Viral Neuropathies in the Temporal Bone (Advances in Otorhinolaryngology, Vol. 60)

Viral Neuropathies in the Temporal Bone

Advances in Oto-Rhino-Laryngology Vol. 60

Series Editor

W. Arnold

Munich

Viral Neuropathies in the Temporal Bone

Richard R. Gacek Mobile, Ala Mark R. Gacek Mobile, Ala

100 figures, and 8 tables, 2002

Basel ⭈ Freiburg ⭈ Paris ⭈ London ⭈ New York ⭈ New Delhi ⭈ Bangkok ⭈ Singapore ⭈ Tokyo ⭈ Sydney

Prof. Richard R. Gacek, Prof. Mark R. Gacek Division of Otolaryngology, Head and Neck Surgery College of Medicine, University of South Alabama 307 University Blvd., N HSB Suite 1600 Mobile AL 36688– 0002 (USA)

Library of Congress Cataloging-in-Publication Data Gacek, Richard R. Viral neuropathies in the temporal bone / Gacek, Richard R., Gacek, Mark R. p. ; cm. – (Advances in oto-rhino-laryngology, ISSN 0065-3071 ; v. 60) Includes bibliographical references and index. ISBN 3805572956 1. Temporal bone–Diseases. 2. Facial nerve–Diseases. 3. Vestibular apparatus–Diseases. 4. Virology. I. Gacek, Mark R. II. Title. III. Series. [DNLM: 1. Temporal Bone–innervation. 2. Temporal Bone–virology. 3. Facial Nerve Diseases–virology. 4. Vestibulocochlear Nerve Diseases–virology. WV 201 G121v2002] RF260 .G334 2002 616.7⬘1–dc21 2002023571

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2002 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0065–3071 ISBN 3–8055–7295–6

Contents

VII Preface XI Acknowledgment Chapter 1

3 The Biology of Neurotropic Viruses Gacek, R.R. (Mobile) Chapter 2

32 Neuroanatomy of the Nerves in the Temporal Bone Gacek, R.R. (Mobile) Chapter 3

32 Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis Gacek, R.R.; Gacek, M.R. (Mobile) Chapter 4

54 Vestibular Neuronitis: A Viral Neuropathy Gacek, R.R.; Gacek, M.R. (Mobile)

Chapter 5

67 Ménière’s Disease: A Form of Vestibular Ganglionitis Gacek, R.R.; Gacek, M.R. (Mobile) Chapter 6

80 The Pathology of Benign Paroxysmal Positional Vertigo Gacek, R.R.; Gacek, M.R. (Mobile) Chapter 7

89 A Classification of Recurrent Vestibulopathy Gacek, R.R.; Gacek, M.R. (Mobile) Chapter 8

305 Efferent System Degeneration in Vestibular Ganglionitis Gacek, R.R. (Mobile) Chapter 9

324 Antiviral Therapy of Vestibular Ganglionitis Gacek, R.R.; Gacek, M.R. (Mobile)

327 Appendix 337 Subject Index

Contents

VI

Preface

A number of otologic disorders have mystified clinicians over the years. These have been referred to as ‘idiopathic’ indicating lack of a known cause. Although animal models are useful in elucidating basic physiologic mechanisms, recurrent neuropathies (vestibular, facial) of the temporal bone (TB) are unique to humans. Therefore, human TB specimens represent the best source of information providing insight into the pathology of these neuropathic disorders. For hundreds of years, Bell’s palsy (IFP) and Ménière’s disease (MD) have been regarded as idiopathic. Although displaced otoconia have been implicated in the mechanism of benign paroxysmal positional vertigo, the precise stimulus for degenerated otoconia has also been unknown (idiopathic). Only vestibular neuronitis was assumed to be an inflammatory disorder of the vestibular nerve because of its clinical association with viral-type illnesses and supported by serologic evidence of elevated viral antibodies. The description of endolymphatic hydrops (EH) in TB from patients with the clinical symptoms of MD [1, 2] provided the impetus for a long series of investigations into the concept of obstruction in longitudinal flow of endolymph to the endolymphatic sac. The theory received support from the experimental demonstration of EH following obstruction of the endolymphatic duct in some animals (guinea pig, gerbil, rabbit) [3, 4]. However, failure to produce EH in nonhuman primates [5] and the absence of vertigo in the successful animal models of EH detracted from the EH theory of MD and accounted for the equivocal results obtained by treatments designed to reduce endolymph.

In a similar way, the previous concept of IFP held that an ischemic event leads to edema of the facial nerve and compression within the surrounding bony canal. Surgical decompression to relieve intraneural pressure did not achieve superior results compared to no treatment in a large number of consecutive patients with IFP [6]. Molecular amplification of herpes simplex virus 1 by PCR on vestibular nerves (ganglia) from patients with MD [7] and IFP [8] supports a viral role in these idiopathic disorders. We have demonstrated in human TB specimens from patients with IFP, MD, vestibular neuronitis and benign paroxysmal positional vertigo a pattern of degenerative changes in the facial nerve (meatal ganglion) and vestibular nerve (and ganglion) which is similar to morphologic changes in herpes zoster of the trigeminal nerve. This evidence has been summarized in the series of reports contained in this volume of Advances in Otorhinolaryngology. Harold F. Schuknecht, MD, predicted a viral cause for MD in his discussion of delayed EH, a form of MD. ‘Assuming that viral labyrinthitis can occur in infants as a subclinical disease that results in delayed endolymphatic hydrops, we may have an explanation for the cause of Ménière’s disease. Viewed in this context the disease entity known as delayed endolymphatic hydrops becomes the missing link in understanding the pathogenesis of Ménière’s disease’ [9]. We dedicate this series of studies to the memory of H.F. Schuknecht whose life-long professional passion was the TB. Armed with this concept of pathogenesis for the recurrent vestibulopathies, the variable features and unpredictable nature of the ‘three faces’ of vestibular ganglionitis can be understood. An antiviral approach is warranted but will require substantive changes in present-day antiviral pharmaceuticals. R.R. Gacek M.R. Gacek

References 1 2 3 4 5 6

Hallpike CS, Cairns H: Observations on the pathology of Ménière’s syndrome. J Laryngol Otol 1938;53:625–655. Yamakawa K: Über die pathologische Veränderung bei einem Ménière-Kranken. J Otorhinolaryngol Soc Jpn 1938;44:2310–2312. Kimura RS, Schuknecht HF: Membranous hydrops in the inner ear of the guinea pig after obliteration of the endolymphatic sac. Pract Otorhinolaryngol 1965;27:343–354. Kimura RS: Animal models of endolymphatic hydrops. Am J Otolaryngol 1982;3:447–451. Swant J, Schuknecht HF: Long term effects of destruction of the endolymphatic sac in a primate species. Laryngoscope 1988;98:1183–1189. Peitersen E, Andersen P: Spontaneous course of 220 peripheral non-traumatic facial palsies. Acta Otolaryngol Suppl (Stockh) 1967;224:296–300.

Preface

VIII

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8

9

Pitovski DZ, Robinson AM, Garcia-Ibanez F, Wirt R: Presence of HSV-I gives products characteristic of active infection in the vestibular ganglia of patients diagnosed with acute Ménière’s disease (abstract 457). 22nd Annu Midwinter Res Meet Assoc Res Otolaryngol, St Petersburg Beach, February 1999. Burgess RC, Michaels L, Bale JF, Smith RH: Polymerase chain reaction amplification of herpes simplex viral DNA from the geniculate ganglion of a patient with Bell’s palsy. Ann Otol Rhinol Laryngol 1994;103:775–779. Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febiger, 1993, pp 235–244.

Preface

IX

Acknowledgment

The authors are grateful to L. Nan Johnson for excellent secretarial assistance in manuscript preparation. The professional help in medical illustrations by Lynda Touart and Frank Vogtner is much appreciated. Financial support for this publication was provided by Glaxo Smithkline Pharmaceutical Co. and the University of South Alabama School of Medicine.

Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 1–11

Chapter 3

The Biology of Neurotropic Viruses Richard R. Gacek

Neurotropic (NT) viruses are characterized by their affinity for neural structures, specifically sensory neurons. One group of NT viruses commonly associated with neuropathy is the ␣-herpes virinae subfamily [1]. This group of viruses has a propensity for invading sensory neurons, the establishment of latency within ganglion cells and a possibility of reactivation at some later date by a stressful stimulus. The best known members of this group of viruses are the herpes simplex (HSV) types 1 and 2, and the herpes zoster or varicella virus [2]. These viruses are responsible for the clinical syndromes of HSV labialis and herpes zoster [3]. Other members of this family of NT viruses are the cytomegalic inclusion virus, pseudorabies and the Epstein-Barr virus [1]. Within these types are hundreds of strains representing mutant varieties of the virus type. NT viruses are important clinically because of the high incidence of exposure to HSV in the population worldwide [4]. Exposure to the virus and the establishment of latency in sensory nerves may occur in individuals as early as the first 10 years of life. The incidence of exposure and establishment of latency by virus increases with age and lower socioeconomic status [5]. It is estimated that by the age of 25 years 75% of the population has elevated antibodies to the HSV group, and by the age of 60 years the exposure is over 90%. Therefore, the potential for latency in various sensory ganglia of the body is high. Exposure to viral organisms in the human body is high in the soft palate, oropharynx, hypopharynx, nose and nasopharynx where viral invasion of the mucous membrane epithelium occurs. Virus presence in the epithelium of the oral cavity represents an opportunity for invasion of a sensory neuron dependent on complementary surface structures of the virus envelope and the sensory neuron. Virus invasion of the sensory neuron is mediated by glycoproteins in the virus envelope. These glycoproteins have specific and sometimes overlapping functional roles. At least 10 glycoproteins in the HSV virus envelope play a role in virus behavior. Only glycoprotein B (gB), glycoprotein D (gD), glycoprotein H (gH) and glycoprotein L (gL) are vital to

the process of infection [6–11]. The remaining 6 glycoproteins contribute in some way to virus invasion and infectivity in host cells. These glycoproteins are a reflection of the genetic makeup of the viral organism and therefore confer a particular level of infectivity for each virus strain. Infection of a sensory neuron occurs first by virus attachment to the cell plasma membrane, followed by penetration of the virus nucleocapsid into the cell cytoplasm and nucleus [12]. This virus attachment involves different glycoproteins in the virus envelope and receptors on the sensory cell surface. gB and gC are primarily responsible for the initial attachment phase which depends on the combination of positively charged viral envelope glycoprotein moieties with negatively charged heparan sulfate receptors on the cell surface [13, 14]. The heparan sulfate proteoglycan receptors are also genetically programmed cell features that permit successful attachment and infection of the neuron by a viral organism [6]. The initial attachment process facilitates a second attachment phase in which gD binds to a cellular receptor belonging to the tumor necrosis factor and nerve growth factor family [15]. gD is essential for fusion of the viral envelope to the cell membrane and finally penetration of the cell membrane by the virus [11, 12]. It has been determined in genetic studies that gB, gD and gH are necessary for this fusion-penetration process. Virus-binding receptors are unevenly distributed over the plasma membrane of the neuron. The adsorption of both HSV-1 and HSV-2 is efficient in mouse synaptosomal and glial cell preparations but virtually absent on neuronal cell bodies [16, 17]. Synaptosomes adsorb virus better than glial cells. Such a favorable uptake in synapses may account for the efficiency of virus uptake by nerve terminals and transmission along multisynaptic neuronal linkages when used as a neurobiologic tracer. The lack of receptors on neuronal perikarya might be responsible for a reduction in HSV spread from cell to cell in peripheral ganglia. However, cell-to-cell virus spread may occur as a result of virus movement across cell junctions between adjacent neurons or by a viral precursor rather than the fully formed virus [18]. The animal model of HSV infection in a murine sensory ganglion indicates that after arrival of the virus in the ganglion cell, it accumulates within the nucleus but after a productive infection may leave the nucleus and the cytoplasm acquiring a double envelope from the nuclear and the plasma membranes [19]. Upon arrival in the extracellular space, the virus particles are surrounded by an increased number of satellite cells (SC) which incorporate the virus within the SC nucleus and cytoplasm (fig. 1). As virus particles are enveloped by the SC, they are replaced by cytoplasmic extensions of the SC which proliferate membrane in layers. These membrane layers fuse into thick membranous envelopes in a whorl-like pattern (fig. 2). In this manner, the enveloping SC surround and replace the ganglion cell body (fig. 3). The cytoplasm of the ganglion cell may become vacuolated by the

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Stages of Herpetic Ganglionitis

A

Retrograde

Anterograde

Satellite Cell

B

C

Fig. 1. A schematic summary of the major morphologic features in NT viral ganglionitis. Drawing A represents the acute inflammatory phase, while B and C illustrate degenerative phases based on the histologic features shown in figures 2 and 3.

infection and replaced by SC which have increased in number (fig. 4). The SC may replace the cell perikaryon leaving nuclear remnants at the epicenter. After the NT virus has entered the peripheral process of a sensory neuron, the virion is carried by axoplasmic transport to the ganglion cell body (fig. 1). This process has been demonstrated to require 20–24 h. Once the virus has successfully reached the cytoplasm of the ganglion cell, it may spread to adjacent ganglion cells by several mechanisms [19]. The virus may simply leave the infected cell and attach to membrane receptors on nearby cells with subsequent invasion. Alternatively, the virus may move across junctions where cells are closely attached (tight junctions, desmosomes) and thereby elude antibodies circulating

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Fig. 2. The vestibular ganglion in a 75-year-old female with recurrent vertigo (duration 20–40 min) and positional vertigo shows ganglion cells being replaced by SC (open arrows) and a collagen-like substance replacing another (solid arrow).

Fig. 3. The meatal ganglion (MG) in a 44-year-old man with a history of episodic vertigo without hearing loss for several years (case 5, table 1, see Appendix). Several ganglion cells (arrowheads) have been replaced by a collagen-like material surrounding nuclear remnants. FN ⫽ Facial nerve; VN ⫽ vestibular nerve.

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Fig. 4. The trigeminal ganglion in case 19 (table 1, see Appendix) shows vacuolated ganglion cells surrounded by SC (open arrows). The solid arrow points to lipofuchsin granules in a ganglion cell.

within the extracellular space [20]. Finally SC may spread the virus to nearby ganglion cells. The tendency of NT viruses to involve adjacent neurons in a ganglionic mass results in clusters of infected ganglion cells (fig. 5). Reactivation of virus in a group of infected ganglion cells will then result in lesions (vesicles) that are tightly grouped (i.e. herpes simplex labialis, herpes zoster). Degeneration of a cluster of ganglion cells produces a group of degenerated axons in the nerve trunk (fig. 6). If the virus does not leave the neuron completely after the initial infection, it may assume a latent (subviral) state within the nucleus of the cell. All the factors necessary to develop latency are not known. However, a transformation in the necessary RNA genome for establishing latency, i.e. latency-associated transcript, is an essential event [21, 22]. Once latency has been established, reactivation of the virus into an active or productive infection may occur following a stimulus that is unusually stressful or traumatic, physically or chemically. The animal model of latent HSV infection has shown adrenaline to be capable of reactivating latent HSV [23]. An additional underlying factor is host resistance; in the immunocompromised host or in the host with a senescent immune response, the tendency for reactivation of a latent virus form is greater than in the young uncompromised host subject.

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Fig. 5. The vestibular ganglion in case 3 (table 1, see Appendix), a 62-year-old male with recurrent vertigo and no hearing loss, contained clusters of ganglion cells in various phases of degeneration (arrows). Some cells are surrounded by dark SC and inflammatory cells, while others have been replaced. VN ⫽ Vestibular nerve.

Fig. 6. Vestibular nerve from a 61-year-old female with otosclerosis who died from ovarian cancer. Two fascicles of degenerated axons (arrows) are seen in the nerve trunk. VG ⫽ Vestibular ganglion.

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The mode of virus presence in the cell is also determined by the genotype of host neurons. Margolis et al. [24] presented evidence that two types of neurons in the mouse dorsal root ganglion allowed a different virus presence following a single inoculation of virus. In one population of ganglion cells, viral protein synthesis was high, but transcription of latency-associated transcripts was minimal, while in a second type of neuron viral gene expression was restricted but latency-associated transcript synthesis was abundant. These observations suggest that following virus uptake in a nerve, latent infection will occur in one type of neuron and active productive infection in another type of ganglion cell within the same ganglion. The SC has long been felt to be intimately related to its ganglion cell. SC support the neuron metabolically during prolonged activity. This suggestion is supported by the decreased nucleic acid content in SC while neuronal nucleic acid is increased in the superior cervical ganglion following prolonged (3-hour) stimulation [25, 26]. The role of SC in the NT viral infection of a ganglion may represent a response to increased neural activity as well as the need to limit the spread of virions released from ganglion cells. The increased density associated with membrane proliferation may be responsible for the collagen layers found in the onion bulb pattern observed in some types of neuronal degeneration (fig. 2, 3) [27]. The number of SC associated with normal ganglion cells varies in different cranial nerves. This variation may be dependant on the embryologic origin of the ganglionic mass. The ganglion cells of the eighth cranial nerve (vestibular and cochlear) are derived from the otic placode and typically have 1–2 SC per ganglion cell [28]. However, the ganglion cells of the seventh cranial nerve (geniculate and meatal) are derived from the epibranchial placode and the neural crest epithelium; these ganglia are normally surrounded by many SC, the precise number is not known. Since the SC increase is part of the host response to NT virus infection in a ganglion, a significant increase in SC in the vestibular ganglion can be recognized with confidence, but not in the ganglia of the seventh nerve where a large number of SC is found normally. Therefore, evidence of ganglion cell degeneration is necessary to conclude that NT virus has infected the geniculate and meatal ganglia. Since direct evidence of ganglion cell degeneration is uncommonly seen in the vestibular ganglion, it is necessary to rely on indirect evidence in the form of axonal degeneration to reflect NT damage of the vestibular ganglion. Since NT virus will typically also infect adjacent ganglion cells (clusters), focal axonal degeneration in the vestibular nerve trunk represents virus destruction of ganglion cells. Focal axonal degeneration has been described in trigeminal nerve zoster [29]. Although viruses are protected within the environment of the ganglion cell and nucleus, and therefore shielded from antibodies or antiviral drugs, their

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infectious effects may be manifested by the release of nucleic acids [20]. Nucleic acids (DNA and RNA) have a low level of infectivity compared to the virus from which they are derived. However, their release is capable of producing clinical syndromes similar to that resulting from virus infection and yet be unaffected by the antibody response of the host since nucleic acids are not a viral protein. Nucleases released from blood components are capable of neutralizing nucleic acids. White blood cells may release nuclease inhibitors and consequently disturb the normal equilibrium between nucleic acid infectivity and nuclease control during infection with fever (i.e. sinusitis). Fever as a precipitating effect in the clinical manifestation of a latent virus neuropathy may be understood in the context of this hypothesis. Since exposure of the population to HSV is so high, reasons for the absence of a similarly high incidence of cranial neuropathies should exist. Although this evidence has not been reported, several possibilities exist. (1) The makeup of the virus envelope as well as receptors on host neuronal membrane represent a major determinant of virus invasion of a sensory ganglion. The glycoprotein composition of the virus envelope and compatible proteoglycan receptors in the neuronal plasma membrane are genetically determined features of the virus-host neuron complex. The absence of surface structures essential for virus attachment and invasion would present a major deterrent to NT invasion and establishment of latency in sensory nerves. (2) The availability of sufficient ganglion cells to harbor a virus pathogen may be important when the ganglion represents the initial repository for the invading virus. The meatal ganglion of the facial nerve represents the location for neuronal pathology associated with vestibular ganglion degeneration in recurrent vertigo possibly because it receives input from the soft palate and nasopharynx where virus invasion occurs [27, 30]. Since the meatal ganglion is represented by a very small ganglion cell population in most human temporal bones (TB), the likelihood of a large virus load in this region of the facial nerve is correspondingly low. (3) Host resistance reflects the genetic makeup of prospective neuronal elements (i.e. No. 1), as well as the genotype of the immune system (i.e. lymphocytes) that are important for controlling virus invasion. The recrudescence of virus from latency has frequently been noted with the immunocompromised state (chemotherapy, radiation therapy) as well as with senescent immune systems. NT viruses and their reactivation from latency assume a direction of flow within the central or peripheral processes of a sensory neuron dependent on virus strain [31, 32]. The flow from neuron to the brainstem is referred to as anterograde flow, since it is in the direction of normal axoplasmic flow in the neuron, whereas flow toward the periphery (over the dendrite of the sensory

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neuron) is regarded as retrograde flow (fig. 1). The herpes family viruses are characterized by their ability to flow bidirectionally between the neuron and its peripheral or central terminus. Certain strains of the HSV preferentially travel in a retrograde direction (toward the periphery), and others flow preferentially in an anterograde direction. The H 129 strain of HSV-1 flows in an anterograde direction while the McIntyre B strain follows a retrograde direction of flow. This correlation is important, as to a large degree it may determine the clinical presentation of reactivated virus. This principle provides the basis for the use of NT viruses as a neurobiologic tracing method, since the anterograde virus strain will allow it to be transported centrally over several synaptic connections to demonstrate the higher neuronal members of a sensory system. Intracellular pathogens have long been known to produce plaques as a result of their cytopathic effect [33]. Uncommonly associated with bacterial pathogens such as Ehrlichia but commonly seen with viral agents such as vaccinia, psittacosis, western equine encephalomyelitis virus and HSV, plaques have been used to detect and quantify virus presence in vitro because of the linear relationship of plaque number with the number of virus particles. Plaque size may differ with virus type and strain. Plaque shape is roughly spherical with a sharp border and represents necrosis of tissue. Histological changes visible by light microscopy may reflect the accumulation of viral nucleic acids and antigen in cells infected with HSV. HeLa cells infected with HSV in tissue culture show that virus DNA accumulates intracellularly before viral antigen can be detected [34]. Successive stages show that more diffuse DNA accumulates as viral antigen is synthesized. These changes are also associated with the formation of giant cells which may represent fusion of infected individual cells. Since the nucleic acid content in cells is responsible for nuclear staining, it is possible that nuclear stains can demonstrate high intracellular levels of DNA accumulation. One component of the hematoxylin and eosin stain used in human TB histopathology is an excellent nuclear (nucleic acid) stain. Hematoxylin (C16H14O6) is the compound which results after ether extraction from the wood portion of Haematoxylon campechianum. Upon oxidation, hematoxylin is converted to hematein which stains certain structures (i.e. nuclei) a deep blue. Histopathologic TB studies are important to our understanding of disorders caused by viral organisms. Understanding the events which accompany NT viral infection and reactivation in sensory ganglia of the cranial nerves associated with the TB can guide the interpretation of morphologic changes caused by these microorganisms. Complemented by direct immunofluorescence microscopy and molecular biology, an informative research approach can enhance the value of human TB collections.

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19 20 21

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Meier J, Straus S: Comparative biology of latent varicella-zoster virus and herpes simplex virus infections. J Infect Dis 1992;166(suppl I):S13–S23. Straus SE: Clinical and biological differences between recurrent herpes simplex virus and varicella-zoster virus infections. JAMA 1989;262:3455–3458. Baringer R, Swoveland M: Persistent herpes simplex virus infection in rabbit trigeminal ganglia. Lab Invest 1974;30:230 –240. Smith IW, Peutherer JF: The incidence of herpes virus hominis antibody in the population. J Hyg (Camb) 1967;65:395– 408. Whitley RJ: Herpes simplex viruses; in Fields BN, Knipe DM (eds): Virology, ed 2. New York, Raven Press, 1990, pp 1843–1888. Laquerre S, Argnani R, Anderson D, Zucchini S, Manservigi R, Glorioso J: Heparan sulfate proteoglycan binding by herpes simplex virus type I glycoproteins B and C attachment, which differ in their contributions to virus penetration, and cell-to-cell spread. J Virol 1998;72:6119– 6130. Forrester AJ, Farrell G, Wilkinson G, Kaye J, Davis-Poynter N, Minson AC: Construction and properties of a mutant herpes simplex type I deleted for glycoprotein H sequences. J Virol 1992;66:341–348. Roop C, Hutchinson L, Johnson D: A mutant herpes simplex virus type I unable to express glycoprotein L cannot enter cells and its particles lack glycoprotein H. J Virol 1993;67:2285–2297. Ligas MW, Johnson DC: A herpes simplex virus mutant in which glycoprotein D sequences are replaced by B-galactosidase sequences binds to but is unable to penetrate into cells. J Virol 1998;62:1486 –1494. Ca W, Gu B, Person S: Role of glycoprotein B of herpes simplex virus type I in viral entry and cell fusion. J Virol 1988;62:2596 –2604. Campadelli-Eiume G, Arsenakis M, Farabegali F, Roizman B: Entry of herpes simplex virus I in BJ cells that constitutively express viral glycoprotein D is by endocytosis and results in degradation of the virus. J Virol 1988;62:159–167. Nicola AV, Peng C, Lou H, Cohen GH, Eisenberg RJ: Antigenic structure of soluble herpes simplex virus (HSV) glycoprotein D correlates with inhibition of HSV infection. J Virol 1997;71: 2940 –2946. Herold RC, Wu Dunn D, Sultys N, Spear PG: Glycoprotein C of herpes simplex virus type I plays a principal role in the adsorption of virus to cells and infectivity. J Virol 1991;65:1090–1098. Wu Dunn D, Spear PG: Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol 1989;63:52–58. Montgomery RI, Warner MS, Lurn BJ, Spear PG: Herpes simples 1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 1996;87:427–436. Vahlne A, Svennerholm B, Sandberg M, Hamberger A, Lycke E: Differences in attachment between herpes simplex type 1 and type 2 viruses to neurons and glial cells. Infect Immun 1980; 28:675–680. Haywood A: Mini review – Virus receptors: Binding, adhesion strengthening, and changes in viral structure. J Virol 1994;68:1–5. Dingwell KS, Brunetti CR, Hendricks RL, Tang Q, Tang M, Rainbow AJ, Johnson DC: Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread in vitro and across junctions of cultured cells. J Virol 1994;68:834–845. Cook ML, Stevens JG: Pathogenesis of herpetic neuritis and ganglionitis in mice: Evidence for intra-axonal transport of infection. Infect Immun 1973;7:272–288. Herriott RM: Infectious nucleic acids, a new dimension in virology. Science 1961;134:256–260. Croen KD, Ostrove JM, Dragovic LJ, Smialek JE, Straus SE: Latent herpes simplex virus in human trigeminal ganglion: Detection of an immediate-early gene ‘antisense’ transcript. N Engl J Med 1987;317:1423–1432. Dealty AH, Spivack JG, Lavi E, O’Boyle DR, Fraser NW: Latent herpes simplex virus type I transcripts in peripheral and central nervous system tissues of mice map to similar regions of the viral genome. J Virol 1988;62:749–756.

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Schmidt J, Rasmussen AF: Activation of latent herpes simplex encephalitis by chemical means. J Infect Dis 1960;106:154 –158. Margolis TP, Sedarati F, Dobson AT, Feldman LT, Stevens JG: Pathways of viral gene expression during acute neuronal infection with HSV-I. Virology 1992;189:150–160. Pevzner LZ: Topochemical aspects of nucleic acid and protein metabolism within the neuronneuroglia unit of the superior cervical ganglion. J Neurochem 1965;12:993–1002. Schwyn RC: An autoradiographic study of satellite cells in autonomic ganglion. Am J Anat 1967; 121:727–739. Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210. Ona AI: The mammalian vestibular ganglion cells and the myelin sheath surrounding them. Acta Otolaryngol (Stockh) 1993;503:143–149. Denny-Brown D, Adams RD, Fitzgerald PJ: Pathologic features of herpes zoster: A note on geniculate herpes. Arch Neurol Psychiatry 1949;51:216–231. Gacek RR: On the duality of the facial nerve ganglion. Laryngoscope 1998;108:1077–1086. Zemanick MC, Strick PL, Dix RD: Direction of transneural transport of herpes simplex virus I in the primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88:8048–8051. Kuypers HG, Ugolini G: Viruses as transneuronal tracers. Trends Neurosci 1990;13:71–75. Dulbecco R: Production of plaques in monolayer tissue cultures by single particles of an animal virus. Proc Natl Acad Sci USA 1952;38:747–752. Ross RW, Orlans E: The redistribution of nucleic acid and the appearance of specific antigen in Hela cells infected with herpes virus. J Pathol Bacteriol 1958;76:393–402.

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Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 12–31

Chapter 2

Neuroanatomy of the Nerves in the Temporal Bone Richard R. Gacek

The cranial nerves associated with the temporal bone (TB) have both sensory and motor components and may be invaded by neurotropic (NT) viruses. These are the fifth, seventh, eighth and ninth cranial nerves. NT (herpetic) involvement of the trigeminal nerve is a common viral neuropathy which has been studied clinically by microbiologic and histopathologic methods [1, 2]. However, virus-mediated neuropathy of the seventh, eighth and ninth cranial nerves has been a controversial subject. A viral etiology for idiopathic facial palsy (Bell’s palsy) is now generally recognized [3–5]. Virus-mediated neuropathy of the eighth cranial nerve has only recently been supported by morphologic evidence in human TB [6]. Evidence to support a similar pathology in the ninth nerve is lacking thus far. Viral neuropathy of the tenth cranial nerve is also probable but is not included in this discussion since its anatomic course through the TB is not included in routine specimens. The eleventh cranial nerve is not affected by NT viruses because it does not have a sensory component. The relationship of these cranial nerves to areas of the oral cavity, oropharynx, nasopharynx and nose which are a habitat for NT viruses represents a basis for virus recrudescence from latency later in life.

Trigeminal Nerve

The trigeminal (fifth cranial) nerve is the largest of the cranial nerves and conveys common sensation from the superficial and deep regions of the face as well as a smaller motor component to the muscles of mastication [7]. The fifth nerve trunk is attached to the lateral part of the pons by a large sensory root and a small motor root. The two nerve roots travel forward in the posterior cranial

Fig. 1. Low-power view of the trigeminal ganglion (T) in Meckel’s cave on the superior surface of the petrous apex (PA). Figure 4 in the previous chapter 1 was taken from this section.

fossa to enter the middle cranial fossa after passing between the attachment of the tentorium cerebelli and the upper border of the petrous portion of the TB. The sensory root overlies the motor root as they pass into the trigeminal ganglion lying in Meckel’s cave on the superior surface of the petrous apex (fig. 1). The ganglion gives rise to the three main divisions of the nerve: ophthalmic, maxillary and mandibular. Details of the diverse functional components in these three divisions may be found in texts of anatomy [7]. An overview of the sensory input conveyed by these divisions aids the understanding of the vulnerability of this cranial nerve to virus invasion. Although each division conveys common sensation from the upper, middle and lower thirds of the face as well as the anterior half of the scalp, deeper structures lined with mucous membrane within bony cavities of the skull are also richly innervated by the corresponding division. Accordingly, the ophthalmic division carries sensory input from the nasal cavity and ethmoid sinuses over the ethmoidal nerves, the maxillary division conveys input from the alveolar ridge, maxillary and sphenoid sinuses (sphenopalatine nerves), and the mandibular division supplies the floor of the mouth and alveolus. NT viral invasion of the terminals (synaptosomes) and ganglion of the trigeminal nerve is made possible by nature of the epithelial surfaces in these areas.

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Fig. 2. Photo of the FN (F) and vestibular nerve (V) in the internal auditory canal of a dissected human TB. The myelinated nerves are stained with Sudan black. M ⫽ Location of the meatal ganglion adjacent to the vestibular ganglion; G ⫽ geniculate ganglion; S ⫽ saccule; U ⫽ utricular macula; LC, SC, PC ⫽ lateral, superior and posterior canal cristae.

Facial Nerve

After emerging from the brainstem, the facial nerve (FN) travels together with the vestibular division of the eighth cranial nerve the length of the internal auditory canal (fig. 2). The FN then enters the labyrinthine segment of the fallopian canal which conveys it throughout a tortuous course through the TB. The FN is derived from the second branchial arch and innervates structures that are derived from Reichert’s cartilage. Four groups of functional neurons constitute the FN complex [8]. (1) The special efferent FN axons supply the striated muscles of facial expression, as well as the stapedius muscle, the stylohyoid muscle and the posterior belly of the digastric muscle. (2) General visceral efferent fibers represent the preganglionic portion of the autonomic pathway to glandular and vascular structures (fig. 3). The main glandular structures are the lacrimal gland and the seromucinous glands in the nasal

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VI

Superior Salivary Nucleus Motor Nucleus N VII

Autonomic Pathways

Fig. 3. Diagram of the pre- and postganglionic parasympathetic motor pathways of the FN. VI ⫽ Abducens nucleus; N VII ⫽ seventh cranial nerve.

cavity. These fibers travel in the greater superficial petrosal nerve (GSPN) to synapse in the sphenopalatine ganglion, which contains the postganglionic neurons providing secretomotor function. Secretory fibers are carried by the chorda tympani nerve and synapse with postganglionic neurons in the submandibular ganglion innervating the submandibular and sublingual salivary glands. (3) Special sensory fibers (taste) (fig. 4) are carried over two pathways. The majority of the taste receptors inputting to the FN are located in the anterior two thirds of the tongue. Peripheral dendrites supplying these sensory receptors in the chorda tympani nerve join their cell bodies in the geniculate ganglion (GG). A second group of taste receptors are located in the soft palate and nasopharyngeal mucosa and are innervated by fibers in the GSPN which belong to ganglion cells (meatal ganglion, MG) located in the meatal segment of the FN. (4) Somatic sensory neurons supply the skin of the external auditory canal and the concha. The brainstem nuclei which give rise to FN axons are: (1) the motor nucleus of the FN, which is located in the caudal brainstem adjacent to the superior olivary nucleus of the auditory system; just caudal to the facial nucleus is the rostral limit of the nucleus ambiguus which provides motor innervation to the intrinsic laryngeal musculature; the number of facial motor neurons has been estimated at approximately 10,000–20,000; the motor neurons for various facial muscle groups are topographically arranged in subnuclei

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Lacrimal Gland Trigeminal G.

VI Nasal & Palatine Glands

GSPN

Meatal G. Nucleus & Tract Solitarius

Geniculate G. Palate

Pterygopalatine Ganglion

Motor Nucleus N VII

Lingual Nerve Submandibular G.

Motor Facial Nerve

Sublingual & Submandibular Glands

Special Sensory Pathways

Fig. 4. Diagram of the special sensory pathways of the FN. G ⫽ Ganglion; VI ⫽ abducens nucleus; N VII ⫽ seventh cranial nerve.

within the facial nucleus [9]; however, the axons from these subnuclei intermix as they leave the facial nucleus in a dorsal direction to loop around the abducens nucleus near the floor of the fourth ventricle [10]; the axons converge at this point and then bend in a ventrolateral direction just medial to the vestibular nerve (VN) root before exiting the brainstem; (2) the location of motor neurons for the stapedius muscle and the posterior belly of the digastric muscle are separately clustered in the brainstem; stapedius motor neurons are located in the interface between the facial nucleus and the superior olivary nucleus, where they are strategically located to receive stimuli from the afferent auditory pathway and carry out reflex contraction of the stapedius muscle (stapedius reflex); the motor neurons for the posterior belly of the digastric muscle are located along the course of the emerging FN root in the lateral brainstem region; (3) the superior salivary nucleus is responsible for secretomotor (autonomic) neurons in the FN system; this nucleus is located dorsally to the motor facial nucleus and gives rise to the preganglionic parasympathetic secretomotor neurons entering the submandibular and the sphenopalatine ganglia; (4) the nucleus of the solitary tract, also located in the medulla, receives taste input over sensory fibers of the FN. The major portion of the FN is comprised of motor axons to the facial musculature. Although arising from regional groups of motor neurons in the facial

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Fig. 5. Low-power view of the tympanic (T), geniculate (G), petrosal (P) and meatal (M) segments of the FN. V ⫽ Vestibular ganglion; C ⫽ basal turn of the cochlea.

nucleus, these fibers intermix throughout the course of the FN in its intracranial and intratemporal segments [10]. After exiting the stylomastoid foramen, the motor axons gather together in functional groups before forming the 4–5 branches which supply the regional facial muscle groups. For purposes of this discussion, the important divisions of the FN trunk are the meatal segment, the labyrinthine (petrosal) portion, the geniculate portion and the tympanic part (fig. 5). Except for the meatal portion which lies free in the internal auditory canal, the remaining segments of the FN are contained within a bony canal (fallopian). Accompanying the FN trunk is the nervus intermedius which carries secretomotor axons of the preganglionic neurons in the superior salivary nucleus, as well as proximal axons of sensory neurons in the FN ganglia (geniculate and meatal), traveling to the nucleus solitarius in the brainstem.

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Fig. 6. a Photograph of the GG (G) at the junction of the tympanic (T) and petrosal (P) segments of the FN. b The MG of the FN (F) is located adjacent to the vestibular ganglion (V).

100

Composition (%)

80

60

40

20

0 0

20

40

60

80

100

Cases (n)

Fig. 7. Graphic ordering of the percentage composition of the FN ganglia (geniculate and meatal) in 100 human TB.
⫽ Meatal;  ⫽ geniculate.

The sensory ganglia of the FN (geniculate and meatal) are important to the subject of virus-mediated neuropathy (fig. 6). A quantitative study of 100 TB described these ganglionic masses quantitatively (fig. 7) [11]. These two ganglia are derived from different embryologic anlagen, the GG from the epibranchial placode (second branchial arch), while the MG develops from the neural crest primordium. In most TB (88%), the GG contains most of the sensory neurons in the FN while the MG is very small. In approximately 12% of FN, the MG may

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Fig. 8. a In this case where the GG is absent (*), the greater superficial petrosal nerve (GSP) travels toward the labyrinthine segment (L) of the FN. T ⫽ Tympanic FN. b A large MG represents the sensory ganglion of the FN (F) when the GG is missing. V ⫽ Vestibular ganglion.

equal or exceed the number of ganglion cells in the GG. The study found that the number of neurons in the GG ranged from 66 to 4,017 (mean 1,713) while the MG contained from 0 to 2,764 cells (mean 448). Fourteen percent of the GG contained less than 1,000 cells, while 88% of the MG contained under 1,000 cells. Sixty-four percent of the MG held fewer than 500 cells, and 34% had less than 200. In approximately 2% of TB, the MG represents the entire ganglion associated with the FN. In instances where the GG is absent and the MG represents the only sensory ganglion of the FN, TB specimens indicate that the GSPN inputs to the MG (fig. 8). This observation supports a conclusion that the afferent input from taste receptors in the soft palate and nasopharynx is carried over the GSPN to the MG, while the GG contains sensory neurons for taste receptors in the anterior two thirds of the tongue [11]. Furthermore, the MG location in the inner auditory canal portion of the FN is juxtaposed to the vestibular ganglion (Scarpa’s ganglion; fig. 6b). Although these two ganglionic masses are derived from two separate embryologic sources, their intimate anatomic association permits a common involvement in inflammatory processes [6].

Eighth Cranial Nerve

The eighth cranial nerve is made up of two portions, the vestibular and the cochlear, supplying the balance and the auditory portions of the labyrinth, respectively. Both of these nerve divisions are primarily afferent in function and

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Kinocilium

KC

Stereocilia

Cuticle

Supporting cell

Nerve chalice Efferent nerve ending

Synaptic bar Efferent nerve ending

Afferent nerve ending

Type 2

Type 1 Hair cells

Fig. 9. Drawing of the afferent and efferent innervation of type 1 and 2 vestibular hair cells. KC ⫽ Kinocilium.

composed of bipolar ganglion cells derived from the auditory vesicle [8]. They are of placodal origin. The human VN is comprised of approximately 18,000 bipolar neurons, of which a third are classified as large afferents and two thirds are small afferents. The large and small afferent neurons supply hair cells in all five vestibular sense organs. The large afferents supply the type 1 hair cells with a calyx-like ending, in a 1 : 1 or 1 : 2 ratio (fig. 9). The small afferents supply type 2 hair cells in the vestibular sense organs with small bouton-type endings. Each small afferent fiber branches generously to contact type 2 hair cells over a wide area in the sensory epithelium. There is an orderly distribution of type 1 and type 2 hair cells in the sense organs [12]. In the crista of the three semicircular canals, type 1 hair cells are located primarily at the crest of the crista, whereas type 2 hair cells predominate along the slopes. In the maculae of the utricle and the saccule, type 1 hair cells predominate near the striola line of the macula, whereas the type 2 hair cells are denser over the peripheral regions. The two

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SCA HCA

Utricle PCA Saccule

SG

Saccular nerve OCB Utricular nerve PCN

Fig. 10. Drawing of the input from vestibular sense organs in the ear. The dark area from the superior (SCA) and lateral (HCA) canals is closest to the FN. PCA ⫽ Posterior canal crista; SG ⫽ Scarpa’s ganglion; OCB ⫽ olivocochlear bundle; PCN ⫽ posterior canal nerve.

types of afferent neurons in the VN possess different neurophysiologic properties. The large afferents supplying type 1 hair cells display an irregular spontaneous discharge pattern, while the small afferents to type 2 hair cells exhibit a regular spontaneous discharge pattern [13, 14]. Each ganglion cell in the human VN is normally surrounded by 1–2 satellite cells which have an important and close metabolic relationship to its ganglion cell [15]. The distribution and course of the bipolar afferent neurons in the VN are organized as to their projection pattern from sense organs (fig. 10) [16]. The lateral and superior canal cristae of the superior vestibular division input to the brainstem over large afferent ganglion cells in the most anterior portion of the vestibular trunk, which are closest to the MG in the FN. The small afferents supplying type 2 hair cells in the lateral and superior canal cristae are located in a more caudal portion of the superior division of the VN, while the ganglion cells supplying the utricular macula lie in

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Cerebellum

LVN LVN

MVN

MVN VII

VII VI

DCN VCN V VCN

V

VII

ASO

LSO

ASO

Coch. eff.

Fig. 11. Drawing of the origin and course of the efferent vestibular pathway. The stippled area denotes the efferent cochlear pathway. DCN ⫽ Dorsal cochlear nucleus; VCN ⫽ Ventral cochlear nucleus; LVN ⫽ Lateral vestibular nucleus; MVN ⫽ Medial vestibular nucleus; V ⫽ Descending trigeminal nucleus; VII ⫽ Facial nerve genu; ASO ⫽ Accessory superior olivary nucleus; VI ⫽ Abdueens nucleus; LSO ⫽ Lateral superior olivary nucleus; Coch. eff. ⫽ Cochlear efferent.

the inferior portion of the superior vestibular division. The ganglion cells for the posterior canal crista are located most caudally in the inferior vestibular ganglion and project their axons rostrally to join those of the superior division cristae before entering the brainstem. The saccular ganglionic input is located in the most caudal portion of the VN trunk. The distal process (dendrite) of vestibular ganglion cells is approximately half the diameter of the proximal axon and is intermixed in the nerve branches before terminating in the sense organ neuroepithelium. On the other hand, the proximal axons of ganglion cells project in a straightforward fashion from Scarpa’s ganglion cells to the brainstem. Therefore, degeneration of the thicker proximal axons in the nerve trunk is more easily detected by light microscopy than degeneration of the thinner distal process (dendrite) in VN branches. The efferent pathway to the vestibular labyrinth arises from small neurons located bilaterally near the medial vestibular nucleus and the abducens nucleus close to the floor of the fourth ventricle (fig. 11) [17]. The number of efferent neurons supplying the cat labyrinth is approximately 200–300 [18]. However, because of a profuse branching pattern, the number of efferent terminals almost

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Fig. 12. Cross-section of the seventh and eighth nerves of the cat stained for acetylcholinesterase. EF ⫽ Efferent fibers (cochlear and vestibular) bundle in the VN (V); C ⫽ cochlear nerve; F ⫽ FN; NI ⫽ nervus intermedius.

equals the number of afferent terminals provided by 12,000 afferent neurons [19]. Fine efferent axons collect as they travel laterally before entering the vestibular root in the brainstem, join the efferent cochlear fibers (olivocochlear bundle) and travel together as a compact group of small axons in the VN (fig. 12). These fine axons emerge from the brainstem between the superior and inferior VN divisions [19]. At the saccular portion of Scarpa’s ganglion, the efferent axons pass through the ganglionic mass and then diverge toward the sense organs (fig. 13). Vestibular efferents are dorsally located in the parent efferent bundle before dispersing into the superior and inferior vestibular divisions, first in fascicles and then as individual fibers which branch as they travel peripherally (fig. 14). After penetrating the basement membrane of the sense organs, they ramify further before forming many vesiculated small bouton terminals contacting type 2 hair cells predominantly [20, 21]. Efferent termination also occurs on the large calyx-like endings which engulf type 1 hair cells. The density of efferent terminals is greatest on the type 2 hair cells along the slopes of the cristae and in peripheral regions of the maculae [21]. Efferent fibers are cholinergic and the distribution of efferent fibers can be selectively demonstrated by using a histochemical method to localize acetylcholinesterase activity [19].

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Fig. 13. A more distal section of the same specimen as in figure 12 demonstrates the olivocochlear bundle (OCB) as it leaves the saccular nerve (S) to join the cochlear nerve (C). Vestibular efferent fibers (VE) travel as bundles in the superior division and as scattered fibers in the posterior canal nerve (PC) and saccular nerve. F ⫽ FN.

The human cochlear nerve is composed of approximately 30,000 bipolar ganglion cells, of which 95% are type 1 with myelinated axons, and 5% are type 2 ganglion cells with unmyelinated cell processes [22]. The type 1 spiral ganglion cells project in a straightforward manner to the inner hair cells (IHC) of the organ of Corti where they terminate directly on the IHC (fig. 10). Since approximately 10–20 type 1 dendrites terminate on each IHC, the innervation pattern is very dense at the base of the IHC (fig. 15). The spontaneous discharge pattern of these type 1 ganglion cells is irregular, somewhat similar to the large afferents in the vestibular ganglion which terminate on type 1 vestibular hair cells. The small type 2 spiral ganglion cells project fine unmyelinated dendrites along the floor of the tunnel space in the organ of Corti, enveloped by tunnel cell processes to form spiral fiber bundles between Deiters’ cells and terminate on outer hair cells (OHC) in a diffuse pattern (fig. 16). They travel basally in a longitudinal direction before terminating on OHC [22]. The central termination of type 2 ganglion cells is unknown, although it has been suggested that they terminate in the dorsal cochlear nucleus. The function of type 2 spiral ganglion cells is unknown at this time.

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Fig. 14. A high-power view of the posterior canal nerve shows the individual efferent nerve fibers (arrows) scattered throughout the nerve. Ganglion cells are in the upper left corner.

The efferent cochlear system (olivocochlear bundle) has been described for over 50 years as having a bilateral origin with the major portion of the efferent axons to one cochlea arising from periolivary neurons near the contralateral accessory superior olivary nucleus in the brainstem (fig. 17) [24–26]. These myelinated axons pass in a dorsal direction before decussating under the floor of the fourth ventricle with the contralateral olivocochlear bundle and interdigitate with FN fibers before merging with the vestibular efferent bundle in the VN root. They are then joined by the ipsilateral limb of the olivocochlear bundle which is given off by small neurons surrounding the lateral superior olivary nucleus. The efferent neuronal supply to the cat cochlea numbers 1,500–2,000 compared to 50,000 afferent ganglion cells in the cat [26]. As with vestibular innervation, extensive branching in the efferent system accounts for near equality in the number of afferent and efferent terminals within the organ of Corti. Numerically, the ipsilateral limb of the olivocochlear bundle is about 25% of the size of the contralateral limb. Furthermore, the axons in the ipsilateral olivocochlear bundle are unmyelinated or thinly myelinated while those in the contralateral limb are well myelinated. These cochlear efferent axons, together with vestibular efferent fibers, travel in the VN through the saccular portion of the

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Fig. 15. A transmission electron micrograph of the base of IHC shows bundles of nerve fibers (NF) and endings (NE) tightly surrounded by supporting cells (S) after penetrating the basilar membrane (BM). Efferent fibers in a spiral bundle (E) pass near the hair cell.

Fig. 16. A phase contrast micrograph of the organ of Corti in the cat illustrates the relationship of outer spiral bundles (open arrows) at the base of OHC. D ⫽ Deiters’ cells; H ⫽ Hensen’s cells; P ⫽ pillars; S ⫽ supporting cells with IHC; T ⫽ tectorial membrane.

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Fig. 17. Drawing of the origin and course of the olivocochlear efferent bundle by Rasmussen [24].

vestibular ganglion before the efferent cochlear fibers emerge as the vestibulocochlear anastomosis (Oort’s), enter Rosenthal’s canal and then travel apically in a spiral direction as the intraganglionic spiral bundle. As the bundle travels apically in the cochlea, it gives off individual fibers which mix with afferent dendrites within the osseous spiral lamina before exiting through the habenula perforata to enter the organ of Corti. Since cochlear efferent axons are also cholinergic, the acetylcholinesterase technique has been used to demonstrate their course and termination. The fibers of the contralateral olivocochlear bundle cross high in the tunnel space and give rise to large vesiculated terminals which contact the base of OHC (fig. 18, 19). The density of the efferent innervation of OHC is greatest in the upper basal turn, with decreasing innervation density in both apical and basal directions [27]. This decrease is seen first in the outermost row of OHC, then the middle and innermost OHC in the apical direction. The smaller fibers of the ipsilateral efferent system form a dense inner spiral bundle of fibers under the IHC which provides contact by small bouton-shaped endings on afferent axons near their termination on IHC.

Glossopharyngeal Nerve (Ninth Cranial Nerve)

Although the ninth cranial nerve has a motor component to the stylopharyngeus muscle, it is largely a sensory nerve which innervates the carotid body,

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Fig. 18. An acetylcholinesterase preparation of the guinea pig organ of Corti demonstrates the course and termination of efferent fibers (EF). Large terminal swellings are located at the base of OHC, while the large accumulation under an IHC represents inner spiral fibers as well as terminals on afferent endings.

Fig. 19. An electron micrograph at the base of an OHC in the guinea pig demonstrates large efferent terminals (E) filled with vesicles and an afferent ending (A) from type 2 spiral ganglion cells.

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Middle ear Inferior salivatory nucleus

Jugular foramen

Otic ganglion

Motor nucleus

Parotid Tympanic nerve

Superior ganglion

Nucleus solitarius

Brainstem alate

Soft p

Tonsil

Tongue

Stylopharyngeus muscle

Internal carotid artery

Inferior ganglion

External carotid artery

Carotid body

Fig. 20. Drawing summarizing the afferent and efferent projections of the glossopharyngeal (ninth) nerve. Note that the tympanic nerve contains both afferent and efferent nerve fibers.

the pharyngeal tonsil, the base of the tongue and the lingual surface of the epiglottis. Sensory taste receptors located in the posterior third of the tongue, the adjacent epiglottis and the soft palate project over the glossopharyngeal nerve and ganglion to the nucleus solitarius in the brainstem (fig. 20). Ganglion cells responsible for these sensory inputs are located in the inferior ganglion within the jugular foramen. A smaller superior ganglion is variably present and may contain sensory neurons of the tympanic branch. The tympanic branch of the ninth nerve is important clinically because it carries preganglionic efferent parasympathetic axons as well as afferents from middle ear mucosa through the middle ear space as Jacobson’s nerve which continues as the lesser superficial petrosal nerve before synapsing in the otic ganglion. Postganglionic neurons in the otic ganglion complete the efferent link to the parotid salivary gland. The presence of sensory ganglion cells carrying input from taste receptors in the oral cavity over the seventh and ninth cranial nerves represents a common pathway for entrance of NT viruses into these cranial nerves. NT viral ganglionitis as a cause of recurrent ear pain requires morphologic evidence in human TB.

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References 1 2 3 4

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9 10 11 12 13 14

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Baringer JR, Griffith JF: Experimental herpes simplex encephalitis: Early neuropathologic changes. J Neuropathol Exp Neurol 1970;29:89–104. Baringer RJ, Swoveland MA: Persistent herpes simplex virus infection in rabbit trigeminal ganglia. Lab Invest 1974;80:230–240. Adour K, Bell DN, Hilsinger R: Herpes simplex virus in idiopathic facial paralysis (Bell’s palsy). JAMA 1975;233:527–530. Burgess RC, Michaels L, Bole JF, Smith RH: Polymerase chain reaction amplification of herpes simplex viral DNA from the geniculate ganglion of a patient with Bell’s palsy. Ann Otol Rhinol Laryngol 1994;103:775–779. Gacek R, Gacek M: Meatal ganglionitis: Clinical pathologic correlation in idiopathic facial paralysis (Bell’s palsy). Otorhinolaryngol Nova 1999;9:229–238. Gacek R: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210. Dunward A: Peripheral nervous system – Trigeminal nerve; in Brash JC (ed): Cunningham’s Text Book of Anatomy. Oxford, Oxford University Press, 1951, pp 1018–1028. Gacek R, Gacek M: Anatomy of the auditory and vestibular systems; in Ballenger J, Snow J (eds): Ballenger’s Otorhinolaryngology, Head and Neck Surgery, ed 16. San Diego, Singular Publications, San Diego, in press. Radpour S, Gacek RR: Further observations on the organization of the facial nucleus. Laryngoscope 1980;90:685–692. Gacek RR, Radpour S: Fiber orientation of the facial nerve: An experimental study in the cat. Laryngoscope 1982;92:547–556. Gacek RR: On the duality of the facial nerve ganglion. Laryngoscope 1998;108:1077–1086. Wersall J, Flock A, Lundquist RG: Structural basis for directional sensitivity in cochlear and vestibular sensory receptors. Cold Spring Harbor Symp Quant Biol 1965;30:115–132. Walsh BT, Miller JB, Gacek RR, Kiang NYS: Spontaneous activity in the eighth cranial nerve of the cat. Int J Neurosci 1972;3:221–236. Goldberg JM, Fernandez C: Physiology of peripheral neurons innervating semi-circular canals of the squirrel monkey. I. Resting discharge and response to constant angular accelerations. J Neurophysiol 1971;34:635–660. Ona A: The mammalian vestibular ganglion cells and the myelin sheath surrounding them. Acta Otolaryngol (Stockh) 1993;suppl 503:143–149. Gacek RR: The course and central termination of first order neurons supplying vestibular end organs in the cat. Acta Otolaryngol (Stockh) 1969;suppl 254:1– 66. Gacek RR, Lyon M: The localization of vestibular efferent neurons in the kitten with horseradish peroxidase. Acta Otolaryngol (Stockh) 1974;suppl 77:92–101. Gacek RR: Efferent component of the vestibular nerve; in Rasmussen GL, Windle WF (eds): Neural Mechanisms of the Auditory and Vestibular Systems. Springfield, Thomas, 1960, pp 276 –284. Gacek RR, Nomura Y, Balogh K: Acetyl cholinesterase activity in the efferent fibers of the statoacoustic nerve. Acta Otolaryngol 1965;59:541–533. Wersall J: Studies on the structure and innervation of the sensory epithelium of the cristae ampullares in the guinea pig: A light and electron microscope investigation. Acta Otolaryngol (Stockh) 1956;suppl 126:1–85. Smith CA, Rasmussen GL: Nerve endings in the maculae and cristae of the chinchilla vestibule, with a special reference to the efferents. 3rd Symp Role Vestib Organs Space Exploration, NASA Status Post-152, Washington, USGPO, pp 183–201. Spoendlin H, Schrott A: The spiral ganglion and the innervation of the human organ of Corti. Acta Otolaryngol (Stockh) 1990;105:403–410. Spoendlin HH, Gacek RR: Electron microscopic study of the efferent and afferent innervation of the organ of Corti in the cat. Ann Otol Rhinol Laryngol 1963;72:660–687. Rasmussen GL: The olivary peduncle and other fiber projections of the superior olivary complex. J Comp Neurol 1946;84:141–220.

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Rasmussen GL: Further observations of the efferent cochlear bundle. J Comp Neurol 1953; 99:61–74. Warr B, Guinan J, White JS: Organization of the efferent fibers: The lateral and medial olivocochlear systems; in Altschuler RA, Hoffman GW, Bobbin RP (eds): Neurobiology of Hearing: The Cochlea. New York, Raven Press, 1986, pp 333–348. Ishii D, Balogh K: Distribution of efferent nerve endings in the organ of Corti: Their graphic reconstruction in cochleae by localization of acetylcholinesterase activity. Acta Otolaryngol (Stockh) 1968;66:282–288.

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Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 32–53

Chapter 3

Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis Richard R. Gacek, Mark R. Gacek

Evidence from many sources has accumulated to support the concept that idiopathic facial paralysis (IFP) is an inflammatory neuropathy caused by a neurotropic (NT) virus of the herpes simplex or zoster family [1–10]. Because of the high exposure to these viruses in the general population, numerous nerves in the body are exposed to NT viruses which then have the tendency to acquire a latent form within sensory ganglion cells of peripheral nerves. The previous chapters have described the biology of herpes simplex ganglionitis and the propensity of the virus to remain in a latent form within the ganglion from which it can be reactivated at a later time [11]. Although the sensory ganglion cell is the locus of inflammation, the motor portion of the facial nerve (FN) may be affected because of a demyelinating autoimmune response to the viral agent in the ganglion cells [12, 13]. It is also probable that various virus types and strains, as well as host resistance, play a role in the clinical manifestation of IFP. Although it has generally been assumed that the geniculate ganglion (GG) is the site of virus accumulation in IFP [14], ganglion cell degeneration within the GG has never been described. On the other hand, recent attention has been called to the meatal ganglion (MG) which is located in the meatal segment of the FN [15, 16]. While the MG is present in all human temporal bones (TB), it has a relatively minor presence compared to the GG in most TB. However, in 12% of TB, the MG may be as large or even exceed the GG in ganglion cell number. Clinical observations made by Fisch and Esslen [17] indicated that the most prominent location of FN swelling and edema is in the meatal segment (that portion of the nerve that is proximal to the meatal foramen). The postulated dural constriction at the entrance to the labyrinthine fallopian canal was felt to be responsible for obstruction of axoplasmic flow which then causes a physiologic decrease in nerve conduction. Surgical decompression of this portion of the FN canal was felt to be important in the treatment of IFP.

In 1999, we reported TB findings in a patient with IFP 6 years before death, with subsequent complete recovery of the facial paralysis [18]. This patient had undergone radiation therapy to the spleen for chronic lymphocytic leukemia. No degenerated ganglion cells were found in the GG of the TB, but there were several degenerated ganglion cells in the MG. The adjacent vestibular ganglion to the MG carrying innervation to the lateral and superior canal cristae was completely degenerated, and focal axonal degeneration was also seen in the vestibular nerve trunk. The concept is formed that IFP results from meatal ganglionitis rather than geniculate ganglionitis. It is possible that the GG is involved in the progression of IFP, since the two ganglia are connected by the nervus intermedius. The present report describes 6 TB from 4 patients with IFP. The major finding was a confirmation of degenerated ganglion cells in the MG of the FN and not the GG.

Materials and Methods (1) A case report describes the MRI findings in a patient with IFP that was monitored at 1, 8 and 15 weeks after the onset of paralysis. Spontaneous and complete recovery of facial function occurred within 2 months in this patient. Six additional patients with IFP were followed with MRI. (2) Eleven published studies [19–29] describing the use of MRI in IFP were reviewed comparing the location of enhancement in the FN during the disorder. These studies included patients who were monitored within 7 days as well as several weeks to months following the onset of paralysis. (3) Six horizontally sectioned TB from 4 patients with a history of IFP were examined for morphologic changes in the FN as well as vestibular and cochlear ganglia which correlate with the FN paralysis. These TB were formalin fixed, decalcified, embedded in celloidin and sectioned at 20
m thickness. Every tenth section was stained with hematoxylin and eosin, cover-slipped and examined in a light microscope.

Results

Case Report A 51-year-old female with a 7-day history of complete left facial paralysis (grade VI/VI House-Brackman), otalgia and vertigo had an otherwise normal head and neck examination. The remaining cranial nerve function including hearing was normal. The patient had been treated with oral prednisone (40 mg daily) since the onset of facial weakness. Famvir (500 mg t.i.d.) was added to the steroid management. An enhanced MRI at this time revealed localized enhancement in the meatal segment of the left FN (fig. 1).

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Fig. 1. Coronal (a) and axial (b) Gd-DTPA MRI demonstrates localized enhancement in the internal auditory canal of a left TB (arrow) 7 days after onset of left IFP.

Medical treatment was discontinued after 1 additional week because the patient demonstrated spontaneous partial recovery of function (grade III/VI). Six weeks later, when the left facial weakness had improved significantly (grade I/VI), an MRI with gadolinium showed enhancement of the geniculate, tympanic and mastoid FN segments in addition to the meatal FN enhancement (fig. 2). MRI 15 weeks after onset of IFP demonstrated enhancement of the GG and greater superficial petrosal nerve but none in the meatal segment (fig. 3). We have performed MRI on 6 additional patients with IFP. All demonstrated enhancement in the meatal segment of the FN during the first 2 weeks after onset of paralysis.

MRI Studies Table 1 lists 11 MRI studies of the FN in IFP reported from the years 1989– 1997 [19–29]. These studies are representative of the FN imaging studies dealing with IFP likely caused by herpes simplex virus type 1 (HSV-1) and varicella-zoster

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Fig. 2. Coronal (a) and axial (b) enhanced MRI 6 weeks after IFP onset demonstrates enhancement in the geniculate (G), proximal tympanic and mastoid (MA) segments of the FN.

Fig. 3. Axial enhanced MRI at 15 weeks after onset of IFP demonstrates enhancement in the GG (G) and greater superficial petrosal nerve (GSP) but minimal change in the labyrinthine segment (L) of the FN.

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Table 1. MRI of FN in IFP Authors

Year

Daniels et al. [19] Schwaber et al. [20] Tien et al. [21] Doringer et al. [24] Matsumoto et al. [23] Murphy and Teller [25] Yanagida et al. [26] Korzec et al. [22] Engstrom et al. [27] Kohsyu et al. [28] Engstrom et al. [29]

1989 1990 1990 1991 1991 1991 1991 1991 1993 1994 1997

Patients

4 17 8 11 46 25 63 10 21 22 11

Enhancement

No enhancement

ME

L

G

T

MA

3 15 2 9 11 3 15 7 10 18 8

3 13 8 10 13 11 20 7 – 22 3

3 13 8 – 37 16 25 4 2 22 4

3 12 8 7 32 11 25 4 0 22 1

3 13 8 8 28 2 49 3 2 22 3

1 1 0 1 – 7 – 3 9 0 3

–  Not given; ME  meatal; L  labyrinthine; G  geniculate; T  tympanic; MA  mastoid.

virus. Careful evaluation of enhancement in the FN in an inflammatory disorder such as IFP requires consideration of enhancement in the geniculate, tympanic and mastoid FN segments caused by pooling of gadolinium in the vascular network of the sheath surrounding the nerve in these portions of the fallopian canal. Enhancement of the FN in these regions is frequently seen with increased time after onset of IFP. This is due to increased intraneural edema and inflammatory dilatation of the perineural vessels in these segments [30]. Therefore, enhancement in the FN most reliably reflects an inflammation in the meatal and labyrinthine segments. In 7 of the studies [19, 20, 22, 24, 27–29], enhancement occurred in the meatal FN segment in the majority of the patients with IFP. All 11 series reported enhancement in the meatal FN. Seven studies recorded patients where no enhancement was found in the ipsilateral FN. Of the remaining 4 reports, 2 series [21, 28] recorded no FN without enhancement while 2 other reports [23, 26] gave no information.

TB Reports Table 2 summarizes morphologic changes in the seventh and eighth cranial nerves in the TB of the 4 patients with IFP. The ages of the 4 patients with IFP ranged from 56 to 74 years; there were 2 males and 2 females. One patient

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Table 2. Pathology in IFP (n  6 TB) Patient

Age Sex (years)

Otologic diagnosis

Cause of death

FP

FS

Degeneration GG

MG

vestibular spiral ganglion ganglion

A.B.

81

F

SOM

chronic lymphocytic leukemia

R

0

0



 (SC and LC)

moderate deg.

R.D.

56

F

deg. coch. and vest. nerves

oat cell carcinoma of the lung/terminal pneumonia

P

0

0



total loss

total loss

W.R. (L) 74

M

SNHL (severe)

myocardial infarction

T



0



 (LC)

50% loss

W.R. (R) 74

M

SNHL (severe)

myocardial infarction

T



0

0

0

60% loss

E.J. (R)

72

M

herpes zoster oticus, otosclerosis

leukemia

T

0

0

meatal FN comp. deg.

 severe deg.

90% loss

E.J. (L)

72

M

otosclerosis

leukemia

0

0

0



0

90% loss

FP  Facial paralysis; R  resolved; P  partial; T  total; FS  facial nerve swelling; SOM  serous otitis media; deg.  degeneration; coch.  cochlear; vest.  vestibular; comp.  complete; SNHL  sensorineural hearing loss; SC  superior semicircular canal; LC  lateral semicircular canal.

(A.B.) had a history of a partial facial paralysis with complete recovery 6 years before her death from chronic lymphocytic leukemia. This TB has previously been reported [18]. The remaining 3 patients had facial paralysis (partial 1, total 2) at the time of death. Patient E.J. had right total facial paralysis from herpes zoster oticus. Degeneration of ganglion cells or the FN in its meatal segment was seen in all but 1 TB. No degenerated cells were observed in the GG of any of the 6 TB. The vestibular ganglion was partially or totally degenerated in 4 TB, and cochlear neurons were significantly degenerated in all 6 TB. In 1 case with bilateral facial paralysis, there was significant swelling of the FN proximal to the meatal foramen on both sides. Case 1 At the age of 78 years, this patient experienced sudden onset of partial right FN paralysis which recovered completely in 10 days. She did not complain of hearing loss or vertigo. Three years before she had been diagnosed as having chronic lymphocytic leukemia which was treated by radiation therapy to the spleen. During the remaining 6 years of life she had recurrent episodes of

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Fig. 4. The GG in an 81-year-old female (case 1) with recovered IFP contained many satellite cells (arrows) but no degenerated ganglion cells.

septicemia treated with antibiotics. Her death was caused by overwhelming septicemia. Histopathology of the Right TB: Postmortem Time 13 h. The middle ear mucosa was hypertrophic and contained numerous foci and diffuse infiltration of lymphocytes. There were numerous fascicles of regenerating myelinated nerve fibers passing around the GG. Numerous mononuclear cells resembling satellite cells filled the space between GG neurons. No degenerated ganglion cells were seen in the GG (fig. 4). Ganglion cells in the MG and scattered between sensory fibers of the FN were surrounded by an increased number of satellite cells. There were several degenerated ganglion cells in the MG (fig. 5), and degenerated axons were found in the nervus intermedius of the FN. There was a loss of dendrites to the cristae ampullares of all three semicircular canals (fig. 6) while the utricular (fig. 7) and saccular nerve branches were normal. Scarpa’s ganglion contained approximately 30% loss of ganglion cells and the remaining cells were surrounded by an increase in satellite cells. Focal axonal degeneration was present in the vestibular nerve trunk (fig. 8). There was a patchy loss of the organ of Corti throughout the basal turn of the cochlea. Atrophy of the stria vascularis was present in the middle and upper basal turns.

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Fig. 5. The MG (case 1) was composed of degenerated (arrow) as well as intact ganglion cells (M). F  FN.

Fig. 6. There was complete degeneration of vestibular nerve fibers to the superior and lateral (LC) canal sense organs (arrow).

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Fig. 7. The innervation of the utricular macula (U) was intact (arrow).

Fig. 8. Focal axonal degeneration (arrow) was seen in the vestibular nerve trunk. VG  Vestibular ganglion.

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Fig. 9. Case 2. Complete degeneration of innervation (arrow) to the lateral canal (LC) and superior canal cristae.

Case 2 This female experienced dysphagia from the age of 53 years to 55 years when she underwent surgery to relieve a stenosed cardiac sphincter. At the age of 56 years, she experienced hearing loss in her left ear and vertigo. A hearing test revealed a profound hearing loss in the left ear (discrimination  0%) and a mixed hearing loss in the right ear (speech reception threshold  22 dB; discrimination  96%). There was a spontaneous nystagmus to the right and no caloric response in the left ear but a normal response in the right ear. She subsequently developed weakness of the upper arms, hands and neck, and a partial weakness of the muscles of the left side of the face. Postmortem examination revealed oat cell carcinoma of the right upper lobe with hilar lymph node metastases. Histopathology of the Left TB: Postmortem Time 13 h. The organ of Corti was normal except for the basal 9 mm where there was a total loss of hair cells. There was a total loss of vestibular neurons (fig. 9, 10). Efferent axons remained in Rosenthal’s canal as well as in the peripheral vestibular nerve branches. The vestibular sense organs were normal. Several degenerated and intact ganglion cells in the MG of the FN were surrounded by a plethora of satellite and inflammatory cells (fig. 11). Although there were many satellite cells in the GG, no degenerated ganglion cells were found (fig. 12). Case 3 This 74 year old male had mild difficulty walking at the age of 61 years. He had progressive difficulty walking and occasionally fell. At the age of 70 years,

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Fig. 10. Degeneration (arrow) of the utricular (U) nerve was also noted.

he noted clumsiness of his hands. At the age of 71 years, he exhibited a cogwheel rigidity of his upper extremities and facial weakness bilaterally. He was diagnosed as having Charcot-Marie-Tooth syndrome and Parkinson’s disease. Since facial weakness is not part of Charcot-Marie-Tooth syndrome, it was felt that his facial weakness was idiopathic or part of Parkinson’s disease. Histopathology of both TB: Postmortem time 3 h. There was total loss of the organ of Corti in the right ear and a scattered partial loss in the left ear. Severe atrophy of the stria vascularis and spiral ligament was present in the second and third turns of both ears. There was 50% loss of cochlear neurons in all turns of both cochleae. The vestibular labyrinths were severely distorted by artifact incurred during removal of the TB. The facial nerves in both TB showed marked enlargement proximal to the meatal foramen (fig. 13). There were no degenerated neurons in the GG, but many satellite cells surrounded neural elements (fig. 14). There were 1–2 degenerated ganglion cells in the MG of the left FN (fig. 15) adjacent to a fascicle of degenerated axons in the vestibular nerve trunk (fig. 16). Case 4 At the age of 70 years, a hearing test revealed bilateral sensorineural hearing loss with a descending audiometric pattern. Discrimination was 72% in the right ear and 40% in the left ear. At the age of 71 years, he was diagnosed as

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Fig. 11. The MG (M) contained several degenerated ganglion cells (arrows) surrounded by a heavy infiltrate of satellite and inflammatory cells. F  FN.

having leukemia and treated with Ovocin, methotrexate, Purinethol and prednisone with some improvement. Two months later, he developed complete right facial paralysis and herpetic involvement of the right auricle and soft palate. A hearing test at this time revealed bilateral sensorineural hearing loss which was worse than before. He died of leukemia 2 months later. Histopathology of the TB: Postmortem Time 4 h. In the right TB, the central part of the FN in the meatus of the internal auditory canal (IAC) was normal. However, there was a gradation over a 5-mm segment from normal nerve to total degeneration (fig. 17). The FN demonstrated a change from normal to granular degeneration and finally absence of all axons except the sensory bundle at the distal end of the IAC. The GG had a large number of satellite cells but no degenerated ganglion cells (fig. 18). There was a severe loss of cochlear neurons with only 5% remaining. The hair cell population in the organ of Corti was normal. There was moderate degeneration of all cristae ampullares. The maculae of the utricle and saccule showed advanced atrophy with loss of hair cells.

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Fig. 12. There were no degenerated ganglion cells in the GG of case 2.

Fig. 13. a Low-power view of the nerves in the internal auditory canal. There is marked swelling of the FN (F) proximal to the meatal foramen. V  Vestibule; C  basal turn of the cochlea. b The MG (M) is located in the edematous segment of the FN. V  Vestibular nerve.

Vestibular neurons to the cristae of superior division canals were markedly degenerated with some preservation of innervation to the maculae (fig. 19). In the left TB, the FN and GG were normal. There were several degenerated neurons in the MG (fig. 20) but none in the GG. There was a severe loss of spiral ganglion cells with only 5% of neurons remaining, and the organ of Corti was normal. The vestibular sense organs and ganglion were normal.

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Fig. 14. The GG in case 3 contained normal ganglion cells and satellite cells.

Fig. 15. The MG contained some degenerated ganglion cells and many satellite and inflammatory cells (arrows).

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Fig. 16. Focal axonal degeneration (arrow) in the vestibular nerve (V) was located next to the nervus intermedius (NI).

Discussion

It is generally accepted that IFP (Bell’s palsy) is an inflammatory neuritis caused by the herpes simplex or herpes zoster viruses [1–10]. However, there have been reports associating Epstein-Barr [31, 32], mumps [33] and cytomegalic inclusion virus [34] with IFP. The NT viruses gain access to cell bodies of sensory neurons by entering nerve endings at an epithelial surface followed by retrograde transport to the cell body. It has been assumed that the GG represented the site of accumulation of the virion responsible for the inflammatory neuritis in IFP since HSV and varicella-zoster virus DNA has been recovered from the GG of patients with IFP [14] and herpes zoster oticus. The motor paralysis has been assumed to be a result of reaction to the virus protein. TB of patients with a recent onset of IFP (1–2 weeks) demonstrate fragmentation, swelling and degeneration of FN axons, degeneration and phagocytosis of myelin and lymphocytic infiltration of FN bundles [35–37]. The TB from a patient 10 years after incomplete recovery of facial function revealed a partial loss of axons beginning in the IAC segment of the FN and progressing with severity toward the mastoid segment [37]. The IAC location of FN degeneration in this TB as well as the TB from herpes zoster oticus (table 2)

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Fig. 17. a Case 4. Low-power view of the nerves in the IAC in a case of herpes zoster oticus. There is degeneration of all the nerves in the canal. The central portion of the FN (F) is normal but degenerated in the IAC (*). b A higher-power view shows the gradation from normal (F) to degenerated (*) FN.

Fig. 18. The GG is normal in case 4, and the sensory portion (S) of the FN is intact.

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Fig. 19. Vestibular ganglion (VG) cells were enucleated and pale. F  Degenerated FN.

suggests the meatal segment of FN as the primary focus of infection. The presence of degenerated ganglion cells in the MG rather than the GG and the repeated observation that early enhancement within the IAC is recorded on MRI in IFP point toward the MG as the initial site of viral accumulation. The pattern of axonal loss beginning in the IAC segment of the FN supports the concept of a demyelinating autoimmune response to the virion in the MG cells [12, 13]. The location of early MRI enhancement in the meatal FN segment also indicates that the initial site of viral ganglionitis in IFP is the MG. Fisch and Esslen [17] provided the first description of segmental involvement of the FN in IFP. During surgical exposure of the FN in the IAC and the labyrinthine facial canal, they noted swelling and increased vascularity of the meatal FN segment. They interpreted the swelling to reflect blockage of axoplasmic flow by a constriction at the entrance to the labyrinthine facial canal. Decompression of the labyrinthine canal was felt to be critical for the successful treatment of IFP. More than a decade later, MRI studies of FN in IFP (table 1) described localized enhancement of the FN in the IAC as characteristic of IFP. The location

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Fig. 20. The contralateral FN (F) and MG (M) contained a few degenerated ganglion cells (arrow).

and sequential development of FN enhancement in our case report are typical of IFP. With increased time after the onset of facial paralysis, enhancement of more distal portions of the FN usually occurs. Pooling of gadolinium in dilated vessels surrounding [30] and within the FN [38] in the tympanic and mastoid portions of the fallopian canal is likely responsible for delayed enhancement in the distal segments of the facial canal. The initial location of virus infection may spread from the MG to the GG along the nervus intermedius. The characteristic lymphocytic infiltrate between nerve bundles typifies a viral infection. The recovery of viral DNA from the geniculate region in IFP is not contradictory. Degeneration of vestibular neurons adjacent to the MG accounts for the occurrence of vestibular symptoms in patients with IFP [18, 39–43]. Enhancement of the meatal FN in IFP is dependent on several factors: (1) timing of the MRI; early in the course of the paralysis (within 7 days of onset), it is likely that only the initial focus of inflammation would be enhanced;

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enhancement is thought to be caused by pooling of contrast in the area with increased vascularity and edema; (2) the size of the MG is responsible not only for enhancement but also for the paralysis; the virus load is dependent on the number of ganglion cells containing virus; the MG may be as large, or larger than the GG in almost 20% of TB; in the remaining 80%, although the MG is small, enhancement may be increased because of spread of virus to the adjacent vestibular ganglion; the incidence of vertigo in patients with IFP and herpes zoster oticus is caused by viral involvement of the vestibular ganglion; (3) the technique of MRI can increase enhancement in the meatal FN segment; in the early studies that used a 0.5-tesla unit, FN enhancement was low compared to the more recent studies using a 1.5-tesla unit as the magnet source (table 1). Degeneration was seen in the MG (or meatal segment) of the FN in 5 of 6 TB associated with facial paralysis. In none of the 6 TB were degenerated ganglion cells found in the GG. Degeneration of the vestibular nerve or ganglion was found in 4 out of the 6 TB. In 2 TB, marked swelling of the FN was seen proximal to the meatal foramen. This swelling is at the point where the inflammatory response of the FN and the MG would be constricted at the meatal foramen. Although the MG could not be identified in the TB of herpes zoster oticus because of complete destruction of the FN, the FN was normal proximal to the midportion of the IAC. These findings indicate that the focus of FN degeneration was located in the meatal segment of the FN, near the degenerated vestibular ganglion. This pattern of degeneration is consistent with pathology located at the MG. In addition to virus load in the MG, virus strain and host resistance are factors in determining the severity of infection. In most (80%) FN, the MG is very small, and in 20% of TB the MG is large enough to produce an inflammatory focus that can be detected on MRI. It is possible that the lack of FN enhancement on MRI series in IFP (table 1) represents those FN where the MG is very small (fig. 10). Spread of virus to the adjacent vestibular ganglion may be responsible for vestibular symptoms. The TB (patient A.B., table 2) with resolved IFP demonstrated that vestibular afferent neurons nearest to the FN were degenerated while those (otolith organs) farthest from the FN were intact. This pattern of degenerative changes in IFP follows spread of virus from the MG to the vestibular ganglion. The absence of meatal FN enhancement may have prognostic value in determining the outcome in IFP. In 2 series [25, 27] of patients, those with no FN enhancement usually experienced a satisfactory outcome. In the series of Murphy and Teller [25], 6 of the 7 patients with no enhancement exhibited grade I recovery while 1 had a grade VI/VI outcome. Of 9 patients with no FN enhancement

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in Engstrom et al. [29], 3 patients with no enhancement had the lowest electroneurographic values at the initial clinical and MRI examination. Certain incidence features of IFP are explained by the biologic characteristics of the herpes virus family. After retrograde transport, the NT viruses have the ability to assume a latent state within the sensory ganglion cell bodies. In response to external stressors or lowered immune states, the virus may reactivate and replicate leading to the clinical manifestations. Surgical stress is capable of reactivating latent virus in facial nerve ganglion cells producing palsy. Bonkowsky et al. [44] investigated 5 of 7 ipsilateral delayed facial palsies which occurred in over 1,800 uncomplicated middle ear procedures. They detected HSV-1 genome with PCR in 4 out of the 5 patients. Furthermore, the mean antibody titer (IgG) was higher than in a control group with herpes labialis. A high incidence (80%) of subclinical contralateral facial neuropathy has been reported in patients with early IFP [45]. This high incidence of subclinical bilaterality is consistent with a viral etiology for the neuropathy. A familial incidence of IFP has been recorded in several reports [3, 46, 47]. This suggests a genetic influence on the anatomical substrate that determines an individual’s susceptibility to IFP. Sensory systems as well as some motor nerves depend on neurotropins to regulate the size (in number of neurons) they assume following the programmed death of excess neurons in the developing neonatal nervous system. Brain-derived NT factor and neurotropin 3 have been shown in knockout mice to determine the size of the GG [48, 49]. The relative proportions of contributions from the GG and MG in human TB are compatible with an inheritance model. Neurotropins could regulate a large MG in several family members allowing a large virus load sufficient to cause IFP after exposure to herpes simplex or varicella-zoster virus. A familial occurrence of IFP may also be related to intimate exposure to the causal viral agent.

Conclusion

Clinical, radiologic and pathologic observations support the contention that the MG of the FN represents the primary location of the viral inflammation responsible for IFP. The term ‘meatal ganglionitis’ may be used to designate this pathologic correlate in IFP. References 1 2

McCormick DP: Herpes simplex virus as a cause of Bell’s palsy. Lancet 1972;i:937–939. Adour K, Bell DN, Hilsinger R: Herpes simplex virus in idiopathic facial paralysis (Bell’s palsy). JAMA 1975;233:527–530.

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3 4 5 6 7 8 9

10

11 12 13 14

15 16 17 18 19

20 21 22

23 24 25 26

Adour K, Byl F, Hilsinger R, Kahn Z, Sheldon M: The true nature of Bell’s palsy: Analysis of 1,000 consecutive cases. Laryngoscope 1978;88:787–801. Djupesland G, Berdal P, Johannessen T, Degre M, Stien R, Skrede S: Viral infection as a cause of acute peripheral facial palsy. Arch Otolaryngol 1976;102:403–406. Nakamura K, Yanagihara N: Neutralization antibody to herpes simplex virus type I in Bell’s palsy. Ann Otol Rhinol Laryngol Suppl 1988;137:18–21. Ishii K, Kurata T, Sata T, Hao M, Nomura Y: An animal model of type I herpes simplex virus infection of facial nerve. Acta Otolaryngol Suppl (Stockh) 1988;446:157–164. Jonsson L, Alm G, Thomander L: Elevated serum interferon levels in patients with Bell’s palsy. Otolaryngol Head Neck Surg 1989;115:37–40. Ishii K, Kurata T, Nomura Y: Experiments on herpes simplex virus infection of the facial nerve in the tympanic cavity. Eur Arch Otorhinolaryngol 1990;247:165–167. Sugita T, Murakami S, Yanagihara N, Fujiwara Y, Hirata Y, Kurata T: Facial nerve paralysis induced by herpes simplex virus in mice: An animal model of acute and transient facial paralysis. Ann Otol Rhinol Laryngol 1995;104:574–581. Murakami S, Mizobuchi M, Nakashino Y, Doi T, Hato N, Yanagihara N: Bell’s palsy and herpes simplex virus: Identification of viral DNA in endoneural fluid and muscle. Ann Intern Med 1996;124:27–30. Meier JL, Straus SE: Comparative biology of latent varicella zoster virus and herpes simplex virus infections. J Infect Dis 1992;166:S13–S23. Weiner LP, Johnson RT, Herndon RM: Viral infections and demyelinating diseases. N Engl J Med 1973;228:1103–1110. Abramsky O, Webb C, Teitelbaum D, Arnon R: Cellular immune response to peripheral nerve basic protein in idiopathic facial paralysis (Bell’s). J Neurol Sci 1975;26:13–20. Burgess RC, Michaels L, Bale JF, Smith RH: Polymerase chain reaction amplification of herpes simplex viral DNA from the geniculate ganglion of a patient with Bell’s palsy. Ann Otol Rhinol Laryngol 1994;103:775–779. Gacek RR: On the duality of the facial nerve ganglion. Laryngoscope 1998;108:1077–1086. Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20: 202–210. Fisch U, Esslen E: Total intratemporal exposure of the facial nerve. Arch Otolaryngol 1972;95: 335–341. Gacek R, Gacek M: Meatal ganglionitis: Clinical pathologic correlation in idiopathic facial paralysis (Bell’s palsy). Otorhinolaryngol Nova 1999;9:229–238. Daniels DL, Czervionke LF, Millen SJ, Haberkamp TJ, Meyer GA, Hendrix LE, Mark LP, Williams AL, Haughton VM: MR imaging of facial nerve enhancement in Bell’s palsy or after temporal bone surgery. Radiology 1989;171:807–809. Schwaber M, Larson T, Zealar D, Creasy J: Gadolinium enhanced MRI in Bell’s palsy. Laryngoscope 1990;100:1264–1269. Tien R, Dillon W, Jackler R: Contrast-enhanced MR imaging of the facial nerve in 11 patients with Bell’s palsy. AJNR Am J Neuroradiol 1990;11(AJR 155):735–741. Korzec K, Sobol S, Kubal W, Mester S, Winzelberg G, May M: Gadolinium-enhanced magnetic resonance imaging of the facial nerve in herpes zoster oticus and Bell’s palsy: Clinical implications. Am J Otol 1991;12:163–168. Matsumoto Y, Yanagihara N, Sadamoto M: Gd-DTPA enhanced MR imaging in Bell’s palsy. Facial Nerve Res Jpn 1991;11:93–96. Doringer E, Albegger K, Sinzinger G, Schmoller H: Idiopathische Fazialisparese und Magnetresonanztomographie (MRT). HNO 1991;39:362–366. Murphy T, Teller D: Magnetic resonance imaging of the facial nerve during Bell’s palsy. Otolaryngol Head Neck Surg 1991;105:667–674. Yanagida M, Ushiro K, Yamashita T, Kumazawa T, Katoh T: Depicting of affected facial nerve with gadolinium-enhanced magnetic resonance imaging in peripheral facial palsy. Facial Nerve Res Jpn 1991;11:107–114.

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27

28 29

30 31 32 33 34 35 36 37 38

39 40 41 42 43 44

45 46 47 48 49

Engstrom M, Thomas K-A, Naeser P, Stalberg E, Jonsson L: Facial nerve enhancement by different gadolinium-enhanced magnetic resonance imaging techniques. Arch Otolaryngol Head Neck Surg 1993;119:221–225. Kohsyu H, Aoyagi M, Tojima H, Tada Y, Inamura H, Ikarishi T, Koike Y: Facial nerve enhancement in Gd-MRI in patients with Bell’s palsy. Acta Otolaryngol Suppl (Stockh) 1994;511:165–169. Engstrom M, Abdsaleh S, Ahlstrom H, Johansson L, Stalberg E, Jonsson L: Serial gadoliniumenhanced magnetic resonance imaging and assessment of facial nerve function in Bell’s palsy. Otolaryngol Head Neck Surg 1997;117:559–566. Gebarski S, Telian S, Niparko J: Enhancement along the normal facial nerve in the facial canal: MR imaging and anatomic correlation. Radiology 1992;183:391–394. Grose C, Heule G, Feorlino PM: Primary Epstein-Barr virus infections in acute neurologic diseases. N Engl J Med 1975;292:392–395. Michel RG, Pope TH, Patterson CN: Infectious mononucleosis, mastoiditis and facial paralysis. Arch Otolaryngol 1975;101:486–489. Beardwell A: Facial palsy due to mumps virus. Br J Clin Pract 1969;23:37–38. Djupesland G, Berdal P, Johannessen T, Degre M, Stien R, Skrede S: Viral infection as a cause of acute peripheral facial palsy. Arch Otolaryngol 1976;102:403–406. Proctor B, Corgill D, Proud G: The pathology of Bell’s palsy. Trans Am Acad Ophthalmol Otolaryngol 1976;82:70–80. Liston S, Kleid M: Histopathology of Bell’s palsy. Laryngoscope 1989;99:23–26. Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febiger, 1993, pp 330–331. Balkany T, Fradis M, Jafek B, Rucker N: Intrinsic vasculature of the labyrinthine segment of the facial nerve – Implications for site of lesion in Bell’s palsy. Otolaryngol Head Neck Surg 1991;104:20–23. Aschan G, Stahle J: Vestibular neuronitis. J Laryngol Otol 1956;70:497–511. Pfaltz C: Diagnose und Therapie der vestibularen Neuronitis. Pract Otorhinolaryngol 1955;17: 454– 461. Philipszoon AJ: Nystagmus and Bell’s palsy. Pract Otorhinolaryngol 1962;24:233–238. Lämmli K, Fisch U: Vestibular symptoms in idiopathic facial paralysis. Acta Otolaryngol (Stockh) 1974;78:15–18. Rauchbach HE, May M, Stroud J: Vestibular involvement in Bell’s palsy. Laryngoscope 1975;85: 1396–1398. Bonkowsky V, Kochanowski B, Strutz J, Pere P, Hosemann W, Arnold W: Delayed facial palsy following uneventful middle ear surgery: A herpes simplex virus type I reactivation? Ann Otol Rhinol Laryngol 1998;107:901–905. Safman BL: Bilateral pathology in Bell’s palsy. Arch Otolaryngol 1971;93:55–57. De Santo LW, Schubert HA: Bell’s palsy, ten cases in a family. Arch Otolaryngol 1969;89: 700–702. Willbrand JW, Blumhagen JD, May MM: Inherited Bell’s palsy. Ann Otol Rhinol Laryngol 1974; 83:343–346. Ernfors P, Lee KF, Jaenisch R: Mice lacking brain-derived NT factor develop with sensory deficits. Nature 1994;368:147–150. Farinas I, Jones KR, Backus C, Wang Y, Reichardt L: Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Nature 1994;369:658–661.

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Chapter 4

Vestibular Neuronitis: A Viral Neuropathy Richard R. Gacek, Mark R. Gacek

Vestibular neuronitis (VN) or neuritis has long been regarded as an inflammatory lesion of the vestibular nerve responsible for recurrent vertigo without hearing loss. The clinical picture described by Nylen [1], Dix and Hallpike [2], Lumio and Aho [3] and others [4–10] was a sudden onset of acute vertigo, without auditory symptoms, with resolution over days. In many patients, an upper respiratory illness or infection (sinusitis) preceded the appearance of vertigo, and affected patients often appeared in clusters during a season with a high incidence of respiratory illness. The association with sinusitis was so strong that one author [9] identified a subset of patients with vestibular symptoms and sinusitis. Viral antibody titers were also elevated in VN [11]. It was appreciated that recurrent vertigo could have a shorter duration (hours or minutes) in some patients. The clinical feature differentiating VN from Ménière’s disease is the absence of hearing loss, and the diagnosis of VN is dependent on a unilateral or bilateral vestibular deficit. Although the strict criterion for a diagnosis of VN required total or subtotal loss of vestibular function, it was recognized that less vestibular hyposensitivity was possible in VN. Furthermore, some patients with a significant vestibular loss on the initial examination eventually recovered vestibular function on the follow-up evaluation. Several temporal bone (TB) reports have described total or subtotal degeneration of the vestibular nerve in VN [12–14]. The auditory sense organ and neurons were normal or near normal. Description of fibrosis in the perilymphatic space surrounding the ampullary ends of the semicircular canals supported an inflammatory nature of the lesion [12]. Enhancement of the vestibular nerve in the internal auditory canal with contrast-enhanced MRI has been reported in patients with VN [15]. Such focal enhancement may have been interpreted as vestibular schwannoma in the past. However, follow-up imaging of the enhancing portion of the vestibular nerve demonstrated resolution in other patients.

Estimation of vestibular nerve degeneration in patients with VN, Ménière’s disease, benign paroxysmal positional vertigo and other recurrent vestibulopathies was reported in a series of 51 TB with an axonal degeneration pattern of bundles of fibers in the vestibular nerve trunk [16]. Clusters of degenerated ganglion cells were seen in some of the vestibular ganglia (VG). The meatal ganglion (MG) of the facial nerve adjacent to the vestibular nerve contained degenerating ganglion cells in almost all of the TB. Measurement of the axonal degeneration was based on a point-counting technique which strictly measured focal areas of degenerating fibers and therefore underestimated the extent of pathology since smaller fascicles and individual fibers were overlooked with this technique of measurement. The control that such MG and vestibular nerve degeneration was not related to age, sex, artifact in TB acquisition or labyrinthine disease was provided by 24 TB that were matched for age, sex and presence of other labyrinthine disease. These TB did not show focal axonal degeneration in the vestibular nerve nor degenerated ganglion cells in the MG. The view that VN presents only as a single attack of vertigo is probably too restrictive. Frequently VN can manifest itself as recurring attacks of vertigo without hearing loss occurring anytime in adult life and usually preceded by a stressful event such as sinusitis, upper respiratory tract infection or idiopathic facial paralysis [12]. Although hearing loss is usually not part of this clinical picture, some patients may complain of tinnitus and fullness in the affected ear. A decreased vestibular response (⬎25%) at some point in the patient’s evaluation is necessary to identify the affected ear. The TB described in this report (table 1, see Appendix) is compared to 20 TB that were age and sex matched but without a history of vertigo (table 4, see Appendix). Degeneration in the vestibular nerve and the MG of the vestibulopathic TB suggests a viral neuropathy. Morphologic changes in the facial and vestibular nerves will be described in this report. Other findings recorded in table 1 are discussed in a later chapter.

Materials and Methods TB Specimens Twenty TB had been fixed in 10% formalin, decalcified and embedded in celloidin, then horizontally sectioned at 20 ␮m and stained with hematoxylin and eosin. Twelve of these TB had a recorded history of vertigo without hearing loss. Although a history of vertigo was not recorded in the remaining 8 TB, degenerative changes in the MG and vestibular nerve were similar to those found in the 12 TB with a vertigo history. Twenty TB from patients without vestibular symptoms and representing an age- and sex-matched group were also examined for degeneration in the MG, the VG and the spiral ganglion.

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The percentages of degeneration in the MG, VG and spiral ganglia were estimated in the following way: (1) the total number of degenerated ganglion cells in all sections that contained the MG was divided by the total number of ganglion cells (both normal and degenerated) in the ganglion; this fraction was used to compute the percentage of degenerated ganglion cells in the MG; (2) vestibular nerve and VG degeneration was estimated using 20% to represent each vestibular nerve branch; if the superior division was degenerated, with the exception of the utricular nerve, it was computed as 40% degenerated; if peripheral branch degeneration was not present, the fraction of the total vestibular nerve trunk area occupied by focal axonal degeneration was estimated and used to compute the percentage of degeneration; (3) spiral ganglion cell loss was estimated similar to the approach used by previous investigators [12]; in this way, the percentage of ganglion cells in Rosenthal’s canal of the cochlear turns was recorded. Degeneration in two additional nerve bundles of the TB was assessed and recorded. (1) Degeneration in the tympanic nerve (Jacobson’s nerve) was recorded in sections of the TB that included the promontory and round window niche. The tympanic nerve was judged to be normal or degenerated. (2) The vestibulocochlear anastomosis was identified as it emerges from the saccular ganglion in the internal auditory canal. It was judged intact or degenerated. The presence of deposits in the labyrinthine sense organs was also determined in these TB; criteria for their identification and significance are described in chapter 8. Illustration The histories and histopathologic findings in 2 TB are presented to illustrate early and advanced VN.

Results

TB Specimens Table 1 (Appendix) summarizes the morphologic findings in 20 TB with a diagnosis consistent with VN. Twelve of these 20 donors had a history of vertigo prior to the acquisition of their TB. In 3 individuals, the diagnosis of VN was made prior to death. In the remaining 9 patients with a vertigo history, no specific vestibular syndrome was identified. All but 1 of these 20 TB revealed degeneration in the MG, and all 20 TB contained focal axonal degeneration in the vestibular nerve. In case 10, the entire vestibular nerve and its branches were degenerated. This TB has been reported previously [12]. In 15 TB, degeneration of the spiral ganglion was either minimal or limited to the basal turn, and considered consistent with the patient’s age and occupation. In 3 TB, the apical turn degeneration was significant. In 2 TB, severe degeneration of the spiral

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ganglion was felt to be related to the pathologic process. The tympanic branch of the ninth nerve was normal in 12 TB and partially degenerated in 8. The presence of tympanic nerve degeneration did not correlate with the severity of the vestibular nerve degeneration. In 20 TB without a history of vertigo, evidence of degeneration was found in the MG of 1. No degeneration was found in the vestibular ganglia or nerves of all 20 TB. The spiral ganglion was normal or degenerated only in the basal turn in all 20 TB. The tympanic nerve was normal in 16 TB and partially degenerated in 4 TB.

Illustration Two TB illustrate the morphologic changes in mild and severe VN. Case 1: 87-Year-Old Female At the age of 84 years, the patient experienced a sudden episode of vertigo throwing her to the right which was accompanied by nausea and vomiting. Although improved the following day, she complained of unsteadiness when walking. Audiometric studies revealed a bilateral sensorineural hearing loss. Speech discrimination was 92% on the right and 64% on the left. Caloric responses to 10 ml of ice water were absent on the right and normal on the left. Positional and turning tests were negative. The Romberg test showed a tendency to fall to the right. She still exhibited unsteadiness when walking at the age of 85 years. A hearing test at the age of 85 years showed discrimination at 72% on the right and 80% on the left. At the age of 87 years before her death from myocardial infarction, she still complained of unsteadiness. Histopathology: Right TB, Postmortem Time 12 h. There was severe atrophy of the spiral ligament in the apical half of the cochlea. Although the organ of Corti showed clumping, hair cells were present throughout. There was a 50% loss of cochlear neurons in the basal turn. The cochlear and vestibular nerves had been avulsed from the internal auditory canal. The MG in the facial nerve contained several degenerated neurons and intact neurons surrounded by satellite cells (fig. 1). The lateral and superior canal cristae were atrophic, and their innervation was completely degenerated (fig. 2). The sense organs and innervation for the utricle (fig. 3), saccule (fig. 4) and the posterior canal (fig. 5) were normal. Case 2: 92-Year-Old Female This TB was reported by Schuknecht and Kitamura [12] to illustrate VN. However, the histopathology in the VG was not described in that report. At the

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Fig. 1. Case 1. There were several degenerated ganglion cells (arrows) in the MG of the facial nerve.

Fig. 2. Vestibular neurons to the lateral canal (LC) crista were completely degenerated (arrow).

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Fig. 3. The utricular nerve (arrow) and macula (U) were normal.

Fig. 4. The saccular macula (S) and its nerve supply (arrow) were normal.

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Fig. 5. The posterior canal crista (PC) and its nerve (arrow) were normal.

age of 72 years, the patient fell in her cabin while on a cruise ship and remained unsteady for several weeks following this episode. She walked with a broad base and was unsteady on turns. Audiometric studies revealed a bilateral sensorineural hearing loss. The unsteadiness increased over the next year until she suddenly experienced severe vertigo with nausea and vomiting which was documented by a spontaneous right beating nystagmus. The vertigo subsided after 3 days. Bithermal caloric tests revealed a marked directional preponderance to the right. By the age of 80 years, she continued to have a constant feeling of unsteadiness and several episodes of falling at home. Caloric tests revealed a 1-min 49-second response on the right and no response on the left. Repeat hearing tests showed 64% speech discrimination on the left and 42% on the right. Between the ages of 80 and 92 years, she continued to experience repeated falling episodes; while in a nursing home her health deteriorated, and she died at the age of 92 years from cardiac and renal failure. Histopathology: Left TB, Postmortem Time 16 h. Except for atrophy in a small segment of the extreme basal end of the cochlea, the organ of Corti was present with hair cells. A loss of cochlear neurons of 80% at the 11-mm location, a 50% loss from 11 to 16 mm and a normal amount in an apical direction was consistent with her age. Mild atrophy of the stria vascularis was present. There was almost complete degeneration of nerve fibers to the lateral and superior

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Fig. 6, 7. Case 2. There was almost complete degeneration of innervation (arrows) to the superior division sense organs. LC ⫽ Lateral canal crista; U ⫽ utricular macula.

Fig. 8, 9. Case 2. The innervation to the inferior division sense organs (arrows) was intact. S ⫽ Saccular macula; PC ⫽ posterior canal crista.

canal cristae (fig. 6) as well as the utricular macula (fig. 7). The innervation to the saccular macula (fig. 8) and the posterior canal crista (fig. 9) was intact. The vestibular nerve branches had been avulsed from the cribrose portion of the bony labyrinth, but the VG was located in the proximal end of the internal auditory canal. The VG showed a chronic inflammatory process with satellite and inflammatory cells surrounding ganglion cells which were in various stages of degeneration (fig. 10). In some areas of the ganglion where neurons were

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Fig. 10. Case 2. The VG showed ganglion cells in various stages of degeneration (arrows) surrounded by an increased number of satellite and inflammatory cells. The solid material on the left may represent plaque formation by the virus.

absent, a dense blue matrix had replaced the ganglion. There were also numerous spherical masses which had a laminated appearance. The MG of the facial nerve contained several degenerated ganglion cells replaced by a pale collagen-like substance (fig. 11).

Discussion

The morphologic changes in 20 TB consisted of degenerated ganglion cells in the MG and focal axonal degeneration in the vestibular nerve and VG. Except for 1 TB (case 10) with extensive vestibular nerve degeneration, the pattern of focal degeneration in the vestibular nerve represents projections from clusters of ganglion cells in the VG. Focal axonal degeneration had been described in trigeminal nerve zoster by Denny-Brown et al. [17]. Degenerated ganglion cells surrounded by normal ones in the MG are explained by a pathology specific for neurons. Ischemic injury is not cell specific enough to preserve adjacent neurons. In none of the TB were degenerated ganglion cells found in the geniculate ganglion. The absence of degenerated cells or axons in the facial and

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Fig. 11. The MG (M) contained several degenerated ganglion cells replaced by collagen (arrow). F ⫽ Facial nerve.

vestibular nerves in the control group of TB supports the conclusion that these changes are not age, sex or peripheral pathology related. Furthermore, in the TB with extensive degeneration of vestibular nerve branches (case 10), the VG contained histologic changes similar to those described in animal models of herpetic ganglionitis. Increased numbers of satellite and inflammatory cells surround intact and degenerated ganglion cells. The basophilic stained ground substance between ganglion cells may be similar to plaque formation produced by viruses. It is not surprising to see enhancement of the VG on MRI where pooling of contrast material in the vasculature of an inflamed ganglion creates a localized enhancement [15, 18]. The association of vertigo with the development of VN, Ménière’s disease or benign positional vertigo following idiopathic facial paralysis may be based on the proximity of the VG to the MG [19]. This proximity and, in some TB, the contiguity of the MG and VG may be responsible for virus spread from the MG to the vestibular nerve earlier in life when latency is established. Reactivation of latent virus in the MG and adjacent VG acquired early in life is an expected sequela of neurotropic viruses (i.e. herpes simplex virus, HSV) which have the ability to travel bidirectionally in sensory ganglion cells [20]. Since this flow is strain dependent [21–23] flow toward the brainstem accounts for the absence of hearing loss and occasional central signs in VN [24]. The demonstration of HSV nucleic acids in a large proportion of human geniculate

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Vestibular Nuclei U

Stapes

VG

Brainstem

S

RW

Fig. 12. Schematic of anterograde virus flow after reactivation in the VG. This direction of virus flow avoids hearing loss but may account for passage of virus to second-order neurons in the vestibular nuclei. U ⫽ Utricle; S ⫽ saccule; RW ⫽ round window.

ganglia and VG provides molecular evidence of a reactivated HSV infection of the vestibular nerve [25]. If the HSV strain follows anterograde flow in the vestibular nerve (toward the brain), hearing is preserved (fig. 12). Such anterograde flow may carry viral products transsynaptically to second-order neurons in the brainstem. Central nervous system signs have been described in patients with VN [24]. Arbusow et al. [26] have demonstrated HSV-1 bilaterally in the TB and brainstems of 5 patients. Clinical findings in patients with VN are dependent on the amount and location of viral involvement of the VG. Infection of ganglion cells supplying the cristae is responsible for rotatory vertigo while the neurons innervating otolith sense organs (i.e. the utricular macula) will give rise to ataxia or drop attacks. It is not unusual for the level of vestibular sensitivity to change depending on virus activity [27]. Therefore, finding an initially decreased vestibular response following caloric stimulation which recovers to a normal level following resolution of vestibular symptoms is not unexpected. When a sufficient number of VG cells have degenerated, especially in the superior vestibular division, a decreased response can be recorded following caloric stimulation. In the present series there were 4 patients in whom caloric testing had been performed prior to death. A significantly decreased response (none or decreased) was recorded in all 4 patients. Degeneration of the VG was estimated at 40% in 3 and 90% in 1 of these TB. The 40% degeneration represents affected VG cells innervating the lateral and superior canal cristae which are located adjacent to the MG of the facial nerve.

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In some patients with recurrent vertigo and normal hearing, vestibular examination (electronystagmography) is normal because there is insufficient degeneration of vestibular neurons to produce a diminished response using present criteria of 25 –30% reduced response (compared to the intact side). Perhaps the current criteria for defining a vestibular weakness should be reconsidered. Differences of less than 25% in the vestibulocular response may reflect minimal VG degeneration. Since it is possible with MRI to demonstrate an inflammatory process in the VG, neuroimaging should also be considered part of the vestibular examination. Conclusion

Degeneration of the VG initially in clusters of ganglion cells which may eventually lead to widespread ganglion cell loss by neurotropic viral reactivation is similar to the axonal degeneration pattern typical of herpes zoster trigeminus. Molecular studies amplifying HSV DNA from vestibular nerves in human TB support a viral etiology of VN. The close association of the VG and MG together with the frequency of degenerated neurons in these ganglia suggests that the portal of entry of the virus may be over the greater superficial petrosal nerve. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Nylen C: Some cases of ocular nystagmus due to certain positions of the head. Acta Otolaryngol (Stockh) 1924;6:106 –123. Dix M, Hallpike C: The pathology, symptomatology, and diagnosis of certain common disorders of the vestibular system. Ann Otol Rhinol Laryngol 1952;61:987–1016. Lumio JS, Aho J: Vestibular neuronitis. Ann Otol Rhinol Laryngol 1964;74:264 –270. Aschan G, Stahle J: Vestibular neuritis. J Laryngol Otol 1956;70:497–511. Hart C: Vestibular paralysis of sudden onset and probably viral etiology. Ann Otol Rhinol Laryngol 1965;74:33– 47. Harrison M: Epidemic vertigo: Vestibular neuronitis, a clinical study. Brain 1962;85:613– 620. Merifield DO: Self-limited idiopathic vertigo (epidemic vertigo). Arch Otolaryngol 1965;81: 355–358. Pedersen E: Epidemic vertigo: Clinical picture, epidemiology, and relation to encephalitis. Brain 1959;82:566 –580. Coats A: Vestibular neuronitis. Acta Otolaryngol Suppl (Stockh) 1969;251:1–32. Clemis JD, Becker GW: Vestibular neuronitis. Otolaryngol Clin North Am 1973;6:139–155. Shimizu T, Sekitani T, Hirata T, Hara H: Serum viral antibody titer in vestibular neuronitis. Acta Otolaryngol Suppl (Stockh) 1993;503:74–78. Schuknecht HF, Kitamura K: Vestibular neuritis. Ann Otol Rhinol Laryngol 1981;90(suppl 78): 1–19. Nadol JB: Vestibular neuritis. Otolaryngol Head Neck Surg 1995;112:162–172. Baloh RW, Lopez I, Ishiyama A, Wackym P, Honrubia V: Vestibular neuritis: Clinical-pathologic correlation. Otolaryngol Head Neck Surg 1996;114:586–592. Fenton JE, Shirazi A, Turner J, Fagan P: Atypical vestibular neuritis: A case report. Otolaryngol Head Neck Surg 1995;112:738–741.

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16 17 18 19 20 21 22 23 24 25

26 27

Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210. Denny-Brown D, Adams RD, Fitzgerald PJ: Pathologic features of herpes zoster: A note on geniculate herpes. Arch Neurol Psychiatry 1949;51:216–231. Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol, in press. Gacek R: On the duality of the facial nerve ganglion. Laryngoscope 1998;108:1077–1086. Meier JL, Straus SE: Comparative biology of latent varicella zoster virus and herpes simplex virus infections. J Infect Dis Suppl 1992;166:S13–S23. Zemanick MC, Strick PL, Dix RD: Direction of trans-neural transport of herpes simplex virus I in the primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88:8048–8051. Card JP: Exploring brain circuitry with neurotropic viruses: New horizons in neuroanatomy. Anat Rec (New Anat) 1998;253:176–185. Kuypers HG, Ugolini G: Viruses as transneuronal tracers. Trends Neurosci 1990;13:71–75. Silvoniemi P: Vestibular neuronitis: An otoneurological evaluation. Acta Otolaryngol Suppl (Stockh) 1988;453:1–72. Arbusow V, Schulz P, Strupp M, Dieterich M, et al: Distribution of herpes simplex virus type I in human geniculate and vestibular ganglion: Implications for vestibular neuritis. Ann Neurol 1999;46:416 – 419. Arbusow V, Strupp M, Wasicky R, Horn AKE, Schultz P, Brandt T: Detection of herpes simplex virus type I in human vestibular nuclei. Neurology 2000;55:880 –882. Ohbayashi S, Oda M, Yamamoto M, et al: Recovery of vestibular function after vestibular neuronitis. Acta Otolaryngol Suppl (Stockh) 1993;503:31–34.

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Chapter 5

Ménière’s Disease: A Form of Vestibular Ganglionitis Richard R. Gacek, Mark R. Gacek

The treatment of Ménière’s disease (MD) remains controversial because its cause is incompletely understood. Endolymphatic hydrops (EH) has been described consistently as the hallmark pathology in MD [1–3]. EH has been produced following occlusion of the endolymphatic duct in some animal models. The successful animal models are in lower mammalian forms such as the guinea pig, gerbil and chinchilla [4–7], whereas only mild or no EH develops in nonhuman primates even years after obstruction of the endolymphatic duct [8]. Nevertheless, the demonstration of extensive EH in the human temporal bone (TB) as well as some animal models supports the theory that ruptures of a dilated membranous labyrinth result in a release of high-potassium endolymph that is toxic to neural function in both the auditory and vestibular systems [9]. However, major differences exist between human TB observations and the animal models of EH. Animals with experimental EH are not observed to have vertigo [4], and their TB do not demonstrate perilymphatic fibrosis in the vestibule and cochlea as seen in human TB specimens from MD patients [10]. In addition, other features in MD such as the occasional (10–15%) loss of apical spiral ganglion cells in MD [11] as well as delayed-onset ipsilateral (IDEH) or contralateral (CDEH) hydrops are difficult to explain on the basis of EH alone [12–14]. A number of investigators have suggested that the labyrinth prior to the onset of MD is predisposed to the development of EH as a result of a stressful event [15]. These include head trauma, infections of the sinuses or ear and allergy. Although it is possible that the target for the transformation of a predisposed labyrinth is EH, no morphologic, functional or immunologic evidence has shown that the endolymphatic sac is responsible for MD. Clinical treatments designed to relieve EH by surgical or medical approaches are equivocal in controlling symptomatic MD. It is possible that a latent viral infection of the

vestibular ganglion (VG) could represent a predisposed state of the labyrinth which can then be triggered (activated) by various stressful events resulting in the clinical presentation of MD. A number of observations have suggested a viral etiology, and some reports point to the focus of pathology in the vestibular nerve or VG. However, although an elevated herpes simplex virus (HSV) antibody response is detected in patients with MD [16 –19], the latency-associated transcript (LAT) was not found in the ganglion [20] or in the endolymphatic sac [21]. Adour et al. [22, 23] were among the first to suggest that MD is part of a polyganglionitis caused by reactivation of a neurotropic virus such as HSV following a stressor. Nonetheless, the lack of morphologic evidence in the vestibular nerve of MD TB as well as the persuasive features of the EH theory prevented acceptance of the viral ganglionitis theory in MD. Palva et al. [24] investigated the presence of viral particles in the VG excised from patients with MD using transmission electron microscopy. Structures resembling viral organisms were identified but could not be differentiated from similar structures in normal vestibular nerves. Attempts to amplify viral DNA in vestibular nerves excised from MD patients [25] have been unsuccessful until recently. Pitovski et al. [26] and Rosenstein and Pitovski [27] demonstrated HSV LAT and thymidine kinase genes in VG in patients with MD. They had previously demonstrated that HSV LAT was present in more than 70% of normal VG. These data support the concept that a recurrent neuropathy such as MD may occur in a fraction of the population that harbor latent HSV in vestibular nerves and then may be subjected to a stressful incident that triggers reactivation of the virus later in life. Since MD is unique to the human species, evidence of ganglionitis should be found in the TB from patients who exhibit the clinical features of the disease. Our TB collection indicates that there are morphologic changes in the TB of MD patients similar to those from patients with vestibular neuronitis supporting the concept of vestibular ganglionitis [28]. Similar changes were found in the vestibular nerves of patients with benign paroxysmal positional vertigo, a disorder also frequently associated with a viral insult. A unitary concept of the pathophysiology in these three recurrent neuropathies will be discussed in a subsequent chapter.

Materials and Methods Ten TB from 7 patients who had been diagnosed as having MD before death were studied. The TB had been fixed in 10% formalin, embedded in celloidin, sectioned in a horizontal plane at 20 ␮m thickness, and every 10th section was mounted after staining with hematoxylin and eosin. The sections were examined under the light microscope. The amount

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Fig. 1. a The vestibular nerve trunk carried many fascicles of degenerated axons (arrows) of similar size. b These fascicles (arrowheads) were devoid of nerve fibers and filled with Schwann cell nuclei aligned parallel to the direction of the nerve. of degeneration in the meatal ganglion and the VG were estimated according to the techniques described in the chapter on vestibular neuronitis. The spiral ganglion was similarly evaluated for ganglion cell loss in various turns of the cochlea. The tympanic nerve (Jacobson’s nerve) was examined in sections at the promontory level for evidence of degeneration. Additional morphologic changes found in TB with MD were also recorded. These were: the presence of EH, fibrosis in the vestibular cistern, outpouchings of the pars superior of the membranous labyrinth and apical spiral ganglion cell loss. The vestibulocochlear anastomosis was examined as it emerges from the saccular ganglion in all TB and was judged to be either degenerated or normal. The presence of concretions in the sense organs and associated structures of the labyrinth were recorded and mapped on a cochleogram and vestibulogram. The significance of these deposits is discussed in chapter 8.

Results

Table 2 (Appendix) includes a demographic description for the MD patients who donated these TB. The patients with MD ranged in age from 58 to 83 years. There were 5 females and 2 males in this series. Their cause of death is listed along with the otologic diagnosis. All 10 TB contained focal axonal degeneration in the vestibular nerve or ganglion with some measuring up to 40% but most in the range of 10–20% (fig. 1). The VG cells in these TB were surrounded by an increased number of satellite cells (more than 4 per ganglion cell) compared to the normal 1–2 satellite cells per ganglion cell in the human vestibular nerve [29]. All but 1 TB demonstrated degenerated neurons in the MG of the facial nerve (fig. 2). In no TB were there any degenerated geniculate

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Fig. 2. The meatal ganglion demonstrated degeneration of ganglion cells (arrows) in all but 1 TB.

ganglion cells. The spiral ganglion was judged to be normal in both TB of patient 3 (58-year-old male) . The other 8 TB revealed a loss of ganglion cells in the basal turn consistent with age, and in 3 of these there was degeneration of spiral ganglion cells in the apical region (fig. 3). All 10 TB demonstrated EH of the pars inferior. Three TB contained evidence of outpouchings or herniations in the membranous wall of the pars superior of the labyrinth. These outpouchings were located in the region of the utricular wall and/or one or more of the semicircular canal ampullary walls (fig. 4). No outpouchings were found in the membranous limb of the semicircular canals. Six TB contained fibrosis which interfaced a dilated saccular wall with the undersurface of the footplate (fig. 5). The morphologic changes in the labyrinthine sense organs in MD TB will be described in chapter 8. Degeneration of the vestibulocochlear anastomosis and the tympanic nerve is also discussed in this later chapter.

Discussion

The observations in the present study support the concept that the clinical manifestations and the morphologic findings in patients with MD are the result

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Fig. 3. Degeneration of apical ganglion cells (*, arrowhead) was seen in 3 TB with MD. R ⫽ Distended Reissner’s membrane.

of vestibular ganglionitis, probably of viral etiology. The changes in 10 TB from 7 patients with MD demonstrated EH of the pars inferior along with focal axonal degeneration in the vestibular nerves in all TB. The vestibular nerve degeneration is unique to the MD diagnosis because a series of control TB indicated that focal axonal degeneration is not related to age, sex or to a variety of other otologic pathologies (table 4, see Appendix). Furthermore, focal degeneration of axons has been described in herpes zoster of the trigeminal nerve [30]. The concept of VG pathology in MD is supported by quantitative measurements of the vestibular nerve and ganglion in TB from MD. Spoendlin et al. [31] measured a decrease in both the superior and inferior VG cell count of the affected TB compared to the unaffected control side in a single patient with MD. Tsuji et al. [32] demonstrated a significant loss of VG cells in 30 TB from 24 patients with MD compared to age- and sex-matched normative data. Six out of the 10 TB contained fibrosis in the vestibular cistern, an observation that has been reported in 15 –20% of MD TB [12]. The fibrous

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Fig. 4. The arrow indicates outpouching in the posterior ampullary wall of a TB with MD. The asterisk indicates fibrosis in the perilymphatic compartment.

Fig. 5. A distended saccular (S) wall is attached to the undersurface of the stapes footplate (FP) by fibrous tissue (*).

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tissue attachment of a dilated saccular wall to the footplate is thought to be responsible for Hennebert’s sign in MD. This fibrosis is indicative of an inflammatory component in MD. Outpouchings in the pars superior and a loss of apical ganglion cells were noted in 3 TB in this series. It may be significant that the outpouchings were located in the membranous labyrinth wall near the termination of vestibular nerve branches. It is possible that such membranous wall deformities are caused by a weakening of the membranous wall as a result of an inflammatory process. Isolated degenerated neurons in the MG and focal axonal degeneration in the vestibular nerve are consistent with a virus-induced ganglion cell lesion. As described in the previous chapter and the chapter on the biology of neurotropic viruses, the process of entrance of a neurotropic virus into the sensory nerve takes place earlier in life, providing that complementary receptors in the plasma membrane of the sensory neuron attract glycoproteins in the viral envelope responsible for attachment and invasion of the sensory neuron by the virus [33, 34]. After active infection, the virus may subside into a latent state within the nucleus of the ganglion cell where it resides for decades waiting to be reactivated at a later point in life [35]. The focal vestibular axonal degeneration found in the TB of this series lends support to earlier reports of fibrosis [36], degeneration as well as loss of VG cells [31, 32] in TB with MD indicating a VG location for the cause of MD. Rosenstein and Pitovski [27], using PCR and in situ PCR, detected HSV LAT in over 70% of the VG from normal adults. This high incidence agrees with longitudinal studies showing a majority of the population having elevated HSV antibody levels with increased age. The Pitovski group also used the technique of in situ reverse-transcriptase PCR to detect and localize HSV-1, LAT and thymidine kinase transcript gene sequences in vestibular nerves excised from patients with MD [26]. The thymidine-kinase- and LATpositive VG cells are strong evidence of a viral infection in patients with MD. While the absence of auditory symptoms in vestibular neuronitis is expected in the presence of vestibular ganglionitis, the association of auditory deficits with recurrent vertigo in MD seems incompatible with vestibular ganglionitis. However, recent evidence on virus behavior offers a basis for this paradox [37–40]. Viruses such as the McIntyre strain of HSV flow in a retrograde direction (toward the periphery) while the H 129 strain of HSV flows in an anterograde direction (toward the brain). Therefore, reactivation of a latent H 129 strain of virus in the VG will cause the flow of toxic nucleic acids and virus particles toward the brainstem where it may even cause central features if infectivity is carried transsynaptically to the vestibular nuclei. However, if the latent vestibular ganglionitis is caused by the McIntyre strain of HSV, the flow of nucleic acids and viral toxicity is over vestibular nerve branches toward the labyrinth (fig. 6). This retrograde release of nucleic acids and toxic proteins into

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Vestibular nuclei U

Stapes

VG

Brainstem

S

RW

Fig. 6. Schematic retrograde virus flow from the VG. Release of toxic viral products into the perilymphatic space causes fibrosis in the vestibule (stippled area) and toxicity to apical spiral ganglion cells. U ⫽ Utricle; S ⫽ saccule; RW ⫽ round window.

the perilymphatic space may be responsible for inciting fibrosis in the vestibular cistern where the utricular nerve is generously surrounded by perilymph. Retraction of vestibular fibrosis could displace the saccular wall to the undersurface of the footplate. The outpouchings typically found in the utricular and ampullary walls of the pars superior are located in areas where nucleic acid release would be greatest and could weaken the structure of the membranous wall resulting in herniations or outpouchings. The occurrence of low-frequency sensorineural hearing loss and loss of apical ganglion cells is best explained by a migration of nucleic acid and viral protein toxicity from the vestibular cistern up the scala vestibuli and through the helicotrema to contact the apical ganglion cells by penetrating the undersurface of the osseous spiral lamina in the apical turn [12]. It has been shown in patients with vestibular neuronitis or MD that enhanced MRI can demonstrate high signal enhancement in the region of the VG simulating eighth-nerve tumor but actually representing an increased blood flow through the inflamed ganglion [41]. Specimens of VG excised from patients with MD with an enhancing lesion in the auditory canal have shown pathology that is consistent with vestibular ganglionitis [41]. Vestibular ganglionitis provides an explanation for the delayed presentation of EH. In both IDEH and CDEH, the unilateral profound hearing loss occurs in childhood (about the age of 4 years) as a result of viral labyrinthitis, mastoid surgery, head injury or influenza, while the onset of the late phase is delayed about 20 years [13, 14]. In IDEH, the late phase is characterized by episodic

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vertigo caused by EH in the deaf ear, while in CDEH the late phase presents with a fluctuating low-frequency sensorineural hearing loss associated with pressure and tinnitus. Episodic vertigo occurs in about half the patients with CDEH. A prominent feature of the pathology in delayed EH is the incidence of reduced vestibular function in both ears. Schuknecht’s series of 31 patients with IDEH and 31 with CDEH revealed that 11 of the 31 CDEH patients showed profound vestibular loss in the deaf ear, but only 4 of the IDEH had a similar loss in the deaf ear [12]. Furthermore, there was a profound loss of vestibular function in 12 of the opposite ears in CDEH but in only 1 of the IDEH cases. Abnormal vestibular responses in the deaf and contralateral ears were even more telling. The deaf ear in IDEH revealed a reduced or absent vestibular response in 25 cases, while 22 patients with CDEH had a reduced or absent response. The contralateral ear in CDEH revealed a normal vestibular response in 11 out of 31. These observations suggest that the event responsible for decreased vestibular function is severer when both ears develop EH than when delayed EH is restricted to the deaf ear. Recurrent viral activation from a latent state in the VG is a suitable hypothesis accounting for the clinical expression and histopathologic features of MD. Schuknecht [12] expressed insight toward this possibility in summarizing the significance of the delayed forms of progressive EH: ‘Assuming that viral labyrinthitis can occur in infants as a subclinical disease that results in delayed EH, we may have an explanation for the cause of MD. Viewed in this context, the disease entity known as delayed EH becomes the missing link in understanding the pathogenesis of Ménière’s disease.’ Recurrent vertigo is the central and most prominent symptom in MD. Yet vestibular sensitivity measured by the caloric method of provoking an ocular response does not follow a progressive decrease as would be expected if repeated potassium intoxication of vestibular nerve terminals were responsible for recurrent vertigo. A telling report on caloric test abnormalities in MD was given by Proctor [42]. One hundred twenty-two cases of unilateral MD out of more than 700 patients were tested at least twice with a mean interval of 2.4 years between tests. Canal paresis was found on the involved side in 58% of patients and on the normal side in 19%. Complete paralysis was found in 7%. Twenty-six percent of patients tested more than twice showed both increases and decreases in caloric responses. Only 1 of 8 patients examined after an acute attack showed a decreased response on the affected side. Three patients showed no difference and 4 showed an increased response after an attack. Two mechanisms for the development of EH have been demonstrated: (1) obliteration of the endolymphatic duct in some animals, especially the guinea pig and chinchilla, results in EH of the Passinferior because of

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obstructed longitudinal flow of endolymph to the endolymphatic sac; (2) EH may develop following the deposition of foreign proteins in the perilymph as in serous labyrinthitis [43]. A major difference in the histopathology of these 2 mechanisms experimentally induced in the animal is that fibrous tissue in the perilymphatic space is lacking when the endolymphatic duct is blocked, but it is a typical feature of toxic labyrinthitis. Furthermore, outpouching in the pass superior space are not seen in the EH of animals following endolymphatic duct obstruction. Any concept of MD must address the differences between EH in the MD patient and the experimental animal model of EH. The absence of vertigo in the animal model of EH, together with vestibular responses in MD patients which do not reflect a progressive deterioration that should result from repeated chemical paralysis weakens the theory that ruptures of the membranous labyrinth with release of endolymph toxic to neural elements in the perilymphatic space are responsible for balance disturbances. On the other hand, vestibular ganglionitis with repeated reactivation and release of virus into the perilymph accounts for the unpredictable recurrence of vertigo in MD. The rupture theory would be expected to produce similar episodes of imbalance. The tissue response to virus release in the perilymph may account for the histopathologic features of MD. A low-frequency fluctuating sensorineural hearing loss is typical of early MD while a flat one with no fluctuation is seen late in MD. The low-frequency threshold pattern has been attributed to a gradient of changes in the motion mechanics of the cochlear partition produced by an increased volume of endolymph (EH). However, a physical change in the cochlear duct does not account for the poor speech discrimination or recruitment which is a frequent finding in MD. The threshold elevation should be evenly graded throughout the frequency spectrum if it is determined by the physical characteristics of the cochlear partition. The low-frequency threshold elevation in early MD rises abruptly to a normal threshold for 1 or 2 kHz. This feature of the ascending threshold pattern in MD is explained by neurotoxicity of apical turn sensorineural units. Possible sources of neurotoxicity are potassium-dominated endolymph released through a rupture in the membranous labyrinth or virus expressed from terminal vestibular nerve branches (i.e. utricular nerve) into the perilymph. Perilymph fibrosis is a more likely response to an inflammatory toxin than to an ionic one. After traveling up the scala vestibuli from the basal to apical turn through the helicotrema, these neurotoxins first enter the apical turn scala tympani where they can disturb the neurophysiology of the apical ganglion cell dendrites. A low-frequency threshold elevation with decreased word recognition results. The sharp rise to a normal threshold for 1 or 2 kHz in MD reflects stimulation of adjacent basal portions of the basilar membrane by the envelope of activation

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which spreads from the apex to base. With longevity of MD, the neurotoxic effect on the spiral ganglion increases in a basal turn direction resulting in an even frequency spectrum threshold elevation and poor word discrimination. A repeated neurotoxic effect on dendrites of spiral ganglion cells may lead to a retrograde degeneration of ganglion cells. This pathway for adverse effects on the spiral ganglion is supported by histologic changes in the apical scala tympani observed in toxic labyrinthitis. End-stage MD is characterized by profoundly decreased vestibular and auditory sensitivity with minimal balance symptoms and severe-to-profound sensorineural hearing loss.

Conclusion

A preponderance of immunologic, morphologic, radiologic and molecular evidence indicates that the clinical syndrome described by Prosper Ménière is the result of a latent neurotropic viral vestibular ganglionitis which may be reactivated by a multitude of stressful stimuli to a host immune system unable to prevent recrudescence of the viral organism. MD differs from vestibular neuronitis, also a reactivated neurotropic viral vestibular ganglionitis, in that the virus strain in MD follows a retrograde direction of flow to the perilymphatic compartment where toxicity to cochlear neurons occurs.

References 1 2 3 4 5 6 7 8 9 10 11 12 13

Hallpike CS, Cairns H: Observations on the pathology of Ménière’s syndrome. J Laryngol Otol 1938;53:625–655. Yamakawa K: Über die pathologische Veränderung bei einem Ménière-Kranken. J Otorhinolaryngol Soc Jpn 1938;44:2310 –2312. Lindsay JR: Labyrinthine dropsy and Ménière’s disease. Arch Otolaryngol 1942;37:853–867. Kimura RS, Schuknecht HF: Membranous hydrops in the inner ear of the guinea pig after obliteration of the endolymphatic sac. Pract Otorhinolaryngol 1965;27:343–354. Schuknecht HF: Pathology of the Ear. Cambridge, Harvard University Press, 1974. Kimura RS: Animal models of endolymphatic hydrops. Am J Otolaryngol 1982;3:447–451. Schuknecht HF, Northrop C, Igarashi M: Cochlear pathology after destruction of the endolymphatic sac in the cat. Acta Otolaryngol (Stockh) 1968;65:479–487. Swart JG, Schuknecht HF: Long-term effects of destruction of the endolymphatic sac in a primate species. Laryngoscope 1988;98:1183–1189. Tasaki I, Fernandez C: Modification of cochlear microphonics and action potentials by direct currents. J Neurophysiol 1952;15:497–512. Schuknecht HF, Igarashi M: Pathophysiology of Ménière’s disease; in Pfaltz CR (ed): Controversial Aspects of Ménière’s Disease. New York, Thieme, 1986, pp 46–54. Schuknecht HF, Richter E: Apical lesions of the cochlea in idiopathic endolymphatic hydrops and other disorders: Pathophysiological implications. ORL J Otorhinolaryngol Relat Spec 1980;42:46–76. Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febiger, 1993, pp 235–244. Schuknecht HF: Delayed endolymphatic hydrops. Ann Otol Rhinol Laryngol 1978;87:743–748.

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Schuknecht HF, Suzuka Y, Zimmerman C: Delayed endolymphatic hydrops and its relationship to Ménière’s disease. Ann Otol Rhinol Laryngol 1990;99:843–853. Ruckenstein MJ: Immunologic aspects of Ménière’s disease. Am J Otolaryngol 1999;20: 161–165. Bergstrom T, Edstrom S, Tjellstrom A, et al: Ménière’s disease and antibody reactivity to herpes simplex virus type I polypeptides. Am J Otol 1992;13:295–300. Williams LL, Lowery HW, Shannon BT: Evidence of persistent viral infection in Ménière’s disease. Arch Otolaryngol Head Neck Surg 1987;113:397–400. Calenoff E, Zhao J, Derlacki EL, et al: Patients with Ménière’s disease possess IgE reacting with herpes family viruses. Arch Otolaryngol Head Neck Surg 1995;121:861–864. Arnold W, Niedermeyer HP: Herpes simplex virus antibodies in the perilymph of patients with Ménière’s disease. Arch Otolaryngol Head Neck Surg 1997;123:53–56. Furuta Y, Takasu T, Fukuda S, et al: Latent herpes simplex virus type I in human vestibular ganglia. Acta Otolaryngol Suppl (Stockh) 1993;503:85–89. Ikeda M, Sando I: Endolymphatic duct and sac in patients with Ménière’s disease: A temporal bone histopathological study. Ann Otol Rhinol Laryngol Suppl 1984;93:540–546. Adour KK, Hilsinger R, Byl FM: Herpes simplex polyganglionitis. Otolaryngol Head Neck Surg 1980;88:270 –274. Adour KK, Byle FM, Hilsinger R: Ménière’s disease as a form of cranial polyneuritis. Laryngoscope 1980;90:392–398. Palva T, Horling L, Ylikoski J, et al: Viral culture and electron microscopy of ganglion cells in Ménière’s disease. Acta Otolaryngol 1979;86:269–275. Welling DB, Miles BA, Western L, Prior T: Detection of viral DNA in vestibular ganglion tissue from patients with Ménière’s disease. Am J Otol 1997;18:734–737. Pitovski DZ, Robinson AM, Garcia-Ibanez E, Wiet R: Presence of HSV-1 gene products characteristic of active infection in the vestibular ganglia of patients diagnosed with acute Ménière’s disease (abstract 457). 22nd Annu Midwinter Res Meet Assoc Res Otolaryngol St Petersburg Beach, February 1999. Rosenstein, Pitovski D: Detection of herpes simplex virus type I latency associated DNA in human vestibular ganglion by in situ polymerase chain reaction (abstract 261). 21st Meet Assoc Res Otolaryngol, St Petersburg Beach, February 1998. Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20:202–210. Ona A: The mammalian vestibular ganglion cells and the myelin sheath surrounding them. Acta Otolaryngol Suppl (Stockh) 1993;503:143–149. Denny-Brown D, Adams RD, Fitzgerald PJ: Pathologic features of herpes zoster: A note on geniculate herpes. Arch Neural Psychiatry 1949;51:216–231. Spoendlin H, Balle V, Bock G, Bredberg G, Danckwardt-Lillieström N, Felix H, Gleeson M, Johnsson LG, Luciano L, Rask-Andersen H, Reale E, Reiss G, Schrott-Fischer A, Iurato S: Multicentre evaluation of the temporal bones obtained from a patient with suspected Ménière’s disease. Acta Otolaryngol Suppl (Stockh) 1992;499:1–21. Tsuji K, Velázques-Vallasenor L, Rauch S, Glynn R, Wall C III, Merchant S: Ménière’s disease: Temporal bone studies of the human peripheral vestibular system. Ann Otol Rhinol Laryngol 2000;109 (Suppl 181):26 –31. Baringer JR, Swoveland P: Recovery of herpes simplex virus from human trigeminal ganglions. N Engl J Med 1973;288:648–650. Meier JL, Straus SE: Comparative biology of latent varicella zoster virus and herpes simplex virus infections. J Infect Dis 1992; 166(Suppl 1):S13–S23. Cook ML, Stevens JG: Pathogenesis of herpetic neuritis and ganglionitis in mice: Evidence for intra-axonal transport of infection. Infect Immun 1973;7:272–288. Galic M, Helms J: Elektronenmikroskopische Befunde am Bindegewebe von Nervus und Ganglion vestibuli bei Morbus Ménière. Arch Otorhinolaryngol 1982;236:67–79. Kuypers HG, Ugolini G: Viruses as transneuronal tracers. Trends Neurosci 1990;13:71–75. Card JP: Exploring brain circuitry with neurotropic viruses: New horizons in neuroanatomy. Anat Rec (New Anat) 1998;253:176–185.

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LaVail JH, Topp KS, Giblin PA, Garner JA: Factors that contribute to the transneural spread of herpes simplex virus. J Neurosci Res 1997;49:485– 496. Zemanick MC, Strick PL, Dix RD: Direction of transneural transport of herpes simplex virus I in the primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88:8048–8051. Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol, in press. Proctor LR: Results of serial vestibular testing in unilateral Ménière’s disease. Am J Otol 2000; 21:552–558. Wittmaack K: Die entzündlichen Erkrankungsprozesse des Gehörorganes; in Wittmaack K (ed): Handbuch der speziellen pathologischen Anatomie und Histologie. Berlin, Springer, 1926, vol 2, pp 102–379.

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Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 80–88

Chapter 6

The Pathology of Benign Paroxysmal Positional Vertigo Richard R. Gacek, Mark R. Gacek

Our knowledge of the pathology in benign paroxysmal positional vertigo (BPV) has increased greatly since the clinical syndrome was first described more than 70 years ago by Bárány [1]. BPV represents the most common vestibular disturbance seen in otology. Many clinical and histopathological observations acquired over the past 35 years indicate that the sense organ usually responsible for the position-provoked vertigo and vestibulo-ocular response is the posterior canal crista of the undermost ear in the Hallpike positioning test [2–4]. Much less commonly, the lateral canal crista may be the responsible sense organ based on the observation of a horizontal fatigable nystagmus in the provocative position. Together with the description of highly specific gravity deposits within the posterior canal or its cupula, these observations have led to the development of nonsurgical (repositioning) [5–8] and surgical (singular neurectomy, posterior canal occlusion) [9–11] procedures to relieve the symptoms of BPV with preservation of hearing. Based on the observations that basophilic deposits, presumably degenerated otoconia, representing gravity-sensitive particles in the posterior canal ampulla, are present either attached to or near the cupula of the posterior canal [2, 10, 12, 13], it was hypothesized that the highly specific gravity otoconia transform the posterior canal crista into a gravity-sensitive sense organ. It has been assumed that these otoconia are dislodged from the utricular macula by either concussive or ischemic forces acting on the superior vestibular division sense organs [2, 12]. It has also been suggested that the otoconial debris may be either embedded in the cupula (cupulolithiasis) or remain in a suspended state within the endolymph fluid compartment (canalolithiasis) [10]. These two arrangements of dislodged otoconial debris are thought to be responsible for the persistent and the intermittent clinical presentations of BPV. However, some clinical features of BPV are not sufficiently explained by the concept of cupulolithiasis or canalolithiasis [2]. These are: the limited

duration of the attack in spite of a maintained provocative head position, the fatigability of the vestibulo-ocular response on repeated testing and the prolonged remissions of BPV in some patients. Furthermore, the onset of BPV following very different forms of injury is difficult to explain purely on a mechanical basis. Most commonly, the preceding historical event prior to the onset of BPV is a vestibular disturbance suggestive of acute vestibular neuronitis. However, head injury, aging and various types of general surgery on other parts of the body under general anesthesia are well known as events that may precede the onset of BPV. A neural component in BPV had been suggested by Citron and Hallpike [4] and Lindsay and Hemenway [14], on the basis of degeneration in the superior vestibular nerve of the temporal bone (TB) from patients whose onset of BPV was idiopathic rather than traumatic. However, superior vestibular nerve degeneration was considered an unusual finding in BPV because most patients with BPV demonstrate a normal vestibular response to caloric stimulation. These observations were used to support the contention that with its nerve supply intact the posterior canal crista is responsible for vertigo and the rotatory vestibulo-ocular response following the provocative test. Morphologic evidence of a neural component in BPV was described in the form of inferior vestibular ganglion degeneration and inflammation with a normal superior vestibular ganglion in the TB of 3 patients with the clinical findings of BPV [15]. Furthermore, the cupulae of the posterior canal crista in all 3 TB did not contain basophilic material resembling otoconial debris. Basophilic particles were not identified within the lumen of the posterior semicircular canal or its ampulla either. These findings suggest that the pathophysiology in BPV consists of a mechanical and a neural component. The mechanical component is the transformation of the posterior canal crista into a gravity-sensitive receptor while the neural component consists of a change in the physiology of inferior vestibular ganglion cells caused by viral inflammation. In this report, 2 additional TB specimens from patients with chronic BPV were examined for pathologic changes in the posterior canal crista, the vestibular ganglion and meatal ganglia of the facial nerve.

Material and Methods Additional TB TB were removed from 2 patients with clinical findings of BPV, placed in formalin fixative and decalcified. The TB were then embedded in celloidin, sections cut at 20 ␮m and stained with hematoxylin and eosin. Every tenth section was mounted and examined under the light microscope.

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Previously Examined TB TB of the affected ear (downmost ear in the Hallpike test) from 3 previously reported patients with BPV were reviewed. Morphologic changes in the seventh and eighth cranial nerves were estimated by the techniques described in chapter 4 and listed in table 3 (Appendix). Deposits in the labyrinthine sense organs and degeneration of the vestibulocochlear anastomosis and tympanic nerve were also described. These TB were horizontally sectioned and stained with hematoxylin and eosin.

Results

Additional TB One TB is illustrated in detail since both TB show similar findings. Case 1: TB Removed 5.5 h after Death Clinical History. This 48-year-old female was admitted to the hospital at the age of 43 years for treatment of porphyria which was successful. Later that same year, she experienced sudden hearing loss in her left ear and vertigo. A hearing test revealed profound sensorineural hearing loss in the left ear and normal hearing in the right. Caloric testing revealed a normal response in the right and a decreased response in the left ear. She was treated with vestibular suppressants and multivitamins with the vertigo resolving after several days. The patient subsequently complained of brief vertigo on turning over in bed. Positional testing revealed a rotatory nystagmus lasting 15 s when the head was turned to the left. There was no nystagmus when the head was turned to the right. The patient died from a myocardial infarction. Histopathology of the Left TB. The organ of Corti was atrophic and totally absent in the basal 17 mm of the cochlea. It was flattened in the 17- to 23-mm area of the cochlea and possessed a few scattered hair cells in the 23- to 32-mm region. The ganglion cell loss averaged 30% throughout the cochlea with a greater loss in the basal turn. There were several concretions in the stria vascularis of the upper basal turn. The geniculate ganglion of the facial nerve contained the normal number of satellite cells (SC) around intact ganglion cells. No degenerated ganglion cells were found in the geniculate ganglion. Almost 50% of the ganglion cells in the meatal ganglion were degenerated with an onion bulb form of collagen replacement (fig. 1). Vestibular sense organs were normal and the superior division ganglion cells were each surrounded by 1–2 SC (fig. 2). Ganglion cells supplying the saccular macula and the posterior canal crista were surrounded by an increased number of SC (more than 4 per ganglion cell). There were several Gacek /Gacek

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Fig. 1. a The meatal ganglion (MG) and facial nerve (F) are pulled away from the vestibular nerve and ganglion (VG). A few meatal ganglion cells (arrow) are left attached to the vestibular nerve trunk. Degenerated ganglion cells (arrowhead) are present in the meatal ganglion. b A higher-power view shows the circular deposition of collagen in degenerated ganglion cells (arrowheads) of the meatal ganglion.

Fig. 2. The superior vestibular ganglion contained a normal number (1–2) of SC per ganglion cell. The Pathology of Benign Paroxysmal Positional Vertigo

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Fig. 3. Several fascicles of degenerated axons (arrows) were present in the inferior vestibular nerve trunk.

small blue-stained plaques in the inferior vestibular ganglion and several fascicles of degenerated axons in the inferior vestibular nerve trunk (fig. 3). The posterior canal crista was also capped by a shrunken cupula with a small basophilic deposit (fig. 4).

Previously Examined TB Three previously reported TB (table 3, see Appendix) contained degenerated ganglion cells in the meatal ganglion of the seventh cranial nerve and focal axonal degeneration in the inferior vestibular nerve [15]. The superior division vestibular nerve and ganglion were normal in all 3 TB. Degeneration in the spiral ganglion was present in the basal turn and consistent with an age-related decrease. The vestibulocochlear anastomosis was partially degenerated in all 3 TB, and the tympanic nerve was degenerated in 1 but normal in 2 TB. Concretions were found in vestibular sense organs of 2 and the organ of Corti of

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Fig. 4. The cupula of the posterior canal crista contained a small basophilic deposit (arrow).

1 TB. No concretions were observed in 1 TB. The concretions will be discussed in chapter 8.

Discussion

The observations in the 2 current TB and 3 previously reported TB support a role for an inflamed inferior vestibular ganglion in the pathogenesis of BPV. Morphologic changes consisted of focal axonal degeneration in the inferior vestibular nerve trunk and/or an increased number of SC and inflammatory cells around ganglion cells of the inferior division which supply the saccular macula and the posterior semicircular canal crista. Focal axonal degeneration in the inferior vestibular nerve trunk reflects loss of ganglion cell clusters degenerated because of past viral infection, while the increase in the supporting and inflammatory cells around the ganglion cells represents a response to inflammatory changes in the ganglion [16]. The acute inflammatory process in ganglion cells may be responsible for active periods of BPV. The exact pathoneurophysiology is not known, but it may represent a change in the ionic gradient across the ganglion cell membrane caused by repeated viral passage through the membrane with exacerbation of latent virus. Membrane defects in the cell wall could be responsible for loss of the ionic gradient making the cell hyperexcitable in response to a mechanical stimulus at the end organ. Sufficiently severe or repeated exacerbations of virus recrudescence would be capable of cell destruction, leading to axonal degeneration [17]. The limited duration of the vestibulo-ocular response in the maintained provocative position as well as

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the fatigability of the response to repeat testing are characteristics that could be explained by a ganglion cell that is unable to maintain a sustained response. Therefore, the presence and reappearance of BPV intermittently over long periods of time may be caused by virus recrudescence and return to a latent state [18]. A mechanical component remains a part of this concept, not only because of the reported basophilic deposits in the posterior canal cupula in TB of BPV patients, but also because the mechanical stimulus is provided by the headpositioning maneuver. Basophilic deposits were not seen in the posterior canal cupula of the 3 previously reported patients with inferior vestibular ganglionitis. However, a small deposit was found in the posterior canal cupula of the TB reported. The argument can be made that in some of these cases the deposits were free floating in the membranous limb of the posterior canal. This contention cannot be answered with confidence based on the available material. In all 5 TB, the superior vestibular division ganglion was normal; there were no degenerated ganglion cells, and a normal low density of SC surrounded the ganglion cells. Evidence of past and current inflammatory changes was found in the inferior vestibular ganglion and/or the inferior vestibular nerve trunk. These changes consisted of an increased number of SC and/or inflammatory cells around ganglion cells in the inferior vestibular ganglion or focal axonal degeneration in the proximal nerve trunk of 1 TB. The inflammatory nature of the change in the vestibular ganglion is supported by a decreased caloric response initially in the affected ear of case 1 following the initial episode of vertigo which had recovered by the time of TB removal years later when the superior vestibular ganglion was found to be normal. Such a reversal in vestibular sensitivity can be explained by an inflammatory lesion. The role of reactivated neurotropic virus in the ganglion is supported by the divergent events that precede the onset of vestibular neuronitis [19] or BPV [20–22]. These are: head trauma, association with an inflammatory process in the upper aerodigestive tract (sinusitis), the stress of recovering from a major surgical procedure with general anesthesia as well as a decreased host response due to a senescent immune system. Examples of stressors capable of reactivating virus are: upper respiratory tract infection, ultraviolet light, trauma, surgery, emotional upset, headache, dental infection and pregnancy. Until now it has been difficult to causally relate the onset of BPV following surgery under general anesthesia. Since the use of singular neurectomy [23] in patients disabled by BPV, we have encountered 16 patients with chronic disabling BPV of the posterior canal following surgery on other areas of the body [21]. These have included frontal sinus surgery, back surgery, gynecological surgery, heart surgery and abdominal surgery. The peak incidence of BPV in the adult years (⬎50 years) is typical of reactivation of latent virus.

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Numerous authors have observed the co-occurrence of BPV in the ear with vestibular neuronitis [19] or Ménière’s disease [22]. Proctor [22] reported that 44% of the 122 patients with Ménière’s disease whom he followed for several years experienced BPV in the involved ear. The report of Lindsay and Hemenway [14] of BPV in a patient with degeneration of the superior vestibular ganglion was one of the early descriptions of co-occurrence of vestibular neuronitis and BPV. The concept of various forms of recurrent vestibulopathy caused by vestibular ganglionitis provides a logical basis for the coexistence of different vestibular syndromes in the same ear.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Bárány R: Diagnose von Krankheitserscheinungen im Bereiche des Otolithenapparates. Acta Otolaryngol (Stockh) 1921;2:434 – 437. Schuknecht HF, Ruby RR: Cupulolithiasis. Adv Otorhinolaryngol 1973;20:434–443. Gacek RR: Transection of the posterior ampullary nerve for the relief of benign paroxysmal positional vertigo. Ann Otol Rhinol Laryngol 1974;83:596–605. Citron L, Hallpike CS: Observations upon the mechanism of positional nystagmus of the so-called ‘benign paroxysmal type’. J Laryngol 1956;70:253–259. Brandt T, Daroff RB: Physical therapy for benign paroxysmal positional vertigo. Arch Otolaryngol 1980;106:484 – 485. Semont A, Freyss G, Vitte E: Curing BPPV with a liberatory maneuver. Adv Otorhinolaryngol 1988;42:290–293. Epley JM: The canalith repositioning procedure: For treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 1992;107:399– 404. Epley JM: Particle repositioning for benign paroxysmal positional vertigo. Otolaryngol Clin North Am 1996;29:323 –331. Gacek RR: Technique and results of singular neurectomy for the management of benign paroxysmal positional vertigo. Acta Otolaryngol (Stockh) 1995;115:154–157. Parnes LS, McClure JA: Posterior semicircular canal occlusion for intractable benign paroxysmal positional vertigo. Ann Otol Rhinol Laryngol 1990;99:330–334. Parnes LS: Update on posterior canal occlusion for benign paroxysmal positional vertigo. Otolaryngol Clin North Am 1996;29:333–342. Hall SF, Ruby RR, McClure JA: The mechanics of benign paroxysmal vertigo. J Otolaryngol 1979;8:151–158. Moriarty B, Rutka J, Hawke M: The incidence and distribution of cupular deposits in the labyrinth. Laryngoscope 1992;102:56 –59. Lindsay JR, Hemenway WG: Postural vertigo due to unilateral sudden partial loss of vestibular function. Ann Otol Rhinol Laryngol 1956;65:692–708. Gacek R, Gacek M: Update on the pathology and management of benign paroxysmal positional vertigo. Otorhinolaryngol Nova 1998;8:235–244. Cook ML, Stevens JG: Pathogenesis of herpetic neuronitis and ganglionitis in mice: Evidence for intra-axonal transport of infection. Infect Immun 1973;7:272–288. Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20: 202–210. Meier JL, Straus SE: Comparative biology of latent varicella-zoster virus and herpes simplex virus infections. J Infect Dis 1992;166(suppl 1):S13–S23. Schuknecht HF, Kitamura K: Vestibular neuronitis. Ann Otol Rhinol Laryngol Suppl 1981; 90:1–19.

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20 21 22 23

Katsarkas A, Outerbridge JS: Nystagmus of paroxysmal positional vertigo. Ann Otol Rhinol Laryngol 1983;92:146 –150. Gacek RR: Singular neurectomy update II: Review of 102 cases. Laryngoscope 1991;101: 855–862. Proctor LR: Results of serial testing in unilateral Ménière’s disease. Am J Otol 2000;21:552–558. Gacek RR: Singular neurectomy update. Ann Otol Rhinol Laryngol 1982;91:469–473.

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Chapter 7

A Classification of Recurrent Vestibulopathy Richard R. Gacek, Mark R. Gacek

Intermittent vertigo represents one of the most disabling symptoms encountered in otologic practice. The recurrent nature of this disability implies a reversible alteration in vestibular nerve physiology caused by changes in the neuron or its environment. Three of the most common clinical syndromes manifesting as recurrent vertigo are benign paroxysmal positional vertigo (BPV), Ménière’s disease (MD) and vestibular neuronitis (VN). The morphologic evidence presented in previous chapters supported by molecular [1, 2], immunologic [3–6] and clinical observations [7–19] indicates that these common, and some less common, recurrent vestibulopathies are manifestations of reactivation of latent viral vestibular ganglionitis. The agents responsible for the ganglionitis are neurotropic (NT) viruses, likely herpes simplex (HSV) or zoster virus. Other NT viruses that may be included in this group are cytomegalovirus, Epstein-Barr and pseudorabies virus. The ubiquity of HSV accounts for the high exposure rates recorded in the world population. Elevated serum antibody titers to HSV-1 have been recorded in 70% of 25-year-olds, while at the age of 60 years the rate is over 90% [20]. After the NT virus has entered a sensory nerve, it may acquire a latent state in its ganglion cells. Reactivation of the virus from latency is reflected in clinical signs and symptoms. Because the clinical syndromes with recurrent vertigo are varied, it is useful to construct a classification system based on vestibular ganglionitis [21]. We propose a new classification system based on three bodies of information: (1) a review of temporal bone (TB) specimens, (2) case reports and (3) a clinical series. Review of TB Specimens

A review of 20 TB with VN, 10 TB with MD and 3 with BPV is summarized in tables 1, 2 and 3 in the Appendix. The similarity of morphologic

changes in the facial nerve meatal ganglion (MG) and vestibular nerves supports a common etiology. The vestibular nerve and ganglion (VG) pathology was limited to the inferior vestibular division in all cases of BPV and in both superior and inferior divisions in VN and MD. These changes were not found in TB from patients with similar age, sex and sense organ disorders but without a vestibular disorder (table 4, see Appendix).

Case Reports

TB case reports illustrate the location of VG pathology in VN, MD and BPV. Vestibular Neuronitis A 71-year-old male with a 5-year history of prostatic cancer with orbital and brain metastases was admitted to the hospital for severe vertigo and nausea. A hearing test showed a bilateral high-frequency sensorineural hearing loss with discrimination scores of 88% (right) and 68% (left). There was a spontaneous nystagmus to the right and a diminished caloric response on the left. He died 19 days later from brainstem and cerebellar infarction. Histopathology (Left TB) The geniculate ganglion did not have degenerated neurons, but the ganglion cells were surrounded by an abundant number of satellite cells (SC). In the MG, there were several scattered degenerated ganglion cells replaced by collagen-like material (fig. 1a, b). Intact ganglion cells were surrounded by many SC. The cristae and maculae appeared to contain a normal number of hair cells and supporting cells. Several fascicles of axonal degeneration were observed in the superior vestibular nerve trunk (fig. 2). Smaller fascicles of degenerated nerve fibers passed between neurons surrounded by many SC and inflammatory cells in the VG. Consistent with normal hearing thresholds and word discrimination for his age of 71 years, the organ of Corti was shrunken, but the pillar cells separated a normal number of internal and external hair cells. The organ of Corti was missing in the lower basal turn. The spiral ganglion cells appeared reduced in number except for the extreme basal end of the cochlea where they were absent. Benign Paroxysmal Positional Vertigo A 65-year-old male alcoholic suffered head injury with several hours of unconsciousness. Six months later, he was diagnosed as having posttraumatic

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Fig. 1. a Photomicrograph of the MG in a case of VN (case 9, tab. 1). Arrowheads indicate degenerated ganglion cells replaced by a collagen-like material. F ⫽ Facial nerve. b A higher-power view of the degenerated ganglion cells in a illustrates the laminated pattern of collagen deposition (arrowheads).

Fig. 2. The vestibular nerve in the case of VN contained many fascicles of degenerated axons (arrows).

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Fig. 3. In the case of BPV (case 2, tab. 3), the posterior canal crista revealed round basophilic deposits (arrow) in the cupula. These are artifacts, not degenerated otoconia.

normotensive hydrocephalus. During admission to the hospital, he complained of recurrent vertigo for several months. The vertigo lasted a few minutes and was associated with nausea and vomiting. There was a mild spontaneous nystagmus to the left and a tendency to fall to the left. Positional (Hallpike) tests revealed – in the position with the left ear down – a rotatory clockwise nystagmus with a brief latency, a short duration and fatigability on repeat testing. When the right ear was placed down, no nystagmus was observed. Bithermal caloric stimulation was normal and symmetric. A hearing test revealed a high-frequency sensorineural hearing loss on the left. Speech discrimination was normal in both ears. Histopathology (Left TB) The tympanic membrane, ossicles and mastoid air cell system were normal. No evidence of TB fracture was present. There was a loss of hair cells in the basal turn of the cochlea (basal 6 mm) and atrophy of the stria vascularis in the upper turns of the cochlea. The spiral ganglion had a slight loss of neurons in the basal turn. The cupula of the posterior canal crista was reasonably formed but shrunken and contained a few small basophilic deposits (fig. 3). The facial nerve MG contained a heavy infiltration of satellite cells, which surrounded intact and degenerated ganglion cells (fig. 4). The ganglion of the superior vestibular division contained intact ganglion cells surrounded by a normal

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Fig. 4. The MG in a BPV case contained several degenerated (arrowheads) and intact ganglion cells surrounded by many SC (open arrows). F ⫽ Facial nerve.

density of SC (fig. 5a). No degenerated axons were detected in the superior vestibular nerve trunk. The inferior VG was comprised of ganglion cells surrounded by an increased number of SC and inflammatory cells (fig. 5b). Several fascicles of degenerated axons in the inferior nerve trunk could be traced through the ganglion toward the singular nerve (fig. 6).

Ménière’s Disease A 76-year-old female had had a fluctuant but slowly progressive hearing loss for many years. An audiogram at the age of 72 years revealed a bilateral severe sensorineural hearing loss with flat audiometric patterns at 70 dB on the right and 90 dB on the left. Speech discrimination scores were 28% in the right ear and 0 in the left. At the age of 73 years, she began to experience sudden episodes of vertigo with falling occasionally. At the age of 76 years, she died of cerebral hemorrhage and pontine infarction. Histopathology (Right TB) There was severe endolymphatic hydrops of the cochlear and vestibular labyrinth. Reissner’s membrane was displaced to make contact with the walls of the scala vestibuli. There was atrophy of the stria vascularis in a patchy pattern

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Fig. 5. a The superior vestibular division ganglion cells were surrounded by a normal number of SC. b The inferior vestibular division ganglion cells were surrounded by a heavy infiltrate of SC and inflammatory cells. A fascicle of degenerated nerve fibers (*) is seen passing through the ganglion.

throughout the middle and apical turns. There was a scattered loss of hair cells in the organ of Corti. The spiral ganglion was markedly reduced to 25% of normal. The saccule was distended, and the saccular wall was attached to the stapes footplate by a layer of fibrous tissue (fig. 7). There were outpouchings in the walls of the utricle and all three ampullae. The geniculate ganglion did not have any degenerated ganglion cells and a normal density of SC. The MG contained intact and degenerated neurons surrounded by an abundance of SC (fig. 8). Superior and inferior VG cells were surrounded by many SC. Fascicles of degenerated axons were seen in the vestibular nerve trunk (fig. 9). Clinical Series

Forty-five consecutive patients evaluated for recurrent vertigo during a 14-week period demonstrated coexistence of multiple cranial neuropathies with

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Fig. 6. There were fascicles of degenerated axons (arrow) in the vestibular nerve trunk.

Fig. 7. A distended saccular wall was attached to the stapedial footplate (FP) by fibrous tissue (arrow) in MD TB. S ⫽ Saccular macula.

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Fig. 8. There were degenerated (arrows) and intact ganglion cells in the MG of the facial nerve (F) in MD.

same-sidedness (table 1). There were 29 female and 16 male patients ranging from 31 to 93 years in age (mean ⫽ 62 years). Thirteen patients had a diagnosis of MD and BPV in the same ear; 4 of these patients also gave a history of herpes labialis or herpes zoster on the side of the affected ear. Fourteen patients manifested VN and BPV in the same ear; 3 gave a history of herpes labialis on the side of the affected ear. All 9 patients with BPV alone gave a history of herpes labialis or herpes facialis on the side provoking vertigo. Five patients with a history of idiopathic facial paralysis developed VN (n ⫽ 2), BPV (n ⫽ 2) or MD (n ⫽ 1) in the same ear. One of these experienced sequential idiopathic facial paralysis and VN bilaterally. The 4 remaining patients in the series presented a single vestibulopathy (MD ⫽ 2, BPV ⫽ 2) without an associated cranial neuropathy. The onset of vestibular symptoms in 2 of these patients followed surgery on the eye (n ⫽ 1) and sinus infection (n ⫽ 1). MRI was performed on 2 patients in this clinical series. Patient A.P. is a 52-year-old female with a 2-year history of right aural fullness, fluctuating hearing loss and recurrent vertigo (from 15 min to 1 h in duration). The right ear had a low-frequency sensorineural hearing loss (40 dB) and 88% word discrimination

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Fig. 9. Several fascicles of degenerated nerve fibers (open arrows) were present in the vestibular nerve trunk. Table 1. Polyneuropathy in patients with vertigo (n ⫽ 45) Vestibular nerve

Facial nerve

Trigeminal nerve

n

MD ⫹ BPV VN ⫹ BPV BPV VN (2), BPV (2), MD (1) MD BPV

0 0 0 5 0 0

4 3 9 0 0 0

13 14 9 5 2 2

IFP ⫽ Idiopathic facial paralysis; n ⫽ number.

with normal hearing in the left ear. ENG demonstrated a 70% right canal paresis. MRI with contrast revealed focal enhancement in the distal internal auditory canal (fig. 10). A middle cranial fossa approach was used to excise the vestibular nerve and VG. Pathology reported neural tissue with ganglion cells surrounded by many small dark cells and focal axonal fibrosis (fig. 11). Immunoperoxidase staining with antibodies to HSV was positive in ganglion cells.

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Fig. 10. Enhanced MRI of a 52-year-old female with a history of right MD and 70% right canal paresis showed focal enhancement (arrow) in the internal auditory canal.

Fig. 11. The excised right vestibular ganglion revealed an increased number of SC and inflammatory cells surrounding ganglion cells (open arrows) and focal axonal degeneration (*).

Patient K.M. is a 45-year-old male with an 8-month history of recurrent vertigo (several hours duration) without hearing loss and positional vertigo (20–25 s) with the right ear down. ENG demonstrated a 32% right canal paresis and a positive right Hallpike positional test. Hearing was normal. An enhanced

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Fig. 12. a Enhanced MRI of a 45-year-old male with a history of VN and BPV in the right ear. Focal enhancement is seen in the internal auditory canal (arrow). b The focal enhancement (arrow) is decreased 2 months later. Note the ‘tail’ of the enhanced area.

MRI revealed focal enhancement in the right internal auditory canal (fig. 12a). Repeat MRI 2 months later showed decreased enhancement in the right internal auditory canal (fig. 12b).

Discussion

Morphologic [21, 22], immunologic [3–6] and molecular [1, 2] evidence supports a role for NT virus (herpes subfamily) vestibular ganglionitis as the cause of recurrent vertigo in VN, MD and BPV. Degeneration of ganglion cells in the MG of the facial nerve with absence of degenerated neurons in the geniculate ganglion suggests a role of the MG in transmission of NT virus to the adjacent VG during the early introduction of virus [22]. In the 33 TB of VN, MD and BPV patients, only 2 MG did not contain degenerated ganglion cells, while all 33 vestibular nerves exhibited axonal degeneration. If the virus

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assumes a latent state following initial infection of the neuron, it may be reactivated and replicated at some later time by unusual stress [23]. When the NT virus is reactivated, it travels by axoplasmic transport along the neuron’s appendages. If the transport is in an anterograde direction, the virus is carried toward the central nervous system, while retrograde transport will carry the virus in the peripheral nerve branches to the sense organ [24–27]. The direction of intra-axonal flow is dependent on the virus strain, especially with HSV. The H 129 strain of HSV-1 is carried preferentially in an anterograde direction, while the McIntyre B strain follows a retrograde direction of flow to the periphery. This directionality of flow determines to a large degree the clinical expression of NT viral ganglionitis. The mechanism by which vestibular neuronal activity is altered to produce vertigo is not known. However, virus activation and release into the extracellular space disrupts the ganglion cell wall with leakage of ionic levels on either side of the cell wall [28]. Since neuronal excitability is dependent on the ionic gradient across the cell membrane, loss of this gradient by flow of K⫹ to the outer coat of the membrane where it displaces bound Ca2⫹ may be part of the explanation. Recurrent disruption of the ganglion cell membrane may eventually cause neuronal death. The whorl-like replacement of the neuronal cytoplasm by SC may be an attempt to repair the plasma membrane disrupted by virus release. The SC has long been felt to be intimately related to its ganglion cell [29, 30]. SC may support the neuron metabolically during prolonged activity. This suggestion is supported by a decreased nucleic acid content in SC while neuronal nucleic acid is increased in the superior cervical ganglion following prolonged (3-hour) stimulation [29]. Furthermore, SC proliferate in response to increased metabolic or synaptic activity. The role of SC in the NT viral infection of a ganglion may represent a response to increased neural activity as well as the need to limit the spread of virion release from ganglion cells. Spread of virus to adjacent ganglion cells may be carried over SC which proliferate as they envelope virus protein. Therefore, it is common for groups of ganglion cells to be involved in the inflammatory process. Degeneration of clusters of ganglion cells in the superior vestibular division was reflected in focal axonal degeneration of the nerve trunk in TB of VN and MD. The inferior VG was also involved in the inflammatory process in some TB with these two vestibulopathies. However, degeneration was restricted to the inferior vestibular nerve in TB with BPV. The coexistence of more than one vestibular syndrome in the same ear has frequently been observed in clinical practice [17]. Proctor [31] reported that almost half of 122 patients with unilateral MD demonstrated BPV in the same ear. The co-occurrence of BPV and VN in the same ear was noted by Lindsay

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Fig. 13. a A normal tympanic nerve with 2 ganglion cells (arrows) in the TB from a 61-year-old male with exostoses of the ear canal. b A partially degenerated (*) tympanic nerve in an 80-year-old female with BPV.

and Hemenway [32] and Schuknecht and Kitamura [17]. The coexistence of multiple vestibulopathies in the same labyrinth is not explained by current concepts of MD and BPV. However, the morphologic evidence of inflammatory/degenerative changes in different regions of the VG for MD or VN and BPV offers a basis for multifocal vestibulopathy. Idiopathic otalgia is a frequent associated symptom in patients with recurrent vertigo. Neuropathy of the glossopharyngeal (ninth cranial) nerve can be assumed to be caused by NT viral organisms. However, this assumption has not been supported by clinical or TB evidence. The clinical presentation is that of recurrent pain deep in the ear canal. The tympanic branch of the ninth nerve is the likely neural structure responsible for such recurrent otalgia. Occasionally the act of swallowing initiates the pain syndrome. The afferent neural pathways from the oropharynx, tonsils, base of tongue and epiglottis offer a portal of entry for NT viruses of the herpes family similar to that into the seventh nerve system (chapter 2, fig. 20). The integrity of the tympanic nerve (Jacobson’s) was assessed in its location on the lateral surface of the promontory in the vestibulopathic and the control TB (tables 1– 4, Appendix). The nerve in this location was judged to be normal or degenerated (fig. 13). The nerve was partially degenerated in 11 out of 33 vestibulopathic

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Table 2. Classification of recurrent (viral) vestibulopathies Anterograde virus strain (hearing preserved) Superior vestibular ganglionitis (vestibular neuronitis, vestibular MD) Inferior vestibular ganglionitis (BPV) Superior and inferior vestibular ganglionitis (vestibular neuronitis and BPV) Retrograde virus strain (hearing affected) Superior vestibular ganglionitis (MD, neurolabyrinthitis) Subtype: utricular ganglionitis (Tumarkin’s otolithic crisis) Superior and inferior vestibular ganglionitis (MD and BPV)

TB (33%) with a similar ratio for VN, MD and BPV. In 4 out of 20 control TB (20%), the tympanic nerve was partially degenerated. The segregation of degenerated fibers in the TN supports the notion that a functional component (sensory) is affected.

Conclusion

These observations support the view that the syndromes of VN, BPV and MD are clinical expressions of viral vestibular ganglionitis, probably from the ␣-herpes virinae family. Several factors may determine the ‘face’ presented in individual patients. These are: (1) the amount of virus present (viral load); (2) the virus type and strain; (3) the location and number of affected VG cells, and (4) host resistance. It is possible that other clinical presentations of recurrent vertigo are expressions of vestibular ganglionitis. Innovative clinical terms have been used to describe these presentations (i.e. atypical vestibular neuritis, recurrent vestibulopathy, idiopathic vestibulopathy and psychogenic vestibulopathy). The correlation of clinical and functional deficits with histopathologic changes may be used to classify vestibular disorders caused by vestibular ganglionitis. The portion of VG affected and the type of NT virus responsible are two major descriptors in such a classification (table 2). Since the spread of NT virus typically occurs in clusters of ganglion cells [33], separate divisions or branches of the vestibular nerve may be affected leading to end-organ-specific expressions of vertigo. When the superior or inferior divisions of the VG are affected, the clinical picture is vestibular neuronitis or BPV, respectively. The occurrence of both VN and BPV in the same ear reflects infection of both VG divisions. It is possible that a small cluster of inflamed ganglion cells representing neural input from a single sense organ (i.e. utricle) may produce a specific type of balance disturbance (Tumarkin’s

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otolithic crisis). The absence of auditory defects in two ‘faces’ would reflect an anterograde virus strain in the VG. On the other hand, the presence of a sensorineural hearing loss together with episodic vertigo (MD) is caused by a retrograde strain of virus, which is transported along vestibular nerve branches and released into the perilymphatic compartment causing a toxic labyrinthitis.

References 1

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Pitovski DZ, Robinson AM, Garcia-Ibanez E, Wiet R: Presence of HSV-1 gene products characteristic of active infection in the vestibular ganglia of patients diagnosed with acute Ménière’s disease (abstract 457). 22nd Annu Midwinter Res Meet Assoc Res Otolaryngol, St Petersburg Beach, February 1999. Arbusow V, Schulz P, Strupp M, Dieterich M, et al: Distribution of herpes simplex virus in type I in human geniculate and vestibular ganglion: Implications for vestibular neuritis. Ann Neurol 1999;46:416– 419. Williams LL, Lowery HW, Shannon BT: Evidence of persistent viral infection in Ménière’s disease. Arch Otolaryngol Head Neck Surg 1987;113:397–400. Bergstrom T, Edstrom S, Tjellstrom A, et al: Ménière’s disease and antibody reactivity to herpes simplex virus type I polypeptides. Am J Otol 1992;13:295–300. Calenoff E, Zhao J, Derlacki EL, et al: Patients with Ménière’s disease possess IgE reactivating with herpes family viruses. Arch Otolaryngol Head Neck Surg 1995;121:861–864. Arnold W, Niedermeyer HP: Herpes simplex virus antibodies in the perilymph of patients with Ménière’s disease. Arch Otolaryngol Head Neck Surg 1997;123:53–56. Schuknecht HF: Pathology of the Ear. Cambridge, Harvard University Press, 1974. Adour KK, Byl FM, Hilsinger R: Ménière’s disease as a form of cranial polyneuritis. Laryngoscope 1980;90:392–398. Schuknecht HF, Igarashi M: Pathophysiology of Ménière’s disease; in Pfaltz CR (ed): Controversial Aspects of Ménière’s disease. New York, Thieme, 1986, pp 46–54. Hallpike CS, Cairns H: Observations on the pathology of Ménière’s syndrome. J Laryngol Otol 1938;53:625 – 655. Schuknecht HF: Delayed endolymphatic hydrops. Ann Otol Rhinol Laryngol 1978;87: 743–748. Harrison M: Epidemic vertigo – Vestibular neuronitis, a clinical study. Brain 1962;85: 613–620. Pedersen E: Epidemic vertigo: Clinical picture, epidemiology, and relation to encephalitis. Brain 1959;82:566–580. Coats A: Vestibular neuronitis. Acta Otolaryngol (Stockh) 1969;suppl 251:1–32. Dix M, Hallpike C: The pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Ann Otol Rhinol Laryngol 1952;61:987–1016. Shimizu T, Sekitani T, Hirata T, Hara H: Serum viral antibody titer in vestibular neuronitis. Acta Otolaryngol (Stockh) 1993;suppl 503:74–78. Schuknecht HF, Kitamura K: Vestibular neuritis. Ann Otol Rhinol Laryngol Suppl 1981;90:1–19. Nadol JB: Vestibular neuritis. Otolaryngol Head Neck Surg 1995;12:162–172. Fenton JE, Shirazi A, Turner J, Fagan P: Atypical vestibular neuritis: A case report. Otolaryngol Head Neck Surg 1995;112:738–741. Smith IW, Peutherer JF, MacCallum OF: The incidence of herpes virus hominis antibody in the population. J Hyg 1967;65:395– 408. Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol, in press. Gacek RR: The pathology of facial and vestibular neuronitis. Am J Otolaryngol 1999;20: 202–210.

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25 26 27 28 29 30 31 32

Meier JL, Straus SE: Comparative biology of latent varicella zoster virus and herpes simplex virus infections. J Infect Dis Suppl 1992;166:S13–S23. Zemanick MC, Strick PL, Dix RD: Direction of trans-neural transport of herpes simplex virus I in the primate motor system is strain-dependent. Proc Natl Acad Sci USA 1991;88: 8048–8051. LaVail JH, Topp KS, Giblin PA, Garner JA: Factors that contribute to the trans-neural spread of herpes simplex virus. J Neurosci Res 1997;49:485–496. Card JP: Exploring brain circuitry with neurotropic viruses: New horizons in neuroanatomy. Anat Rec (New Anat) 1998;253:176–185. Kuypers HG, Ugolini G: Viruses as trans-neuronal tracers. Trends Neurosci 1990;13:71–75. Lehninger AL: The neuronal membrane. NAS Symp 1968;60:1069–1080. Pevzner LZ: Topochemical aspects of nucleic acid and protein metabolism within the neuron – Neurologia unit of the superior cervical ganglion. J Neurochem 1965;12:993–1002. Schwyn RC: An autoradiographic study of satellite cells in autonomic ganglion. Am J Anat 1967;121:727–739. Proctor LR: Results of serial vestibular testing in unilateral Ménière’s disease. Am J Otol 2000;21:552–558. Lindsay JR, Hemenway WG: Postural vertigo due to unilateral sudden partial loss of vestibular function. Ann Otol Rhinol Laryngol 1956;65:692–708.

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Chapter 8

Efferent System Degeneration in Vestibular Ganglionitis Richard R. Gacek

It has been customary for otologists to regard the function and dysfunction of the inner ear in terms of the afferent pathway from the auditory and vestibular sense organs. Hearing and balance are major forms of the body’s interaction with the environment. In the preceding chapters, the pathology in the vestibular system’s conduit to the brainstem has been described which accounts for recurrent disruptions in the physiology of balance. The neuron-specific nature of these degenerative changes suggests recrudescent neurotropic virus injury in sensory ganglia. Degeneration of the auditory sense organ and/or ganglion may be on the same basis as the vestibular nerve pathology or coexist because of age, noise exposure, ototoxic drug exposure and other unknown causes. The concept that recurrent disruption of vestibular nerve physiology is caused by a neurotropic virus is supported by an enlarging body of immunologic, morphologic and molecular evidence. The efferent neural system has been largely ignored in the evaluation of auditory and vestibular symptoms in patients with labyrinthine pathology. Dysfunction of efferent axons is likely in vestibular ganglionitis because of their close anatomical relationship in Scarpa’s ganglion. Efferent axons to the labyrinth emerge from the brainstem in the center of the vestibular nerve (chapter 2, fig. 12, 13) where they diverge at the saccular portion of Scarpa’s ganglion. The cochlear efferents (olivocochlear bundle, OCB) leave in the vestibulocochlear anastomosis (VCA) to enter Rosenthal’s canal as the intraganglionic spiral bundle whence efferent axons (myelinated and unmyelinated) are given off toward the habenula perforata and the organ of Corti [1–5]. Vestibular efferents also diverge from the parent bundle within Scarpa’s ganglion (chapter 2, fig. 11, 13). In the superior vestibular division, they first appear in fascicles and individual fibers which gradually disperse and branch as they enter the vestibular nerve branches [4, 6]. Efferent nerve fibers to the saccular and posterior ampullary nerves maintain a dispersed pattern throughout their course toward the sense organs.

This chapter presents morphologic evidence observed in the 53 temporal bones (TB) summarized in tables 1–4 in the Appendix which suggest a degenerative effect on the efferent system by vestibular ganglionitis.

Materials and Methods TB Specimens The TB included in this report are those described in the chapters on vestibular neuronitis (VN), Ménière’s disease (MD) and benign paroxysmal positional vertigo (BPV). They consist of 33 TB (VN ⫽ 20, MD ⫽ 10, BPV ⫽ 3) that were formalin fixed, celloidin embedded, sectioned at 20 ␮m in a horizontal plane and stained with hematoxylin and eosin (tables 1–3, Appendix). Twenty TB without evidence of vestibular ganglion degeneration or a history of vertigo represent a control series of TB examined in the light microscope (table 4, Appendix).

Light Microscopy Examination in a light microscope of all sections from each TB were made at both low (⫻40) and high (⫻100, ⫻200) magnifications. In addition to morphologic changes in the labyrinth and its nerve supply described in chapters 4–7, the following structures were examined. (1) The integrity of the OCB was evaluated in the VCA at its takeoff from the inferior vestibular (saccular) ganglion. The VCA was determined to be normal (fig. 1) or degenerated, based on the presence or absence of myelinated nerve fibers. Total degeneration of the bundle was based on the absence of myelinated nerve fibers and a presence of Schwann cell nuclei (fig. 2). More often, the VCA was partially degenerated (fig. 3) as compared to a normal VCA. Efferent vestibular axons do not travel in a bundle separated from afferent axons and cannot be identified without special techniques (acetylcholinesterase localization). (2) The sense organs and associated epithelial structures of the labyrinth were examined for degenerative changes. Deposits (concretions) in the labyrinth have been used to designate degeneration in the past. The following criteria were used to establish the presence of a concretion: (a) concretions were usually circular with slight irregularities (fig. 4); sometimes they appeared flattened if there was end organ compression from the preparation process (fig. 5); they appeared dark or light blue with the hematoxylin component of the stain; the solid nature of the deposit prevented visualization of underlying cellular structures; stain material deposited as artifact allows visualization of underlying structures (fig. 6); (b) concretions were located between supporting and sensory cells of the neuroepithelium; (c) the deposits were usually found within the boundaries of the neurosensory epithelium but sometimes in a nerve branch supplying the sense organ; concretions located in the meninges of the internal auditory canal were not included in this assessment.

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Fig. 1. A normal VCA is shown after its takeoff from the saccular nerve (S) which is partially degenerated (*). Case 3, table 1 (Appendix).

Fig. 2. Completely degenerated VCA at its divergence from the saccular nerve (S). Case 12, table 1 (Appendix).

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Fig. 3. Partially degenerated VCA after its emergence from the saccular nerve (S). Open arrow ⫽ concretion in internal auditory canal. Case 7, table 2 (Appendix).

Fig. 4. Three concretions (open arrows) are shown in the neuroepithelium of the posterior canal crista.

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Fig. 5. This deposit in the organ of Corti (open arrow) is somewhat flattened due to compression artifact.

Fig. 6. Saccular macula with a concretion (open arrow) in a nerve approaching the neuroepithelium and a blue stain droplet (a) as artifact.

Concretions The concretions listed in tables 1–4 (Appendix) were reconstructed on a cochleogram and a vestibulogram to illustrate the spatial arrangement of end organ concretions in the 53 TB (33 experimental, 20 control).

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Fig. 7. The organ of Corti in case 2 (table 1, Appendix) shows a large concretion (open arrow) under the IHC (i). OHC (o) are present.

Results

Concretions were found in two groups of structures. Most were located in the auditory and vestibular neurosensory epithelium and their nerve bundles. These morphologic changes have not been previously described. The second group of deposits was found in areas associated with cochlear blood flow. These included the stria vascularis and the spiral prominence. Deposits or concretions in these structures have been described by others [7–11]. The majority of concretions (deposits) appeared as spherical accumulations of dense material which takes the nuclear (hematoxylin) stain in the technique used for routine human TB histopathology. Most of the deposits were found within the neuroepithelium of the labyrinthine sense organs. In the organ of Corti, they were located mainly under the inner (IHC; fig. 7) and outer (OHC) hair cells (fig. 8). However, a small number was found among the nerve fibers in the osseous spiral lamina (fig. 9) and near the spiral ganglion in Rosenthal’s canal (fig. 10). In the vestibular labyrinth, these concretions were usually located on the slopes of the cristae (fig. 11) and throughout the maculae (fig. 12). A small number of deposits was found in the ampullary, saccular and utricular nerve bundles near the end organs (fig. 13). The concretions usually stained deep blue, but many in the organ of Corti were light blue in color and surrounded by a limiting membrane (fig. 14). Some of the larger concretions under OHC had a laminated appearance (fig. 8). The concretions in the vestibular organs were invariably dark blue in color (fig. 15).

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Fig. 8. There are 2 concretions (open arrows) under OHC in the organ of Corti in case 1 (table 1, Appendix).

Fig. 9. a Two concretions (open arrow) are shown near the habenula perforata in the osseous spiral lamina of case 4 (table 1, Appendix). b A higher magnification of the deposits shown in a demonstrates the laminated structure.

Deposits in the stria vascularis (fig. 16) and spiral prominence (fig. 17) were of variable size and a dark blue color. They did not follow any specific pattern of distribution. The location of concretions in the TB of VN (n ⫽ 20), MD (n ⫽ 10) and BPV (n ⫽ 3) is summarized in tables 1–3 (Appendix). Concretions were found in the labyrinthine sense organs or their nerve branches in all except 1 TB (table 3). Eleven of the 20 VN TB contained deposits in both vestibular and auditory end organs, while 6 revealed them in vestibular organs only and 3 only in the organ

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Fig. 10. A concretion (open arrow) can be seen in Rosenthal’s canal where the intraganglionic course of efferent fibers is adjacent to spiral ganglion cells (SG). ST ⫽ Scala tympani. Case 7, table 2 (Appendix).

of Corti. Four of the MD TB contained concretions in both vestibular and auditory sense organs and 6 only in the vestibular organs. Of the 2 BPV TB with concretions, 1 contained them in both vestibular and auditory sense organs while the other revealed only vestibular organ deposits. The 33 TB in tables 1–3 contained 133 concretions (44 in the cochlea; 89 in the vestibular organs) in the labyrinthine sense organs. The distribution of these deposits was plotted on a cochleogram and vestibulogram (fig. 18). Cochlear end organ deposits were concentrated in the upper basal turn with a diminishing frequency toward the apical and lower basal turns. In the vestibular sense organs, the deposits were located mostly along the slopes of the cristae and in all areas of the maculae. Deposits were found in the stria vascularis of 3 TB and in the spiral prominence of 1 TB from the VN group. Two MD TB contained concretions in the stria vascularis and 2 in the spiral prominence. No deposits were found in the stria vascularis or spiral prominence of the 3 BPV TB. The VCA was examined at its takeoff from the saccular ganglion. It was found to be totally (n ⫽ 1) or partially (n ⫽ 15) degenerated in 16 of the VN TB and normal in 1 TB. The anastomosis was not available in 3 VN TB because of avulsion of the eighth nerve in the internal auditory canal. In 9 TB with MD, the VCA was totally (n ⫽ 1) and partially (n ⫽ 8) degenerated but intact in 1. The VCA was partially degenerated in all 3 TB with BPV.

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Fig. 11. Two concretions (open arrows) are shown in the neuroepithelium of the posterior canal crista. Case 3, table 2 (Appendix).

Fig. 12. Typical location for a concretion (open arrow) in the saccular macula. Case 3, table 2 (Appendix).

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Fig. 13. Large concretion in the utricular nerve (open arrow) with a small artifactual (a) deposit. Case 10, table 2 (Appendix).

Fig. 14. A small light blue deposit (open arrow) near the base of OHC in the organ of Corti. Case 1, table 1 (Appendix).

The 20 control TB were selected on the basis of absence of vestibular ganglion degeneration and a history of vertigo. These TB represent patients with age, sex and occupational demographics similar to those in the VN, MD and BPV groups. Several of these control TB contained concretions in sense organs: 2 in both vestibular and auditory end organs, 4 in only vestibular sense organs,

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Fig. 15. A concretion (open arrow) in the neuroepithelium (*) of the utricular macula. Case 7, table 2 (Appendix).

Fig. 16. Two large deposits (open arrow) in the stria vascularis. Case 1, table 2 (Appendix).

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Fig. 17. Two small deposits in the spiral prominence region are indicated by an open arrow. Case 1, table 2 (Appendix).

1 in the organ of Corti and 1 in the osseous spiral lamina. The control TB contained 14 deposits in the end organs (6 in cochlear; 8 in vestibular organs). These concretions were plotted on a cochleogram and vestibulogram (fig. 19). The cochlear end organ deposits were located in the upper basal and middle turns, while the vestibular deposits were distributed over the sense organ epithelium. Five control TB revealed six concretions in the stria vascularis and 2 contained deposits in the spiral prominence. These strial deposits were randomly located along the cochlear duct. Two spiral prominence deposits in the vestibulopathic and 2 in the control TB were located in the upper basal turn. The VCA was normal in 15 control TB, degenerated in 3 and not available (nerve avulsion) in 2 TB.

Discussion

The validity of deposits in the TB from VN, MD and BPV is supported by several bodies of evidence. (1) The concretions were based on criteria which differentiate them from artifacts of staining. The spherical and solid nature (sometimes laminated) with

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Concretions – VN, MD, BPV TB Cochleogram VN MD BPV Osseous spiral lamina Spiral prominence

G

Pillar head

G

Stria vascularis

a Vestibulogram

b

Utricle

Saccule

Posterior canal

Lateral canal

Superior canal

Fig. 18. The spatial localization of concretions in the 33 vestibulopathic TB is represented on a cochleogram (a) and a vestibulogram (b). G ⫽ spiral ganglion.

a limiting border are primary criteria for the blue-colored concretions. Blue droplets of the stain sometimes found in TB sections are smaller and semitranslucent when viewed at high power under the light microscope. The deposits were typically located between supporting and hair cells in the sense organ or between nerve bundles leading to the sensory epithelium.

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Concretions – Control TB Cochleogram

a Vestibulogram

Saccule

b

Posterior canal

Lateral canal

Superior canal

Fig. 19. The spatial localization of concretions in 20 control TB is shown in this cochleogram (a) and vestibulogram (b).

(2) The majority of concretions were located along neural pathways or within the neurosensory epithelium of labyrinthine sense organs. Deposits in the stria vascularis and spiral prominence were found with equal frequency and randomness in the control and the vestibulopathic TB. These have been thought to be related to degenerative effects from renal and cardiovascular disease [8–11].

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(3) Dark bodies below the IHC and OHC of the organ of Corti in a patient with long-standing sensorineural hearing loss were described in transmission electron microscopy of TB by Nadol [12]. These structures in the region under OHC were filled with either dark or light vesicles resulting in dark- and lightappearing bodies within a limiting membrane. Bud-like profiles under IHC filled with mitochondria were also described. Spoendlin and Suter [13] regarded these bud-like bodies as regenerating efferent axons several months after the eighth nerve had been transected in cats. Nadol’s patient had experienced sudden profound deafness early in life and his TB revealed endolymphatic hydrops in all turns of the cochlea. Although the subject gave no history of vertigo, it is possible that the TB findings represented delayed endolymphatic hydrops, a variant of MD. (4) A comparison of the 133 concretions in 33 vestibulopathic TB with 14 deposits in 20 control TB indicates a higher occurrence in the TB with focal axonal degeneration of the vestibular ganglion. The small number of concretions in the auditory (n ⫽ 6) and vestibular (n ⫽ 8) organs found in 20 TB without vestibular ganglion degeneration may suggest a subclinical form of vestibular ganglionitis in patients without vestibular symptoms. Although the distribution of concretions in the labyrinthine sense organs follows neural pathways, it is probable that they are associated with the efferent rather than the afferent neuron. A greater number of deposits was found under the OHC than under IHC, and the concretions under IHC were much larger than those under OHC. These features parallel the efferent innervation pattern in the organ of Corti (see chapter 2). Furthermore, the concentration of organ of Corti concretions is greatest in the upper basal turn with decreasing frequency toward the apex and similarly the lower basal turn. The distribution of efferent terminals is similar to that displayed by histochemical techniques [4]. The arrangement of concretions in vestibular organs also suggests deposition in fibers of the efferent system [4, 14, 15]. Most deposits were found on the slopes of the cristae and in all regions of the maculae. A smaller number of deposits was seen at the crest of the cristae. Arguments exist against an afferent neural location of the concretions. Since 95% of the afferent innervation to the auditory sense organ terminates on IHC [5, 16], the majority of deposits would be expected under IHC rather than OHC if they represent afferent fibers. Moreover, type 1 cochlear neurons do not regenerate after injury. Type 1 spiral ganglion cells do not contact OHC where most of the concretions were located [16]. OHC are supplied by type 2 spiral ganglion cells which survive destruction of their dendrite or axon [3, 5]. Moreover, the innervation of OHC by type 2 ganglion cells is greatest at the apical turn with diminishing frequency toward the base of the cochlea.

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The location of the concretions near terminal portions of the efferent system may reflect an attempt at regeneration of axons interrupted by pathology in the vestibular ganglion where they are anatomically intimate with ganglion cells and their satellite cells. Evidence of a degenerated OCB in the VCA was present in 28 out of 33 vestibulopathic TB and in only 3 of 20 control TB. The occurrence of concretions in the organ of Corti was proportionate to the number of TB with a degenerated VCA. Since efferent neurons have a vigorous regenerative capacity following eighth-nerve transection [13], deposits within sense organs and nerve branches may represent structures similar to growth cones in regenerating peripheral nerve. The presence of concretions in nerve branches to the end organs (osseous spiral lamina, Rosenthal’s canal, vestibular nerve branches) suggest regenerating efferent axons which have turned back on themselves before reaching the end organ epithelium. Two deposits were found near the spiral ganglion (fig. 10) in the location of the intraganglionic spiral course of the OCB. This type of regenerating nerve fiber was described by Spoendlin and Suter [13] proximal to the habenula perforata several months after eighth-nerve transection in cats. The presence of deposits in the vestibular nerve branches also suggests turned back regenerating axons. The greater incidence of deposits in preterminal rather than proximal nerve branch segments supports the phenomenon of regenerating efferent axons doubling back after meeting resistance near the basement membrane of the neurosensory epithelium. The number of concretions detected by light microscopy is probably an underestimate of their actual number in human TB. Examination of these TB by transmission electron microscopy could reveal a larger number of sub-light-microscopic profiles characteristic of neural regeneration. Since new information on auditory and vestibular physiology is available, the clinical effects of efferent system paralysis should be considered. It has long been known that the OCB exerts an inhibitory effect on sound-provoked eighthnerve action potentials [17, 18]. Since the demonstration that the sensitivity (tuning) of auditory units is provided by a normal OHC system, a cochlear amplifier function by OHC has been assumed [19, 20]. The OHC exert a mechanical effect on cochlear partition mechanics [21, 22] and thus give rise to energy released as otoacoustic emissions (OAE) in the ear canal [23]. Inhibitory action on OHC contractibility by an intact OCB normally provides a regulatory control over this amplifier system [19, 20]. When the OCB has been transected (i.e. vestibular nerve transection), OAE are increased and resist reduction by contralateral sound stimulation [24, 25]. Although the frequencies of tinnitus and spontaneous OAE do not match in most subjects when this has been studied, there have been reports of a precise match of OAE with the tinnitus [26]. Furthermore, increased spontaneous OAE have been reported in patients with

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MD [27], and relief of tinnitus has been achieved by intratympanic application of anti-inflammatory [28] or cholinergic drugs [29]. By the reduction of inflammation and reinstitution of efferent neural transmission, a beneficial effect on tinnitus may be possible through the efferent system. Vestibular efferent activity has been mostly inhibitory [30–34] when studied experimentally although some reports of an excitatory effect have appeared [35]. The hypothesis of function with the most solid experimental and evolutionary support is that of an efferent feed-forward mechanism. Most of this evidence is provided from studies of lateral line organs in fish [36– 40]. In such a theory, the vestibular organs are subject to an efferent influence that adjusts for the stimuli affecting the sense organs during movement of the animal. It has been demonstrated in the lateral line organ that efferents are activated before movement of the animal [36, 38]. By reducing the sensitivity of input from the sense organ, this activity prevents self-stimulation during vigorous swimming movements. By analogy to these experiments in fish, a common complaint in patients with VN, MD or BPV is that of motion intolerance with sudden head movement. Based upon morphologic changes in the afferent and efferent labyrinthine pathways in TB from patients with VN, MD and BPV, two categories of dysfunction (symptoms) seem possible. The primary pathology is a reactivated latent neurotropic viral vestibular ganglionitis which is responsible for episodic vertigo. Depending on the strain of virus (anterograde vs. retrograde), hearing loss may be absent (VN) or associated with vertigo (MD). A secondary pathology is the inflammatory paralysis or degeneration of efferent pathways to the labyrinth. This effect occurs at the point where efferent axons pass through the vestibular (saccular) ganglion. Loss of efferent function may result in increased OAE (auditory) which could give rise to tinnitus as well as motion intolerance (vestibular). It may be useful in the evaluation of patients with recurrent vestibulopathy to classify symptoms as ‘primary’ and ‘secondary’ depending on the neural system affected by vestibular ganglionitis.

References 1 2 3 4 5 6

Rasmussen GL: The olivary peduncle and other fiber connections of the superior olivary complex. J Comp Neurol 1946;84:141–219. Rasmussen GL: Further observations of the efferent cochlear bundle. J Comp Neurol 1953; 99:61–74. Spoendlin H, Gacek RR: Electron microscopic study of the efferent and afferent innervation of the organ of Corti in the cat. Ann Otol 1963;72:660–686. Gacek RR, Nomura Y, Balogh K: Acetylcholinesterase activity in the efferent fibers of the stato-acoustic nerve. Acta Otolaryngol 1965;59:541–553. Spoendlin H: The innervation of the organ of Corti. J Laryngol 1967;81:717–738. Gacek RR: Efferent component of the vestibular nerve; in Rasmussen GL, Windle WF (eds): Neural Mechanisms of the Auditory and Vestibular Systems. Springfield, Thomas, 1960, pp 276–284.

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Rollin H: Über Kalkablagerungen in der Stria vascularis des Labyrinthes. Arch Klin Exp Ohren Nasen Kehlkopfheilkd 1934;138:1–5. Friedmann I, Fraser GR, Froggatt P: Pathology of the ear in the cardio-auditory syndrome of Jervell and Lange-Nielsen (recessive deafness with electrocardiographic abnormalities). J Laryngol Otol 1966;80:451–470. Naunton R, Lindsay J, Stein L: Concretions in the stria vascularis. Arch Otolaryngol 1973; 97:376–380. Oda M, Preciado MC, Quick CA, Paparella MM: Labyrinthine pathology of chronic renal failure patients treated with hemodialysis and kidney transplantation. Laryngoscope 1974; 84:1489–1506. Zaytoun GM: Basophilic deposits in the stria vascularis – A clinicopathologic update. Ann Otol Rhinol Laryngol 1983;92:242–248. Nadol JB: Electron microscopic observations in a case of long-standing profound sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86:507–517. Spoendlin HH, Suter P: Regeneration in the VIII nerve. Acta Otolaryngol 1976;81:228–238. Gacek RR: Anatomical evidence for an efferent vestibular pathway. 3rd Symp Role Vestibular Organs Space Exploration, NASA, Pensacola, FL., 1967, pp 203–212. Spoendlin H: Ultrastructural studies of the labyrinth in squirrel monkeys. 1st Symp Role Vestibular Organs Space Exploration, NASA, Pensacola, FL., 1965, pp 7–22. Spoendlin H: Innervation patterns in the organ of Corti of the cat. Acta Otolaryngol 1969; 67:239–254. Galambos R: Suppression of auditory nerve activity by stimulation of efferent fibers to the cochlea. J Neurophysiol 1956;19:424– 437. Fex J: Auditory activity in centrifugal and centripetal cochlear fibers in cat. Acta Physiol Scand 1962;189(suppl):1–68. Zenner HP, Reuter G, Plinkert PK, Zimmerman U, Glitter AH: Outer hair cells possess acetylcholine receptors and produce motile responses in the organ of Corti; in Wilson JP, Kemp DT (eds): Cochlear Mechanisms. London, Plenum Press, 1989, pp 93–98. Dallos P, Evans BN, Hallworth R: Nature of the motor element in electrokinetic shape changes of cochlear outer hair cells. Nature 1991;350:155–157. Reuter G, Zenner HP: Active radial and transverse motile responses of outer hair cells in the organ of Corti. Hear Res 1990;43:219–230. Brownell WE: Outer hair cell electromotility and otoacoustic emissions. Ear Hear 1990;11:82–92. Kemp DT: Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am 1978;64:1386–1391. Williams EA, Brookes GB, Prasher DK: Effects of contralateral acoustic stimulation on otoacoustic emissions following vestibular neurectomy. Scand Audiol 1993;22:197–203. Williams EA, Brookes GB, Prasher DK: Effects of olivocochlear bundle section on otoacoustic emissions in humans: Efferent effects in comparison with control subjects. Acta Otolaryngol (Stockh) 1994;114:121–129. Plinkert PK, Gitter AH, Zenner HP: Tinnitus associated spontaneous otoacoustic emissions. Acta Otolaryngol (Stockh) 1990;110:342–347. Haginomori S, Makimoto K, Tanaka H, Araki M, Takenaka H: Spontaneous otoacoustic emissions in human with endolymphatic hydrops. Laryngoscope 2001;111:96–101. Shulman A, Goldstein B: Intratympanic drug therapy with steroids for tinnitus control: A preliminary report. Int Tinnitus J 2000;6:10–20. DeLucchi E: Transtympanic pilocarpine in tinnitus. Int Tinnitus J 2000;6:37–40. Sala O: Vestibular efferent system: Electrophysiological research. Acta Otolaryngol 1965; 59:329–337. Llinas R, Precht W: The inhibitory vestibular efferent system and its relation to the cerebellum in the frog. Exp Brain Res 1969;9:16–29. Dieringer N, Blanks RH, Precht W: Cat efferent vestibular system: Weak suppression of primary afferent activity. Neurosci Lett 1977;5:285–290.

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Dechesne C, Sans A: Control of the vestibular nerve activity by the efferent system in the cat. Acta Otolaryngol 1980;90:82–85. Russell IJ, Roberts BL: Inhibition of spontaneous lateral line activity by efferent nerve stimulation. J Exp Biol 1972;57:77–82. Goldberg JM, Fernandez C: Efferent vestibular system in the squirrel monkey: Anatomical location and influence on afferent activity. J Neurophysiol 1980;43:986–1026. Klinke R, Galley N: Efferent influence on the vestibular organ during active movements of the body. Arch Ges Physiol 1970;318:325–332. Roberts BL, Russell IJ: Efferent activity in the lateral line nerve of dogfish. J Physiol (Lond) 1970; 208:37. Roberts BL, Russell IJ: The activity of lateral line efferent neurons in stationary and swimming dogfish. J Exp Biol 1972;57:435–448. Russell IJ, Roberts BL: Inhibition of spontaneous lateral line activity by efferent nerve stimulation. J Exp Biol 1972;57:77–82. Flock A, Russell IJ: Inhibition by efferent nerve fibers: Action on hair cells and afferent synaptic transmission in the lateral line organ of the burbot Lota lota. J Physiol (Lond) 1976;257:45–62.

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Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 124–126

Chapter 9

Antiviral Therapy of Vestibular Ganglionitis Richard R. Gacek, Mark R. Gacek

The material presented in the preceding chapters suggests an antiviral approach in the treatment of recurrent balance disorders caused by vestibular ganglionitis. Attempts at treating vestibular neuronitis and Ménière’s disease with oral antiviral drugs have not been effective for several reasons. In addition to insensitivity of the virus strain to the current generation of antiviral drugs, some features of neurotropic virus biology represent barriers to virus neutralization by these chemical substances. The intranuclear location of latent virus in ganglion cells offers a shield against antiviral drugs and circulating antibodies. Nucleic acids released by virus are only neutralized by nuclease enzymes in white blood cells. Antiviral drugs can be effective only when the virus is reactivated and released from the ganglion cell into the extracellular space. Even then, virus particles are offered some isolation by satellite cells of the ganglion. Finally, the blood-brain barrier limits the amount of antiviral drug that reaches the neuron. Increasing the intake of antiviral drugs to overcome this barrier is restricted by increasing undesirable side effects of drug ingestion. These features of neurotropic virus biology and of the current generation of antiviral drugs represent some reasons for the failure of orally administered antiviral drugs in the treatment of recurrent vestibulopathies. As discussed in chapter 8, it is useful in these vestibulopathies to recognize symptoms that result from an intracellular (intraganglionic) location of the virus and those that are produced by the extraganglionic effect of the viral organism. We might refer to these as primary and secondary symptoms. Primary symptoms of vestibular ganglionitis are produced by the viral effect on the physiology of the ganglion cell in the eighth nerve. The precise mechanism by which a disturbance in cell physiology results from reactivation of the virus is unknown. It may have something to do with disruption of the ionic gradient across the cell and/or nuclear membrane. The symptoms and signs

caused by virus in this location are vertigo and/or hearing loss if the virus also reaches a spiral ganglion location. Secondary symptoms are produced by release of the reactivated virus or its nucleic acids through the ganglion cell membrane into the extracellular space. In the extracellular space, the toxic proteins and/or nucleic acids are taken up by an increased number of satellite cells. These satellite cells are related to and in continuity with Schwann cells of nearby neuronal fiber pathways. Passing neural systems closely located to the vestibular ganglion are the efferent pathways to the vestibular and auditory sense organs. Paralysis of function and degeneration of efferent axons may result from extraganglionic spread of infection within the vestibular ganglion. Chapter 8 defined a possible symptom arising from dysfunction of the efferent auditory bundle as tinnitus produced by enhanced otoacoustic emissions which result from a lack of olivocochlear bundle inhibitory function on outer hair cells in the organ of Corti. In the vestibular system, loss of an inhibitory efferent effect on vestibular sense organs may lead to disequilibrium caused by activity in the sense organs caused by self-stimulation. The loss of an efferent system effect may be reversible if the paralysis of efferents is only physiologic. The loss would be irreversible if the inflammatory effect on efferent fibers resulted in degeneration of the efferent pathways. Since the toxic effect on efferent pathways is extraganglionic in location, it can be reached by antiviral drugs delivered into the extracellular compartment (plasma). The following are some comments formed after a year of using antiviral drugs to treat vestibular neuronitis and Ménière’s disease. (1) Oral antivirals such as acyclovir and valacyclovir mediate their effect by interference in the thymidine kinase enzyme systems necessary for virus replication. The administration of acyclovir in a dose of 800 mg three times a day for a 3-week period, or valacyclovir 1 g three times a day for 3 weeks, is a starting point for the oral administration of antiviral drugs in recurrent vestibulopathies. If a beneficial effect is observed within the 3-week period, it is repeated for a second 3-week course to a total of 6 weeks as the initial treatment for recurrent vestibular ganglionitis. (2) If the oral administration of the antiviral drug is unsuccessful as evidenced by lack of relief in primary symptoms, if its side effects (gastrointestinal) prevent its use or if a higher dose of the antiviral drug is desired, intratympanic administration of the antiviral compound for diffusion through the round window membrane into the perilymphatic compartment is a reasonable next step. Since ganciclovir (Cytovene) is the only antiviral drug approved for intraorgan use, this has been selected for intratympanic antiviral administration in balance disorders. The antiviral agent is administered over a microwick which is inserted through a subannular tunnel into the round window niche under local anesthesia. The antiviral substance is applied daily on the wick for

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5 days, following which the wick is removed from the ear canal. Some relief of primary but more of secondary symptoms has been obtained using this method. However, ganciclovir has an irritative effect on the soft tissues of the ear canal and the tympanic membrane, leading to discomfort in the ear being treated in some patients. (3) Intralabyrinthine implantation of ganciclovir has been considered but not yet employed. The ganciclovir implant may be placed within the perilymphatic compartment, preferably of the pars superior, but would require a surgical procedure such as simple mastoidectomy and fenestration of the bony labyrinth for placement of the implant. Such an application of an antiviral drug is experimental and should not be employed in a hearing ear. In consideration of the antimicrobial approach, it must be realized that there may be a virus effect through nucleic acid release. Therefore it may be necessary to design nuclease pharmaceuticals for use in the neutralization of toxic viral products. Further research is necessary to design and produce new antiviral or nuclease substances for the treatment of recurrent vestibulopathies.

Gacek/Gacek

126

Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone. Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 127–136

Appendix

Abbreviations for Tables 1– 4 MG ⫽ Meatal ganglion VG ⫽ Vestibular ganglion SG ⫽ Spiral ganglion TN ⫽ Tympanic nerve OCB ⫽ Olivocochlear bundle OSL ⫽ Osseous spiral lamina SV ⫽ Stria vascularis SP ⫽ Spiral prominence EH ⫽ Endolymphatic hydrops Vest. fib. ⫽ Vestibular cistern fibrosis Outpouch. ⫽ Outpouching (pars superior) PC ⫽ Posterior canal crista LC ⫽ Lateral canal crista SC ⫽ Superior canal crista AGL ⫽ Apical ganglion loss MI ⫽ Myocardial infarction SNHL ⫽ Sensorinerual hearing loss CVA ⫽ Cerebrovascular accident BPV ⫽ Benign paroxysmal positional vertigo

* ⫽ History of vertigo AT ⫽ Apical turn BT ⫽ Basal turn VR ⫽ Vestibular response NA ⫽ Not available N ⫽ Normal D ⫽ Degenerated OC ⫽ Organ of Corti IHC ⫽ Inner hair cell OHC ⫽ Outer hair cell U ⫽ Utricular macula S ⫽ Saccular macula SOM ⫽ Secous otitis media GI ⫽ Gastrointestinal COM ⫽ Chronic otitis media GM ⫽ Gram TM ⫽ Tympanic membrane Figures after abbreviations indicate Indicate number of concretions.

Appendix

128

44/M*

52/M*

87/F*

5

6

7

71/M*

87/F

4

9

62/M*

3

68/F*

67/M

2

8

59/M

1

Age/ sex

Atrophy SV and spiral ligament

Presbycusis Strial atrophy

Vestibular neuronitis

Unknown vestibulopathy

Hemolabyrinth

Neomycin toxicity

Meningioma SOM

Stimulation deafness

Neural presbycusis Noise deafness

Otologic diagnosis

Brainstem infarction Carcinoma prostate

Pulmonary embolus

MI Multisystem embolism

MI

Subarachnoid hemorrhage

Pneumonia

Meningioma middle and posterior fossa

Ruptured aortic aneurysm

Metastatic carcinoma thyroid

Cause of death

22%

12%

2%

10%

23%

11%

3%

20%

13%

MG

40% VR ⇓

40%

40% VR-0

N

N

N

D

D

N

N

D

TN

AT D several

N

BT 50%

N

N

⬍10% 30%

BT 30%

N

⬍10%

10%

N

AT 50%

⬍10% 15%

SG

VG

Degeneration

Table 1. Histopathology of temporal bones: vestibular neuronitis

D

NA

D

D

D

D

N

D

D

U-1

U-1

OC-6 OHC PC-4

U-2 S-1

U-1 S-1

0

PC-1

OC-2 IHC S-3

OC-7 OHC LC-2

OCB end organ

Concretions

0

0

0

1

0

3

0

0

0

OSL

1

0

0

2

0

0

0

1

0

SV

0

0

0

0

0

0

0

0

0

SP

Appendix

129

Strial atrophy Neural presbycusis

Otosclerosis

Otosclerosis

69/F

81/F

81/M* (left)

81/M* (right)

80/M

14

15

16

17

18

Neural presbycusis Acoustic trauma

Otosclerosis

Leukemia GI bleed

Cardiac arrest

Cardiac arrest

MI Heart failure

Breast cancer with metastases Pneumonia

Pneumonia

73/F

13

Presbycusis Strial atrophy

Atrophy organ of Corti, Hypertension with SV and SP ganglion cerebral hemorrhage

58/M*

12

Cardiac failure

Atherosclerosis

Stimulation deafness Viral labyrinthitis

Vestibular neuronitis Atrophy SV and organ of Corti

67/M

92/F*

11

10

16%

0

40%

8%

5%

15%

8%

20%

6%

AT 50%

⬍10%

BT 40%

⬍10%

BT 30%

AT 50%

⬍10%

10%

BT 50%

N

BT 50%

30%

30%

40% VR-0

N

⬍15%

D

N

D

N

N

N

N

N

AT N several

10% VR-0

D

D

D

D

D

D

D

NA

NA

OC-1 OHC OC-1 IHC

OC-2 OHC U-1

OC-2 OHC U-1 S-1

OC-1 IHC OC-1 OHC S-2 PC-1

OC-1 IHC U-1 S-1

OC-1 IHC OC-1 OHC

OC-2 IHC U-1 S-1

OC-2 OHC OC-1 IHC U-1

LC-1 U-1 S-4 PC-2

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

Appendix

130

Neural presbycusis Inactivated COM

SNHL Strial atrophy Vertigo

62/M

70/M*

20

Otologic diagnosis

19

Age/ sex

Table 1. (continued)

Brainstem infarction

Unknown

Cause of death

1%

8%

MG

SG BT 30% N

VG ⬍10% ⬍10%

Degeneration

D

D

TN

D

D LC-2 S-2 PC-2

S-1 U-4

OCB end organ

Concretions

0

0

OSL

0

0

SV

0

0

SP

Appendix

131

BT 30% AT 30%

⬍10%

16%

20% 0

5 83/F* Ménière’s disease Leukemia (left)

6 83/F* Ménière’s disease Leukemia (right)

7 78/M* Ménière’s disease Cardiac arrest (left)

BT 30% AT 50%

N

⬍15%

7%

4 58/M* Ménière’s disease CVA (right) Pneumonia

⬍10%

N

⬍5%

8%

3 58/M* Ménière’s disease CVA (left) Pneumonia

BT 20%

BT 30%

20%

17%

2 71/F* Ménière’s disease Brain infarction

10%

AT 50%

⬍10%

N

N

N

D

N

N

N

D

D

D

D

D

D

N

U-1 S-1 SC-5 OC-1 IHC OC-1 OHC

U-2

LC-1

S-1 PC-1

S-1 PC-4 OC-2 OHC

OC-2 OHC PC-4

U-2 S-2

end organ

OCB

MG

TN

Concretions

Degeneration

1 83/F* Ménière’s disease Respiratory failure 7% Ovarian carcinoma

Cause of death SG

Otologic diagnosis VG

Age/ sex

Table 2. Histopathology of temporal bones: Ménière’s disease

2

SV

0

0

0

0

1 (SG) 0

0

0

0

0

1 (SG) 0

0

OSL

0

0

0

0

0

0

1

SP

EH Outpouch. AGL

Vest. fib. EH

Vest. fib. Outpouch. EH AGL

Vest. fib. EH

EH

Vest. fib. EH

EH AGL

Other findings

Appendix

132

TN

OCB

24%

30%

10 65/F* Ménière’s disease Cerebral hemorrhage

40%

15%

10%

BT 30%

BT 75%

BT 30%

N

D

N

D

D

D

U-2 S-2 OC-1 OHC

U-1 LC-1

U-2

end organ

SG

MG

VG

Concretions

Degeneration

9 76/F* Ménière’s disease Cerebral hemorrhage

Cause of death

20%

Otologic diagnosis

8 78/M* Ménière’s disease Cardiac arrest (right)

Age/ sex

Table 2. (continued)

0

0

0

OSL

0

1

0

SV

0

0

0

SP

Vest. fib. EH

Vest. fib. EH Outpouch.

EH

Other findings

Appendix

133

75/F*

65/M*

91/F*

1

2

3

Age/ sex

BPV

BPV

BPV

Cerebral infarction

Pulmonary tuberculosis

Respiratory and cardiac failure

Otologic Cause of diagnosis death TN

OCB

10%

17%

4%

BT 50% BT 10% BT 50%

⬍15% (inferior) ⬍15% (inferior) ⬍15% (inferior)

N

D

N

D

D

D

OC-1 IHC S-1 PC-3 LC-4

U-2

0

end organ

SG

MG

VG

Concretions

Degeneration

Table 3. Histopathology of temporal bones: benign paroxysmal positional vertigo

0

0

0

OSL

0

0

0

SV

0

0

0

SP

Appendix

134

84/M

21/M

81/M

59/M

86/M (right)

87/F

82/F (right)

77/F

1

2

3

4

5

6

7

8

Age/ sex

SNHL TM perforation

Otosclerosis Malleus fixation

Presbycusis

Presbycusis

Furosemide ototoxicity

Otosclerosis Left stapedectomy

TB fracture

Otosclerosis

Otologic diagnosis

MI

MI

Heart failure

GM (–) sepsis

Follicular lymphoma

Intestinal infarction

Head injury Laceration liver, spleen, aorta

MI

Cause of death

Table 4. Histopathology of control temporal bones

TN

OCB

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

BT 50%

N

BT 30%

BT 30%

BT 20%

BT 50%

BT 50%

BT 30%

N

D

N

N

N

N

D

N

N

N

N

N

D

N

NA

N

S-1

0

0

0

OC-2 IHC PC-1

0

0

OC-2 OHC

end organ

SG

MG

VG

Concretions

Degeneration

0

0

0

0

1

0

0

0

OSL

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

SV SP

Appendix

135

91/M

80/F

76/M

38/M

91/F (left)

69/M

76/F

86/M (left)

82/F (left)

11

12

13

14

15

16

17

18

9/M

10

9

Metastatic carcinoma Prostate pneumonia

Cerebral infarction

Liver failure Peritonitis

MI Pulmonary edema

GI hemorrhage

MI Pulmonary embolism

Leukemia

Otosclerosis

Presbycusis

MI

GM (–) sepsis

Chronic otitis media Cerebral and labyrinthitis hemorrhage

Hemolabyrinth

Contralateral BPV

Usher’s syndrome

Neural presbycusis Strial atrophy

Strial atrophy Neural presbycusis

Presbycusis

Labyrinthine hemorrhage

0

9%

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

N

BT 30%

50%

BT 50%

BT 50%

BT 70%

BT 50%

BT 30%

BT 15%

N

N

N

D

N

N

N

N

D

N

N

N

N

D

NA

N

N

N

N

N

N

0

OC-1 IHC S-1 PC-1

S-1

0

PC-2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

1

0

2

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

Appendix

136

54/F

47/M

19

20

Age/ sex

Noise deafness

Subarachnoid hemorrhage Neomycin toxicity (cochlear)

Otologic diagnosis

Table 4. (continued)

Pneumonia Mitral stenosis

Cerebral hemorrhage

Cause of death TN

OCB

0

0

0

0

N

BT 50%

N

N

D

N

PC-1

0

end organ

SG

MG

VG

Concretions

Degeneration

0

0

OSL

1

0

0

0

SV SP

Subject Index

Acyclovir, vestibular ganglionitis treatment 125 Antiviral therapy, vestibular ganglionitis 125, 126 Bell’s palsy etiology 32, 46 geniculate ganglion role 32, 33, 38, 41– 44, 46 herpes simplex virus role 46, 51 magnetic resonance imaging studies 33, 34, 36, 48–51 meatal ganglion role 32, 33, 38, 41– 44, 48 susceptibility of individuals 51 temporal bone studies cranial nerve morphological changes 36, 37, 46, 48 histopathology 37, 38, 41– 44 Benign paroxysmal positional vertigo classification of recurrent vestibulopathies 102, 103 clinical features 80, 81, 85, 86 clinical series for classification 94, 96–99 comorbidity with vestibular disease 87, 100, 101 neurotropic virus reactivation role 86 temporal bone studies histopathology 82, 84–86, 92, 93, 133 overview 81 specimens 81, 82 treatment 80

Cochlear nerve, anatomy 19, 24, 25, 27 Cranial nerve V, see Trigeminal nerve VIII cochlear nerve 19, 24, 25, 27 efferent vestibular pathway 22, 23 hair cell afferent neurons 20, 21 vestibular nerve 19–22 IX, see Glossopharyngeal nerve neurotropic virus sensitivity 12 Efferent system, degeneration in vestibular ganglionitis anatomy 105 primary vs secondary pathology 121 temporal bone studies concretions 109–112, 116, 117, 119 controls 114, 116 electron microscopy 118, 120 light microscopy 106 specimens 106 Endolymphatic hydrops, Ménière disease 67, 70, 71, 74–76 Facial nerve, see also Bell’s palsy anatomy 14–19 brainstem nuclei origins 15, 16 functional neuron groups 14, 15 geniculate ganglion 15, 18, 19 magnetic resonance imaging in Bell’s palsy 33, 34, 36, 48–51 meatal ganglion 15, 18, 19, 21

137

Ganciclovir, vestibular ganglionitis treatment 125, 126 Ganglion cell, neurotropic virus infection 7 Geniculate ganglion Bell’s palsy role 32, 33, 38, 41– 44, 46 facial nerve 15, 18, 19 temporal bone content 32 Glossopharyngeal nerve, anatomy 27, 29 Hematoxylin, staining 9 Herpes simplex virus Bell’s palsy role 46, 51 cranial neuropathy association 8, 9 diseases 1 envelope glycoproteins 1, 2 histological studies of infection 9 incidence of exposure 1 infection cycle 2, 3, 5 latency 5 Ménière disease role 68, 73 receptors 2 recurrent vestibulopathy role 100 vestibular neuronitis role 63, 64 Idiopathic facial paralysis, see Bell’s palsy Inner hair cell concretions with hearing loss 119 nerve termination 24, 27, 119 Magnetic resonance imaging Bell’s palsy studies 33, 34, 36, 48–51 Ménière disease studies 74, 96–99 vestibular neuronitis studies 54, 63, 96–99 Meatal ganglion Bell’s palsy role 32, 33, 38, 41–44, 48 facial nerve 15, 18, 19, 21, 99 temporal bone content 32, 99 vestibular neuronitis changes 55–57, 62–65, 99 Ménière disease animal models 76 antiviral therapy 125, 126 classification of recurrent vestibulopathies 102, 103 clinical features 67, 75–77 clinical series for classification 94, 96–99

Subject Index

comorbidity with vestibular disease 87, 100, 101 endolymphatic hydrops 67, 70, 71, 74–76 etiology 67, 68, 75 herpes simplex virus role 68, 73 magnetic resonance imaging studies 74, 96–99 sensorineural hearing loss 76, 77 temporal bone studies histopathology 69–71, 73, 93, 94, 131, 132 specimen preparation 68, 69 vestibular ganglion changes 69, 71, 74 Neurotropic virus, see also specific viruses cranial nerve sensitivity 12 ␣-herpesviruses 1 infection cycle 2, 3, 5 nucleic acid infectivity 8 recurrent vestibulopathy role 89, 99–102 Olivocochlear bundle anatomy 25, 27 efferent system paralysis 120 Otalgia, recurrent vertigo association 101 Outer hair cell concretions with hearing loss 119 nerve termination 24, 27, 119 Recurrent vestibulopathy classification case reports 90–94 clinical series 94, 96–99 temporal bone specimen review 89–94 neurotropic virus role 89, 99–102 Satellite cell benign paroxysmal positional vertigo changes 82 neurotropic virus infection 2, 3, 5, 7, 100 Temporal bone Bell’s palsy studies cranial nerve morphological changes 36, 37, 46, 48 histopathology 37, 38, 41–44

138

benign paroxysmal positional vertigo studies histopathology 82, 84–86, 92, 93, 133 overview 81 specimens 81, 82 control bone histopathology 134–136 efferent system degeneration in ganglionitis concretions 109–112, 116, 117, 119 controls 114, 116 electron microscopy 118, 120 light microscopy 106 specimens 106 Ménière disease studies histopathology 69–71, 73, 93, 94, 131, 132 specimen preparation 68, 69 vestibular neuronitis studies histopathologic findings 56, 57, 60–63, 90, 128–130 specimen assessment 55, 56 Trigeminal nerve, anatomy 12, 13 Tympanic nerve, degeneration with vestibulopathies 101, 102 Valacyclovir, vestibular ganglionitis treatment 125 Vestibular ganglionitis, efferent system degeneration anatomy 105

Subject Index

antiviral treatment 125, 126 primary vs secondary pathology 121 symptoms, primary vs secondary 124, 125 temporal bone studies concretions 109–112, 116, 117, 119 controls 114, 116 electron microscopy 118, 120 light microscopy 106 specimens 106 Vestibular nerve anatomy 19–22, 105 Ménière disease, vestibular ganglion changes 69, 71, 74 neuronitis antiviral therapy 125, 126 clinical features 54, 55, 64, 65 clinical series for classification 94, 96–99 degeneration of nerve 54, 55, 62–65 herpes simplex virus role 63, 64 magnetic resonance imaging studies 54, 63, 96–99 meatal ganglion changes 55–57, 62–65 temporal bone studies histopathologic findings 56, 57, 60–63, 90, 128–130 specimen assessment 55, 56 vestibular ganglion changes 55, 57, 61–65

139