role in cluster headache for over-the-counter agents or butalbital-containing compounds and little if any need for opiates. Abortives need to show effect usually within 20 minutes as the attacks are short in duration. Table 9-1 lists typical cluster headache abortives. Sumatriptan. Subcutaneous sumatriptan is the most effective medication for the symptomatic relief of cluster headache. In a placebo-controlled study, 6 mg of injectable sumatriptan was significantly more effective than placebo, with 74% of patients having complete relief by 15 minutes compared with 26% of placebo-treated patients (Ekbom, 1991). In long-term, openlabel studies, sumatriptan was effective in 76% to 100% of all attacks within 15
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TABLE 9-1
Abortive Treatment Options
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Sumatriptan: injection or nasal spray are both efficacious, but injection is more effective
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Oxygen: 100% oxygen via face mask at 8 L/min to 15 L/min (70% obtain relief)
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Dihydroergotamine: intramuscular, subcutaneous, or intravenous
" "
Ergotamine: oral, suppository
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Intranasal lidocaine (less than one third respond)
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Greater occipital nerve blockade
Zolmitriptan oral: 10 mg>5mg>placebo
minutes even after repetitive daily use for several months (Ekbom et al, 1995). Interestingly, sumatriptan appears to be 8% less effective in chronic cluster headache than in episodic cluster headache. Sumatriptan is contraindicated in patients with uncontrolled hypertension, history of myocardial infraction, or stroke. As almost all cluster patients have a strong history of cigarette smoking, the physician must closely monitor cardiovascular risk factors in these patients. Sumatriptan nasal spray (20 mg) has been shown to be more effective than placebo in the acute treatment of cluster attacks. In more than 80 patients tested, intranasal sumatriptan reduced cluster headache pain from very severe, severe, or moderate to mild or no pain at 30 minutes in 58% of sumatriptan users versus 30% of patients given placebo on the first attack treated, while the rates were 50% (sumatriptan)
versus 33% (placebo) after the second attack treated (van Vliet et al, 2001). Sumatriptan nasal spray appears to be efficacious for cluster headache but less effective than subcutaneous injection. Sumatriptan nasal spray should be considered a cluster headache abortive in patients who cannot tolerate injections or when situationally (eg, an office setting) injections would be considered socially unacceptable. In many instances cluster headache patients may need to use sumatriptan more than once in a day for days to weeks at a time. Controversy of whether patients with cluster headache can develop analgesic-rebound headache still exists. Hering-Hanit (2000) noted that the use of daily injectable sumatriptan in four cluster patients led to a marked increase in the frequency of cluster attacks 3 to 4 weeks after initiating treatment. Three patients experienced change in the character of the cluster headache, while two patients experienced prolongation of their cluster headache period. Withdrawal of sumatriptan reduced the frequency of headaches. Even though daily sumatriptan may benefit patients with cluster headache, the goal should be to have patients cluster free on preventive medication without the need to use abortives to achieve cluster-free status. Oxygen. Oxygen inhalation is an excellent abortive therapy for cluster headache. Typical dosing is 100% oxygen given via a nonrebreather face mask at 7 L/min to 10 L/min for 20 minutes. In some patients, oxygen is completely effective at aborting an attack if taken when the pain is at maximal intensity, while in others, the attack is only delayed for minutes to hours rather than completely alleviated. It is common for a cluster patient to be headache free while on oxygen but immediately redevelop pain when the oxygen is removed. Oxygen is overall a very attractive therapy as it is
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Patients with cluster headache should not be deemed refractory to oxygen therapy unless flow rates up to 15 L/min have been utilized. Transitional cluster therapy is a short-term preventive treatment that bridges the time between cluster diagnosis and the time when the true traditional maintenance preventive agent becomes efficacious.
completely safe and can be used multiple times during the day. Large oxygen tanks are prescribed for patient’s homes, while portable tanks can be taken to the work-place. In Kudrow’s (1981) landmark study using oxygen. 75% of patients responded to 100% oxygen at 7 L/min, although only 57% of older chronic cluster headache patients had relief. A recent study (Rozen et al, 1999) documented a gender difference in response to oxygen as only 59% of female cluster patients responded to oxygen whereas 87% of men did. In almost every textbook and article written on the subject of cluster headache treatment, patients are instructed to use 100% oxygen via a nonrebreather face mask at 7 L/min to 10 L/min. The rationale behind this prescribed oxygen flow rate is unknown but has become doctrine since the Kudrow (1981) study. Prescribing higher flow rates of oxygen up to 12 L/min has recently been suggested, but no documentation reports that this may improve efficacy. The abortive effect of higher oxygen flow rates (up to 15 L/min) in cluster headache patients refractory to standard oxygen therapy is unknown. Rozen (2004) recently documented three cluster headache patients who demonstrated no response to standard oxygen therapy but had complete cluster relief when exposed to higher oxygen flow rates of 15 L/min. From this clinical observation it appears that patients with cluster headache should not be deemed refractory to oxygen therapy unless flow rates up to 15 L/min have been utilized. Zolmitriptan. Zolmitriptan is one of the second-generation triptan compounds that has shown very good efficacy in migraine. In a double-blind controlled trial, the efficacy of 5 mg and 10 mg of oral zolmitriptan was tested versus placebo in the treatment of individual cluster headache attacks
(Bahra et al, 2000). A 2-point reduction on a 5-point pain intensity scale at 30 minutes was used as a positive response end point. Forty-seven percent of patients taking zolmitriptan 10 mg had a positive response versus 40% on 5 mg and 29% on placebo. The difference reached statistical significance for 10 mg of zolmitriptan versus placebo. Significantly more patients reported mild or no pain 30 minutes after treatment with 5 mg and 10 mg of zolmitriptan (57% and 60% respectively) than after placebo (42%). The response rates for zolmitriptan are not as dramatic as that seen with oxygen or injectable sumatriptan, but this is the first oral triptan to be shown to have efficacy as a cluster abortive and is an alternative treatment option in patients who cannot tolerate injections or intranasal preparations and have either failed oxygen or find it too difficult to use in acute situations. Zolmitriptan nasal spray has also shown efficacy for treating individual cluster attacks. Other. Other effective abortives include ergotamine suppositories and dihydroergotamine (DHE) nasal spray or intramuscular injection. Transitional Therapy Transitional cluster therapy is a shortterm preventive treatment that bridges the time between cluster diagnosis and when the true traditional maintenance preventive agent becomes efficacious. Transitional preventive agents are started at the same time the maintenance preventive medication is begun. The transitional preventive agent should provide the patient with almost immediate pain relief and allow the patient to be headache free or nearly headache free while the maintenance preventive medication dose is being raised to an effective level. When the transitional agent is tapered off, the maintenance preventive agent will have
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kicked in; thus, the patient will have no gap in headache preventive coverage (Table 9-2). Corticosteroids. A short course of corticosteroids is the best-known transitional therapy for cluster headache. Typically within 24 to 48 hours of administration patients become cluster free, and by the time the steroid taper has ended, the patient’s main preventive agent has started to become effective. Prednisone or dexamethasone is the most typically used corticosteroid in cluster. A typical taper would be 80 mg of prednisone for the first 2 days followed by 60 mg for two days, 40 mg for 2 days, 20 mg for 2 days, 10 mg for 2 days, and then discontinuation. There is no set manner in which to dose corticosteroids in cluster headache. Kudrow (1980) noted that prednisone provided substantial cluster pain relief in 77% of 77 episodic cluster patients and partial improvement in another 12%. Patients with chronic cluster headache did not fare as well, with only 40% of 15 patients treated showing marked improvement.
TABLE 9-2
"
Transitional Treatment Options
Corticosteroids: prednisone taper; start 60 mg to 80 mg, taper over 10 to 12 days
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Naratriptan: (2.5 mg) one tab bid for 7 days
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Ergotamine (2 mg): one tab at bedtime or bid for 7 days
"
Dihydroergotamine (DHE): daily intramuscular injections (1 mg every day or bid) for 1 week, intravenous infusion of DHE 1 mg tid for 3 days
"
Occipital nerve blockade
bid = 2 times a day; tid = 3 times a day.
Dexamethasone at a dose of 4 mg twice a day for 2 weeks followed by 4 mg a day for 1 week has also been shown to be effective (Anthony and Daher, 1992). However, when dexamethasone or prednisone is tapered, the cluster attacks frequently recur. Therefore, corticosteroids are primarily useful for inducing a rapid remission in patients with episodic cluster headache, although they may provide a brief respite for patients with chronic cluster headache. Long-term use of corticosteroids in these patients must be resisted. Dihydroergotamine. Intravenous DHE is an attractive transitional treatment but is more labor intensive because patients either need to be admitted or brought to an outpatient infusion center for therapy. Typically within 1 or 2 days of repetitive DHE treatment, cluster attacks stop and will not return for days to months. This allows time for a maintenance preventive agent to be started, and when the effects of the DHE wear off, the true maintenance preventive agent’s effects have already kicked in. Mather and colleagues (1991) reported the use of repetitive intravenous DHE in 54 cluster patients (23 episodic, 31 chronic). At the same time DHE was initiated, a preventive agent was also started. Onehundred percent of patients had complete relief of attacks with DHE. At 3-month follow-up, 93% of the episodic patients remained cluster free and 7% demonstrated a 50% to 74% improvement. Of the chronic cluster patients, 44% were headache free at 3 months and another 52% showed at least a 50% improvement. While a patient is on DHE therapy, sumatriptan and other vasoconstrictive agents cannot be used concomitantly. Occipital nerve blockade. Anthony (1985) was the first to report on the use of occipital nerve blockade to arrest cluster headache attacks. Mitsias and
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Continuing a preventive agent even after the patient has gone out of cycle does not appear to prevent a subsequent cluster period from starting.
colleagues (2001) recently treated 12 patients with greater occipital nerve blocks; a total of 24 blocks were performed on 24 attacks. Twenty-three (96%) were successful in completely aborting a cluster headache cycle within 7 days. Peres and colleagues (2002) treated 14 cluster headache patients with greater occipital nerve block as transitional therapy. The mean number of headache-free days was 13.1. Four patients (28.5%) had a good response, five (35.7%) a moderate response, and five (35.7%) no response. The greater occipital nerve block was well tolerated with no adverse events. Headache intensity, frequency, and duration were significantly decreased comparing the week before with the week after the nerve block (P<.003, P=.003, P<.005, respectively). Anecdotally, occipital nerve blockade using a combination of an anesthetic (eg, lidocaine) and steroid (eg, triamcinolone) will not only break an ongoing single attack of cluster, but when used interictally can prevent cluster attacks from coming on for at least 1 to 2 days and sometimes for up to 6 weeks. Isolated instances have occurred where nerve blockade has terminated an ongoing cluster period. Nerve blockade appears to work in cluster headache even in the absence of defined neck trigger points. Preventive Therapy Preventive agents are absolutely necessary in patients with cluster headache unless the cluster periods last for less than 2 weeks. Preventive medications are used only while the patient is in cycle and are tapered off once a cluster period has ended. Continuing a preventive agent even after the patient has gone out of cycle does not appear to prevent a subsequent cluster period from starting. The maintenance preventive agent should be started at the time a transitional agent is given. Most physicians treating cluster headache
will increase the dosages of the preventive agents very quickly to get a desired response. Very large dosages, much higher than that suggested in the Physician’s Desk Reference, are sometimes necessary when treating cluster headache. A well-recognized trait of cluster patients is that they can tolerate medications much better than noncluster patients. Most of the recognized cluster preventive agents can be used in both episodic and chronic cluster headache. Polypharmacy is not discouraged in cluster headache prevention. If a patient has partial response on one agent, another preventive agent can be added to this rather than starting over from scratch. Not unlike the multiple preventive regimens utilized in trigeminal neuralgia, cluster attacks are so severe that add-on therapy is encouraged (Table 9-3).
TABLE 9-3
Preventive Agents
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Verapamil (80 mg): quick taper up, can push to high levels (greater than 480 mg); order electrocardiogram with every dose change above 480 mg
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Lithium carbonate (300 mg): dose range 300 mg to 900 mg
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Divalproex sodium ER (500 mg): dose range 500 mg to 3000 mg
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Ergot: 1 mg/d to 3 mg/d if short cluster periods (1 to 3 weeks) only
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Topiramate (25 mg): dose range 50 mg to 400 mg (typical dose 75 mg or less)
"
Melatonin (3 mg): 9 mg at bedtime
"
Possibly baclofen and gabapentin
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Verapamil. Verapamil appears to be the best first-line preventive therapy for both episodic and chronic cluster headache. It can be used safely in conjunction with sumatriptan, ergotamine, corticosteroids, as well as other preventive agents. Leone and colleagues (1999) compared the efficacy of verapamil with placebo in the prophylaxis of episodic cluster headache. After 5 days’ run-in, 15 patients received verapamil (120 mg 3 times a day [tid]) and 15 received placebo tid for 14 days. The authors found a significant reduction in attack frequency and abortive agent consumption in the verapamil group. The initial starting daily dosage of verapamil is 80 mg tid or getting up to this dosage within 3 to 5 days. The nonsustained release formulation appears to work better than the sustained release preparation, but no literature proves this. Dosages are typically increased by 80 mg every 3 to 7 days. If a patient needs more than 480 mg per day, an electrocardiogram is necessary before each dose change thereafter to guard against heart block. It is not uncommon for patients with cluster headache to need dosages as high as 800 mg to gain cluster remission. Most headache specialists will push the dose as high as 1 g if tolerated. Constipation is the most common side effect, but dizziness, edema, nausea, fatigue, hypotension, and bradycardia may also occur. Lithium carbonate. Lithium carbonate therapy is still considered a mainstay of cluster prevention, but its narrow therapeutic window and high side effect profile make it less desirable than other newer preventive agents. As of 2001, 28 clinical trials have looked at the efficacy of lithium in cluster therapy. For chronic cluster, 78% of patients treated (in 25 trials) have improved on lithium, while 63% of episodic patients have gained cluster remission on lithium. When lithium was compared with
verapamil in a single trial, both agents were found to be effective, but verapamil caused fewer side effects and had a more rapid onset of action (Bussone et al, 1990). A single double-blind, placebo-controlled trial failed to show superiority of lithium (800 mg sustained release) over placebo. However, this study was stopped 1 week after treatment began, and an unexpectedly high placebo response rate of 31% occurred (Steiner et al, 1997). The treatment period was therefore too short to be conclusive. The initial starting dosage of lithium is 300 mg at bedtime with dose adjustments usually not pushing the dose higher than 900 mg per day. Lithium is often effective at serum concentrations (0.3 mmol to 0.8 mmol) lower than those usually required for the treatment of bipolar disorder. Most cluster patients benefit from dosages between 600 mg/d and 900 mg/d. During the initial treatment stages, lithium serum concentrations should be checked repeatedly to guard against toxicity. Serum lithium concentrations should be measured in the morning 12 hours after the last dose. In addition, prior to starting lithium, renal and thyroid functions need to be checked. Adverse events related to lithium include tremor, diarrhea, and polyuria. Valproic acid. In an open-label investigation, 26 patients (21 chronic cluster, 5 episodic cluster) were treated with divalproex sodium (Freitag et al, 2000). Mean decrease in headache frequency was 53.9% for the chronic cluster patients and 58.6% for the episodic cluster patients. Mean dose of divalproex sodium used was 838 mg, which could be considered a low dose by cluster standards. Recently a double-blind, placebo-controlled study of sodium valproate (1000 mg/d to 2000 mg/d) in patients with cluster headache was completed. Ninety-six patients were included, 50 in the sodium valproate
KEY POINTS:
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Verapamil appears to be the best firstline preventive therapy for both episodic and chronic cluster headache. Lithium carbonate therapy is still considered a mainstay of cluster prevention, but its narrow therapeutic window and high side effect profile make it less desirable than other newer preventive agents.
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Topiramate is a newer antiepileptic that may be efficacious in both migraine and cluster headache prevention.
group and 46 in the placebo group. After a 7-day run-in period, patients were treated for 2 weeks. Primary efficacy was the percentage of patients having an at least 50% reduction in the average number of attacks per week between the run-in period and the last week of treatment. Fifty percent of subjects in the sodium valproate group and 62% in the placebo group had significant improvement (P=.23). Because of the high success rate in the placebo group the authors felt that they could make no conclusion about the efficacy of sodium valproate in cluster (El Amrani et al, 2002). Divalproex sodium is still considered an effective therapy for cluster headache. Suggested dosing is extended-release divalproex sodium starting at 500 mg at bedtime and increasing by 500 mg every 5 to 7 days up to 3000 mg. Cluster patients seem to be very sensitive to developing tremor on the higher doses of divalproex sodium. Topiramate. Topiramate is a newer antiepileptic that may be efficacious in both migraine and cluster headache prevention. Lainez and colleagues (2003) treated 26 patients (12 episodic, 14 chronic) with topiramate to a maximum dose of 200 mg. Topiramate rapidly induced cluster remission in 15 patients, reduced the number of attacks more than 50% in six patients, and reduced the cluster period duration in 12 patients. The mean time to remission was 14 days, but in seven patients remission was obtained within the first days of treatment with very low doses (25 mg/d to 75 mg/d). Six patients discontinued treatment because of side effects (all with daily doses more than 100 mg) or lack of efficacy. Topiramate should be initiated at a dose of 25 mg per day and increased in 25-mg increments every 5 days up to 75 mg. The patient should be monitored at this dose for several weeks before deciding whether the dose needs to be
increased. Dosages up to 400 mg have been needed in some cluster patients. Anecdotally a therapeutic window appears to exist for topiramate in cluster. Some patients have experienced worsening of attacks when the dose is raised above a certain limit and improvement again when the dose is lowered. Melatonin. Serum melatonin levels are reduced in patients with cluster headache, particularly during a cluster period. This loss of melatonin may be the inciting event necessary to produce at least nocturnal cluster attacks. The efficacy of 10 mg of oral melatonin was evaluated in a double-blind, placebocontrolled trial (Leone et al, 1996). Cluster headache remission within 3 to 5 days occurred in five of 10 patients who received melatonin compared with zero of 10 patients who received placebo. Melatonin only appeared to work in episodic cluster patients. Recently melatonin has also been shown to be an effective preventive agent in chronic cluster headache (Peres and Rozen, 2001). A negative study utilizing melatonin for cluster prevention was published, but the dosing was lower than the other studies and a sustained preparation was given (Pringsheim et al, 2002). This author believes that melatonin should be initiated in all cluster patients as a first-line preventive therapy, sometimes even before verapamil. It has very minimal side effects and, in a substantial number of patients, can turn off nocturnal clusters (typically the most severe attacks) within 24 hours. Melatonin also appears to prevent daytime attacks. In addition, even when melatonin does not completely resolve all of the attacks, it appears to lower the dose required for the other add-on preventive agents. For example, a long-standing cluster sufferer always became cluster free on valproic acid at a dose of 1500 mg. After being placed on melatonin, he only needed a valproic acid
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dose of 500 mg to become cluster free. Melatonin appears to work as well in chronic cluster as episodic, and some patients with chronic cluster headaches become cluster free on melatonin monotherapy. The typical dose of melatonin used is 9 mg at bedtime (three 3-mg tablets), but higher doses may be necessary. If one brand of commercial melatonin fails to work, another should be tried because the true amount of melatonin in various over-the-counter brands varies widely. The positive effects of lithium may depend on its ability to increase serum melatonin levels. Other agents that have shown some efficacy in cluster headache include daily triptans (naratriptan and frovatriptan), gabapentin, and baclofen. Surgical Treatment Surgical treatment of cluster headache should only be considered after a patient has exhausted all medical options or when a patient’s medical history precludes the use of typical cluster abortive and preventive medications. Patients with episodic cluster headache should rarely, if ever, be referred for surgery because of the presence of remission periods. Once a cluster patient is deemed a medical failure, only those who have strictly side-fixed headaches should be considered for surgery. If a patient has had past episodes in which cluster attacks have alternated sides, there is a high risk after surgery of having attack recurrence on the side opposite of where the surgery was completed. This can be truly devastating for a patient. Other criteria for cluster surgery include pain mainly localizing to the ophthalmic division of the trigeminal nerve and a psychologically stable individual without an addicting personality. Patients with cluster headache must understand that in most instances, to alleviate their
cluster pain, the trigeminal nerve will have to be injured, leaving them not only with facial analgesia but a risk of developing severe adverse events, including corneal anesthesia and anesthesia dolorosa. Surgical Techniques Anatomically it makes sense that in order to turn off the cluster headache and its associated autonomic symptoms, surgery should be directed toward the sensory trigeminal nerve and the cranial parasympathetic system. Changing the firing pattern of the hypothalamus, possibly the ‘‘cluster generator,’’ would also be an intriguing technique to abort cluster. Surgery on the cranial parasympathetic system. The parasympathetic autonomic pathway can be interrupted by sectioning the greater superficial petrosal nerve, the nervus intermedius, or the sphenopalatine ganglion. Based on the trigeminal autonomic reflex pathway hypothesis for cluster pathogenesis, this technique should obliterate the autonomic symptoms associated with a cluster headache. However, the procedure would appear unlikely to affect the cluster-associated pain because this is a trigeminal nerve–driven response, although the nervus intermedius may have nociceptive fibers. From reports in the literature techniques, targeting the autonomic system in cluster headache has provided very inconsistent pain relief in patients and when deemed initially effective has had high recurrence rates. Surgery on the sensory trigeminal nerve. Procedures directed toward the sensory trigeminal nerve include alcohol injection into supraorbital and infraorbital nerves, alcohol injection into the gasserian (trigeminal) ganglion, avulsion of infraorbital/supraorbital/ supratrochlear nerves, retrogasserian glycerol injection, radiofrequency (RF)
KEY POINTS:
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Patients with episodic cluster headache should rarely, if ever, be referred for surgery because of the presence of remission periods. Literature techniques targeting the autonomic system in cluster headache have provided very inconsistent pain relief in patients and when deemed initially effective have had high recurrence rates.
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Radiofrequency thermacoagulation is the most commonly used surgical technique for cluster headache, and it provides one of the best options for pain relief.
trigeminal ganglio-rhizolysis, and trigeminal root section. Overall, these techniques have been the most successful at alleviating cluster pain, but with some of the procedures the possibility of very severe adverse events is present. Radiofrequency thermocoagulation. RF thermocoagulation is the most commonly used surgical technique for cluster headache, and it provides one of the best options for pain relief. The results of RF rhizotomies in cluster are encouraging, although only a handful of studies in the literature are available. Maxwell (1982) treated eight patients with chronic cluster headache with RF, and all had initial pain relief. In five of eight patients, pain relief lasted for a mean of 32 months. Mathew and Hurt (1988) treated 27 patients with chronic cluster headache with a mean followup of 28 months. The results in 20 of the patients were ‘‘good to excellent.’’ Sweet (1988) treated 20 patients with RF, and 11 of them had continuous pain relief for up to 20 years. Taha and Tew (1995) recently reviewed the charts of seven patients with chronic cluster headache who received RF ganglio-rhizolysis. All patients had immediate pain relief, and at follow-up two patients remained pain free 7 and 20 years later. Three patients had mild pain recurrence that was controlled with medication 6 to 12 months postsurgery, and two patients did poorly with complete pain recurrence within 2 months of surgery. No association was made between patient age, gender, attack duration, preoperative response to lidocaine blockade, and relief with RF. Overall with RF about 50% of patients have done very well, 20% have reported fair to good results, and about 30% have failed the procedure. Adverse events with RF include moderate facial dysesthesia, severe facial dysesthesias, corneal sensory loss, and anesthesia dolorosa. The surgeon can reduce side effects by making the end
point hypoalgesia rather than analgesia. Other less common but devastating side effects include intracranial hemorrhage, stroke, infection, and motor weakness that typically resolves over 1 to 6 months. Advantages of RF include its being a highly specific technique that is safe in elderly persons and has low recurrence and mortality rates. Also, the surgeon can vary the amount of sensory loss. Disadvantages include its being an expensive technique and a tedious skilled procedure, which can result in corneal anesthesia, sensory loss beyond the area affected, possible anesthesia dolorosa, and keratitis. Anesthesia dolorosa or painful numbness has been described by some patients as a much worse sensation than the cluster headaches themselves, especially as it is a constant sensation. New strategy. Hypothalamic stimulation. There has always been a suggestion that a hypothalamic influence over cluster headache is based on the circadian rhythmicity of the syndrome and the neurohormonal changes identified in cluster headache patients. Functional imaging has been able to strengthen this theory. May and colleagues (1998) studied nine cluster headache patients with positron emission tomography (PET). Cluster headaches were triggered with nitroglycerin. During a cluster attack, areas that were activated on PET included anterior cingulate cortex bilaterally, posterior thalamus, insular cortex, and basal ganglia regions, which are all known to be involved in pain processing or response to pain. Unique to cluster headache was activation in the ipsilateral inferior posterior hypothalamic gray matter. Whether the hypothalamus was acting as a cluster headache generator or modulator of cluster pain could not be determined from this study and at present is still a major question in cluster headache pathogenesis.
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Based on the PET findings, Leone and associates began to look at the role of hypothalamic stimulation in the treatment of refractory cluster headache. Leone and colleagues (2004) have now treated more than 14 treatment refractory chronic cluster headache patients with electrode implantation into the posterior inferior hypothalamus. Almost every patient has had a tremendous reduction in cluster frequency, and some have become pain free. No major adverse events have occurred in the Italian group, but a recent pilot study from Belgium had one death (Schoenen et al, 2005). The relationship to the stimulator surgery is unknown. What is exciting about this new surgical technique is that knowledge of pathogenesis helped in the discovery of a therapy for cluster headache. CHRONIC PAROXYSMAL HEMICRANIA Chronic paroxysmal hemicrania (CPH) is a rare syndrome marked by headaches of short duration, high frequency of attacks, and associated autonomic symptoms. It was first described by Sjaastad and Dale in 1974 and has now been diagnosed all over the world (Sjaastad and Dale, 1974). CPH pain location is normally orbital, temporal, and above or behind the ear and is one sided. The pain, described as boring, clawlike, or pulsatile, is severe in intensity and may radiate to the neck or ipsilateral shoulder. Residual mild pain may remain between attacks. Normal headache duration is between 2 and 30 minutes. Unlike cluster headache, a predilection for nocturnal attacks is absent in CPH, although attacks can certainly awaken a patient from sleep. Associated symptoms are marked by autonomic phenomena. Most patients with CHP exhibit lacrimation (62%) followed by nasal congestion (42%),
conjunctival injection and rhinorrhea (36%), and ptosis (33%) (Antonaci and Sjaastad, 1989). Unlike cluster headache, a true Horner’s syndrome is not seen in CPH. Patients with CPH may have photophobia, but gastrointestinal disturbances are rare. CPH attacks can sometimes be triggered by rotating the neck or flexing the head to the side of the headaches or by applying external pressure to the transverse processes of C4-C5 or the C2 nerve root on the symptomatic side. Unlike the cluster patient who would need to ‘‘pace the floors,’’ the patient with CPH may find that sitting still or lying in bed lessens the pain. CPH appears to be a disorder of women. The female-to-male ratio is about 3:1. No difference exists between women and men with CPH in regard to attack duration, frequency, or age of onset. Men experiencing long-duration CPH attacks have a lower frequency of attacks than do men with shortduration attacks. This inverse correlation is not seen in women. CPH appears to occur in all races, and its true prevalence is unknown. CPH normally develops in the second or third decade of life, but it can occur at any age. No one knows the true natural history of CPH as to whether it is a self-limited syndrome or a lifelong condition. In a review of all reported cases as of 1989, Antonaci and Sjaastad (1989) found a mean duration of illness to be 13 years. Patients with CPH do not have a higher familial incidence of cluster headache. About 20% of patients will have a family history of migraine; this is about equal to the percentage of cluster patients with a familial experience of migraine. As CPH is a disorder of women, hormonal factors would appear to play a significant role in its pathogenesis. Like migraine, CPH is influenced by female sex hormones, but no specific pattern has been noted. Women with CPH may have improvement or worsening
KEY POINT:
A
In chronic paroxysmal hemicrania normal headache duration is between 2 and 30 minutes. Unlike cluster headache, there is no predilection for nocturnal attacks, although attacks can certainly awaken a patient from sleep.
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Chronic paroxysmal hemicrania is one of the rare headache disorders that by definition is totally responsive to indomethacin. Individuals requiring high doses of indomethacin (200 mg/d to 250 mg/d) are more apt to have underlying secondary causes of chronic paroxysmal hemicrania.
during menses. Symptoms can improve during pregnancy, and cases of CPH induction just after delivery have been reported. Oral contraceptives do not appear to influence CPH, and no studies are available on the effect of menopause on CPH. Medical history in patients with CPH is usually unremarkable, although head trauma has been reported in up to 15% of patients and neck trauma in about 10% of patients. CPH has developed after surgery for uterine polyps, maxillary sinusitis, and fibromas. No relationship appears to exist between CPH and other primary medical disorders, although a history of diabetes mellitus, hyperthyroidism, malignant melanoma, epilepsy, or idiopathic thrombocytopenia has been noted in documented patients with CPH. In regard to treatment strategies, CPH is one of the rare headache disorders that by definition is totally responsive to indomethacin. Headache specialists will expose a probable CPH patient to a short, therapeutic trial of indomethacin, looking for a response. The normal starting dosage of indomethacin is one 25-mg tablet tid for 3 days; this dose can be increased to two tablets (50 mg) tid if total relief of pain has not occurred. Most individuals will respond with a dosage of 150 mg/d, and the response can be dramatic with quick dissipation of headache symptoms. A beneficial effect will normally be seen within 48 hours after the correct dosage has been found. Some individuals need a dose of indomethacin as high as 300 mg/d, but safety concerns prevent sustaining such a high dose. If no response occurs at 150 mg/d, and the physician still suspects CPH, an extra 25-mg dose of indomethacin can be added every 3 days, to a total of 225 mg/d or the onset of side effects. If the patient does not respond at 75 mg tid, one should consider an alternative diagnosis. Sjaastad and colleagues (1995) found that indi-
viduals requiring high doses of indomethacin (200 mg/d to 250 mg/d) are more apt to have underlying secondary causes of CPH. Side effects of indomethacin therapy are mainly gastrointestinal disturbances with either dyspepsia or ulcer development. The gastrointestinal side effects can normally be controlled with histamine type 2 receptor antagonists, proton pump inhibitors, or prostaglandins. Misoprostol at a dose of 100 mg 4 times a day to 200 mg 4 times a day is very successful for preventing nonsteroidal-induced ulcers. This agent is not well tolerated by patients, however, because of its side effects of diarrhea and abdominal pain. Potentially serious renal implications to long-term indomethacin usage are known, including the development of renal papillary necrosis. Individuals normally require continuous dosing until the CPH syndrome has completed its course (this can be lifetime dosing). Symptoms usually recur as soon as 12 hours or up to several days after discontinuing indomethacin. Boes and Dodick (2002), evaluating 74 patients with CPH, found that 30 (75%) of 40 patients had a consistent response to indomethacin, whereas 25% did not. Some patients (9/13) were able to stop indomethacin without headache recurrence. Very few had to stop indomethacin because of side effects. Two patients had initial responses to indomethacin that did not persist. The literature provides very little assistance when indomethacin is no longer a viable treatment option for CPH. Cyclooxygenase (COX)-2 inhibitors have given relief of CPH in some patients, but the dose required may be higher than that normally prescribed for arthritis, and at these doses the gastrointestinal protection these agents afford may be lost (Mathew et al, 2000; Rozen, 2002b). In addition, the safety of COX-2 inhibitors when used on a continuous basis has come into
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question. Evers and Husstedt (1996) presented alternative drug treatments for CPH. Twenty-two other agents had been studied in CPH; the most successful alternative preventive drug is verapamil in a dose of 240 mg/d to 320 mg/d. Acetylsalicylic acid, naproxen, and a piroxicam derivative have demonstrated some effect in a small number of cases. Acetazolamide was effective in a single case report. Prednisone is effective in high doses for controlling CPH but is not considered an adequate chronic therapy regimen because of its side effect profile. CPH shows a poor response to carbamazepine and oxygen. Sumatriptan has been a good abortive agent in several case reports, although it is not uncommon to see it fail in CPH attacks. Oxygen rarely, if ever, will abort an attack, although in the Boes and Dodick study (2002) oxygen was beneficial in three patients. Every patient with possible CPH must have diagnostic neuroimaging to exclude an underlying secondary cause. Structural mimics of CPH have included a parasellar pituitary microadenoma, maxillary cyst, occipital infarction, gangliocytoma growing from the sella turcica, ophthalmic herpes zoster infection, arteriovenous malformation, cavernous sinus meningioma, frontal lobe tumor, and a Pancoast tumor. Magnetic resonance imaging (MRI) is suggested as the neuroimaging procedure of choice because of its higher sensitivity than computed tomography for visualizing tumors and vascular malformations. Update on Pathogenesis Very recently a PET study of CPH demonstrated contralateral posterior hypothalamic and contralateral ventral midbrain activation during an attack (Matharu et al, 2005). Interestingly, even though the clinical presentation of CPH is similar to cluster headache,
the location of hypothalamic activation is not exactly the same in the two disorders. (Case 9-1). SUNCT SYNDROME The syndrome of short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing, or SUNCT, was first described by Sjaastad and colleagues in 1978 (Sjaastad et al, 1978). The description of the complete syndrome came in 1989 (Sjaastad et al, 1989). SUNCT is one of the rarest of the primary headache disorders. Many headache specialists have stated that they have never seen SUNCT. SUNCT is composed of brief attacks of moderate to severe head pain with associated autonomic disturbances of conjunctival injection, tearing, rhinorrhea, or nasal obstruction. The typical age of onset is between 40 and 70 years; mean age of onset is 51 years. SUNCT pain is normally localized to an orbital or periorbital distribution, although the forehead and temple can be the main sites of pain. Head pain can radiate to the temple, nose, cheek, ear, and palate. The pain is normally side locked and remains unilateral throughout an entire attack. In rare instances SUNCT pain can be bilateral. Pain severity is normally moderate to severe, unlike, for example, cluster headache pain that is always severe. Pain character is described most often as a stabbing, burning, pricking, or electric shocklike sensation. Pain duration is extremely short, lasting between 5 and 240 seconds, with an average duration of 10 to 60 seconds. This extremely brief pain duration sets SUNCT apart from other primary headache syndromes (eg, cluster headache, CPH, and migraine). Pain onset is abrupt, reaching maximum intensity in 2 to 3 seconds. SUNCT pain normally plateaus at a maximum intensity for several
KEY POINT:
A
In SUNCT, pain duration is extremely short, lasting between 5 and 240 seconds, with an average duration of 10 to 60 seconds.
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Case 9-1 A 45-year-old man with a history of episodic cluster headache presents while in a cycle. He relates that something had changed from the previous cycles that he had been experiencing on and off for 20 years. His headache was left-sided as always, but the frequency and duration of attacks were much different. He used to average three headaches in a day, each lasting 75 minutes and associated with ipsilateral ptosis, lacrimation, and nasal rhinorrhea. The headaches were exquisitely sensitive to inhaled oxygen and sumatriptan injections. Now he is having about 15 attacks per day, each lasting 15 minutes, and his oxygen and sumatriptan are no longer effective. The associated autonomic symptoms have not changed. Based on the duration and frequency of attacks a diagnosis of paroxysmal hemicrania is made. The patient receives indomethacin at a dose of 150 mg/d and becomes pain free. Comment. This case illustrates that trigeminal autonomic cephalalgias are a spectrum of headaches and more than one type can occur in a single individual. The attack frequency and duration are essential information when making a diagnosis of a trigeminal autonomic cephalalgia. In this case, prior to the most recent cycle of pain the patient had classic cluster headache, which responded appropriately to typical cluster abortives. The shortening of attack duration and increasing attack frequency suggested a transition to paroxysmal hemicrania and a requisite trial of indomethacin. If this patient would have been diagnosed with atypical cluster headache and never tried on indomethacin, he would have been unlikely to experience any alleviation of his pain. Typical cluster abortives normally will not work on the pain of paroxysmal hemicrania.
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seconds and then quickly abates. Some individuals will experience a ‘‘sawtooth–like’’ pattern, with rapid changes in maximum intensity levels (Pareja and Sjaastad, 1994). SUNCT can occur at any time of the day and shows no tendency toward nocturnal attacks; only 1.2% of reported sufferers have nighttime episodes. Attack frequency varies greatly between sufferers and within an individual sufferer. The usual attack frequency ranges anywhere from 1 to more than 80 episodes a day. Individuals can experience fewer than one attack an hour to more than 30 an hour. Mean attack frequency is 28 attacks per day. Most SUNCT patients will be pain free between attacks, although isolated reports are known of patients experiencing low-background pain interictally. SUNCT is an episodic disorder that presents in a
relapsing or remitting pattern. Each symptomatic period can last from several days to several months, and a person with SUNCT will typically have one to two symptomatic periods a year. The longest documented symptomatic period has been 5 years, and the highest number of reported SUNCT episodes in 1 year is 22. Remissions typically last months but can last years. Symptomatic periods appear to increase in frequency and duration over time. All documented patients with SUNCT experience conjunctival injection and lacrimation (ipsilateral to the side of the head pain) with each attack. Ipsilateral rhinorrhea or nasal obstruction occurs in 67% of individuals. Lessfrequent associated symptoms include eyelid edema, a decreased palpebral issure, facial redness, photophobia, and blepharospasm. Typically, conjunctival
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injection and eye tearing will start within 1 to 2 seconds of pain onset and remain until the head pain ceases, sometimes outlasting the pain by up to 30 seconds. Rhinorrhea, on the other hand, starts in the mid to late part of an attack. Nausea, vomiting, photophobia, and phonophobia are not normally associated with SUNCT. SUNCT can arise spontaneously, but many sufferers have identified triggering maneuvers, including mastication, nose blowing, coughing, forehead touching, eyelid squeezing, neck movements (rotation, extension, and flexion), and ice-cream eating. No refractory period occurs between pain attacks in SUNCT, so if a trigger zone is stimulated during the ending phase of a previous attack, a new one can begin immediately. This is unlike the refractory period of trigeminal neuralgia. General and neurological examinations are normal in patients with SUNCT during and between attacks, except for the documented autonomic signs, which quickly abate when the attack ends. Individuals may have tenderness to palpation over the supraorbital and infraorbital nerves but little else. The true epidemiology of SUNCT is unknown, and no prevalence or incidence data are available. The extremely low number of reported cases suggests it is a very rare syndrome. SUNCT appears to have a male predominance, with a male-to-female ratio of 1.2:1 (Matharu and Goadsby, 2005). In most instances, neuroimaging studies in SUNCT syndrome are normal. Several cases of secondary SUNCT have been caused by cerebellopontine angle arteriovenous malformations, cavernous angioma of the pons, brain stem infarction, basilar impression, craniosynostosis, and human immunodeficiency virus infection (Trucco et al, 2004). Recently a connection between pituitary tumors (prolactinomas and acromegalic) has been documented
(Levy et al, 2005). All patients with SUNCT should have a brain MRI as part of their workup. SUNCT in many instances is refractory to medical therapy. The extremely short duration of head pain would appear to preclude the use of abortive treatment. By the time a patient with SUNCT would take an abortive medication for an individual headache, the attack theoretically would already be completed. Isolated cases of sumatriptan alleviation of SUNCT have been reported, but these probably reflect spontaneous attack remissions rather than drug-induced remissions. Preventive agents that have previously been tried include aspirin, paracetamol, indomethacin, naproxen, ergotamine, DHE, sumatriptan, prednisone, methysergide, verapamil, valproate, lithium, propranolol, amitriptyline, and carbamazepine (Goadsby and Lipton, 1997). Carbamazepine has shown partial effect in some patients. Combining carbamazepine and a short course of corticosteroids at the onset may be more efficacious than starting with carbamazepine alone. Azathioprine was shown to be somewhat effective in one patient. Greater occipital and supraorbital nerve blockades have been unsuccessful. Recently lamotrigine, gabapentin, and topiramate have shown some success in isolated case reports (D’Andrea et al, 2001; Porta-Etessam et al, 2002; Rossi et al, 2003). Surgical procedures that have been tried in SUNCT and have produced mixed results include glycerol rhizotomy, Gamma Knife, microvascular decompression of the trigeminal nerve, and balloon compression of retro-ganglionic fibers.
KEY POINTS:
A
A
In SUNCT, no refractory period occurs between pain attacks, so if a trigger zone is stimulated during the ending phase of a previous attack, a new one can begin immediately. Recently a connection between pituitary tumors (prolactinomas and acromegalic) has been documented.
Update on Pathogenesis As in cluster headache and CPH, hypothalamic activation is also noted in SUNCT on functional imaging. Both ipsilateral activation and bilateral activation have been noted (Sprenger et al,
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KEY POINT:
A
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Patients with hemicrania continua will experience a continuous daily head pain, which is present 24 hours per day, 7 days per week, and pain exacerbation periods that occur with varying frequency from multiple times per week to every third month or less.
2005). Hypothalamic stimulation was recently shown to be efficacious in a single case of refractory SUNCT. HEMICRANIA CONTINUA The term hemicrania continua (HC) was first introduced in 1984 by Sjaastad and Spierings. Initially HC was felt to be a very rare syndrome, although now it is believed to be more common and is probably routinely misdiagnosed. More than 90 cases have been reported in the literature. HC, like migraine and CPH, has a female predominance. Two forms of HC are recognized: nonremitting, which occurs in about 85% of patients (no remission periods), and remitting. The nonremitting form can be continuous from onset or evolve from the remitting form. The clinical characteristics of HC include two patterns of headache. Patients with HC will experience a continuous daily head pain, which is present 24 hours per day, 7 days per week, and pain exacerbation periods, which occur with varying frequency from multiple times per week to every third month or less. The daily continuous pain of HC is usually of mild to moderate intensity, affecting the temple or periorbital region. It is always present on the same side of the head. Some reports have described the pain of HC as switching sides or being bilateral, but in those cases a true diagnosis of HC comes into question. The pain exacerbation periods are marked by moderate to severe pain lasting hours to days in duration with associated symptoms that are seen in patients with migraine and cluster headache. Migrainous symptoms include nausea, vomiting, photophobia, and phonophobia. Autonomic symptoms include unilateral lacrimation, ptosis, nasal congestion, and rhinorrhea. Other key symptoms that are commonly seen during a pain exacerbation period include eyelid swell-
ing, eyelid twitching, and ‘‘ice-pick’’ headaches. Some patients with HC will also complain of a foreign body sensation, such as a piece of sand or an eyelash in the eye, on the same side as their headaches. Patients with HC can also experience auras that typically occur just prior to a pain-exacerbation period. Indomethacin alleviates both the headache and aura. One of the best descriptions of the clinical features of HC has come from an observational study from the Jefferson Headache Center in Philadelphia (Peres et al, 2001). Thirty-four new cases of HC were identified. The baseline continuous headache was mild to moderate in intensity with no headache-related disability and rare associated symptoms. During the headache-exacerbation period, pain was normally severe. Associated symptoms included migrainousphotophobia (59%), phonophobia (59%), nausea (53%), and vomiting (24%); autonomic symptoms consisted of lacrimation (53%), nasal congestion (21%), and ptosis (18%). Seventy-four percent of the patients experienced at least one autonomic symptom during the pain-exacerbation period. The presence of jab/jolt headaches occurred in 41%. Interestingly, the exacerbation headache met the International Headache Society criteria for migraine in 71% of patients. The most common form of HC was the continuous pattern from onset (53%), followed by continuous evolving from remitting (35%) and remitting (12%). In regard to therapy, HC is defined by its responsiveness to indomethacin. Some authors have suggested an indomethacin-resistant form of HC, although this is controversial. The response to indomethacin is one of the most dramatic treatment responses in headache. Patients can literally become pain free after their first dose of indomethacin regardless of duration of their headaches. This author has two
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Case 9-2 A 38-year-old woman presented with a complaint of daily right-sided headache. She had no significant headache history until 6 years prior, when her headache started daily from onset. Her headache was always in a right frontotemporal and periorbital distribution. Typically it was of low-grade intensity. At times it almost felt as if she had no pain, but if she thought about it the pain was always present. Several times per month the headache would become severe. It would never move to the left side. The duration of the severe headache could vary from several hours to several days. During the period of pain exacerbation she would develop nausea and vomiting as well as photophobia. She also noticed that she could develop a right eyelid droop and some lacrimation. Her conjunctiva would never become injected, and she had no complaint of nasal congestion or rhinorrhea. Her right eyelid would sometimes become swollen, and her eye could even swell shut. During these periods of intense pain the patient was unable to function at her job and had trouble completing any of her activities of daily living. She had tried numerous medications for these headaches, including large amounts of ibuprofen (twenty 200-mg tablets per day), triptans, corticosteroids, opiates, and butalbital-containing compounds, all without benefit. Past preventive agents included verapamil, amitriptyline, lithium, valproic acid, and fluoxetine, also with no response. On presentation she was using acetaminophen, which she had been taking daily for the last 2 years. Comment. The patient presents with a primary complaint of a continuous one-sided headache that appears to have started daily from onset and is of mild pain intensity at baseline with pain-exacerbation periods of severe headache. Associated symptoms occurring during the exacerbation periods are both migrainous (nausea, vomiting, photophobia) and clusterlike (ptosis, eyelid swelling, lacrimation). The headache always remains one-sided and never switches sides. Only a few primary headache disorders are side fixed, and each has a very defined presentation. They include cluster headache, paroxysmal hemicrania, SUNCT, and even migraine. What distinguishes this patient’s headaches from cluster, SUNCT, and CPH is the fact that she has persistent pain all the time and the pain-exacerbation periods can last upward of several days. This possibly could be chronic migraine as the patient has migrainous features, has more than 15 headache days per month, and is in analgesic overuse, which can present with daily head pain. What argues against migraine as a diagnosis is the absence of a history of episodic migraine that slowly evolved into a daily headache in the face of analgesic overuse. In this case the patient’s headaches occurred daily from onset, and the analgesic overuse only started after the headaches began. Migraine sufferers absolutely can have autonomic symptoms during headache attacks, so the presence of autonomic symptoms does not rule out a diagnosis of migraine. A daily headache from onset may also be secondary to an underlying pathological condition. One-sided secondary headaches may be the result of a cortical neoplasm, carotid dissection, cerebral vein thrombosis, giant cell arteritis, and rarely spontaneous cerebrospinal fluid leak. This patient would definitely require neuroimaging, including brain MRI with and without gadolinium, magnetic resonance angiography of the brain and neck with dissection protocol, and a magnetic resonance venogram. This patient was given a trial of indomethacin, and her pain was alleviated. As long as she remained on indomethacin she was pain free, but every time she tried to taper off her pain returned. After a successful trial of indomethacin for HC or CPH, the physician then should instruct the patient to find the smallest effective dose of indomethacin (during the trial, patients are escalating from 75 mg to 150 mg; thus they may be pain free at 100 mg). In addition, patients should be prescribed histamine-2 receptor antagonists (H2 blockers) and/or misoprostol to help protect against future gastrointestinal disturbances. Patients need to recognize the long-term gastrointestinal and renal risks associated with the use of indomethacin, but because there are so few, if any, effective alternative treatments, most people will choose to remain on indomethacin after the trial. At least once, probably twice per year, the indomethacin should be tapered off to see if the HC is still present. In some instances the syndrome will remit.
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patients who had undiagnosed HC for over 30 years prior to being exposed to indomethacin, and each had almost immediate pain relief once indomethacin was initiated. The same indomethacin trial used for CPH is completed to make a diagnosis of HC. Other agents that have been employed in HC include ibuprofen, piroxicam-beta cyclodextrin, and naproxen. Even at high doses the effect is not the same as with indomethacin. Recently several authors have documented that the COX-2 inhibitors rofecoxib and celecoxib have shown effect in HC (Peres and Silberstein, 2002). Little is known of the natural history of HC. Studies indicate that some patients are able to taper off indomethacin with no return of symptoms while in others HC is a lifelong illness. HC has been shown to recur as soon as 12 to 120 hours after discontinuation of indomethacin. Pareja and colleagues (2001) carried out a retrospective analysis of 16 patients with HC, assessing the efficacy and tolerability of long-term indomethacin usage in patients with HC and CPH. Follow-up was an average of 3.8 years after the start of indomethacin (range 1 to 11 years). In this group indomethacin dosing never exceeded 150 mg/d. Complete headache relief occurred within 3 days of an effective dose in all patients. Over time, 42% of the patients had a 56% reduction in the amount of the effective indomethacin dose, while 55% could not alter the dose amount because of headache recurrence. Older patients were more likely to be able to decrease their dose. Thirty percent of patients developed adverse events on indomethacin, but none led to drug discontinuation. No tachyphylaxis was noted. Patients with persistent one-sided headaches (even those who are indomethacin responsive) may have an underlying cervicogenic cause. Irritation or inflammation (herniated disc,
facet hypertrophy) at the C2-3 level can produce persistent one-sided headache. Carotid dissection is also in the differential diagnosis of a one-sided headache. Update on Pathogenesis Recently PET imaging has shed some light on the possible pathogenesis of HC (Matharu et al, 2004). Activation was noted in the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in seven patients with indomethacin-sensitive HC. As HC has both migraine and cluster features, one could have predicted activation in the pons (as has been seen in spontaneous migraine) and hypothalamus (as documented in cluster headache). HC has always been classified as a type of chronic daily headache and not a trigeminal autonomic cephalalgia. Because patients with HC have associated autonomic symptoms and, like patients with the other trigeminal autonomic cephalalgias, have hypothalamic activation on neuroimaging during HC attacks, this syndrome could and perhaps should be recognized as a trigeminal autonomic cephalalgia (Case 9-2). CONCLUSION The trigeminal autonomic cephalalgias are a unique group of primary headaches with distinct clinical presentations. They all feature head pain as well as autonomic symptoms. Some are totally responsive to indomethacin, while now it also appears that all have some hypothalamic activation during attacks. Perhaps they should be reclassified as hypothalamic-driven syndromes. Neurologists must recognize the trigeminal autonomic cephalalgias because treatment is different than for migraine and these syndromes can cause great disability until the correct treatment plan is initiated.
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Sjaastad O, Dale I. Evidence for a new (?) treatable headache entity. Headache 1974;14:105–108.
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Sjaastad O, Russell D, Horven I, Bunaes U. Multiple neuralgiform unilateral headache attacks associated with conjunctival injection and appearing in clusters. A nosological problem. Proceedings of the Scandinavian Migraine Society, 1978:31.
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"
Sjaastad O, Saunte C, Salvesen R, et al. Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia 1989;9:147–156.
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Sjaastad O, Spierings EL. Hemicrania continua: another headache absolutely responsive to indomethacin. Cephalalgia 1984;4:65–70.
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Sjaastad O, Stovner LJ, Stolt-Nielsen A, et al. CPH and hemicrania continua: requirements of high indomethacin dosages—an ominous sign? Headache 1995;35;363–367. Important clinical observation that the need of high doses of indomethacin indicates a secondary cause of CPH or hemicrania continua.
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Sprenger T, Valet M, Platzer S, et al. SUNCT: bilateral hypothalamic activation during headache attacks and resolving of symptoms after trigeminal decompression. Pain 2005;113:422–426. Important observation for pathogenesis.
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Steiner TJ, Hering R, Couturier EG, et al. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia 1997;17:673–675.
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Trucco M, Mainardi F, Maggioni F, et al. Chronic paroxysmal hemicrania, hemicrania continua and SUNCT syndrome in association with other pathologies: a review. Cephalalgia 2004;24:173–184. Excellent review of secondary causes of trigeminal autonomic cephalalgias.
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Preventive treatment may prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions.
PREVENTIVE TREATMENT Stephen D. Silberstein, William B. Young
ABSTRACT The treatment of migraine may be acute (abortive) or preventive (prophylactic). Preventive therapy is used in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include enhancing the response to acute treatments, improving a patient’s ability to function, and reducing disability. The major medication groups for preventive migraine treatments include anticonvulsants, antidepressants, ß-adrenergic blockers, calcium channel antagonists, serotonin antagonists, botulinum neurotoxins, nonsteroidal anti-inflammatory drugs, and others (including riboflavin, magnesium, and petasides). If preventive medication is indicated, the agent should be chosen from one of the first-line categories, based on the drug’s relative efficacy in double-blind, placebo-controlled trials, its side effect profile, and the patient’s preference, as well as coexistent and comorbid conditions.
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INTRODUCTION—WHY AND WHEN TO USE MIGRAINEPREVENTIVE MEDICATIONS Migraine varies widely in its frequency, severity, and impact on patients’ quality of life. A treatment plan should consider not only the patient’s diagnosis, symptoms, and any coexistent or comorbid conditions, but also his or her expectations, needs, and goals (Lipton and Silberstein, 1994). The pharmacological treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability. It is possible that preventive treatment may also prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions. Silberstein and
colleagues (2003) retrospectively analyzed resource utilization information in a large claims database. Adding migrainepreventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. During the second 6 months after the initial preventive medication, as compared with the 6 months preceding preventive therapy, office and other outpatient visits with a migraine diagnosis decreased 51.1%, emergency department visits with a migraine diagnosis decreased 81.8%, computerized tomographic (CT) scans with a migraine diagnosis decreased 75.0%, magnetic resonance imaging (MRI) scans with a migraine diagnosis decreased 88.2%, and other migraine medication dispensements decreased 14.1% (Silberstein et al, 2003). The United States Evidenced-Based Guidelines for Migraine (Ramadan et al, 2001) have established the circumstances that might warrant preventive treatment (Box 6-1) (Silberstein, 2004a).
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Prevention is being underutilized. In the American Migraine Study II, 25% of all people with migraine, or more than 7 million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest (Lipton et al, 2001). However, only 5% of all migraineurs currently use preventive therapy to control their attacks (Lipton et al, 2002). Similarly, proven nondrug preventive strategies, including biofeedback, relaxation training, and cognitive behavioral therapy, are underused. The major medication groups for preventive migraine treatment (Table 6-1) include anticonvulsants, antidepressants, -adrenergic blockers, calcium channel antagonists, serotonin antagonists, neurotoxins, nonsteroidal antiinflammatory drugs (NSAIDs), and others (including riboflavin, minerals, and herbs). If preventive medication is indicated, the agent should be preferentially chosen from one of the first-line categories, based on the drug’s side effect profile and the patient’s coexistent and comorbid
conditions (Table 6-2) (Tfelt-Hansen, 2000). MECHANISM OF ACTION OF PREVENTIVE MEDICATIONS Most migraine preventive drugs were designed to treat other disorders. Serotonin antagonists were developed based on the concept that migraine is due to excess 5-hydroxytryptamine (5-HT). Antidepressants down-regulate 5-HT2 and -adrenergic receptors. Anticonvulsant medications decrease glutamate and enhance -aminobutyric acid (GABA)A, and block sodium or calcium channels. Potential mechanisms of migraine preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous system; enhancing antinociception; inhibiting cortical spreading depression; inhibiting peripheral and central sensitization; blocking neurogenic inflammation; and modulating sympathetic, parasympathetic, or serotonergic tone. Oshinsky (personal communication) has shown that descending control from the upper brain stem through serotonergic and noradrenergic systems modulates the trigeminal nucleus caudalis
Box 6-1 United States Evidenced-based Guidelines for Migraine—Preventive Treatment 1. Recurring migraine that significantly interferes with the patient’s
2. 3. 4. 5. 6.
KEY POINTS:
A
A
In the American Migraine Study II, 25% of all people with migraine, or more than 7 million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest. However, only 5% of all migraineurs currently use preventive therapy to control their attacks. If preventive medication is indicated, the agent should be preferentially chosen from one of the first-line categories, based on the drug’s side effect profile and the patient’s coexistent and comorbid conditions.
daily routine despite acute treatment (eg, two or more attacks a month that produce disability that lasts 3 or more days, or headache attacks that are infrequent but produce profound disability) Failure of, contraindication to, or troublesome side effects from acute medications Overuse of acute medications Special circumstances, such as hemiplegic migraine or attacks with a risk of permanent neurological injury Very frequent headaches (more than two a week), or a pattern of increasing attacks over time, with the risk of developing medication overuse headache Patient preference, that is, the desire to have as few acute attacks as possible
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Potential mechanisms of migraine preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous system; enhancing antinociception; inhibiting cortical spreading depression; inhibiting peripheral and central sensitization; blocking neurogenic inflammation; and modulating sympathetic, parasympathetic, or serotonergic tone.
TABLE 6-1
"
Angiotensin-converting Enzyme Inhibitors/ Angiotensins/Receptor Antagonists
"
Anticonvulsants Valproate, gabapentin, topiramate
"
Antidepressants Tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors
"
"-Adrenergic Blockers
o Start the chosen drug at a low dose and increase it slowly until therapeutic effects develop, the ceiling dose for the chosen drug is reached, or side effects become intolerable. o Give each treatment an adequate trial. A full therapeutic trial may take 2 to 6 months. In controlled clinical trials, efficacy is often first noted at 4 weeks and continues to increase for 3 months. o Avoid interfering, overused, and contraindicated drugs. To obtain maximal benefit from preventive
TABLE 6-2
Propranolol/nadolol/ metoprolol/atenolol
"
Calcium Channel Antagonists
"
" "
Mitral valve prolapse
Serotonin Antagonists
Angina/myocardial infarction
Methysergide/ methylergonovine (Methergine)
Stroke
"
Nonsteroidal anti-inflammatory drugs, riboflavin, magnesium, feverfew, butterbur, neuroleptics?
Psychiatric Depression Mania Panic disorder Anxiety disorder
" and prevents central sensitization. Ayata and colleagues (2000) have recently shown that preventive medications given chronically, but not acutely, block cortical spreading depression (Silberstein, 2004b).
Cardiovascular
Raynaud’s syndrome
Neurotoxins
Others
Migraine Comorbid Disease
Hypertension/ hypotension
Verapamil/flunarizine
"
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Preventive Prescription Drugs
Neurological Epilepsy Essential tremor Positional vertigo Restless legs syndrome
"
Gastrointestinal Irritable bowel syndrome
PRINCIPLES OF PREVENTIVE THERAPY The following principles are useful regardless of the chosen preventive medication:
"
Other Asthma Allergies
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o
o
o
o
medication, the patient should not overuse analgesics, opioids, triptans, or ergot derivatives. Reevaluate therapy. Migraine headaches may improve independent of treatment; if the headaches are well controlled, slowly taper and, if possible, discontinue the drug. Many patients experience continued relief with a lower dose of the medication, and others may not require it at all. Be sure that a woman of childbearing potential is aware of any potential risks, and pick the medication that will have the least adverse effect on a fetus (Silberstein, 1997). To maximize compliance, involve patients in their care. Take patient preferences into account when deciding between drugs of relatively equivalent efficacy. Discuss the rationale for a particular treatment, when and how to use it, and what side effects are likely. Address patient expectations. Discuss with the patient the expected benefits of therapy and how long it will take to achieve them. Consider comorbidity, which is the presence of two or more disorders whose association is more likely than chance. Conditions that are comorbid with migraine include stroke, epilepsy, irritable bowel syndrome, Raynaud’s syndrome, and certain psychological disorders, including depression, mania, anxiety, and panic (Table 6-2) (Olerud et al, 1986; Ryan, 1984; Ryan et al, 1983; Sudilovsky et al, 1986).
SPECIFIC MIGRAINE PREVENTIVE AGENTS ß-Adrenergic Blockers Beta-blockers, the most widely used class of drugs in prophylactic migraine treatment, are approximately 50% ef-
fective in producing a greater than 50% reduction in attack frequency. Rabkin and colleagues (1966) serendipitously discovered propranolol’s effectiveness in patients who were being treated for angina (Weber and Reinmuth, 1972). The Agency for Healthcare Policy and Research (AHCPR) Technical Report (Gray et al, 1999) and the United States Headache Consortium (Silberstein, 2000) analyzed 74 controlled trials of beta-blockers for migraine prevention. Evidence consistently showed propranolol to be effective for migraine prevention in a daily dose of 120 mg to 240 mg. No absolute correlation has been found between propranolol’s dose and its clinical efficacy (Andersson and Vinge, 1990). Four trials comparing metoprolol with placebo had mixed results (Kangasniemi et al, 1987; Steiner et al, 1988). Metoprolol was similar to propranolol (Gerber et al, 1991; Olsson et al, 1984; Steardo et al, 1982), flunarizine (Grotemeyer et al, 1990; Sorensen et al, 1991), and pizotifen. Timolol (Stellar et al, 1984), atenolol (Forssman et al, 1983), and nadolol (Freitag and Diamond, 1984; Olerud et al, 1986; Ryan, 1984; Ryan et al, 1983; Sudilovsky et al, 1986) are also likely to be beneficial based on comparisons with placebo or with propranolol. Beta-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol) are not effective for migraine prevention (Fanchamps, 1985). The only factor that correlates with the efficacy of beta-blockers is the absence of partial agonist activity. The action of beta-blockers is probably central and could be mediated by (1) inhibiting central -receptors that interfere with the vigilance-enhancing adrenergic pathway; (2) interaction with 5-HT receptors (but not all effective beta-blockers bind to the 5-HT receptors); and (3) cross-modulation of the serotonin system (Koella, 1985). Propranolol inhibits nitric oxide production
KEY POINTS:
A
A
Beta-blockers, the most widely used class of drugs in prophylactic migraine treatment, are approximately 50% effective in producing a greater than 50% reduction in attack frequency. Beta-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol) are not effective for migraine prevention.
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by blocking inducible nitric oxide synthase. Propranolol also inhibits kainate-induced currents and is synergistic with N-methyl D-aspartate blockers, which reduce neuronal activity and have membrane-stabilizing properties (Ramadan, 2004). All beta-blockers can produce behavioral adverse events, such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations, indicating that they all affect the central nervous system (CNS). In clinical trials of betablockers, the most commonly reported adverse events were fatigue, depression, nausea, dizziness, and insomnia. These symptoms appear to be fairly well tolerated and were seldom the cause of premature withdrawal from trials (Gray et al, 1999). Common adverse events include gastrointestinal complaints and decreased exercise tolerance. Less common are orthostatic hypotension, significant bradycardia, impotence, and aggravation of intrinsic muscle disease. Propranolol has been reported to have an adverse effect on the fetus (Featherstone, 1983). Asthma and insulin-dependent diabetes are contraindications to the use of nonselective beta-blockers. Beta-blockers are not absolutely contraindicated in migraine with aura unless a clear stroke risk is present. Whether this includes prolonged aura is uncertain. The reported migraine strokes experienced by patients on propranolol may have been either coincidental or idiosyncratic, and the actual risk is uncertain. Clinical use. Propranolol (approved by the US Food and Drug Administration [USFDA] for migraine) is a nonselective beta-blocker with a halflife of 4 to 6 hours (Table 6-3). It is also available in a long-acting formulation (Diamond et al, 1987; Pradalier et al, 1989). The therapeutically effective dose ranges from 40 mg/d to 400 mg/d with no correlation between
propranolol and 4-hydroxypropranolol plasma levels and headache relief (Cortelli et al, 1985). The short-acting form can be given three to four times a day (although the authors recommend twice a day) and the long-acting form one or two times a day. Propranolol should be started at a dose of 40 mg/d in divided doses and slowly increased to tolerance. An advantage of the regular propranolol is its greater dosing flexibility. The dose for children is 1 mg/ kg/d to 2 mg/kg/d. Nadolol is a nonselective betablocker with a long half-life. It is less lipid soluble than propranolol and has fewer CNS side effects. The dose ranges from 20 mg/d to 160 mg/d given once daily or in split doses. Some authorities prefer it to propranolol since it has fewer side effects (Sudilovsky et al, 1987). Timolol (approved by the USFDA for migraine) is a nonselective beta-blocker with a short half-life. In studies the effective dose was 20 mg/d to 30 mg/d in divided doses, although in clinical practice it may be used daily (Tfelt-Hansen et al, 1984). It has proven efficacy against placebo and established equivalence with propranolol. The dose ranges from 20 mg/d to 60 mg/d in divided doses. Atenolol is a selective 1-blocker with fewer side effects than propranolol. The dose ranges from 50 mg/d to 200 mg/d once daily. Metoprolol is a selective 1-blocker with a short half-life. The dose ranges from 100 mg/d to 200 mg/d in divided doses. The long-acting preparation may be given once a day. Antidepressants Antidepressants include a number of different classes of drugs with different mechanisms of action. With the exception of neuroleptics, only tricyclic antidepressants (TCAs) have proven efficacy in migraine. The mechanism by which antidepressants work to
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KEY POINT:
TABLE 6-3
Beta-Blockers and Antidepressants in the Preventive Treatment of Migraine
Agent
Daily Dose
Comment
Beta-blockers Atenolol
50 mg to 200 mg
Use qid. Fewer side effects than propranolol.
Metoprolol
100 mg to 200 mg
Use the short-acting form bid. Use the long-acting form qd.
Nadolol
20 mg to 160 mg
Use qid. Fewer side effects than propranolol.
Propranolol
40 mg to 400 mg
Use the short-acting form bid or tid. Use the long-acting form qd or bid. 1 mg to 2 mg/kg in children.
Timolol
20 mg to 60 mg
Divide the dose. Short half-life.
Amitriptyline
10 mg to 400 mg
Start at 10 mg at bedtime.
Doxepin
10 mg to 300 mg
Start at 10 mg at bedtime.
Nortriptyline
10 mg to 150 mg
Start at 10 mg to 25 mg at bedtime. If insomnia, give early in the morning.
Protriptyline
5 mg to 60 mg
Start at 10 mg to 25 mg at bedtime.
A
Only tricyclic antidepressants have proven efficacy in migraine. The mechanism by which antidepressants work to prevent headache is uncertain but does not result from treating masked depression.
Antidepressants Tertiary amines
Secondary amines
Selective serotonin reuptake inhibitors Fluoxetine tablets 10 mg to 80 mg
Evidence in the treatment of migraine is controversial.
Sertraline tablets
Some may worsen the migraine pattern.
25 mg to 100 mg
Paroxetine tablets 10 mg to 30 mg
Adjuvant in the treatment of migraine and severe depression.
Selective serotonin and norepinephrine reuptake inhibitors Venlafaxine
75 mg to 225 mg
Start 37.5 mg in AM.
bid = 2 times daily; qd = every day; qid = 4 times daily; tid = 3 times daily.
prevent headache is uncertain but does not result from treating masked depression. Antidepressants are useful in
treating many chronic pain states, including headache, independently of the presence of depression, and the
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The antidepressants that are clinically effective in headache prevention either inhibit noradrenaline and 5hydroxytryptamine reuptake or are antagonists at the 5-HT2 receptors.
response occurs sooner than the o SSRIs can be given as a single dose expected antidepressant effect (Panerai in the morning, although rigorous et al, 1990). In animal pain models, evidence for activity in migraine is antidepressants potentiate the effects lacking. They are less sedating than of coadministered opioids (Feinmann, the TCAs, and some patients may 1990). The antidepressants that are require a hypnotic for sleep induction. clinically effective in headache preven- o Serotonin-norepinephrine tion either inhibit noradrenaline and reuptake inhibitors have a side 5-HT reuptake or are antagonists at the effect profile similar to SSRIs, 5-HT2 receptors. although they may cause nausea Clinical trials and use. A total of and be more activating. 16 controlled trials have investigated o Bipolar patients can become manic the efficacy of the TCAs amitriptyline on antidepressants. and clomipramine, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine Adverse events are common with TCA and fluvoxamine, and the serotonin- use. The antimuscarinic adverse events norepinephrine reuptake inhibitor ven- are most common; they include dry lafaxine (Adelman et al, 2000; Bank, mouth, a metallic taste, epigastric dis1994; Bulut et al, 2004; Couch and tress, constipation, dizziness, mental conHassanein 1976; Couch and Hassanein, fusion, tachycardia, palpitations, blurred 1979; Gomersall and Stuart, 1973; vision, and urinary retention. AntihistaKangasniemi et al, 1983; Ozyalcin et al, minic activity may be responsible for car2005; Saper et al, 1994; Ziegler et al, bohydrate cravings, which contribute to 1987). Amitriptyline has been more fre- weight gain. Adrenergic activity is requently studied than the other agents sponsible for the orthostatic hypotenand is the only antidepressant with sion, reflex tachycardia, and palpitations fairly consistent support for efficacy in that patients may experience. Any antimigraine prevention. Fluoxetine was depressant treatment may change designificantly better than placebo in one pression to hypomania or frank mania but not a second (Saper et al, 1994) (particularly in bipolar patients). Ten migraine prevention trial. percent of patients develop tremors, Principles of antidepressant use. and some patients (particularly older The following principles are useful patients who are more vulnerable to the when using an antidepressant: muscarinic side effects) develop confuo The TCA dose range is wide and sion or delirium. Antidepressant treatmust be individualized. ments may also reduce the seizure o With the exception of threshold (Baldessarini, 1990), although protriptyline, TCAs are sedating. this is not generally a problem in antiStart with a low dose of the migraine treatment. chosen TCA at bedtime, except Clinical use. Tertiary amines. Amiwhen using protriptyline, which triptyline is a tertiary amine tricyclic should be administered in that is sedating and has antimuscarinic the morning. activity (Table 6-3). Patients with coo If the TCA is too sedating, switch existent depression are more tolerant from a tertiary TCA (amitriptyline, and require higher doses of amitriptydoxepin) to a secondary TCA line. Start at a dose of 10 mg to 25 mg (nortriptyline, protriptyline). If a at bedtime. The dose ranges from patient develops insomnia or 10 mg/d to 400 mg/d. nightmares, give the TCA in the Doxepin is a sedating tertiary amine morning. TCA. Start at a dose of 10 mg at
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bedtime. The dose ranges from 10 mg/ d to 300 mg/d. Secondary amines. Nortriptyline is a secondary amine that is less sedating than amitriptyline. Nortriptyline is a major metabolite of amitriptyline. If insomnia develops, give the drug earlier in the day or in divided doses. Start at a dose of 10 mg to 25 mg at bedtime. The dose ranges from 10 mg/d to 150 mg/d. Protriptyline is a secondary amine similar to nortriptyline. Start at a dose of 5 mg/d. The dose ranges from 5 mg/d to 60 mg/d. Selective Serotonin Reuptake Inhibitors Evidence for the effectiveness of SSRIs in headache management is disappointing. They are helpful for patients with comorbid depression because their tolerability profile is superior to tricyclics. These drugs may produce less weight gain than initially believed (Abramowicz, 1990). The most common adverse events include anxiety, nervousness, insomnia, drowsiness, fatigue, tremor, sweating, anorexia, nausea, vomiting, and dizziness or lightheadedness. Headache was noted in 20.3% of patients on fluoxetine; however, it was also noted in 19.9% of patients on placebo (Barnhart, 1991). A discontinuation syndrome may occur. The combination of an SSRI and a TCA can be beneficial in treating refractory depression (Weilburg et al, 1989) and, in the authors’ experience, resistant cases of migraine. The combination may require dose adjustment of the TCA because levels may significantly increase. Selective Serotonin and Norepinephrine Reuptake Inhibitors Venlafaxine is an antidepressant and treatment for generalized anxiety disorder. Venlafaxine has been shown to be effective in a double-blind, placebo-
controlled trial and a separate placeboand-amitriptyline–controlled trial (Ozyalcin et al, 2005). The effective dose is 150 mg/d. Start with the extended release tablet of 37.5 mg for 1 week, then 75 mg for 1 week, and then 150 mg in the morning. Side effects include insomnia, nervousness, mydriasis, and seizures. As with the TCAs and SSRIs, weight gain may occur.
KEY POINT:
A
Venlafaxine has been shown to be effective in a double-blind, placebocontrolled trial and a separate placebo-andamitriptyline– controlled trial.
Calcium Channel Antagonists Two types of calcium channels exist: calcium entry channels, which allow extracellular calcium to enter the cell, and calcium release channels, which allow intracellular calcium (in storage sites in organelles) to enter the cytoplasm (Greenberg, 1997). Calcium entry channel subtypes include voltage-gated, opened by depolarization; ligand-gated, opened by chemical messengers such as glutamate; and capacitative, activated by depletion of intracellular calcium stores. Mechanism of action in migraine. The mechanism of action of the calcium channel antagonists in migraine prevention is uncertain. They were introduced into the treatment of migraine on the assumption that they prevent hypoxia of cerebral neurons, contraction of vascular smooth muscle, and inhibition of the Ca2+-dependent enzymes involved in prostaglandin formation. Perhaps it is their ability to block 5-HT release, interfere with neurovascular inflammation, or interfere with the initiation and propagation of spreading depression that is critical. The discovery that an abnormality in an 1A subunit (P/Q channel) can produce familial hemiplegic migraine (Ophoff et al, 1996) has led to a search for more fundamental associations. Clinical trials. The AHCPR Technical Report identified 45 controlled trials of calcium antagonists, including flunarizine (25 trials), nimodipine (11 trials), nifedipine (5 trials), verapamil (3 trials),
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Zonisamide, as well as other anticonvulsants (with the exception of valproic acid and topiramate, less than 200 mg/d), may interfere substantially with the efficacy of oral contraceptives.
cyclandelate (3 trials), and nicardipine (1 trial) (Gray et al, 1999). Nimodipine had mixed results in placebo-controlled trials. The evidence for nifedipine was difficult to interpret. The conclusion was that nifedipine is ineffective as a migraine preventive. Verapamil was more effective than placebo in two of three trials, but both positive trials had high dropout rates, rendering the findings uncertain (Gray et al, 1999; Markley et al, 1984). The single negative placebo-controlled trial included a propranolol treatment arm. This trial reported no significant difference between verapamil, propranolol, and placebo (Markley et al, 1984). These authors concluded that no rigorous, randomized, controlled trial evidence supports the use of verapamil in migraine. Diltiazem (60 mg to 90 mg 4 times daily) was effective in two small open studies (Smith and Schwartz, 1984). These studies are insufficient to recommend the use of the drug. Adverse events. Adverse events of the Ca2+ antagonists depend on the drug used. Patients often report an initial increase in headache. Headache improvement often requires weeks of treatment. Two trials of verapamil and one of nifedipine reported high dropout rates due to adverse events (Gray et al, 1999). Adverse events with nifedipine were frequent (54%) and included dizziness, edema, flushing, headache, and mental symptoms (McArthur et al, 1989). Clinical use. Verapamil is available as a 40-mg, 80-mg, or 120-mg tablet or as a 120-mg, 180-mg, or 240-mg sustainedrelease preparation (Table 6-4). Start at a dose of 80 mg 2 to 3 times a day, with a maximum of 640 mg a day in divided doses. The sustained-release preparation of verapamil can be given once or twice a day, but unreliable absorption reduces reliability. The most common adverse event is constipation; dizziness,
nausea, hypotension, headache, and edema are less common. Bioavailability is 20%. The absorbed drug is tightly protein bound. Peak plasma levels occur in 5 hours; the half-life ranges from 2.5 to 7.5 hours. Flunarizine is not available in the United States. The dose is 5 mg/d to 10 mg/d. The most prominent adverse events include weight gain, somnolence, dry mouth, dizziness, hypotension, occasional extrapyramidal reactions, and exacerbation of depression. The elimination half-life of flunarizine is 19 days. Anticonvulsants Anticonvulsant medication (neuromodulators) is increasingly recommended for migraine prevention because of placebo-controlled, double-blind trials that prove it to be effective. Zonisamide, as well as other anticonvulsants (with the exception of valproic acid and topiramate, less than 200 mg/d), may interfere substantially with the efficacy of oral contraceptives. Nine controlled trials of five different anticonvulsants were included in the AHCPR Technical Report ( Jensen et al, 1994; Klapper, 1994; Kuritzky and Hering, 1987; Mathew et al, 1995; Rompel and Bauermeister, 1970). Carbamazepine. The only placebocontrolled trial of carbamazepine suggested a significant benefit, but this trial was inadequately described in several important respects (Rompel and Bauermeister, 1970). Another trial, comparing carbamazepine with clonidine and pindolol, suggested that carbamazepine had a weaker effect on headache frequency than either comparator treatment, although differences from clonidine were not statistically significant. Carbamazepine (Tegretol), 600 mg/d to 1200 mg/d, may be effective in preventive migraine treatment (Table 6-4).
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TABLE 6-4
Selected Calcium Channel Blockers and Selected Anticonvulsants in the Preventive Treatment of Migraine
Agent
Daily Dose
Comment
Verapamil
120 mg to 640 mg
Start 80 mg bid or tid. Sustained release can be given qd or bid.
Flunarizine
5 mg to 10 mg
Take qd at bedtime. Weight gain is the most common side effect.
Carbamazepine
600 mg to 1200 mg
Take tid.
Gabapentin
600 mg to 1200 mg
Dose can be increased to 3000 mg.
Topiramate
100 mg
Start 15 mg to 25 mg at bedtime. Increase 15 mg to 25 mg per week. Attempt to reach 50 mg to 100 mg. Increase further if necessary. Associated with weight loss, not weight gain.
Valproate/ divalproex
500 mg/d to 1500 mg/d
Start 250 mg/d to 500 mg/d. Monitor levels if compliance is an issue. Maximum dose is 60 mg/kg/d.
Selected Calcium Channel Blockers
Selected Anticonvulsants
bid = 2 times daily; qd = every day; qid = 4 times daily; tid = 3 times daily.
Gabapentin. Gabapentin (600 mg to 1800 mg [Table 6-4]) was effective in episodic migraine and chronic migraine in a 12-week open-label study (Mathew, 1996). Gabapentin was not effective in one placebo-controlled, double-blind study (Wessely et al, 1987). In a more recent randomized, placebo-controlled, double-blind trial (Mathew et al, 2001), gabapentin 1800 mg to 2400 mg was superior to placebo in reducing the frequency of migraine attacks. The responder rate was 36% for gabapentin and 14% for placebo (P=.02). The two treatment groups were comparable with respect to treatment-limiting adverse events. Limited data were reported on adverse
events; the most common were dizziness or giddiness and drowsiness. Relatively high patient withdrawal rates due to adverse events were reported in some trials (Gray et al, 1999). Valproic acid. Valproic acid is a simple 8-carbon, 2-chain fatty acid with 80% bioavailability after oral administration. It is highly protein bound, with an elimination half-life between 8 and 17 hours. Five studies provided strong and consistent support for the efficacy of divalproex sodium (approved by the USFDA) (Klapper, 1994; Klapper, 1997; Mathew et al, 1995) and sodium valproate (Jensen et al, 1994). An extended
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release form of divalproex sodium demonstrated comparable efficacy to the tablet formulation (Freitag et al, 2002). The adverse event profile in the clinical trial showed almost identical adverse event rates for the placebo and active treatment arms. Nausea, vomiting, and gastrointestinal distress are the most common adverse events with valproate therapy. When therapy is continued, however, the incidence of gastrointestinal symptoms decreases, particularly after 6 months. Later, tremor and alopecia can occur. On rare occasions, valproate administration is associated with severe adverse events, such as hepatitis or pancreatitis. Valproate is potentially teratogenic and should not be used by pregnant women or women considering pregnancy (Silberstein, 1996). Valproate has little effect on cognitive functions, and it rarely causes sedation. Hyperandrogenism, resulting from elevated testosterone levels, ovarian cysts, and obesity are of particular concern in young women with epilepsy who use valproate (Vainionpaa et al, 1999). It is uncertain if valproate can cause these symptoms in young women with migraine or mania. Absolute contraindications to valproate are pregnancy and a history of pancreatitis or a hepatic disorder such as chronic hepatitis or cirrhosis of the liver. Other important contraindications are hematological disorders, including thrombocytopenia, pancytopenia, and bleeding disorders. Valproic acid is available as 250-mg capsules and as a syrup (250 mg/5 mL) (Table 6-4). Divalproex sodium is a stable coordination complex composed of sodium valproate and valproic acid in a 1:1 molar ratio. An entericcoated form of divalproex sodium is available as 125-mg, 250-mg, and 500-mg capsules and a sprinkle formulation. Start with 250 mg/d to 500 mg/d in divided doses and slowly increase the
dose. Monitor serum levels if there is a question of toxicity or compliance. (The usual therapeutic level is from 50 mg/mL to 100 mg/mL.) The maximum recommended dose is 60 mg/kg/d. An extended-release form of divalproex sodium demonstrated comparable efficacy to the tablet formulation (Freitag et al, 2001). Topiramate. Topiramate is a structurally unique anticonvulsant, which was discovered serendipitously. It was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose 1,6-bisphosphatase, thereby blocking gluconeogenesis, but topiramate has no hypoglycemic activity. Originally marketed for the treatment of epilepsy (Shank et al, 1994), the medication is now USFDA approved for migraine. Topiramate is rapidly and almost completely absorbed (Easterling et al, 1988). It is not extensively metabolized and is eliminated predominantly unchanged in the urine. The average elimination half-life is approximately 21 hours (Easterling et al, 1988). Topiramate readily enters the CNS parenchyma; in rats, the concentration in whole brain was approximately one third of that in blood plasma 1 hour after oral dosing (MacDonald and McLean, 1986). The bioavailability of topiramate from the tablet formulation is about 80% and is not affected by food (Shank et al, 2000). Topiramate is not associated with significant reductions in estrogen exposure at doses below 200 mg/d. At doses above 200 mg/d, there may be a dose-related reduction in exposure to the estrogen component of oral contraceptives. Topiramate has been shown to be effective in a number of open-label and pilot studies and large double-blind, placebo-controlled trials (Brandes et al, 2004; Diener et al, 2004; Edwards et al, 2000; Potter et al, 2000; Shuaib
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et al, 1999; Silberstein et al, 2004). In addition, its chronic use has been associated with weight loss, not weight gain, commonly the basis of discontinuation of preventive medications. Two large, pivotal, multicenter, randomized, double-blind, placebo-controlled clinical trials assessed the efficacy and safety of topiramate (50 mg/d, 100 mg/d, and 200 mg/d) in migraine prevention. In the first trial, the responder rate (patients with 50% or greater reduction in monthly migraine frequency) was 52% with topiramate 200 mg/d (P< .001), 54% with topiramate 100 mg (P<.001), and 36% with topiramate 50 mg/d (P=.039), compared with 23% with placebo (Silberstein et al, 2004). Topiramate treatment was also associated with reduced consumption of acute-treatment medications. The onset of efficacy was observed within the first month of treatment. The 200-mg dose was not significantly more effective than the 100-mg dose. The most common adverse events were paresthesias, fatigue, nausea, anorexia, and abnormal taste. Body weight was reduced an average of 3.8% in the 100mg and 200-mg groups. The second pivotal trial (Brandes et al, 2004) had significantly more patients who exhibited at least a 50% reduction in mean monthly migraines in the groups treated with 50 mg/d of topiramate (39%, P=.009), 100 mg/d of topiramate (49%, P=.001), and 200 mg/d of topiramate (47%, P=.001). A third randomized, double-blind, parallel-group, multicenter trial (Diener et al, 2004) compared two doses of topiramate (100 mg/d or 200 mg/d) with placebo or propranolol (160 mg/d). Topiramate 100 mg/d was superior to placebo as measured by average monthly migraine period rate, average monthly migraine days, rate of rescue medication use, and percentage of patients with a 50% or greater decrease in average monthly migraine period rate (responder
rate 37%). The topiramate 100-mg/d and propranolol groups were similar in change from baseline to the core double-blind phase in average monthly migraine period rate and other secondary efficacy variables. Safety and tolerability. The most common adverse event is paresthesia, which occurred in 51% in the topiramate 100-mg group and 49% in the topiramate 200-mg group, compared with 6% in the placebo group. Paresthesias were rated as mild to moderate in most patients. They were treatment limiting in 8% of these subjects. When bothersome, they can be controlled with potassium supplementation (Silberstein, 2002). The other most common general adverse events were fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthesia, and abdominal pain. Patients on propranolol gained 2.3% of their baseline body weight. The other common CNS adverse events included somnolence, insomnia, difficulty with memory or concentration, language problems, mood problems, and anxiety. Renal calculi can occur with topiramate use. The reported incidence is about 1.5%, representing a twofold to fourfold increase over the estimated occurrence in the general population. Patients receiving topiramate infrequently develop a syndrome consisting of acute myopia associated with secondary angle-closure glaucoma. No cases of this condition were reported in the clinical studies. Symptoms include the acute onset of decreased visual acuity and/or ocular pain. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation, may be helpful (Thomson Healthcare, 2003).
KEY POINTS:
A
A
Topiramate has been shown to be effective for migraine prophylaxis in a number of open-label and pilot studies and large doubleblind, placebocontrolled trials. Patients receiving topiramate infrequently develop a syndrome consisting of acute myopia associated with secondary angle-closure glaucoma. No cases of this condition were reported in the clinical studies.
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Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with an elevation in body temperature. Some of the cases were reported after exposure to elevated environmental temperatures. Most of the reports have involved children. Topiramate should be started at a dose of 15 mg to 25 mg at bedtime (Table 6-4). Increase by a dose of 15 mg/wk to 25 mg/wk. Do not increase the dose if bothersome adverse events develop; wait until they resolve (they usually do). If they do not resolve, decrease the drug to the last tolerable dose, then increase by a lower dose more slowly. Attempt to reach a dose of 50 mg/d to 100 mg/d given twice a day. It is the authors’ experience that patients who tolerate the lower doses with only partial improvement often have increased benefit with higher doses. The dose can be increased to 600 mg/d or higher. Lamotrigine. Lamotrigine blocks voltage-sensitive sodium channels, leading to inhibition of neuronal glutamate release of glutamate. Chen and colleagues (2001) reported two patients with migraine with persistent auralike visual phenomena for months to years. After 2 weeks of lamotrigine treatment, both had resolution of the visual symptoms. Steiner and colleagues (1997) compared the safety and efficacy of lamotrigine (200 mg/d) and placebo in migraine prophylaxis in a double-blind, randomized, parallel-group trial. Improvements were greater on placebo, and these changes, not statistically significant, indicate that lamotrigine was ineffective for migraine prophylaxis. There were more adverse events on lamotrigine than on placebo, most commonly rash. With slow-dose escalation, their frequency was reduced, and the rate of withdrawal for adverse events was similar in both treatment groups.
Lamotrigine may have a special role in the treatment of migraine with aura. Zonisamide. Two retrospective, open-label studies of zonisamide in the preventive treatment of episodic migraine have been reported (Drake et al, 2001; Krusz, 2001). In the study conducted by Drake and colleagues (2001), 34 patients with refractory migraine with or without aura were treated adjunctively with zonisamide at doses as high as 400 mg/d. Headache data were obtained from patient headache diaries and telephone reports. A 40% reduction in headache severity, a 50% reduction in headache duration, and a 25% decrease in headache frequency were found at 3 months compared with baseline values. Four patients (12%) discontinued the drug because of adverse events, and nine stopped the medicine because they believed it was not working. Krusz (2001) reported improvement in 42% (14/33) of patients, with four dropouts due to adverse events. Zonisamide was also examined as monotherapy in a small, prospective, open-label study of nine patients with episodic migraine with or without aura (Cochran, 2002). The drug was titrated to a mean dose of 244 mg/d, and investigator efficacy ratings were made for all patients who remained on a stable dose of drug for 6 weeks. It was effective or very effective in 67% (6/9) of patients. Other Drugs Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Schrader and colleagues (2001) conducted a double-blind, placebocontrolled, crossover study of lisinopril, an angiotensin-converting enzyme inhibitor, in migraine prophylaxis (Table 6-5). Days with migraine were reduced by at least 50% in 14 participants for active treatment versus placebo and 17 patients for active treatment versus run-in period. Days
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with migraine were fewer by at least 50% in 14 participants for active treatment versus placebo. Tronvik and colleagues (2003) performed a randomized, double-blind, placebo-controlled, crossover study of candesartan (16 mg), an angiotensin II receptor blocker, in migraine prevention (Table 6-5). In a period of 12 weeks, the mean number of days with headache was 18.5 with placebo versus 13.6 with candesartan (P=.001) in the intention-to-treat analysis (n = 57). The number of candesartan responders (reduction of 50% or greater compared with placebo) was 18 of 57 (31.6%) for days with headache and 23 of 57 (40.4%) for days with migraine. Adverse events were similar in the two periods. In this study, the angiotensin II receptor blocker candesartan was effective, with a tolerability profile comparable with that of placebo. Nonsteroidal anti-inflammatory drugs. O’Neill and Mann (1978) and Masel and colleagues (1980) found that aspirin (650 mg/d) decreased headache
TABLE 6-5
frequency. Two major multicenter trials, however, proved the efficacy of aspirin in the prophylaxis of migraine. In 1988, the British Physician Trial showed that a daily dose of 500-mg aspirin reduced the frequency of migraine by an average of 30% (Peto et al, 1988). In a doubleblind trial of low-dose aspirin (325 mg every other day) in 22,071 male physicians in the United States (Physician Health Study), Buring and colleagues (1990) found a 20% reduction in headache frequency. In a double-blind crossover trial, aspirin (500 mg daily) was statistically less effective than 200-mg propranolol daily (Grotemeyer et al, 1990). The authors of this chapter use aspirin for patients who have had prolonged or nonvisual aura. Other NSAIDs that may be effective in migraine prophylaxis include sodium naproxen, fenoprofen, ketoprofen, and tolfenamic acid (Pradalier et al, 1988). Although NSAIDs are effective, they must be used with caution because of their gastrointestinal and renal function adverse events (Solomon, 1989).
Miscellaneous Medication in the Preventive Treatment of Migraine
Agent
Daily Dose
Comment
Angiotensin-converting enzyme and angiotensinreceptor antagonists
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Lisinopril
10 mg to 40 mg
Positive small controlled trial
Candesartan
16 mg
Positive small controlled trial
Feverfew
50 mg to 82 mg
Controversial evidence
Petasites
50 mg to 100 mg
75 mg and 100 mg better than placebo in independent trials
Riboflavin
400 mg
Positive small controlled trial
Coenzyme Q
100 mg to 150 mg
Two positive controlled trials
Magnesium
400 mg to 600 mg
Controversial evidence
Others
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KEY POINTS:
A
A
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A 25-U but not a 75-U botulinum toxin type A treatment group fared significantly better than the placebo group by the following measures: reduction in mean frequency of moderate to severe migraines during days 31 to 60, incidence of 50% reduction in mild to severe migraines at days 61 to 90, and improvement by patient global assessment for days 31 to 60 postinjection. Two recent studies showed no difference between different doses of botulinum toxin (105 U to 260 U) and vehicle.
Botulinum toxin. Silberstein and colleagues (2000) evaluated the safety and efficacy of pericranial botulinum toxin type A injections as prophylactic treatment of chronic moderate to severe episodic migraine. One hundred twenty-three patients who had chronic International Headache Society–defined migraine and a history of two to eight moderate to severe migraine attacks during a 1-month baseline were randomized to treatment with either 0 U, 25 U, or 75 U of botulinum toxin type A injected symmetrically into glabellar, frontalis, and temporalis muscles. The 25-U but not the 75-U botulinum toxin type A treatment group fared significantly better than the placebo group by the following measures: reduction in mean frequency of moderate to severe migraines during days 31 to 60, incidence of 50% reduction in mild to severe migraines at days 61 to 90, and improvement by patient global assessment for days 31 to 60 postinjection. The 75-U injection failed to exhibit benefit over placebo. Botulinum toxin type A treatment was well tolerated, but high-dose botulinum toxin type A showed significantly more treatmentrelated adverse events than placebo. No serious treatment-related adverse events were reported. Pericranial injection of botulinum toxin type A 25 U (but not 75 U) showed significant differences compared with vehicle in reducing migraine frequency and associated symptoms during the 90 days following injection. Two recent studies presented as abstracts at the American Headache Society and the European Federation of Neurology showed no difference between different doses of botulinum toxin (105 to 260 U) and vehicle (Aurora, 2006). Medicinal Herbs, Vitamins, and Minerals According to a national survey (Eisenberg et al, 1998), the use of herbal medicinal
products by the general US population increased by a staggering 480% between 1990 and 1997. Feverfew (Tanacetum parthenium), a medicinal herb, has traditionally been used for fever, women’s ailments, inflammatory conditions, psoriasis, toothache, insect bites, rheumatism, asthma, and stomachache. During the last decades, it has also been used for migraine prophylaxis. Pittler and Ernst (2004) conducted a new systematic review of the evidence from rigorous clinical trials of feverfew’s efficacy in migraine prevention. Results from these trials were mixed and did not convincingly establish that feverfew is efficacious for preventing migraine. Only mild and transient adverse events were reported in the included trials. Feverfew’s adverse events include mouth ulceration and a more widespread oral inflammation associated with loss of taste (Gray et al, 1999). Feverfew’s mechanism of action is uncertain. Petasites hybridus root (butterbur) is a perennial shrub whose extracts have been used for therapeutic purposes in traditional medicine for centuries. Lipton and colleagues (2004) conducted a randomized, double-blind, placebo-controlled trial of Petasites 50 mg, Petasites 75 mg, or placebo, each twice a day. Over 4 months of treatment, migraine attack frequency was reduced by 26% for placebo, 48% for Petasites extract 75 mg twice a day (P=.0012 versus placebo), and 36% for Petasites extract 50 mg twice a day (P=.127 versus placebo). The most frequently reported adverse events were mild gastrointestinal events, predominantly burping (eructation). Schoenen and colleagues (1998) compared riboflavin (400 mg) with placebo in migraineurs in a randomized trial of 3 months’ duration. Riboflavin was significantly superior to placebo in reducing attack frequency (P=.005), headache days (P=.012), and migraine index (P=.012). The
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proportion of patients who improved by at least 50% in headache days, ie, ‘‘responders,’’ was 15% for placebo and 59% for riboflavin (P=.002), and the number needed to treat for effectiveness was 2.3. Only three adverse events occurred: two in the riboflavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps). None was serious. Rozen and colleagues (2002) found that coenzyme Q10 (150 mg/d) was effective for prevention of migraine headaches in an open-label trial. Sandor and colleagues (2003) performed a doubleblind, placebo-controlled trial of coenzyme Q10 (100 mg 3 times a day) in 42 patients for 3 months. The 50% responder rate was 47.6% for coenzyme Q10 and 14.3% for placebo. Magnesium supplementation was effective in one of two trials (Peikert et al, 1996; Pfaffenrath et al, 1996). The studies differed in the amount of magnesium (24 mmol versus 20 mmol) and in the salt (dicitrate versus aspartate). Those differences may produce differences in bioavailability and efficacy and account for the reported difference. Monotherapy Versus Combined Therapy Pascual and colleagues (2003) found that combining a beta-blocker and sodium valproate could lead to an increased benefit for patients whose migraine was resistant to either alone. Fifty-two patients (43 women) who had a history of episodic migraine with or without aura and were previously unresponsive to both beta-blockers and sodium valproate monotherapy were treated with a combination of propranolol (or nadolol) and sodium valproate in an open-label fashion. Fifty-six percent had a greater than 50% reduction in migraine days. This open trial supports the practice of combination therapy. Controlled trials
are needed to determine the true advantage of this combination treatment in episodic and chronic migraine. SETTING TREATMENT PRIORITIES The goals of preventive treatment are to reduce the frequency, duration, or severity of attacks; improve responsiveness to acute attack treatment; improve function; and reduce disability. It may also prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions. The medications used to treat migraine can be divided into five major categories: (1) drugs that have documented high efficacy and mild to moderate adverse events (some beta-blockers, amitriptyline, topiramate, and divalproex); (2) drugs that have lower documented efficacy and mild to moderate adverse events (SSRIs, other beta-blockers, calcium channel antagonists, gabapentin, riboflavin, and NSAIDs); (3) drugs with adverse events or complex management issues; (4) drugs that either have documented high efficacy but significant adverse events or are difficult to use (methysergide and monoamine oxidase inhibitors); and (5) drugs that have proven limited or no efficacy (cyproheptadine, lithium, nifedipine, nimodipine, and phenytoin) (Table 6-6). Choice should be made based on a drug’s proven efficacy, the patient’s preferences and headache profile, the drug’s adverse events, and the presence or absence of coexisting or comorbid disease (Table 6-2). The drug used should be the one that has the best riskto-benefit ratio for the individual patient and takes advantage of the drug’s adverse event profile. An underweight patient would be a candidate for one of the medications that commonly produce weight gain, such as a TCA; in contrast, one would try to avoid these drugs in the overweight patient and consider using topiramate. Tertiary
KEY POINT:
A
The goals of preventive treatment are to reduce the frequency, duration, or severity of attacks; improve responsiveness to acute attack treatment; improve function; and reduce disability. It may also prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions.
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TABLE 6-6
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Preventive Drugs
High Efficacy: Low to Moderate Adverse Events Propranolol, timolol, amitriptyline, valproate, topiramate
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Low Efficacy: Low to Moderate Adverse Events Nonsteroidal anti-inflammatory drugs: aspirin, flurbiprofen, ketoprofen, naproxen sodium Beta-blockers: atenolol, metoprolol, nadolol Calcium channel blockers: verapamil Anticonvulsants: gabapentin Other: fenoprofen, feverfew, vitamin B2 Pizotifen
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Unproven Efficacy: Low to Moderate Adverse Events Antidepressants: doxepin, nortriptyline, imipramine, protriptyline, fluvoxamine, mirtazapine, paroxetine, protriptyline, sertraline, trazodone Major adverse events or complex management: Methergine, monoamine oxidase inhibitors
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Proven Not Effective or Low Efficacy Acebutolol, carbamazepine, clomipramine, clonazepam, indomethacin, lamotrigine, nabumetone, nicardipine, nifedipine, pindolol
TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs or calcium channel or beta-blockers,
but could use divalproex or topiramate. In the athletic patient, beta-blockers should be used with caution. Medication that can impair cognitive functioning should be avoided when patients are dependent on their wits (Silberstein et al, 1998; Silberstein and Goadsby, 2002). Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. In some instances, two or more conditions may be treated with a single drug. However, there are limitations to using a single medication to treat two illnesses. Giving a single medication may not treat two different conditions optimally. Although one of the two conditions may be adequately treated, the second illness may require a higher or lower dose, and therefore the patient is at risk that the second illness will not be adequately treated. In an effort to use a single medication to treat two conditions, the physician may choose a second- or third-tier drug for treating either or both conditions, and this may not provide adequate efficacy for either illness. The risk is that one condition is managed appropriately, but the second condition requires a higher dose or additional therapy. Therapeutic independence may be needed should monotherapy fail. For example, a higher or lower dose of medication may be needed for migraine prophylaxis than the dose commonly used for other indications. Usually, medicine is started with a minimally effective dose and then titrated over weeks or months. Avoiding drug interactions or increased adverse events is a primary concern when using polypharmacy. For example, when a patient is undergoing treatment for depression, adding a beta-blocker for migraine management may exacerbate the depression and put the patient at unnecessary risk.
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For some patients, a single medication may adequately manage comorbid conditions. When migraine and hypertension and/or angina occur together, beta-blockers or calcium channel blockers may be effective for all conditions (Solomon, 1989). However, this is likely to be the exception rather than the rule. A beta-blocker may be poorly tolerated (or even contraindicated) in the presence of other conditions, such as depression or coexisting asthma (Case 6-1). Polytherapy may enable therapeutic adjustments based on the status of each illness. TCAs are often recommended for patients with migraine and depression (Silberstein et al, 1995). However, appropriate manage-
ment of depression often requires higher doses of TCAs, which may be associated with more adverse events. A better approach might be to treat the depression with an SSRI or serotoninnorepinephrine reuptake inhibitor and the migraine with a cortical excitability stabilizer (antiepileptic drug, eg, topiramate or gabapentin). For the patient with migraine and epilepsy (Mathew et al, 1995), one may achieve control of both conditions with antiepileptic drugs. Divalproex and topiramate are the drugs of choice for the patient with migraine and bipolar illness (Bowden et al, 1994; Silberstein, 1996) (Case 6-2). The pregnant migraineur who has a comorbid condition
Case 6-1 A 32-year-old woman has a 15-year history of unilateral headaches, which begin in either temple. They are throbbing, of moderate intensity, and associated with nausea, but not vomiting, phonophobia, or photophobia. Attacks occur 3 to 4 times monthly and last 1 day each. Ninety percent of her headaches are preceded by numbness of the left side of the face, left hand, and left forearm and last 15 minutes, followed by ‘‘zigzag’’ lines in the periphery that gradually move across her visual field. At times, she cannot see objects in the center of her vision. She has asthma, which is under control with inhaled steroids. An echocardiogram showed a patent foramen ovale. She takes triptans, but the headaches often recur. She used birth control pills in the past, without any effect upon her headaches. Medical and neurological examinations are normal. Her asthma precludes the use of beta-blockers. Amitriptyline is mildly effective but produces weight gain and fatigue. Verapamil produces constipation and is of no benefit. Comment. This is a woman who principally has migraine with aura. The occurrence of sensory aura before the visual aura is unusual, but not concerning. The patient has failed the first-line preventive (amitriptyline), as well as a second-line preventive with an unproven reputation for working better for migraine with aura (verapamil), and is precluded from using some of the other first-line preventives (beta-blockers). Topiramate would be an appropriate choice, and weight gain would not be a concern. The use of lamotrigine cannot be supported by randomized data, but consistent anecdotal data support its use in preventing aura, which is present in 90% of this patient’s headaches. Venlafaxine is also reasonable but may have some of the weight gain of amitriptyline. Patent foramen ovale closure may be effective in migraine with aura, but the evidence is anecdotal. The procedure is invasive, and the consensus is that its use should be restricted to investigational trials with subjects whose headaches are more refractory and severe than this patient’s.
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Case 6-2 A 21-year-old man has a 6-month history of recurrent headaches. They are severe, bifrontal, throbbing, and associated with nausea, but not vomiting. He denies photophobia and phonophobia, but prefers to lie down in a dark quiet room during a headache. Headaches last hours and occur 4 or 5 times a month. He has missed 5 days of work in the past 3 months. The headaches are triggered by stress, too little sleep, and weather changes. Triptans and NSAIDs are of partial benefit. His medical history is remarkable for motion sickness. His maternal grandmother suffered from migraine. He is a long-distance runner, and his sister had bipolar disorder. After her suicide, he had a 9-month depressive episode. He is currently not depressed. Medical and neurological examinations are normal. He recently had a CT scan of the brain that was ordered by his physician, which was normal. He was started on a beta-blocker but discontinued it because of fatigue and impaired exercise tolerance. Comment. The patient under discussion would likely benefit from pharmacological prevention of his frequent and disabling headaches, which are poorly controlled with standard acute therapy. Given the family history of bipolar disorder, the history of depression, and the increased risk of successful suicide carried out by males, giving an antidepressant alone may destabilize this patient if he has inherited his sister’s bipolar predisposition. Most clinicians would consider these headaches too severe and frequent to be adequately treated by riboflavin, but a trial with careful observation would not be unreasonable. A better choice is divalproex. In a young male athlete, weight gain is not a great danger, and there is no risk of polycystic ovary disease or pregnancy. Divalproex may protect this patient from mania and depression. He has no risk factors for hepatic complications. Liver function tests should be normal before initiating therapy and not repeated unless symptoms develop.
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that needs treatment should be given a medication that is effective for both conditions and has the lowest potential for fetal adverse events. When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, beta-blockers should be used with caution in the depressed migraineur, while TCAs or neuroleptics may lower the seizure threshold and should
be used with caution for the epileptic migraineur. Although monotherapy is preferred, it is often not the best choice, and it may be necessary to combine preventive medications. Antidepressants are often used with beta-blockers or calcium channel blockers, and topiramate or divalproex sodium may be used in combination with any of these medications.
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L I F E L O N G L E A R N I N G I N N E U R O L O G Y®
HEADACHE
PREFERRED RESPONSES Following are the preferred responses and critiques for the multiple-choice items in this course. The questions and answer selections are repeated, and the preferred response appears in bold print. In most cases, this is followed by an explanation and, in some instances, a reference with which you may seek more specific information. No score will be assigned to the answer form you mail in, since the emphasis of this program is on self-assessment. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the course material.
TYPE A QUESTIONS (ONE BEST ANSWER)
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1. A 50-year-old man with a history of hypertension controlled with lisinopril and hyperlipidemia treated with atorvastatin is referred to a neurologist for headaches that began 6 months ago. He states that he was never really bothered by headaches before, but that now he has been getting a throbbing, one-sided headache at least once a week, which has caused him to miss several days of work as a computer technician. He is divorced and lives alone; he drinks two beers after work and does not smoke. He is not sexually active. He states that he used to go to the gym a few times a week, but he stopped going “because it makes my head hurt” and has gained 13.6 kg. Physical examination reveals an obese, fatigued-appearing individual. Vital signs are normal. He is fully oriented but has a blunted affect and does not display humor. He states that he has trouble remembering but can recount items from the day’s news. CT scan ordered by his primary care physician is normal. Identification of which of the following signs would support a presumed diagnosis of clinical depression? A. B. C. D. E.
Decision to quit his job Increase in alcohol consumption Increase in spending habits New hypersomnia Poor compliance with prescribed medicines
The correct answer is D. In addition to developing new headaches, the patient has developed several vegetative symptoms, including weight gain and fatigue; hypersomnia would be consistent with these other symptoms and signs of clinical depression. Poor compliance with prescribed medicines may be seen in normal individuals, as might the decision to quit his job. An increase in spending habits may have more association with mania. An increase in alcohol consumption is nonspecific.
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2. A 35-year-old woman is seen in consultation for headaches, which began about 3 months before her visit. She describes 10 episodes a day of sharp pain over the left eye, which last about 5 minutes and actually cause her to grimace. She is a nonsmoker and nondrinker. She works on a computer for most of the day. She has no nausea during a headache; sometimes she tries to sit or lie quietly until the attack passes. Neurological examination interictally is normal. Which of the following autonomic phenomena is most commonly associated with this type of headache? A. B. C. D. E.
Conjunctival injection Horner’s syndrome Lacrimation Perimenstrual attacks Photophobia
The correct answer is C. The patient described has chronic paroxysmal hemicrania, a disorder found more commonly in women, although no particular pattern has emerged regarding the relationship of attacks to menses. Photophobia is described but is not common, whereas true Horner’s syndrome is not typically seen (as it can be in cluster headache). While conjunctival injection is associated with chronic paroxysmal hemicrania, the most commonly associated autonomic phenomena are lacrimation and nasal congestion. 3. A 25-year-old woman is referred to a neurologist because of chronic headaches. She began to experience bilateral, pressurelike headaches about 6 months before; initially, they were relieved by over-the-counter ibuprofen taken in high doses. The headaches are felt bitemporally and at the base of the skull; they occasionally cause nausea but not vomiting and occur about 5 days out of the week. Past medical history is significant for amenorrhea. On physical examination, findings are blood pressure 140/70, pulse 80, respiration 15, temperature 37°C, weight 120 kg, height 160 cm. Visual fields are normal to confrontation; there is no frank papilledema, but absence of spontaneous venous pulsations is noted. Which of the following studies is most likely to establish a diagnosis in this patient? A. B. C. D. E.
Cervical MRA Cervical MRI CT of the sinuses Magnetic resonance venography (MRV) Serum prolactin level
The correct answer is D. The patient appears to have a syndrome of increased intracranial pressure, which should be confirmed by lumbar puncture after CT scan has been obtained to rule out the presence of a mass lesion. The patient described is a morbidly obese female whose headaches are frequent, although fairly nonspecific in character. She has amenorrhea, which may be associated with either pituitary tumors (suggested by serum prolactin level) or benign intracranial hypertension (suggested by MRV). Serum prolactin level is unlikely given the normal visual field examination; it would also be made more unlikely by the normal head CT obtained before the lumbar puncture. The likelihood of cervical pathology in a patient this age with no history of trauma (cervical MRI) is small; the
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HEADACHE headaches described do not suggest sinus pathology (CT of the sinuses), and the 6-month duration of the syndrome would make an arterial dissection very unlikely. The suggestion of increased intracranial pressure makes MRV the study most likely to yield a diagnosis. 4. Which of the following statements concerning the migraine aura is best supported by available clinical and experimental data? A. Aura has been shown to trigger the remainder of the headache attack. B. Aura is present in the majority of patients with migraine. C. Aura is the human equivalent of cortical spreading depression of Leao. D. Most auras are painful. E. Most auras originate as a channel disturbance involving the parietal cortex. The correct answer is C. Aura is a focal neurological disturbance (visual, sensory, or motor) seen in about 30% of patients with migraine. Visual aura is the most common, with involvement of the occipital cortex. With functional imaging techniques, the aura has been shown to be the human equivalent of the spreading cortical depression of Leao, most probably caused by an ionopathy. Most auras are not painful, and it is not clear that aura is itself a trigger for the remainder of the attack, although cortical spreading depression may be a stimulus to activate trigeminal neurons. 5. A 40-year-old woman with a 20-year history of episodic migraine reports to her physician that she wishes to pursue “natural therapies” for treatment of her headache. In counseling this patient, which of the following medicinal herbs, vitamins, and minerals has the strongest rigorous clinical data to support its use? A. B. C. D. E.
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Calcium citrate Hypericum perforatum (St John’s wort) Petasites hybridus (butterbur) Tanacetum parthenium (feverfew) Vitamin B1 (thiamine)
The correct answer is C. The data to support herbal, vitamin, and mineral therapy in the treatment of migraine is limited. Butterbur, vitamin B2 (riboflavin), coenzyme Q10, and magnesium have all been subjected to double-blinded, placebo-controlled trials and shown to be superior to placebo. Tanacetum parthenium (feverfew) does not appear to be better than placebo in the treatment of migraine. There is no established or theoretical rationale for the use of thiamine, St John’s wort, or calcium citrate in the treatment of migraine. 6. A 25-year-old office assistant comes to the physician for a headache that he states began “out of the blue” 3 months before. He recalls being at a company picnic during which he drank two beers and remained outside on a hot day for several hours. The headache is described as being on both sides, constant, rarely associated with nausea, and not responsive to aspirin or ibuprofen. It does not get worse if he continues his normal activity. He has a history of asthma, treated with albuterol. He smokes half a pack of
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cigarettes daily and drinks an occasional beer. On examination, he is afebrile and has no nuchal rigidity. Fundi demonstrate normal discs. A CT scan of the brain is normal. This patient’s headache conforms to which of the following subtypes? A. B. C. D. E.
Acute cluster Chronic tension-type Hemicrania continua New daily persistent Transformed migraine
The correct answer is D. The patient presents with a history of a recent-onset chronic daily headache for which he can recall the date and circumstances of its origin. Because he gives no previous history of headaches, chronic tension-type headache, transformed migraine, and hemicrania continua are excluded. 7. With respect to the indirect costs (effects on productivity at work and at home) of migraine, which of the following statements is most accurate? A. Among migraine sufferers, more work is lost as a result of absenteeism than reduced work productivity while working with a headache. B. Migraine sufferers have increased health-related absenteeism for reasons other than headache when compared with a control population. C. Reduced productivity at home constitutes a significant economic cost for migraine sufferers. D. The cost of lost productivity due to headache in the US workforce is estimated at $19 million per year. E. The direct costs of migraine from health care expenditure are greater than the indirect costs. The correct answer is B. The cost of lost productivity due to headache in the United States is enormous and has been estimated at $19.6 billion per year, which is much greater than the direct health care costs of headache. The cost of lost productive time while at work with headache was greater than the cost of actual absenteeism by a factor of about 2:1. Migraine sufferers have more health-related absenteeism, even when factoring out the contribution from headache. Although data for lost productivity in household duties are less available, no statistically significant difference appears to exist between migraine sufferers and a control population. 8. A 42-year-old woman has had recurrent episodes of abrupt-onset neurological dysfunction characterized by hemiparesis and aphasia over the past 2 years. These episodes have not been associated with headache. She has a residual spastic right hemiparesis and spastic dysarthria. She has a history of migraine with visual aura that started in her 20s. Her head MRI shows multiple areas of T2 signal abnormality without mass effect or contrast enhancement symmetrically in the deep white matter of both cerebral hemispheres. A cerebral angiogram and transesophageal echocardiogram
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HEADACHE are normal. A spinal fluid examination is unremarkable. Her father also had migraines. He developed “Alzheimer’s disease” in his 50s and died at age 60. Which of the following is the most likely diagnosis? A. Amyloid angiopathy B. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) C. Complicated migraine (persistent aura without infarction) D. Familial hemiplegic migraine type 1 (FHM-1) E. Myopathy, encephalopathy, lactic acidosis, strokelike episodes (MELAS) The correct answer is B. This patient most likely has CADASIL. This progressive disorder is characterized by recurrent episodes of subcortical ischemia, usually with persistent deficits. Many patients develop subcortical dementia. Affected patients usually have a history of migraine with aura. CADASIL is characterized pathologically as a vasculopathy affecting the media of small cerebral vessels. It is associated with mutations in the Notch 3 gene on chromosome 19. MELAS is associated with myopathy and episodes of lactic acidosis. Unless it is a sporadic case, MELAS is inherited through the mother as it is due to a mitochondrial DNA mutation. FHM-1 is not usually associated with MRI abnormalities or progressive motor deficits. The MRI features are not those of amyloid angiopathy, and amyloid angiopathy is not associated with migraine. Complicated migraine (persistent aura without infarction) is usually not associated with persistent motor deficits or MRI abnormalities, and motor deficits would occur in conjunction with the headache phase of migraine.
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9. A 25-year-old man presents with episodic, unilateral, throbbing headaches associated with nausea and light and noise sensitivity. They are triggered by some foods, including cheddar cheese and red wine. Most of his headaches occur without any obvious precipitant. He is having one headache per week, lasting 12 to 48 hours on average. These headaches generally occur on the weekend but keep him from his regular activities on the days they occur. He is thus incurring at least 1 to 2 days per week of at least 50% time loss. He has tried multiple over-the-counter remedies without satisfactory relief. Using the stratified care approach, which of the following medications for symptomatic treatment of his headache would be most appropriate at this time? A. B. C. D. E.
Aspirin with metoclopramide A triptan Butalbital, caffeine, acetaminophen (APAP) combination Codeine with APAP Intranasal butorphanol
The correct answer is B. According to the stratified-care approach, patients with episodic migraine with more than 10 days of at least 50% disability in the past 3 months (Migraine Disability Assessment Scale [MIDAS] score >11) should receive triptan therapy at the outset. This assumes that the patient has no contraindications to receiving triptans. This strategy has been shown to provide better relief and be more cost-effective in the long run than if the
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patient is started on a lower-level medication. Also note that the patient has already tried a “step-care” approach with multiple nonspecific medications before coming to the neurologist. Further nonspecific medication trials will delay optimal outcome. 10. A 30-year-old woman presents to her physician with a 7-year history of episodic migraine without aura. She is having 7 to 10 headaches per month. The headaches are disabling, and she estimates that she misses at least 3 days of work each month. Currently she is using 10 tablets of sumatriptan per month and has been to the emergency department 2 times this month to receive intravenous analgesic medication for headache. Her past medical history is significant for asthma and obesity. Her medications include sumatriptan, ipratropium, acetaminophen, and oral contraceptives. Which of the following medications would be most appropriate as a preventive medication for this patient’s migraine? A. B. C. D. E.
Fluoxetine Propranolol Topiramate Valproic acid Verapamil
The correct answer is C. In this patient with asthma, a beta-blocker is contraindicated. Calcium channel blockers (verapamil) and selective serotonin reuptake inhibitors (fluoxetine) appear to have limited efficacy in the treatment of migraine and generally should not be used as first-line agents in patients with migraine. Valproic acid commonly causes weight gain and probably should be avoided in a patient who is already obese. Valproic acid would not complicate her asthma or compromise the effectiveness of her oral contraceptive. Topiramate at dosages under 200 mg/d does not appear to interact with oral contraceptives. Topiramate has reasonable efficacy in migraine and may actually produce weight loss. 11. Which of the following headache subtypes affects the greatest percentage of patients with chronic daily headaches (CDHs) seen in specialty headache clinics in the United States? A. B. C. D. E.
Chronic cluster Chronic tension-type Hemicrania continua New daily persistent Transformed migraine (chronic migraine)
The correct answer is E. Chronic tension-type, hemicrania continua, and new daily persistent headaches are traditionally classified as CDH while chronic cluster is considered to be a trigeminal autonomic cephalgia. Transformed migraine, or chronic migraine, is felt to represent a large proportion of the patients (from 50% to 80% in various studies) in the United States seen with CDH in specialty clinics.
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12. With respect to race, geographic location, socioeconomic status, and their relationship to migraine prevalence, which of the following statements is most accurate? A. In the United States, migraine is more common in African Americans than whites. B. Migraine is more common among persons with higher household incomes. C. Migraine is more prevalent among persons with higher education. D. Migraine prevalence is highest in Europe. E. The prevalence of migraine is low in Asia and in Asian Americans. The correct answer is E. Migraine is more prevalent among whites than people of other races within the United States. From a geographic context, the adjusted prevalence of migraine is highest in North America and lowest in Asia. Whether these differences are genetically, environmentally, or culturally determined is uncertain. Most population-based studies in the United States have found an inverse relationship between migraine prevalence and household income and educational level. These results, however, have not been replicated outside the United States. 13. A 40-year-old woman with rheumatoid arthritis has been using daily nonsteroidal medications (NSAIDs) for 20 years. In her 20s, she developed periodic headaches that were unilateral, pulsating, and associated with nausea and photophobia and occurred about 6 times per year. Initially, these headaches responded to over-the-counter medication. In her 30s, the headaches became more frequent, occurring at least monthly. She began to use hydrocodone more frequently for the headaches; now the headaches have become daily. The patient’s primary care physician diagnoses depression, and the patient is placed on paroxetine. Physical examination reveals joint deformities in wrists, ankles, and fingers. There is no rheumatoid involvement of the upper cervical spine. A consultant diagnoses medication overuse headache (MOH). Which of the following aspects of this patient’s history represents the greatest risk factor for the development of MOH?
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A. B. C. D. E.
History of concomitant depression Prior history of a systemic disease Prior history of daily NSAID use Prior history of episodic migraine Use of opioids for pain
The correct answer is D. There is no evidence that a patient who has a preexisting condition requiring chronic pain medication without a prior history of headaches will be more likely to develop CDH, but there is some evidence from at least two studies cited that a patient with a chronic pain condition and a prior history of episodic migraine will be at greater risk for developing MOH. No reference is made to a particular type of pain medication conferring a greater risk of MOH or to this type of MOH being more difficult to treat. While there may be some evidence that patients whose prior headache frequency was high are at greater risk for developing MOH, such was not the case in this particular individual’s problem.
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14. A 45-year-old woman comes to a headache clinic because of progressively worsening symptoms. She has had headaches since her 20s for which she has tried multiple medications over the years. Currently, her headaches are described as daily and most commonly dull and “pressurelike,” although she occasionally has a more severe headache associated with nausea and vomiting. Review of her medication use reveals that she receives a prescription for 150 butalbital/acetaminophen/caffeine tablets per month and typically uses all of them. She acknowledges that use of this medication may be excessive but asks what she can do for the pain if she is taken off this drug. Which of the following medications is a useful transition regimen while detoxifying the patient off butalbital? A. B. C. D. E.
Diazepam Hydrocodone Methadone Phenobarbital Zolpidem
The correct answer is D. The patient has developed a chronic daily headache presumed, at least in part, to be due to butalbital overuse. Although different strategies exist regarding abrupt versus gradual tapering of the offending agent, the authors suggest one strategy of a bridging medication during the process of tapering. Prednisone, dexamethasone, and methylprednisolone are all useful choices. Diazepam, hydrocodone, methadone, and zolpidem are all habituating, and thus could create the same dependence and medication overuse headache as butalbital. Phenobarbital seems to be a useful choice as a bridge therapy in patients overusing barbiturates. 15. A 30-year-old woman presents with expressive aphasia and confusion lasting 30 minutes, after which she developed a severe unilateral headache. She has a previous history of migraine with sensory aura since the age of 18. Her migraines are generally perimenstrual. She is afebrile. Her neurological examination now is normal, but she is in severe distress from her headache. An MRI/MRA of the head without contrast is normal. A spinal fluid examination reveals a protein of 50 mg/dL, glucose of 90 mg/dL, white blood cell (WBC) count 200 (100% lymphocytes), red blood cell (RBC) count 0. Cultures and Gram stain are negative. Which of the following diagnoses is the most likely? A. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) B. Complicated migraine C. Headache with neurological deficit and cerebrospinal fluid [CSF] lymphocytosis (HaNDL) syndrome D. Myopathy, encephalopathy, lactic acidosis, strokelike episodes (MELAS) E. Viral meningitis The correct answer is C. This patient most likely has pseudomigraine with lymphocytic pleocytosis, also known as HaNDL. This is an idiopathic benign disorder that may be confused with viral meningitides or other central nervous
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HEADACHE system inflammatory processes. Viral encephalitis would be expected to produce more lingering deficits and be associated with fever. CADASIL and MELAS are associated with abnormalities on MRI and are not usually associated with a prominent CSF pleocytosis. Complicated migraine also is not associated with CSF abnormalities. 16. A 25-year-old woman is seen in a specialty headache clinic for a history of severe bilateral headaches that started at age 15. She states that the headaches initially could be controlled with nonprescription medicines, but that when she reached her last year of high school she missed so many days due to headache that she could not graduate on time. Her headaches are described as bifrontal and behind the eyes and present “all the time.” They have not responded to nortriptyline and topiramate initiated by another practitioner, but hydrocodone “dulls them.” Her primary care physician has been prescribing four hydrocodone daily. She had worked in a store, but states that she hurt her back lifting a box at work and is not currently working. She is living with her boyfriend, who is on disability for psychiatric disease; they have two children. Her parents were divorced when the patient was 4, and she was raised by a grandmother. She has a history of cocaine abuse but denies any illicit drug use since entering a court-ordered program 3 years ago. She tells the neurologist that she feels very lucky to have an appointment with her because she’s heard that “you are the best doctor,” and one of her friends was treated at this clinic. Medical records from the patient’s primary care physician indicate that she has been to three neurologists and that she is known to several local emergency departments for frequent visits for headaches. Her physical examination is normal. She indicates her willingness to try “anything that will work” for the headaches, accepts a prescription for valproic acid, and then states that her primary care physician is on vacation and she is out of her narcotic. When told it could not be refilled at the current appointment, she becomes angry and states, “But what am I supposed to do for the pain?” A follow-up call to her pharmacy reveals that she never filled her valproate prescription. What is the most likely Axis II (personality disorder) diagnosis?
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A. B. C. D. E.
Avoidant Borderline Dependent Narcissistic Schizotypal
The correct answer is B. This patient displays several characteristics of borderline personality disorder: impulsivity in self-destructive behavior (drug abuse), difficulty in controlling anger, idealization and then devaluing of others (in this case, the neurologist). Schizotypal individuals would be unlikely to engage in these types of interactions or relationships; avoidant individuals evade confrontation. A dependent individual, in this case, would more likely bring a family member for “support” and reinforcement of learned helplessness regarding pain. A narcissist would likely involve more self-promotion as an individual deserving of special treatment. The borderline patient described above represents a significant therapeutic challenge.
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17. A 35-year-old woman is seen in consultation for severe daily headaches for 1 year. She has a history of poorly controlled Type I diabetes since childhood, which is treated with an insulin pump and has early retinal changes. Renal function has been normal, but she had a recent episode of chest pain for which she is undergoing cardiac testing. The consultant determines that she has been overusing triptans and has developed medication overuse headache (MOH). Which of the following bridging therapies is indicated in this patient to treat her MOH? A. B. C. D. E.
Dihydroergotamine (DHE) 45 Nonsteroidal anti-inflammatory drugs (NSAIDs) Steroids Topiramate Triptans
The correct answer is B. The patient has MOH from triptans, so triptans are clearly not indicated, although they can be used as a bridging therapy in patients who do not overuse them. Because she is a brittle diabetic, steroids, which are a good choice as a bridging therapy in many patients, would place the patient’s diabetic control at undue risk; DHE would be undesirable because of the patient’s possible problem with ischemic heart disease. Although topiramate is a potentially effective preventive agent, it is not considered a bridge therapy. A short course of NSAIDs in this patient who has been determined to have normal renal function would be a reasonable choice for a bridging medication in the setting of several comorbid medical conditions. 18. Which of the following adverse effects is the most likely to occur in a patient taking oral ergotamine titrate 2 mg in the acute treatment of migraine? A. B. C. D. E.
Chest pain Diarrhea Nasal stuffiness Nausea Paresthesias
The correct answer is D. Nausea is the most common dose-limiting adverse effect in the use of oral or rectal ergotamine. Nasal stuffiness occurs with intranasal dihydroergotamine 45 but not usually with oral ergotamine. Paresthesias and chest pain are relatively rare, occur at higher dosages, and can reflect vascular effects of the drug. 19. When choosing abortive pharmacotherapy for cluster headache, which of the following drug characteristics is most essential to consider? A. B. C. D. E.
Antiemetic action Escalating dosage Long duration of action Rapid onset of action Soporific properties
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HEADACHE The correct answer is D. Because the pain phase in cluster headache is generally very brief (15 to 180 minutes), rapid onset of action of an abortive medication is essential. Either “bridging” or preventive medication is intended to provide a longer duration of action. Most abortive therapies occur in fixed dosages. Antiemetic properties are generally not the key issue, and, since cluster can occur in sleep, medications that promote sleep may not be useful. 20. History of which of the following factors is necessary in order to make a diagnosis of medication overuse headache? A. B. C. D. E.
Accelerating medication use Improvement with medication withdrawal Recent negative neuroimaging Use of a controlled substance Use of at least 10 pills per day
The correct answer is B. Although accelerating medication use is understood to occur in medication overuse headache, criteria to meet this diagnosis according to the International Classification of Headache Disorders, 2nd Edition (ICHD-II) include consumption of acute medication beyond a critical dose, improvement after withdrawal from the medication, and exclusion of a secondary disorder, although that exclusion may be made clinically. Controlled substances are often not the offending drugs, and patients who overuse—for example, triptans—may use far fewer than 10 pills per day. Note is made of the fact that identification and treatment of medication overuse headache is an evolving area among headache specialists; as such, some recently revised criteria do not require resolution of the headache with medication withdrawal as necessary to make the diagnosis.
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21. A 70-year-old man with a history of coronary artery disease, hypertension, and diabetes is referred for a carotid artery ultrasound after suffering an episode of unilateral right visual loss lasting 30 minutes. He is found to have a 90% stenosis of the right internal carotid artery and is referred for carotid endarterectomy. He undergoes surgery uneventfully and returns to his vascular surgeon for a postoperative check 1 week later. At that time, he complains of a severe, pulsating, right-sided headache. He also states that he had a brief (1 hour) episode of difficulty coordinating movements on the left, which he attributed to fatigue. He is sent for a CT scan of the brain, which is unremarkable. He is referred back to the neurologist for this headache. On physical examination, vital signs are normal. No bruit is heard at the neck. Fundi show only arteriolar narrowing. What is the most likely source of the patient’s headache? A. B. C. D. E.
Carotid intimal tear Giant cell arteritis Hyperperfusion syndrome Ipsilateral ischemia Small intracranial bleed
The correct answer is C. Headache, unilateral and ipsilateral to a carotid endarterectomy, is described as occurring, sometimes with focal (contralateral)
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neurological deficits after carotid endarterectomy. This is presumed to be due to reperfusion of a hemisphere with an increased volume of blood at a higher velocity compared to that when the vessel was highly stenosed. Giant cell arteritis is unrelated to the current history, and there is no evidence for a bleed in this patient or a problem at the surgical site. Although the patient presents with focal neurological symptoms, ipsilateral ischemia, which preceded this patient’s surgery, is not felt to be the case. The postendarterectomy syndrome described is usually felt to be associated with positive phenomena, including possible focal seizures. 22. A 25-year-old woman with chronic daily migraine is prescribed amitriptyline 25 mg daily. The medication is gradually titrated upward to 75 mg/d. At this dosage, the medication is highly effective at relieving her headaches but produces intolerable sedation. Lower dosages are not as effective. Which of the following alternative tricyclic antidepressant medications would be least likely to produce sedation? A. B. C. D. E.
Clomipramine Desipramine Doxepin Imipramine Protriptyline
The correct answer is E. Protriptyline is a secondary tricyclic antidepressant and is the least likely to produce sedation. In fact, it often produces insomnia and should be administered in the morning and not at bedtime. Nortriptyline also is less likely to be sedating than amitriptyline. 23. With respect to the direct costs of migraine, which of the following statements is most accurate? A. Emergency department visits were not significantly higher among migraine sufferers than in a control population. B. Migraine sufferers have an increased rate of utilization of health care resources for reasons other than headache. C. No direct relationship exists between headache severity and treatment costs. D. Physician consultation among migraine sufferers has remained stable over the past 15 years. E. Prescription drug costs account for the majority of treatment-related expenditure among migraine sufferers. The correct answer is B. Patients with migraine have higher direct medical costs than a control population largely because of a greater frequency of physician and emergency department visits. This includes an increase in physician consultation for reasons other than headache among migraineurs. Physician consultation has increased over the past 15 years, is more frequent in women compared with men, and increases with age of the patient. Physician visits have been estimated to account for 60% and prescription drugs for 40% of the direct costs of migraine based on a US population-based sample. There is a direct relationship between the severity of the headache and treatment costs.
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24. A 15-year-old girl who has been in good health is referred to a neurologist for several headaches that occurred in the 6 months preceding her appointment. Her first episode presented with inability to see at all for approximately 20 minutes, which came on gradually over approximately 15 minutes and was followed by a unilateral, throbbing headache. The second episode involved vertigo with an onset over approximately 30 minutes followed by an inability to walk straight, both of which lasted approximately 30 minutes and were followed again by a pulsating headache and nausea. Physical examination is unremarkable. The patient is referred for MRI scanning of the brain, along with MRA of the head and neck; these studies are normal, with no evidence of vertebrobasilar pathology. What is the most likely prognosis for this patient’s headaches as she gets older? A. B. C. D. E.
Decrease in associated symptoms Decrease in frequency Evolution to another headache type Increase in associated symptoms Increase in frequency
The correct answer is B. The patient described has basilar migraine, one of the less common migraine syndromes that is more typically seen in young patients and one that tends to abate over time. Associated symptoms are those of brain stem and occipital lobe dysfunction, eg, ataxia, blindness, diplopia. No data suggest that patients with basilar migraine, if they outgrow their syndrome, typically develop another type of headache, but some evidence suggests that the disorder can coexist with more common types of headache.
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25. A 28-year-old woman has recurrent episodes of severe, throbbing, unilateral headache that begin 1 day before her menstrual period and may persist for as long as 3 days during her period. The headache is associated with nausea, phonophobia, photophobia, and profound dysphoria. Some of her headaches have been preceded by unilateral paresthesias, word-finding difficulties, and confusion. She has no headache attacks at other times. Over-the-counter medications have not had significant benefit.Which of the following statements reflects the best approach to counseling this patient? A. B. C. D. E.
Chemical menopause with a GnRH inhibitor would be of benefit. Her headaches will likely persist at the same frequency after menopause. Her headaches would likely improve during pregnancy. Hysterectomy would likely improve her headache problem. Oral contraceptives are a reasonable treatment option.
The correct answer is C. This patient has pure menstrual migraine. Hysterectomy and chemical menopause have not been shown to improve menstrual migraine and are not recommended. Oral contraceptives with low-dose estrogen-containing agents may improve or sometimes worsen migraine. This medication would not be recommended in this patient because of the neurological events she has had with her aura. Oral contraceptives would also be contraindicated if she smoked. Most women experience improvement in their migraines with natural menopause and with pregnancy (particularly from the second trimester on).
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26. A 30-year-old woman is referred to a neurologist after noting a change in her prior pattern of headaches. She initially experienced headaches in her teens, which were unilateral, pulsating, and relieved by sleep. On a few occasions, family and friends noted that before a headache she would become anxious and seem to “space out.” In her 20s, her headaches became somewhat more frequent, occurring about once a month. She was prescribed a butalbital preparation and stayed on that for many years; she now uses about 15 to 20 butalbital tablets per month. At various times, she had been tried on propranolol, nortriptyline, and paroxetine for headache prevention, all without effect. Past medical history is significant for irregular menses and mild depression. One month prior to the appointment, her husband noted an episode during which she muttered something incomprehensible, then appeared to be “out of touch” for about 30 seconds. Afterwards, she reported a headache and went to sleep. The week before her appointment, she had a minor car accident when she swerved off the road. Two weeks ago, her primary physician started her on topiramate for headaches, which she has been titrating up. On neurological examination, mild right facial weakness is present, with no other findings. Which of the following is the most likely cause of this patient’s accelerating headaches? A. B. C. D. E.
Butalbital overuse Hormonal status Major psychosis Organic neurological disease Panic disorder
The correct answer is D. The patient presents a profile of what seem to be typical migraine headaches without aura in the teenaged years that are relieved by sleep, which is not unusual. These headaches accelerated in her 20s and did not respond to several prophylactic drugs, although no antiepileptic drug is mentioned. Because the patient’s pattern later involves some report of alteration of consciousness and finally an unexplained car accident, consideration has to be given to organic neurological disease—in this case, a possible seizure disorder. While the patient may be—although this is not clear—overusing butalbital, and while she may have an abnormal hormonal status and some other confounding factors (mild depression), the suggestion of focal neurological disease has to be investigated. 27. A 50-year-old woman is referred to a neurologist because of headaches that have not responded to multiple medications. She describes a headache that is right sided and unremitting. Initially, her physician felt that she had migraine, and she was given hydrocodone. However, after taking hydrocodone every day for a month, she abandoned it because she still had a daily headache. Some attacks produce tearing and a stuffy nose on the side of the headache. About every month, for a few days she develops a more severe headache, which sometimes causes her to vomit. She has tried sumatriptan and dihydroergotamine without success. The neurologist prescribes indomethacin for the patient, and she has an excellent response, with complete resolution of pain within a day. Activation of which of the following brain areas has recently been associated with this type of headache?
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Contralateral hypothalamus Contralateral midbrain Contralateral pons Ipsilateral hypothalamus Ipsilateral medulla
The correct answer is A. The patient’s headache syndrome—an exquisitely indomethacin-sensitive continuous head pain with migrainelike exacerbations—is consistent with hemicrania continua. Recent positron emission tomographic imaging showed activation of contralateral posterior hypothalamus and ipsilateral rostral pons in some patients with the clinical diagnosis of hemicrania continua. 28. A recent study from two neurology clinics in Spain reported a large series of patients who had headaches that had been present for at least a month and in whom no abnormalities were found on neurological examination. Approximately what percentage of these patients were found to have a “significant intracranial abnormality” on a neuroimaging study? A. B. C. D. E.
0.5% 1% 5% 10% 15%
The correct answer is B. In the Spanish study referred to (Sempere et al, 2005), a large group of almost 1900 patients was studied, over 99% of whom had normal neurological examinations. Imaging studies (primarily CT, although about one third of patients had MRI) detected “significant lesions” in 1.2% of patients; however, of the patients who had normal neurological examinations, the rate of “significant intracranial abnormalities” was 0.9%. Sempere AP, Porta-Etessam J, Medrano V, et al. Neuroimaging in the evaluation of patients with non-acute headache. Cephalalgia 2005;25:30–35.
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29. The risk of stroke in patients with a history of migraine, although debated in several large epidemiological studies, is felt to be higher than that of nonmigraineurs. Among women with migraine with aura who are under age 45 and smoke, use of which of the following substances is felt to further increase the risk of stroke? A. B. C. D. E.
Beta-blockers Ergotamine Opioids Oral contraceptives Triptans
The correct answer is D. Several large epidemiological studies regarding the relative risk of stroke in patients with a history of migraine have been undertaken, not all of which have shown consistent results. However, the data overall suggest that women under age 45 who smoke, use oral contraceptives, and have a history of migraine with aura have the highest
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relative risk of stroke among migraine patients and a significantly higher risk than those without migraine. Ergotamine has no known association to migraine-related stroke, and there is no reason to expect this with opioids. Beta-blockers are used for migraine prevention. 30. A 45-year-old male engineer is seen in an urgent care clinic because of a severe headache that began when he awakened that day. He reports that 2 to 3 times a year he experiences a throbbing headache, typically on the right side. Those headaches are associated with nausea, vomiting, and prostration; he feels that they may be caused by stress. He takes an over-the-counter tablet comprised of aspirin, acetaminophen, and caffeine on average 2 times a week for more minor headaches. On this occasion, he had felt well until 2 days before when he was diagnosed with gastroenteritis, which caused him to stop everything by mouth and stop smoking for 11/2 days, as he had multiple episodes of vomiting and diarrhea. His medical history is significant for hypertension, treated with atenolol. He smokes half a pack of cigarettes daily, drinks 6 to 8 cups of coffee daily, and drinks wine with dinner. On physical examination, vital signs are: blood pressure 120/70, pulse 80, respiration 15, afebrile. He is not orthostatic. He prefers to lie still in a dark room. Pupils, fundi, and visual fields are normal. A noncontrast CT of the brain is normal. There is no nuchal rigidity. He is treated with intravenous metoclopramide and meperidine with relief of his symptoms. Withdrawal from which of the following substances is the most likely cause of this patient’s headaches? A. B. C. D. E.
Acetaminophen Alcohol Atenolol Caffeine Nicotine
The correct answer is D. This patient does not appear to be overusing his over-the-counter medication (acetaminophen) and does not present with other signs consistent with withdrawal from heavy alcohol use. Withdrawal from a beta-blocker (atenolol) might cause a spike in blood pressure or elevated pulse rate, but these are not seen. Nicotine withdrawal presumably could be tolerated and not lead to a migraine-type headache. However, the patient’s caffeine use is substantial and abruptly curtailed by his illness. Of the substances presented, this would be the most likely cause of his acute headache. 31. In a short-duration study of prevalence of risk factors precipitating migraine, several categories of risk factors were studied. Of those considered, which was the most likely to be associated with the onset of a migraine? A. B. C. D. E.
Change in weather Food triggers Menses Psychological stress Sleep disturbances
The correct answer is E. A 3-month study by patient diary of prevalence of headache-associated risk factors among migraineurs found sleep disturbances
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HEADACHE and fatigue to be the leading risk factor by a large margin, followed by psychological stress, change in weather, food triggers, and menses. Interestingly, a counterargument has been advanced by some clinicians that the items identified as risk factors in some situations may represent a prodrome of a headache waiting to happen rather than a precipitant. 32. A 44-year-old woman treats her migraine attacks successfully with an oral triptan. However, at least once yearly, she has an attack that is unresponsive to her oral triptans, either because she awakens with the attack or because she fails to take the oral medication early and misses her “window.” The migraine then builds to vomiting, and she ends up going to an emergency department. What home treatments might keep her out of the emergency department and give her relief? A. B. C. D. E.
Butalbital, aspirin, caffeine, and codeine Celecoxib 200 mg repeated 2 times daily Hydromorphone suppository Intranasal butorphanol Subcutaneous sumatriptan and promethazine suppository
The correct answer is E. Opioids should be avoided both at home and in the emergency department for rescue, and oral COX-2 inhibitors would be inadequate for rescue. Optimal treatments for rescue include parenteral sumatriptan, suppository neuroleptics, self-injected dihydroergotamine, or oral steroids if the patient can take by mouth.
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33. A 50-year-old man comes to the emergency department (ED) 1 day after the onset of a very severe headache. He has been in good health and is treated only for hyperlipidemia with a statin medication. One day ago, he was out jogging when he experienced a lightninglike headache that caused him to vomit. He attributed this to dehydration and returned home where he drank a lot of fluids and rested. His headache persisted, however, and he noted pain upon flexing his neck. In the ED, vital signs are within normal limits except for a temperature of 38°C. He is lying in a dark room and is reluctant to move. Flexion at the neck is resisted, and he grimaces. No other focal signs are found on neurological examination. ED personnel are concerned about subarachnoid hemorrhage and order a noncontrast CT scan of the brain. What is the approximate probability of detecting subarachnoid blood in this patient at this time if he actually had experienced a subarachnoid hemorrhage? A. B. C. D. E.
30% 50% Between 50% and 75% Between 75% and 95% 99%
The correct answer is D. Several series involving detection rates for subarachnoid hemorrhage by CT are reviewed by the author, including a large series of over 3500 patients (1990) and a smaller prospective series of 175 patients (1995). Consistently, the detection rate of subarachnoid
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hemorrhage by CT on the day of the ictus was around 95%. This number drops substantially to 50% after the first week; the percentage of normal CTs by day 1 almost doubled in the large series above. Per Table 11-10, the correct choice is between 75% and 95%. 34. The patient in question 33 undergoes a noncontrast CT scan in the emergency department, which reveals acute hemorrhage in the perimesencephalic region. His physical examination is repeated and again shows a stiff neck, photophobia, and no localizing neurological signs. He is sent for four-vessel digital subtraction angiography, which does not reveal an aneurysm. The patient is told that in about 15% of patients with subarachnoid hemorrhage, no reason is found for the bleed. Of these patients, approximately what percentage demonstrates the pathology described on this patient’s CT scan? A. B. C. D. E.
Less than 1% 5% 10% 30% 50%
The correct answer is E. Perimesencephalic subarachnoid hemorrhage is felt possibly to be due to a vein rupture and is cited as the leading cause of angiogram-negative subarachnoid hemorrhage.
TYPE R QUESTIONS (EXTENDED MATCHING) Theme: Pathophysiology of migraine A. B. C. D. E.
Acetylcholine Butorphanol Calcitonin-gene related peptide (CGRP) Dopamine Sumatriptan
For each of the below descriptions of the role of a medication or neurotransmitter in the pathophysiology or treatment of migraine select the most likely medication or neurotransmitter from the list above. 35. Stimulation of the trigeminal ganglion produces release of this substance by nerve fibers innervating cerebral vessels The correct answer is C. CGRP, substance P, and vasoactive intestinal polypeptide have all been shown in experimental models to be released after stimulation of the trigeminal ganglion. At least for CGRP there seems a clear role in migraine since CGRP receptor blockers are effective acute attack therapies. These neurotransmitters are thought to produce vasodilatation and a sterile inflammatory response around cerebral vessels.
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36. Influences the CGRP promoter and regulates CGRP secretion from neurons The correct answer is E. Sumatriptan has multiple mechanisms for production of analgesia in migraine. One mechanism may be regulation of CGRP secretions via 5-hydroxytryptamine (5-HT [serotonin])1B and 5-HT1D receptors. CGRP appears to be elevated in the headache phase of migraine. 37. Blocks neurogenic plasma extravasation The correct answer is E. Sterile neurogenic inflammation appears to play a role in the pain of migraine and is associated with plasma extravasation from trigeminal-innervated cerebral vessels. Plasma extravasation is blocked by ergots, indomethacin, acetylsalicylic acid, and 5HT1B/1D agonists, including sumatriptan. Theme: International Classification of Headache Disorders. 2nd Edition (ICHD-II) Classifications A. B. C. D. E. F. G. H. I.
Chronic migraine (1.5.1) Chronic tension-type headache (2.3) Episodic cluster headache (3.1.1) Hypnic headache (4.5) Medication overuse headache (8.2) Migraine without aura (1.1) Paroxysmal hemicrania (3.2) Primary stabbing headache (4.1) Short-duration, unilateral, neuralgic, conjunctival injection and tearing headache (SUNCT) (3.3)
For each of the following clinical cases select the most appropriate ICHD-II classification for the patient’s current headache problem.
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38. A 40-year-old woman reports a 20-year history of headache. Initially these headaches were episodic (usually perimenstrual), unilateral, throbbing, and associated with nausea and photophobia. Over the past 5 years they have become more frequent (4 to 5 days each week), holocephalic, nonthrobbing, and unassociated with nausea or photophobia. Currently she is taking 6 to 8 tablets of acetaminophen or a tablet combining acetaminophen, aspirin, and caffeine. Her current headaches are not associated with exertion or Valsalva. The neurological examination is normal, and a CT scan of the head is unremarkable. The patient’s headache frequency is markedly reduced 2 weeks after discontinuing over-the-counter medications. The correct answer is E. This patient has probable medication overuse headache (rebound headache). The diagnosis requires that the headache be present for greater than 15 days per month and occur in conjunction with chronic (usually daily) use of analgesic medications. These headaches typically occur in patients with preexisting headache syndromes, particularly migraine. The diagnosis at this time is “probable” medication overuse headache. A definite diagnosis of this headache type requires that the headache resolve within 2 months of discontinuance of the responsible analgesic medication.
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39. A 50-year-old woman has had recurrent episodic right-sided headaches for the past 4 months. She has no previous history of headache. Her current headache comes on suddenly and is usually centered over the right frontotemporal or orbital region. Each headache lasts only 5 to 10 minutes but may recur as many as 20 times per day. Associated with the headache, she notes tearing and conjunctival injection of the right eye. Her headaches have been prevented by indomethacin, although her internist has advised that she not take this medication due to reduced renal function. The neurological examination and MRI of the head are normal. The correct answer is G. The clinical features suggest paroxysmal hemicrania. These headaches usually have their onset in adulthood and are more common in women. They are characterized by brief (2 to 30 minutes) one-sided headaches usually located around the eye or in the temporal region. Like cluster headache, they are often associated with lacrimation, rhinorrhea, miosis, or ptosis. The headaches are shorter lasting and more frequent than cluster headache. The diagnosis of paroxysmal hemicrania requires an absolute response to indomethacin. 40. A 39-year-old man reports a 1-year history of sharp, stabbing pain behind or above the left eye lasting 5 to 10 seconds and recurring multiple times per day. The patient estimates that he has had as many as 100 attacks on a given day, and he has never gone more than a week without a bout of these head pains. He notes tearing and redness of the left eye associated with the headache. The pain is not triggered by eating, touching his face, or putting in his contacts. His neurological examination is normal as is neuroimaging. The correct answer is I. This patient likely has short duration unilateral, neuralgic, conjunctival injection and tearing (SUNCT). The syndrome is characterized by very brief (5 to 240 seconds) stabbing pain in the orbital or temporal region with tearing and redness of the ipsilateral eye. The attacks are much briefer than those seen in any other trigeminal autonomic cephalalgia. The headaches typically occur multiple times per day. The pain is unilateral and is usually not triggered by touching the face, eating, drinking, or talking, as in trigeminal neuralgia. Causes of secondary headache must be ruled out with clinical examination and neuroimaging. Lesions of the posterior fossa and pituitary gland have been reported to mimic SUNCT.
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Faculty JOEL R. SAPER, MD, FACP, FAAN, Chair Director, Michigan Head Pain and Neurological Institute Ann Arbor, Michigan; Clinical Professor of Medicine (Neurology), Michigan State University, East Lansing, Michigan Relationship and Unlabeled Use of Products/Investigational Use Disclosures: Dr Saper has received honoraria for speaking from GlaxoSmithKline, Merck & Co., Inc., Abbott Laboratories, Inc., Elan Corporation, AstraZeneca Pharmaceuticals, Pfizer Inc, OMP, Valeant Pharmaceuticals International, Bristol-Myers Squibb, Allergan, Inc., Medtronic Inc., Endo Pharmaceuticals, Advanced Bionics, POZEN, Inc., Advanced Neuromodulation Systems, Inc., and Penwest Pharmaceuticals Co. Dr Saper has received personal compensation in an editorial capacity for Pain Watch and Migraine Monitor. Dr Saper holds stock in POZEN, Inc. Dr Saper has received research support from Novartis, OMP, Merck & Co., Inc., GlaxoSmithKline, Allergan, Inc., Eisai Inc., AstraZeneca Pharmaceuticals, Abbott, Advanced Bionics, Medtronic, Renovis, and POZEN, Inc. †Dr Saper may discuss the use of the following US Food and Drug Administration–approved drugs: NSAIDs and analgesics for pain; ergotamine tartrate, triptans, timolol, methysergide, DHE nasal spray, propranolol, metoprolol, valproate, topiramate, and butorphanol [Stadol, Stadol NS] for migraine; and Midrin for headache. Other agents mentioned are off-label.
Learning Objectives
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Upon completion of the Quintessentials Migraine Headache Module, participants will be able to: • Improve their ability to diagnose migraine and nonmigraine headaches • Increase their understanding of the rationale for including patients in the treatment planning process and provide strategies for collaborative decision making • Enhance their understanding of when to recommend and implement various pharmacological and nonpharmacological treatments • Enhance the coordination and communication of recommendations for care
to the patient and the patient’s specialty care provider • Understand a model for making quality improvement changes within their practices
METHOD OF PARTICIPATION Using self-study and enduring materials, you will be guided through a series of plan-dostudy-act quality improvement cycles.
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Opinion leaders and knowledgeable faculty developed a summary of evidence-based and best-practices literature relating to migraine headache. Based on this summary and the information found in this issue, the faculty developed surveys that participants use to assess the process, procedures, policies, and attitudes relating to this topic. The module consists of four phases: 1. Benchmark: Tear out and complete the Baseline Questionnaire and Tips for Practice Questionnaire inserted in the back of this issue. These instruments will help you evaluate your practice’s attitudes, processes, and knowledge of migraine headache. Information gleaned through these documents is aggregated and presented without reference to individuals. Faxing all of these completed documents to the AAN will enroll you in the program. 2. Education: The Pointers for Practice, beginning on page 293, serves as a starting point for the Education Phase of this module. The Pointers for Practice will assist you in identifying areas for improvement in patient care. You will also receive tools to develop an improvement plan and to implement the improvement plan. This information includes Suggestions for Making Changes in Your Practice, Baseline Comparison Report, Tips for Practice Summary, and an Action Plan, which will be mailed to you by the AAN. The suggested time to complete the Education Phase is 60 days. 3. Follow-up: In this phase you will measure the progress you have made. The AAN will send you the Follow-up Questionnaire, Follow-up Tips for Practice Questionnaire, and an Action Plan Evaluation Form to help measure improvements in your practice’s attitudes and behaviors. These instruments are to be completed within 30 days. 4. Feedback: In this last phase of the program you will receive a Follow-up Comparison Report and Follow-up Tips for Practice. These documents allow you to see changes that you and other participants have made. You will also receive a Module Evaluation Form, which must be completed and submitted before CME is granted. ESTIMATED TIME TO COMPLETE THIS MODULE Ten hours. However, time will vary based upon the extent to which changes need to be made within the participant’s practice. ACCREDITATION The American Academy of Neurology (AAN) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AAN designates this educational activity (Quintessentials Migraine Headache module) for a maximum of 10 hours of AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. WELCOME TO THE MIGRAINE HEADACHE MODULE: PHASE 1—BENCHMARK At the back of this issue are two questionnaires for you to complete. These instruments are used to benchmark your practice’s attitudes, processes, and knowledge of migraine headache. Your results will be kept completely private. This information will not be shared with anyone except in the form of aggregated data. It should take you approximately 30 minutes to complete these instruments.
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Baseline Questionnaire––Includes case study questions and general questions regarding attitudes, processes, and knowledge. Tips for Practice Questionnaire––Provides an opportunity for you to share innovative ideas, interventions, or “tips” that you have found to be helpful in your practice. Shortly after you complete these documents and fax them to the AAN, you will receive your personal Baseline Comparison Report and other Phase 2––Education information. (Because at least 25 participant surveys are needed for the comparison report, however, initial participants may experience a delay in receiving Phase 2 material.) At that time, you should read, or re-read, Phase 2––Education, which follows. If you have any questions or concerns at any stage of Quintessentials, please feel free to contact Cecelia Adams at
[email protected] or (800) 879-1960; international: (651) 695-2788.
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PHASE 2––EDUCATION POINTERS FOR PRACTICE––MIGRAINE HEADACHE I. Background A. Working with patients with headache, particularly migraine headache, can be extremely challenging. Barriers contributing to this challenge are: 1. Many patients never seek help from a doctor. 2. Many patients never return for follow-up care (Edmeads et al, 1993). B. Most patients with headache are unhappy with their medical care. Their dissatisfaction is related to: 1. Not getting a clear, understandable explanation of their problem (Edmeads et al, 1993; MacGregor, 1997a) 2. Not receiving treatment that relieves pain and disability (Lipton et al, 1994) 3. Not developing a relationship with their doctor in which they feel that the doctor takes them and their problems seriously and/or spends enough time with them (Edmeads et al, 1993) C. Many physicians feel a time pressure that precludes them from providing the level of care that patients with headache want and need. Consequently, physicians are often dissatisfied when treating patients with headache (Daley, 1993). D. Headache treatment may fail (Table QE-1). II. Diagnosing Headaches A. Most patients with headache will present in a clinician’s office without a headache and have normal neurological and physical examinations. Consequently, careful history taking is important in establishing a diagnosis and establishing a therapeutic relationship with the patient (Silberstein, 1992; Walling, 2001). B. Patients often experience more than one type of headache or have a change in headache pattern. It is important to explore the headache that is of greatest concern to the patient and was the motivation for seeking care. Consider evaluating the patient’s other headaches after gathering key information about the presenting headache problem. C. History and physical examination 1. Headache history a) Key features of headache history include: (1) Attack onset (2) Pain location (3) Attack duration (4) Attack frequency and timing (5) Rate of attack build-up (sudden, gradual, etc) (6) Pain intensity and quality (7) Associated features precipitating and aggravating factors (8) Factors that relieve the headache (9) Previous treatment (10) Medication: Review for excessive and/or inappropriate medication use, including over-the-counter and herbal therapy. b) Social history: Include questions about alcohol, tobacco, and drug use, social and occupational relationships, stressors, and exposure to toxic materials.
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TABLE QE-1
Why Headache Treatments Fail
Headache Diagnoses Are Incorrect or Incomplete Misdiagnosis: A primary headache disorder is misdiagnosed Underdiagnosis: An undiagnosed secondary headache disorder is present Patient has two or more types of headaches; one or more is not diagnosed
Associated Factors Not Identified and Managed Medication overuse (both prescription, over-the-counter, and herbal) Medication interaction triggering headaches Dietary and lifestyle triggers Caffeine overuse Hormonal triggers Comorbid physical conditions
Psychosocial Factors Not Identified and Managed Patient expectations Depression Anxiety Behavioral barriers to improvement
Problematic Pharmacotherapeutic Management Ineffective medications prescribed Initial dosing too high Inadequate final dosing Inadequate/inappropriate duration of treatment Absence of creative pharmacotherapy
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Data from Saper JR, Silberstein SD, Gordon CD, et al. Handbook of headache management: A practical guide to diagnosis and treatment of head, neck, and facial pain. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s headache and other head pain. 7th edition. New York: Oxford University Press, 2001.
c) Medical history: A review of previous or present problems in all body systems may uncover factors that contribute to a headache diagnosis other than migraine. d) Psychological history e) General medical examination (1) Evaluate: (a) General physical appearance (b) Heart rate and blood pressure (c) Cardiac status (d) Sinuses, scalp arteries, cervical paraspinal muscles, and temporomandibular joints (e) Cervical spine: range of motion, localized tenderness, etc (2) Consider using a mnemonic such as SNOOP to carefully review clinical features for pathological/organic origin (Dodick, 2003). (See chapters “Diagnostic Testing and Secondary Causes of Headache” and “Approach to the Intractable Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Headache Case: Identifying Treatable Barriers to Improvement” that address those issues in this issue.) (a) Systemic symptoms (fever, weight loss) or Secondary risk factors (human immunodeficiency virus, systemic cancer) (b) Neurological symptoms or abnormal signs (confusion, impaired alertness or consciousness) (c) Onset: sudden, abrupt or split-second (d) Older: new-onset and progressive headache, especially in middle age (greater than 50 years) (think giant cell arteritis, ischemia, cervical disease, etc) (e) Previous headache history: first headache or different (change in attack frequency, severity, or clinical features) f) Neurological examination is performed to detect intracranial or systemic disease. Consider evaluating these key signs: (1) Evidence of papilledema (2) Nuchal rigidity due to meningeal irritation (3) Focal neurological deficits (4) Indications of giant cell arteritis (5) Horner’s syndrome D. Consider neuroimaging for patients with (Silberstein, 2000): 1. Unexplained abnormal neurological examination 2. Rapidly increasing headache frequency 3. History of lack of coordination, localized neurological signs, or numbness and tingling 4. Headaches causing awakening from sleep 5. Refractoriness to appropriate treatment III. Classification of Headaches
A. The International Headache Society (IHS) classification system may be used by clinicians and researchers to classify 13 principal and more than 70 subtypes of headaches (Table QE-2). B. Walling (2001) and Silberstein and colleagues (1999) provide practical tools for diagnosing headache. C. Consider using the mnemonic SULTANS to assist with the diagnosis of migraine (Table QE-3). IV. Assessing Migraine Comorbidities (Coexisting Conditions)
A. Some conditions coexist in persons with migraine. B. These diseases include stroke, myocardial infarction, Raynaud’s phenomenon, epilepsy, depression, and anxiety (Ramadan et al, 2000). C. Assessment of comorbidity is based on the following rationale: 1. Diagnostic implications when symptoms overlap 2. Treatment implications because comorbidities can impose therapeutic limitations or create therapeutic opportunities D. Strategies for treating coexisting conditions (Ramadan et al, 2000): 1. Select medication that will treat both disorders. 2. Ensure that the treatment of the coexisting disorder is not a contraindication for the selected migraine therapy. Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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TABLE QE-2
International Headache Society Classification System for Primary Headache Disorders
Part 1. Primary headache disorders 1. Migraine 1.1. Migraine without aura A. At least five attacks fulfilling B through D B. Headache lasting 4 to 72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe intensity 4. Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache, at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributed to another disorder 1.2. Migraine with aura A. At least two attacks fulfilling criterion B B. Migraine aura fulfilling criteria B and C for one of the subforms 1.2.1–1.2.6 C. Not attributed to another disorder 1.2.1 Typical aura with migraine headache A. At least two attacks fulfilling criteria B through D B. Aura consisting of at least one of the following, but no motor weakness:
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1. Fully reversible visual symptoms including positive features (eg, flickering lights, spots, or lines) and/or negative features (ie, loss of vision) 2. Fully reversible sensory symptoms including positive features (ie, pins and needles) and/or negative features (ie, numbness) 3. Fully reversible dysphasic speech disturbance C. At least two of the following: 1. Homonymous visual symptoms and/or unilateral sensory symptoms 2. At least one aura symptom develops gradually over 5 minutes or longer and/or different aura symptoms occur in succession over 5 minutes or longer 3. Each symptom lasts between 5 and 60 minutes D. Headache fulfilling criteria B through D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes E. Not attributed to another disorder
continued on next page
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TABLE QE-2
Continued
1.2.2 Typical aura with nonmigraine headache 1.2.3 Typical aura without headache 1.2.4 Familial hemiplegic migraine 1.2.5 Sporadic hemiplegic migraine 1.2.6 Basilar-type migraine 1.3 Childhood periodic syndromes that are commonly precursors of migraine 1.3.1 Cyclical vomiting 1.3.2 Abdominal migraine 1.3.3 Benign paroxysmal vertigo of childhood 1.4 Retinal migraine 1.5 Complications of migraine 1.5.1 Chronic migraine 1.5.2 Status migrainosus 1.5.3 Persistent aura without infarction 1.5.4 Migrainous infarction 1.5.5 Migraine-triggered seizures 1.6 Probable migraine 1.6.1. Probable migraine without aura 1.6.2 Probable migraine with aura 1.6.5 Probable chronic migraine 2. Tension-type headache (TTH) 2.1 Infrequent episodic TTH
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2.2 Frequent episodic TTH 2.3 Chronic TTH 2.4 Probable TTH 3. Cluster headache and other trigeminal autonomic cephalalgias (TACs) 3.1 Cluster headache 3.1.2 Episodic cluster headache 3.1.3 Chronic cluster headache 3.2 Paroxysmal hemicrania 3.2.1 Episodic paroxysmal hemicrania 3.2.2 Chronic paroxysmal hemicrania 3.3. Short duration, unilateral, neuralgic conjunctival injection and tearing (SUNCT)
continued on next page
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MIGRAINE HEADACHE
TABLE QE-2
Continued
3.4. Probable TAC 3.4.1 Probable cluster headache 3.4.2 Probable paroxysmal hemicrania 3.4.3 Probable SUNCT 4. Other primary headaches 4.1 Primary stabbing headache 4.2 Primary cough headache 4.3 Primary exertional headache 4.4 Primary headache associated with sexual activity 4.4.1 Preorgasmic headache 4.4.2 Orgasmic headache 4.5 Hypnic headache 4.6 Primary thunderclap headache 4.7 Hemicrania continua 4.8 New daily persistent headache Data from Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1): 9 –160.
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3. Choose treatments that do not exacerbate migraine headaches. 4. Select treatment with the lowest risk of adverse effects to a fetus if treatment is needed for women who are pregnant or who are considering trying to conceive. E. Depression and anxiety are two of the more common coexisting conditions. When screening/assessing for depression, consider asking the patient: 1. “Have you been feeling sad, blue, or depressed?” or 2. “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” or TABLE QE-3
S-U-L-T-A-N-S
The mnemonic S-U-L-T-A-N-S can help with migraine diagnosis First Criteria
Second Criteria
Severe
Nausea
UniLateral
Sensitivity
Throbbing Activity Worsens Headache (need at least two from this list)
(need one from this list)
Developed by Morris Maizels, MD, Kaiser Permanente. Reprinted with permission.
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3. “During the past month, have you often been bothered by little interest or pleasure in doing things?”(Whooley et al, 1997) and/or 4. Consider using a standardized screening instrument (Table QE-4). F. When screening/assessing for anxiety, consider asking the patient: 1. “Have you been feeling restless, keyed up, or on edge?” or 2. “Have you had difficulty concentrating?” or 3. “Have you been having difficulty falling asleep or staying asleep?” G. Consider using chart reminders and/or having the patient complete easily scored screening forms to increase the recognition of depression and anxiety (Gilbody et al, 2001).
TABLE QE-4
Tools for Screening for Depression
The information provided below is for informational purposes only. No endorsement of these instruments is implied.
Beck Depression Inventory-II (BDI-II) This instrument consists of 21 items to assess the intensity of depression in clinical and healthy patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. This screening tool is recommended for people aged 13 through 80 years. Average administration time is 5 minutes.
Primary Care Evaluation of Mental Disorders (PRIME-MD) This instrument is self-administered and contains 15 questions assessing somatoform disorders, two questions each for depression and anxiety, one for panic, and four for alcoholism. The PRIME-MD has been validated in 1000 primary care patients. Average administration time is 5 to 10 minutes.
Zung Self-Rating Depression Scale (Zung) This instrument is a 20-question self-rating scale used to screen for depression. Items cover affective, psychological, and somatic symptoms. This screening tool has been used for many years in primary care settings. Patients can complete this assessment in 5 to 10 minutes.
Other Strategies One-Question Screen for Depression 1. Are you feeling depressed, sad, or blue? Two-Question Screen for Depression 1. During the past month have you often had little interest or pleasure in doing things? 2. During the past month have you often felt down, depressed, or hopeless? If the patient answers positively to either the One- or Two-Question Screen, consider gathering additional information that conforms to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criterion for mood disorders. The mnemonic SALSA is a good cue for inquiring about the vegetative signs of: • Sleep disturbance • Anhedonia • Low Self-esteem • Appetite change
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V. Assessing Impact of Disability or Impairment
A. Migraine interferes with the patient’s ability to function. A large portion of migraine sufferers report severe disability/impairment or the need for bed rest during a migraine attack (Lipton et al, 1998). B. Many clinicians use the patient’s perception of pain as a marker of patient disability, impairment, or functional status. C. Assessment of disability, impairment, or functional status is important because it: 1. Helps clinicians develop an individualized treatment and education plan for the patient through stratification of headache 2. Assists clinicians manage patients’ treatment expectations 3. Provides a basis on which to track treatment progress for individual patients D. When assessing disability, impairment, or functional status, consider asking the patient: 1. “How have headaches affected your life?” or 2. “What do you hope to happen as a result of our getting together?” or 3. “How will your life be different if you do not have as many or as severe headaches as you currently have?” and/or 4. Consider using one of the standardized disability assessment tools (Table QE-5).
TABLE QE-5
Tools for Disability Assessment
The information provided below is for informational purposes only. No endorsement of these instruments is implied.
Henry Ford Hospital Disability Inventory (HDI) This instrument is designed to evaluate the self-perceived disabling effects of headache. It contains 25 questions subgrouped into emotional and functional domains. Patients can complete this instrument in 5 to 10 minutes.
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Headache Impact Test (HIT and HIT-6) This six-question instrument is designed to assess the functional status of a patient with headache. The instrument focuses on symptoms, activity limitation, and health-related quality of life. The test is available in paper and Web-based formats. Patients can complete this instrument in approximately 2 minutes.
Migraine Disability Assessment Scale (MIDAS) This five-question instrument focuses on lost time in three domains: school or work for pay; household work or chores; and family, social, and leisure activities. This instrument is available in paper and Web-based formats. Patients can complete this instrument in approximately 2 minutes. (See Table 5-1 in the chapter “Acute Treatment of Migraine.”)
Migraine-Specific Quality of Life Questionnaire (MSQ) This 14-question instrument measures the long-term impact of migraine on quality of life in three domains: role function restrictive, role function preventive, and emotional function. This instrument is available in paper and Web-based formats. Patients can complete this instrument in approximately 5 to 10 minutes.
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VI. Managing Migraines—Clinician-Patient Communications Strategies
A. Advise the patient that migraine is a manageable, inherited biochemical condition of the brain that is experienced by many people. 1. Empower patients by demystifying migraine, providing patients with hope of relief, and increasing their ability to function. 2. Empowered patients are more likely to follow treatment recommendations and will experience greater satisfaction. B. Determine and address the patient’s goals or expectations for treatment. 1. Patient’s goals or expectations are important motivators for following treatment recommendations and providing an insight into the patient’s interpersonal relationships. 2. Helping patients to establish and manage expectations that are realistic can: a) Improve patient adherence to treatment recommendations b) Increase patient satisfaction and quality of life c) Enhance clinician satisfaction 3. To facilitate collecting patient expectations/goals, consider using: a) Structured interview forms containing a section for patient goals/expectations b) Chart reminder/tickler forms to gather patient goals/expectations c) Patient questionnaires that specifically ask the patient about their treatment goals/expectations C. Create a formal treatment or management plan that includes patient’s expectations, responsibilities of patient and clinician, treatment goals, and timelines (Table QE-6). 1. Involve the patient in the development of the plan to help individualize the plan and increase patient adherence to treatment recommendations. 2. Provide the patient with a copy of the plan. 3. Place a copy of the plan in the patient’s chart to review when the patient returns to track treatment progress. D. Provide patients with educational information that is educationally and culturally appropriate for them (Table QE-7). E. Encourage patients to use a headache diary or calender to track days of disability, pain, triggers, medications and relief strategies (Appendix B). 1. Using a diary a) Promotes patient accountability b) Helps open a dialogue between the clinician and the patient c) Provides a diagnostic tool for the clinician d) Presents a visual way to track disability, headache-related symptoms, and relief strategies 2. Recommendations for “getting the best” of using a headache diary include: a) Consider sharing the importance of keeping the diary with the patient because it: (1) Reinforces the importance of the diary (2) Facilitates compliance with treatment recommendations b) Consider saying: (1) “The diary is an important way for us to treat/manage your headaches” or (2) “The diary can help us determine what works and does not work for you.” c) Chart reminders indicating that the diary was provided to the patient or that the calender was reviewed may prove helpful. Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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TABLE QE-6
Sample Headache Treatment Plan
I would like to get better control of my headaches so I might:
I know that I have a headache coming on when I have (check all that apply): ❍ Vision changes ❍ Mood changes
❍ Numbness ❍ Weakness
❍ Food cravings ❍ Trouble talking ❍ Nausea or vomiting ❍ Yawning
❍ Increase in energy ❍ Other ________________
Things that trigger my headaches are (check all that apply): Food/drinks
Exposure to
Feeling
Other things ❍ Medications I take
❍ Alcoholic drinks
❍ Meats
❍ Bright lights
❍ Angry
❍ Artificial sweeteners
❍ MSG
❍ Loud noises
❍ Stressed
❍ Salty foods ❍ Sugary foods/ candy
❍ Pollens or things ❍ Tired I am allergic to ❍ Other ❍ Changes in the weather
❍ Vegetables
❍ Other
❍ Breads ❍ Coffee, tea, or colas ❍ Chocolates ❍ Dairy products
❍ Spicy foods
❍ Other
❍ Exercising ❍ My menstrual period ❍ Not eating enough or eating too much ❍ Sleeping too much or not enough
❍ Fruits
❍ Other
I get relief from my headaches by (check all that apply): ❍ Avoiding lights ❍ Exercising
❍ Sleeping
❍ Deep breathing ❍ Reducing my stress
❍ Taking medication
❍ Using biofeedback ❍ Using heat
❍ Using ice ❍ Other
I use the following medications to treat my headaches:
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Medication
How much to take
When to take it
Did it work
Things I can do to partner with my doctor/health care provider to manage my headaches: ❍ ❍ ❍ ❍ ❍ ❍ ❍ ❍
Take an active role in getting better control of my headaches. Ask for information and help when I need it. Keep a headache diary and share it with my doctor/health care provider. Pay attention to signs/triggers that indicate a headache is coming on. Plan ahead to avoid a trip to the emergency department and have my medications available. Talk to my doctor/health care provider about options available to treat my headaches. Use a written list to help me remember to ask all my questions. Remember what I would like to do if I could better control my headaches.
_____________________________ Patient Signature
____________________________________ Doctor/Health Care Provider Signature
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TABLE QE-7
Patient Education Resources
American Academy of Neurology 1080 Montreal Avenue St. Paul, MN 55116 Phone: (651) 695-1940 Toll free: (800) 879-1960 Email:
[email protected] Web site: http://www.aan.com • Patient Education Pamphlets • Headache Encounter Kit (for American Academy of Neurology Members only) http://www.aan.com/professionals/patient/headache.com
American Academy of Family Physicians 11400 Tomahawk Creek Parkway Leawood, KS 66211-2672 Telephone: (913) 906-6000 Toll free: (800) 274-2237 E-mail:
[email protected] Web site: http://www.aafp.org Health information for the whole family from the American Academy of Family Physicians (AAFP) at http://familydoctor.org/. This site contains many types of patient information that can either be downloaded from the Web site or ordered from the AAFP. • Tension Headaches—http://www.familydoctor.org/handouts/172.html • Migraine Headaches: Ways to Deal With the Pain—American Academy of Family Physicians Family Health Facts—http://www.familydoctor.org/healthfacts/127/ • Headaches/Self-Care Flowcharts/Family Health and Medical Guide— http://www.familydoctor.org/flowcharts/502.html • Cluster Headaches—http://www.familydoctor.org/handouts/035.html
American Council for Headache Education (ACHE)
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19 Mantua Rd Mt. Royal, NJ 08061 Phone: (856) 423-0258 Fax: (856) 423-0082 Email:
[email protected] Web site: http://www.achenet.org/
MAGNUM (Migraine Awareness Group: A National Understanding for Migraineurs) 113 S. Saint Asaph St, Suite 300 Alexandria, VA 22314 Phone: (703) 349-1929 Fax: (703) 349-1930 Web site: http://www.migraines.org/
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MIGRAINE HEADACHE
TABLE QE-7
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National Headache Foundation 820 N Orleans, Suite 217 Chicago, IL 60610-3132 Phone: (312) 274-2650 Toll free: (888) 643-5552 Fax: (312) 640-9049 Web site: http://www.headaches.org
National Institute of Neurological Disorders and Stroke (Part of the National Institutes of Health) Includes fact sheets on migraine and information on institute research projects. NIH Neurological Institute PO Box 5801 Bethesda, MD 20824 Phone: (301) 496-5751 Toll free: (800) 352-9424 Web site: http://www.ninds.nih.gov/
VII. Managing Migraines—General Considerations
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A. Treatment goals include (Silberstein, 2000): 1. Reducing attack frequency, severity, and resultant disability 2. Decreasing reliance on poorly tolerated, ineffective, or unwanted acute therapies 3. Improving the quality of life of persons with migraine 4. Avoiding transformation to “rebound” or medication overuse headache 5. Empowering patients to manage their migraines 6. Reducing headache-related psychological symptoms and distress B. Tailor treatment to both the patient and type of attack (Silberstein, 2000). 1. Step care is the use of medication in a sequential order, based on a predetermined plan. Therapy starts with the lowest level of treatment, independent of the attack characteristics. 2. Stratified care is treatment based on attack characteristics, including peak intensity, time to peak intensity, associated symptoms, disability, and patient preferences for treatment. VIII. Managing Migraines—Acute Treatment
A. Use migraine-specific agents (triptans, dihydroergotamine, ergotamine tartrate) in patients with more severe migraine and whose headaches respond poorly to nonsteroidal anti-inflammatory drugs or combination analgesics such as aspirin plus acetaminophen plus caffeine. B. Select a nonoral route of administration for patients whose migraines are associated early with nausea or vomiting as a significant component of the symptom complex. C. Consider a self-administered rescue medication for patients with severe migraine that does not respond well to (or fails) other treatments. Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
D. Provide antinausea and alternate routes of delivery. E. Guard against medication overuse headache (also known as rebound or drug-induced headache). IX. Preventive Therapy
A. A diary is extremely helpful as a clinician diagnostic tool and as a way for patients to visually track triggers, duration and frequency of attack, and response to treatment. B. General principles of preventive management include the use of nonpharmacological therapies and patient preferences (Silberstein, 2000). 1. Consider relaxation training, thermal biofeedback combined with relaxation training, electromyogram biofeedback, and cognitive-behavioral therapy as treatment options to prevent migraine. 2. Behavioral therapies may be combined with preventive pharmacological therapy to achieve additional clinical improvement for migraine relief. X. Managing Migraines—Rescue Medication
A. Patients use rescue medication (RM) to treat break-through migraine when initial and back-up medications have failed to provide relief. 1. RMs help decrease discomfort and may decrease the need to visit the emergency department or make phone calls for advice and/or medication. 2. RMs can be seen by the patient as self-empowering and can diminish the fear of headache symptoms. 3. Consider the patient’s comorbid/coexisting medical and behavioral conditions (eg, depression, anxiety, epilepsy, stroke, menopause) when prescribing RMs. 4. Medications of choice include antinauseants, neuroleptics, and hypnotics. 5. Advise the patient that RMs may not completely eliminate pain and facilitate their return to normal activities. 6. Opioids should be used with caution, if at all, in patients with frequent headaches since new evidence suggests that opioids may have a deleterious effect on headache progression. Use should be selective and rare and only in compliant patients (Saper and Lake, 2006). XI. Managing Migraines—Considerations When Treating Women
A. Women may experience migraines when estrogen levels drop. These times are (Mannix and Calhoun, 2001): 1. With menses (MacGregor, 1997b): a) Menstrually associated migraine (MAM) is migraine without aura that occurs during the perimenstrual period (day 1 of menses plus or minus 2 days). b) Menstrual migraine (MM) occurs exclusively with menses. 2. During the placebo days of oral contraceptives: Patients often note a clustering of headaches in the week of inactive drug use, typically within the first 2 days of stopping the active pills. 3. With pregnancy: Migraines may worsen during or after the first trimester but often improve during the second and third trimesters. The migraines may remit until shortly after delivery and/or resume in earnest following pregnancy. 4. Migraines typically improve at menopause; however, hormonal therapies may negate this improvement. Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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B. Treatment of MM and MAM are based upon general principles of migraine treatment. C. Hormonal manipulation may be considered when treating MAM and MM (Mannix and Calhoun, 2001). XII. Managing Headache—Rebound Headaches, Transformed Migraine, or Medication Overuse Headache
A. Patients with frequent headaches often overuse medications (Table QE-8). B. These headaches may be both a response to chronic pain or a consequence of chronic pain, or in headache-prone patients, medication overuse may produce drug-induced rebound headache accompanied by a dependence on symptomatic medication. C. Medication overuse can make headaches refractory to preventive medication. D. Consider a referral to a clinician specializing in the treatment of headache. E. Treatment should include: 1. Withdrawal of offending medication 2. Appropriate treatment of escalating pain and anxiety 3. Implementation of preventive and abortive treatment 4. Addressing behavioral and psychological factors related to overuse 5. Referral to a specialty center when appropriate XIII. Managing Headache—Follow-up Visits
A. Follow-up visits are used to assess efficacy, side effects, and patient satisfaction with the current treatment plan. Consider: 1. Reviewing the patient’s headache diary in conjunction with the patient’s providing oral feedback on her or his headache experiences a) Checking for consistency between the diary and oral report b) Using the consistency check as a teachable moment relating to: (1) The need to keep a diary (2) Why there may be a difference between what the patient records and what the patient says
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Revised Criteria for Medication Overuse Headache
Appendix 8.2 Medication overuse headache Diagnostic criteria: A. Headache present on ≥15 days per month B. Regular overuse for >3 months of one or more acute/symptomatic treatment drugs as defined under sub forms of 8.2. 1. Ergotamine, triptans, opioids, or combination analgesic medications on ≥10 days per month on a regular basis for >3 months 2. Simple analgesics or any combination of ergotamine, triptans, analgesics opioids on ≥15 days per month on a regular basis for >3 months without overuse of any single class alone C. Headache has developed or markedly worsened during medication overuse From Headache Classification Committee, Olesen J, Bousser MG, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26:742–746. Copyright © 2006. Reprinted with permission from Blackwell Publishing Ltd.
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2. Reassessing impact of disability utilizing the interview and/or standardized assessment strategy and documenting in the patient’s chart and headache diary 3. Determining the patient’s satisfaction and preferences with the current treatment plan B. Consider charting the patient’s impact of disability (disability rating scores) and/or perceptions of pain to provide a quick way to visually check the patient’s progress over the course of treatment. XIV. Managing Headache—Referrals
A. Consider referral to a clinician with a special interest in diagnosing and treating headache if the patient: 1. Has unusually frequent or debilitating headaches 2. Is unresponsive to multiple medication trials 3. Has symptoms of a “worrisome” headache (see SNOOP above) 4. Presents with complex medical and/or psychiatric comorbidities 5. Presents with symptoms of rebound, transformed, or medication overuse headache B. Consider referring patient for lifestyle and/or behavioral assessment and treatment. C. There often is a breakdown in communication in the referral process. To ensure communications, consider: 1. Reason for referral (assist in diagnosing and/or developing a treatment plan or in diagnosing and treating) 2. Providing direction on how and when you would like feedback (phone, fax, email, surface mail) (Appendix C)
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Headache Classification Subcomittee of the International Headache Society. The International Classification of Headache Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):9–160. Holmes WF, MacGregor EA, Sawyer JP, Lipton RB. Information about migraine disability influences physicians’ perceptions of illness severity and treatment needs. Headache 2001;41:343–350. Lipton RB, Amatniek JC, Ferrari MD, Gross M. Migraine. Identifying and removing barriers to care. Neurology 1994;44:S63–S68. Lipton RB, Hamelsky SW, Kolodner KB, et al. Migraine, quality of life, and depression. A population-based case-control study. Neurology 2000;55:629–635. Lipton RB, Stewart WF, Simon D. Medical consultation for migraine: results from the American Migraine Study. Headache 1998;38:87–96. MacGregor EA. The doctor and the migraine patient: improving compliance. Neurology 1997a;48:S16–S20. MacGregor EA. Menstruation, sex hormones, and migraine. Neurol Clin 1997b;15:125–141. Mannix LK, Calhoun A. Menstrual migraine: designing a treatment strategy. Female Patient 2001;26:46–51. Packard RC. What does the headache patient want? Headache 1979;19:370–374. Ramadan NM, Silberstein SD, Freitag FG, et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. [online] 2000 [cited July 18, 2006]. Available from: http://www.aan.com/professionals/practice/guideline/index.cfm. Saper JR, Lake AE 3rd, Opioid therapy should rarely be administered to headache patients: clinical observations, literature review, and proposed guidelines. Headache Curr 2006;3:67–70. Saper JR, Lake AE 3rd, Hamel RL, et al. Daily scheduled opioids for intractable head pain: long-term observations of a treatment program. Neurology 2004;65:1687–1694.
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