viral neuropathies in the temporal bone karger

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
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© 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
7
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
Gacek
2
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
The Biology of Neurotropic Viruses
3
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.
Gacek
4
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.
The Biology of Neurotropic Viruses
5
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.
Gacek
6
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
The Biology of Neurotropic Viruses
7
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
Gacek
8
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.
The Biology of Neurotropic Viruses
9
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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.
The Biology of Neurotropic Viruses
11
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.
Neuroanatomy of the Nerves in the Temporal Bone
13
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
Gacek
14
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
Neuroanatomy of the Nerves in the Temporal Bone
15
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
Gacek
16
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.
Neuroanatomy of the Nerves in the Temporal Bone
17
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
Gacek
18
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
Neuroanatomy of the Nerves in the Temporal Bone
19
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
Gacek
20
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
Neuroanatomy of the Nerves in the Temporal Bone
21
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
Gacek
22
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].
Neuroanatomy of the Nerves in the Temporal Bone
23
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.
Gacek
24
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
Neuroanatomy of the Nerves in the Temporal Bone
25
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.
Gacek
26
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,
Neuroanatomy of the Nerves in the Temporal Bone
27
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.
Gacek
28
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.
Neuroanatomy of the Nerves in the Temporal Bone
29
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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.
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Ona A: The mammalian vestibular ganglion cells and the myelin sheath surrounding them. Acta
Otolaryngol (Stockh) 1993;suppl 503:143–149.
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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.
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ampullares in the guinea pig: A light and electron microscope investigation. Acta Otolaryngol
(Stockh) 1956;suppl 126:1–85.
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with a special reference to the efferents. 3rd Symp Role Vestib Organs Space Exploration, NASA
Status Post-152, Washington, USGPO, pp 183–201.
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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.
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The Cochlea. New York, Raven Press, 1986, pp 333–348.
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(Stockh) 1968;66:282–288.
Neuroanatomy of the Nerves in the Temporal Bone
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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).
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
33
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
Gacek/Gacek
34
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.
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
35
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
Gacek/Gacek
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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
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
37
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.
Gacek/Gacek
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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).
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
39
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.
Gacek/Gacek
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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,
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
41
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
Gacek/Gacek
42
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.
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
43
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.
Gacek/Gacek
44
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).
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
45
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)
Gacek/Gacek
46
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.
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
47
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
Gacek/Gacek
48
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;
Meatal Ganglionitis: A Pathologic Correlate in Idiopathic Facial Paralysis
49
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
Gacek/Gacek
50
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.
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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.
Vestibular Neuronitis: A Viral Neuropathy
55
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
Gacek /Gacek
56
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
Vestibular Neuronitis: A Viral Neuropathy
57
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).
Gacek /Gacek
58
Fig. 3. The utricular nerve (arrow) and macula (U) were normal.
Fig. 4. The saccular macula (S) and its nerve supply (arrow) were normal.
Vestibular Neuronitis: A Viral Neuropathy
59
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
Gacek /Gacek
60
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
Vestibular Neuronitis: A Viral Neuropathy
61
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
Gacek /Gacek
62
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
Vestibular Neuronitis: A Viral Neuropathy
63
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.
Gacek /Gacek
64
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.
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Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 67–79
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
Gacek/Gacek
68
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
Ménière’s Disease: A Form of Vestibular Ganglionitis
69
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
Gacek /Gacek
70
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
Ménière’s Disease: A Form of Vestibular Ganglionitis
71
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 (*).
Gacek /Gacek
72
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
Ménière’s Disease: A Form of Vestibular Ganglionitis
73
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
Gacek /Gacek
74
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
Ménière’s Disease: A Form of Vestibular Ganglionitis
75
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
Gacek /Gacek
76
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.
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Galic M, Helms J: Elektronenmikroskopische Befunde am Bindegewebe von Nervus und Ganglion
vestibuli bei Morbus Ménière. Arch Otorhinolaryngol 1982;236:67–79.
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Card JP: Exploring brain circuitry with neurotropic viruses: New horizons in neuroanatomy.
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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.
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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.
The Pathology of Benign Paroxysmal Positional Vertigo
81
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
83
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
Gacek /Gacek
84
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
The Pathology of Benign Paroxysmal Positional Vertigo
85
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.
Gacek /Gacek
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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
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2
3
4
5
6
7
8
9
10
11
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14
15
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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.
The Pathology of Benign Paroxysmal Positional Vertigo
87
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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Gacek RR, Gacek MR: Viral Neuropathies in the Temporal Bone.
Adv Otorhinolaryngol. Basel, Karger 2002, vol 60, pp 89–104
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).
A Classification of Recurrent Vestibulopathy
91
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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92
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
A Classification of Recurrent Vestibulopathy
93
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.
A Classification of Recurrent Vestibulopathy
95
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.
A Classification of Recurrent Vestibulopathy
97
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
Gacek/Gacek
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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
A Classification of Recurrent Vestibulopathy
99
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
A Classification of Recurrent Vestibulopathy
101
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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102
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.
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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.
Gacek
106
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).
Efferent System Degeneration in Vestibular Ganglionitis
107
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.
Gacek
108
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).
Efferent System Degeneration in Vestibular Ganglionitis
109
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).
Gacek
110
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
Efferent System Degeneration in Vestibular Ganglionitis
111
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.
Gacek
112
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).
Efferent System Degeneration in Vestibular Ganglionitis
113
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,
Gacek
114
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).
Efferent System Degeneration in Vestibular Ganglionitis
115
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
Gacek
116
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.
Efferent System Degeneration in Vestibular Ganglionitis
117
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].
Gacek
118
(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.
Efferent System Degeneration in Vestibular Ganglionitis
119
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
Gacek
120
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.
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5
6
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Spoendlin H: Ultrastructural studies of the labyrinth in squirrel monkeys. 1st Symp Role
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Galambos R: Suppression of auditory nerve activity by stimulation of efferent fibers to the
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Brownell WE: Outer hair cell electromotility and otoacoustic emissions. Ear Hear 1990;11:82–92.
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59:329–337.
Llinas R, Precht W: The inhibitory vestibular efferent system and its relation to the cerebellum in
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Dechesne C, Sans A: Control of the vestibular nerve activity by the efferent system in the cat. Acta
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Russell IJ, Roberts BL: Inhibition of spontaneous lateral line activity by efferent nerve stimulation.
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Klinke R, Galley N: Efferent influence on the vestibular organ during active movements of the
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208:37.
Roberts BL, Russell IJ: The activity of lateral line efferent neurons in stationary and swimming
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Russell IJ, Roberts BL: Inhibition of spontaneous lateral line activity by efferent nerve stimulation.
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Efferent System Degeneration in Vestibular Ganglionitis
123
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
Antiviral Therapy of Vestibular Ganglionitis
125
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