Otology & Neurotology
xx:xx–xx ß 2017, Otology & Neurotology, Inc.
Diagnosis and Treatment of Vestibular Neuritis/Neuronitis
or Peripheral Vestibulopathy (PVP)? Open Questions and
Possible Answers
yzStefan C. A. Hegemann and §Angela Wenzel
Balance-Clinic; yFaculty of Medicine, Zurich University; zZurich Center for Integrative Human Physiology (ZIHP), Zürich,
Switzerland; and §Universitäts-HNO-Klinik Mannheim, Mannheim, Germany
The acute vestibular syndrome is a clinically defined entity and new treatment options, contraindicated measures, the
consisting of vertigo or dizziness that develops acutely over differential diagnosis, and the prognosis of vestibular neur-
minutes to hours and is accompanied by nausea/vomiting, itis/neuronitis/neuropathy or vestibulopathy. Possibly, other
gait instability, head motion intolerance, and nystagmus, structures than the vestibular nerve are also involved in the
while persisting over a day or more. When it is caused by a pathogenetic process and the label peripheral vestibulopathy
peripheral vestibular lesion and is not associated with would be more apt. Key Words: Individualized
clinically manifest auditory deficits, it is mostly labeled diagnosis—Peripheral vestibulopathy—Therapy—Vestibular
vestibular neuritis/neuronitis/neuropathy or sometimes per- neuritis.
ipheral vestibulopathy. Here, we propose hypotheses and
discuss current research advances on viral or vascular factors
in the pathogenesis, the recurrence, the site of lesion, old Otol Neurotol 38:xxx–xxx, 2017.
Acute vestibular neuritis (VN) or peripheral vestibul- While most neurologist feel reasonably comfortable
opathy (PVP) is estimated to have an annual incidence of with the clinical diagnosis of VN, open questions remain
3.5–15/100,000 (1,2), an equal or near-equal sex distri- regarding the exact pathophysiology of VN/PVP, its
bution (1). It is the disease classification for an acute differentiation from central disorders and the best treat-
vestibular syndrome (AVS) caused by a peripheral lesion ment options in each individual patient.
of the vestibular nerve or the vestibular labyrinth. Audi-
tory structures are not affected to a clinically relevant If VN Is Caused by Viruses, Is It Contagious?
degree in this disease although subtle auditory deficits There is evidence that VN/PVP is caused by the reac-
have been noted in small studies (3). AVS is clinically tivation of a latent herpes virus, most likely a herpes
defined and consists of vertigo or dizziness developing simplex virus type 1 (HSV-1) infection. HSV-1 DNA
acutely over minutes to hours—accompanied by nausea/ has been detected in human autopsy samples of vestibular
vomiting, gait instability, head motion intolerance and ganglia (VG) and the vestibular labyrinth by using poly-
nystagmus and persists over a day or more (4,5). Accord- merase chain reaction. Additionally, HSV-1 latency-
ing to the first consensus document of the Committee for associated transcript, a marker of virus capable of reac-
the Classification of Vestibular Disorders of the Bárány tivation, has also been found in the VG (7–9). CD8 T-cells
Society ‘‘symptom definitions in vestibular syndromes that are present in the VG latently infected with HSV-1
should be as phenomenological as possible without suggest an active ongoing immune process (10). The
reference to a theory on pathophysiology or a particular animal model confirmed that HSV-1 can latently infect
disease’’ (6). This makes sense in light of the fact that VG neurons and that reactivation from these neurons is
AVS cannot only be caused by lesions to different possible (11). However, also herpes simplex virus
peripheral vestibular structures but also by central ves- type 6 (HHV-6) has been detected in some VG, its role
tibular lesions (5). in the pathogenesis of VN remains to be elucidated (12).
The viral etiology of VN/PVP is further supported
by the observation of preceding infections and possible
seasonal differences described in some epidemiological
Address correspondence and reprint requests to Stefan C. A. studies (13) but not in others (1). The disease seems
Hegemann, Prof. Dr. med, M.D., Balance-Clinic, CH-8001 Zurich,
Switzerland; E-mail:
to be mostly sporadic although some cases of epidemic
The authors disclose no conflicts of interest. vertigo have been described (14). It is quite likely
DOI: 10.1097/MAO.0000000000001396 that possible seasonal or population-based clustering is
1
Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
, 2 S. C. A. HEGEMANN AND A. WENZEL
due to viral agents other than HSV-1 or due to a preceding trigeminal or geniculate ganglion compatible with the
infection capable of inducing HSV-1 reactivation with migration route of the virus (10). It is, however, also
some latency (15). Histopathology demonstrated a possible that the reactivation differences are due to
reduction in the number of nerve fibers in the superior differences in neuronal phenotypes and their suscepti-
portion of the vestibular nerve, the vestibular neuroepi- bility for latency and reactivation, as has been demon-
thelium, and vestibular ganglion, compatible with viral strated in the trigeminal ganglion (29). Reactivations
infection (16,17). could also go unnoticed due to the high presence
In Bell’s palsy, which is thought to have a similar of vestibular deficits (30).
pathogenesis like VN/PVP, HSV-1 DNA could, in most
studies, not be detected in the saliva of patients (18) Where Is the Lesion in PVP, in the Nerve
although it was found during surgery in the nerve sheath or in the Ear?
(19). The virus does obviously not reach the ‘‘surface,’’ Even if there is no central cause of the symptoms but a
and the same is probably true in VN/PVP (20). While it is pure peripheral origin, it is unclear, whether the symp-
in theory possible to transmit HSV-1 virus via facio- toms are caused by a lesion of the vestibular nerve or the
vestibular anastomosis via saliva to other people, this vestibular organ, i.e., intralabyrinthic. This problem has
event is very unlikely due to the high rates of immunity. already been discussed in 1975 by Meran and Pfalz (31),
If HSV-1 is transmitted, it would cause herpetic gingivo- who could not decide in an individual patient, what exact
stomatitis in a none immune subject as a primary infection. nosologic entity was causing his symptoms. While in
1975 the ancillary caloric testing was the only standard
What Role Do Vascular Processes Play in PVP? vestibular testing procedure, multiple new diagnostic
There seems to be consensus that a proinflammatory tests have arisen meanwhile. We are nowadays able to
state often exists in patients with VN/PVP, reflected by measure the function of all five vestibular receptors with
significant elevations in plasma fibrinogen and CRP relatively simple tests by performing video-head-impulse
concentrations in afflicted patients (21). Elevated levels testing (v-HIT) for all semicircular canals (SCC) as well
in the marker CD40 were found on monocytes/macro- as cervical and ocular vestibular-evoked myogenic
phages in patients with VN/PVP, a situation that is known potentials (c- and oVEMP) for assessing saccular and
to cause formation of platelet-monocyte aggregates utricular functions respectively. In a recent retrospective
thereby leading to reduced perfusion and microvascular study (32), we found that 4 of 25 patients with acute PVP
occlusions (22). So CD40 might be one of the factors and testing of all 5 vestibular receptors within 1 week
linking the inflammatory and a possible vascular process after the onset of symptoms had a lesion pattern exactly
in VN/PVP (23). Changes in platelet monocyte inter- fitting to the innervation pattern of VN, i.e., a most
actions can also be induced by mental stress, which probable VN. Two of 25 had a lesion pattern allowing
usually is present in patients with acute VN/PVP due a possible VN. So 24% showed a VN pattern, but the
to vertigo and nausea/vomiting (24). The significance of others had lesion patterns that could be better explained
immunological dysregulation in VN/PVP is underscored by an intravestibular process than by VN (32). Two other
by its association with specific HLA subtypes and by case reports (33,34) described similar findings but did not
alterations in the CD4/CD8 ratio (25). So it is quite likely conclude about the etiology.
that vascular changes that might occur in VN/PVP as an A very recent study (35) reported about similar testing
epiphenomenon mediated by inflammation. in 43 patients shortly after onset of symptoms. Unfortu-
On the other hand, small vessel arterosclerosis has been nately, the authors did not mention or discuss the differ-
described as a cause for acute vestibular syndrome (26). ences in strength of receptor lesion of receptors
Unfortunately, we did not find a study comparing the innervated by the same nerve. They only mentioned
incidence of acute vestibular syndrome and leucence- ‘‘binary outcomes (normal or abnormal) of different
phalopathy, the latter being very common in elderly tests,’’ i.e., they used only black or white affection types
people. There are not even community-based studies and missed the many gray tones. Nevertheless, they
available on the prevalence or incidence of VN/PVP (27). described 7% of patients with abnormal horizontal canal
(HC) video Head Impulse Test (vHIT) but normal
Why Is There No Such Thing as Recurrent VN/PVP? anterior canal (AC) vHIT, and oVEMP results were
In a long-term follow-up study of 103 patients with so- not concordant with HC vHIT in 26% of patients and
called VN, only two patients (1.9%) developed a recur- with AC vHIT in 33%. These results are still less than
rence, which occurred 29 to 39 months after the first VN/ mentioned in our article but this may be explained by the
PVP case. The second case affected the contralateral ear gray tones we incorporated in our analysis. In general, an
in both patients. Unlike Bell’s palsy or herpes zoster, a intralabyrinthic lesion was not even mentioned as a
real relapse of VN/PVP has not been documented (28), possibility to explain the nonconcordant results. Maybe,
arguing against a viral infection. On the other side, it their article was already submitted, because our article
might be due to the lower numbers of LAT copies in the appeared 2 months before. A reanalysis in a similar way
VG, or differences in immune response or in the neuronal like we did would be very interesting. A meta-analysis of
phenotype of the ganglia. Numbers of the HSV-1 latency- all three studies with a total of 108 aPVP patients would
associated transcript are lower in the VG than in the probably shed light into this dark place of knowledge.
Otology & Neurotology, Vol. 38, No. xx, 2017
Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
xx:xx–xx ß 2017, Otology & Neurotology, Inc.
Diagnosis and Treatment of Vestibular Neuritis/Neuronitis
or Peripheral Vestibulopathy (PVP)? Open Questions and
Possible Answers
yzStefan C. A. Hegemann and §Angela Wenzel
Balance-Clinic; yFaculty of Medicine, Zurich University; zZurich Center for Integrative Human Physiology (ZIHP), Zürich,
Switzerland; and §Universitäts-HNO-Klinik Mannheim, Mannheim, Germany
The acute vestibular syndrome is a clinically defined entity and new treatment options, contraindicated measures, the
consisting of vertigo or dizziness that develops acutely over differential diagnosis, and the prognosis of vestibular neur-
minutes to hours and is accompanied by nausea/vomiting, itis/neuronitis/neuropathy or vestibulopathy. Possibly, other
gait instability, head motion intolerance, and nystagmus, structures than the vestibular nerve are also involved in the
while persisting over a day or more. When it is caused by a pathogenetic process and the label peripheral vestibulopathy
peripheral vestibular lesion and is not associated with would be more apt. Key Words: Individualized
clinically manifest auditory deficits, it is mostly labeled diagnosis—Peripheral vestibulopathy—Therapy—Vestibular
vestibular neuritis/neuronitis/neuropathy or sometimes per- neuritis.
ipheral vestibulopathy. Here, we propose hypotheses and
discuss current research advances on viral or vascular factors
in the pathogenesis, the recurrence, the site of lesion, old Otol Neurotol 38:xxx–xxx, 2017.
Acute vestibular neuritis (VN) or peripheral vestibul- While most neurologist feel reasonably comfortable
opathy (PVP) is estimated to have an annual incidence of with the clinical diagnosis of VN, open questions remain
3.5–15/100,000 (1,2), an equal or near-equal sex distri- regarding the exact pathophysiology of VN/PVP, its
bution (1). It is the disease classification for an acute differentiation from central disorders and the best treat-
vestibular syndrome (AVS) caused by a peripheral lesion ment options in each individual patient.
of the vestibular nerve or the vestibular labyrinth. Audi-
tory structures are not affected to a clinically relevant If VN Is Caused by Viruses, Is It Contagious?
degree in this disease although subtle auditory deficits There is evidence that VN/PVP is caused by the reac-
have been noted in small studies (3). AVS is clinically tivation of a latent herpes virus, most likely a herpes
defined and consists of vertigo or dizziness developing simplex virus type 1 (HSV-1) infection. HSV-1 DNA
acutely over minutes to hours—accompanied by nausea/ has been detected in human autopsy samples of vestibular
vomiting, gait instability, head motion intolerance and ganglia (VG) and the vestibular labyrinth by using poly-
nystagmus and persists over a day or more (4,5). Accord- merase chain reaction. Additionally, HSV-1 latency-
ing to the first consensus document of the Committee for associated transcript, a marker of virus capable of reac-
the Classification of Vestibular Disorders of the Bárány tivation, has also been found in the VG (7–9). CD8 T-cells
Society ‘‘symptom definitions in vestibular syndromes that are present in the VG latently infected with HSV-1
should be as phenomenological as possible without suggest an active ongoing immune process (10). The
reference to a theory on pathophysiology or a particular animal model confirmed that HSV-1 can latently infect
disease’’ (6). This makes sense in light of the fact that VG neurons and that reactivation from these neurons is
AVS cannot only be caused by lesions to different possible (11). However, also herpes simplex virus
peripheral vestibular structures but also by central ves- type 6 (HHV-6) has been detected in some VG, its role
tibular lesions (5). in the pathogenesis of VN remains to be elucidated (12).
The viral etiology of VN/PVP is further supported
by the observation of preceding infections and possible
seasonal differences described in some epidemiological
Address correspondence and reprint requests to Stefan C. A. studies (13) but not in others (1). The disease seems
Hegemann, Prof. Dr. med, M.D., Balance-Clinic, CH-8001 Zurich,
Switzerland; E-mail:
to be mostly sporadic although some cases of epidemic
The authors disclose no conflicts of interest. vertigo have been described (14). It is quite likely
DOI: 10.1097/MAO.0000000000001396 that possible seasonal or population-based clustering is
1
Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
, 2 S. C. A. HEGEMANN AND A. WENZEL
due to viral agents other than HSV-1 or due to a preceding trigeminal or geniculate ganglion compatible with the
infection capable of inducing HSV-1 reactivation with migration route of the virus (10). It is, however, also
some latency (15). Histopathology demonstrated a possible that the reactivation differences are due to
reduction in the number of nerve fibers in the superior differences in neuronal phenotypes and their suscepti-
portion of the vestibular nerve, the vestibular neuroepi- bility for latency and reactivation, as has been demon-
thelium, and vestibular ganglion, compatible with viral strated in the trigeminal ganglion (29). Reactivations
infection (16,17). could also go unnoticed due to the high presence
In Bell’s palsy, which is thought to have a similar of vestibular deficits (30).
pathogenesis like VN/PVP, HSV-1 DNA could, in most
studies, not be detected in the saliva of patients (18) Where Is the Lesion in PVP, in the Nerve
although it was found during surgery in the nerve sheath or in the Ear?
(19). The virus does obviously not reach the ‘‘surface,’’ Even if there is no central cause of the symptoms but a
and the same is probably true in VN/PVP (20). While it is pure peripheral origin, it is unclear, whether the symp-
in theory possible to transmit HSV-1 virus via facio- toms are caused by a lesion of the vestibular nerve or the
vestibular anastomosis via saliva to other people, this vestibular organ, i.e., intralabyrinthic. This problem has
event is very unlikely due to the high rates of immunity. already been discussed in 1975 by Meran and Pfalz (31),
If HSV-1 is transmitted, it would cause herpetic gingivo- who could not decide in an individual patient, what exact
stomatitis in a none immune subject as a primary infection. nosologic entity was causing his symptoms. While in
1975 the ancillary caloric testing was the only standard
What Role Do Vascular Processes Play in PVP? vestibular testing procedure, multiple new diagnostic
There seems to be consensus that a proinflammatory tests have arisen meanwhile. We are nowadays able to
state often exists in patients with VN/PVP, reflected by measure the function of all five vestibular receptors with
significant elevations in plasma fibrinogen and CRP relatively simple tests by performing video-head-impulse
concentrations in afflicted patients (21). Elevated levels testing (v-HIT) for all semicircular canals (SCC) as well
in the marker CD40 were found on monocytes/macro- as cervical and ocular vestibular-evoked myogenic
phages in patients with VN/PVP, a situation that is known potentials (c- and oVEMP) for assessing saccular and
to cause formation of platelet-monocyte aggregates utricular functions respectively. In a recent retrospective
thereby leading to reduced perfusion and microvascular study (32), we found that 4 of 25 patients with acute PVP
occlusions (22). So CD40 might be one of the factors and testing of all 5 vestibular receptors within 1 week
linking the inflammatory and a possible vascular process after the onset of symptoms had a lesion pattern exactly
in VN/PVP (23). Changes in platelet monocyte inter- fitting to the innervation pattern of VN, i.e., a most
actions can also be induced by mental stress, which probable VN. Two of 25 had a lesion pattern allowing
usually is present in patients with acute VN/PVP due a possible VN. So 24% showed a VN pattern, but the
to vertigo and nausea/vomiting (24). The significance of others had lesion patterns that could be better explained
immunological dysregulation in VN/PVP is underscored by an intravestibular process than by VN (32). Two other
by its association with specific HLA subtypes and by case reports (33,34) described similar findings but did not
alterations in the CD4/CD8 ratio (25). So it is quite likely conclude about the etiology.
that vascular changes that might occur in VN/PVP as an A very recent study (35) reported about similar testing
epiphenomenon mediated by inflammation. in 43 patients shortly after onset of symptoms. Unfortu-
On the other hand, small vessel arterosclerosis has been nately, the authors did not mention or discuss the differ-
described as a cause for acute vestibular syndrome (26). ences in strength of receptor lesion of receptors
Unfortunately, we did not find a study comparing the innervated by the same nerve. They only mentioned
incidence of acute vestibular syndrome and leucence- ‘‘binary outcomes (normal or abnormal) of different
phalopathy, the latter being very common in elderly tests,’’ i.e., they used only black or white affection types
people. There are not even community-based studies and missed the many gray tones. Nevertheless, they
available on the prevalence or incidence of VN/PVP (27). described 7% of patients with abnormal horizontal canal
(HC) video Head Impulse Test (vHIT) but normal
Why Is There No Such Thing as Recurrent VN/PVP? anterior canal (AC) vHIT, and oVEMP results were
In a long-term follow-up study of 103 patients with so- not concordant with HC vHIT in 26% of patients and
called VN, only two patients (1.9%) developed a recur- with AC vHIT in 33%. These results are still less than
rence, which occurred 29 to 39 months after the first VN/ mentioned in our article but this may be explained by the
PVP case. The second case affected the contralateral ear gray tones we incorporated in our analysis. In general, an
in both patients. Unlike Bell’s palsy or herpes zoster, a intralabyrinthic lesion was not even mentioned as a
real relapse of VN/PVP has not been documented (28), possibility to explain the nonconcordant results. Maybe,
arguing against a viral infection. On the other side, it their article was already submitted, because our article
might be due to the lower numbers of LAT copies in the appeared 2 months before. A reanalysis in a similar way
VG, or differences in immune response or in the neuronal like we did would be very interesting. A meta-analysis of
phenotype of the ganglia. Numbers of the HSV-1 latency- all three studies with a total of 108 aPVP patients would
associated transcript are lower in the VG than in the probably shed light into this dark place of knowledge.
Otology & Neurotology, Vol. 38, No. xx, 2017
Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
