causative factors and epidemiology of bilateral vestibulopathy in 255 patients

Causative Factors and Epidemiology ofBilateral Vestibulopathy in 255 Patients

Vera C. Zingler, MD, Christian Cnyrim, MD, Klaus Jahn, MD, Eva Weintz, Julia Fernbacher, Claudia Frenzel,Thomas Brandt, MD, FRCP, and Michael Strupp, MD

Objective: To determine the causative factors and epidemiology of bilateral vestibulopathy (BV).Methods: This is a retrospective review of 255 patients (mean age, 62 � 16 years) with BV diagnosed in our dizziness unitbetween 1988 and 2005. All patients had undergone a standardized neurophthalmological and neurootological examination,electronystagmography with caloric irrigation, cranial magnetic resonance imaging or computed tomography (n � 214), andlaboratory tests.Results: Sixty-two percent of the study population were male subjects. Previous vertigo attacks had occurred in 36%, indicatinga sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%: The most commoncauses were ototoxic aminoglycosides (13%), Meniere’s disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellarsigns. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients withoutcerebellar signs. Hypoacusis occurred bilaterally in 25% and unilaterally in 6% of all patients. It appeared most often in patientswith BV caused by Cogan’s syndrome, meningitis, or Meniere’s disease.Interpretation: The cause of BV remains unclear in about half of all patients despite intensive examinations. A large subgroupof these patients have associated cerebellar dysfunction and peripheral polyneuropathy. This suggests a new syndrome that maybe caused by neurodegenerative or autoimmune processes.

Ann Neurol 2007;61:524–532

Bilateral vestibulopathy (BV) is the impairment or lossof function of both peripheral labyrinths or of theeighth nerves. BV is rare among vestibular disorders. Itaccounts for 4% in a sample of more than 6,000 out-patients of our dizziness unit. Patients with BV typi-cally present with the following symptoms: (1) un-steadiness of gait (particularly in the dark or on unlevelground when vision and proprioception cannot substi-tute for a lack of vestibulospinal function); (2) appar-ent motion of the visual scene during head movementsand locomotion (oscillopsia) caused by involuntary ret-inal slip with insufficient vestibuloocular reflexes(VORs); and (3) impaired spatial memory and naviga-tion associated with hippocampal atrophy secondary tochronic loss of vestibular input.1 When BV is sus-pected, the diagnosis can be easily confirmed by twoinvestigations: the head-thrust test (first described byHalmagyi and Curthoys2 in 1988), a simple bedsidetest for high-frequency VOR function during rapidhead turns; and caloric irrigation of the external audi-tory canal with oculographic recordings.

BV is distinct from other vestibular disorders be-cause it has numerous causes such as ototoxic drugs,

meningitis, and inner ear autoimmune and degenera-tive disorders. In a considerable percentage the causeremains unclear.3 Rinne and coworkers4 reported on aseries of 53 patients with BV and concluded that theprobable cause of BV could be defined in approxi-mately 80% of the patients. However, it is our experi-ence that the proportion of idiopathic BV is consider-ably greater. This led us to retrospectively analyze thehistories, clinical presentations, and causative factors of255 patients with BV seen in our dizziness unit, all ofwhom had undergone a standardized complete neu-rophthalmological and neurootological workup. Weevaluated (1) the relation among definite, probable,and unknown cause; (2) the course of manifestation ofthe disease; (3) associated clinical signs, symptoms, anddiseases; and (4) epidemiological parameters.

Patients and MethodsThe medical records of all patients who were diagnosed withBV in the Department of Neurology of the University ofMunich in the 18 years between 1988 and 2005 were re-viewed. Inclusion criteria were: (1) a pathological head-thrusttest (Halmagyi and Curthoys2), which indicates a high-

From the Department of Neurology, Ludwig-Maximilians Univer-sity, Klinikum Grosshadern, Munich, Germany.

Received Sep 29, 2006, and in revised form Jan 3, 2007. Acceptedfor publication Jan 26, 2007.

Published online Mar 28, 2007 in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/ana.21105

Address correspondence to Dr Zingler, Department of Neurology,Ludwig-Maximilians University, Klinikum Grosshadern, Mar-chioninistrasse 15, D-81377 Munich, Germany.E-mail: [email protected]

ORIGINAL ARTICLES

524 © 2007 American Neurological AssociationPublished by Wiley-Liss, Inc., through Wiley Subscription Services

frequency deficit of the VOR, and/or (2) bilaterally dimin-ished or absent caloric responses on an electronystagmogram(ENG), indicating a low-frequency deficit.5,6

Complete BV was characterized by pathological head-thrust tests and the absence of caloric responses on bothsides.

Incomplete BV was characterized by one of the followingresponses: bilateral pathological head-thrust tests and a calor-ically elicited nystagmus with a mean peak slow-phase veloc-ity of less than 5 degrees/sec on both sides, bilateral patho-logical head-thrust test and caloric responses more than 5degrees/sec on one or both sides, or normal head-thrust testsand loss of bilateral or reduced responses (�5 degrees/sec) tocaloric irrigation on both sides.

Definition of etiology of BV: Patients were differentiatedas having either a “definite” or a “probable” cause of BV.This classification was based on previously published litera-ture on BV3,4 and was reassessed carefully by the senior au-thors.

All physicians had been trained on how to obtain a stan-dardized detailed history from all patients. Moreover, twoauthors (M.S., T.B.) saw more than 95% of all patients per-sonally. The following parameters were assessed: (1) recur-rent (preceding or current) attacks of vertigo or dizziness—onset, duration, time course, frequency, associated symptomssuch as oscillopsia or other visual and ocular motor symp-toms including double vision, blurred vision, or loss of sight,phonophobia, photophobia, headache, nausea, vomiting; (2)unsteadiness of gait, particularly in the dark or on unlevelground; (3) oscillopsia during head movements or during lo-comotion; (4) recurrent or sustained ear symptoms (tinnitus,hearing loss, fullness of the ear); (5) medical history withespecially migraine, polyneuropathy, exposure to toxins, an-tibiotics or diuretics, cardiovascular risk factors (eg, arterialhypertension, diabetes mellitus), or other neurological, oph-thalmological, ENT (ear, nose, throat), and internal diseases(eg, autoimmune disorders, cancer); and (6) family history ofimpaired audiovestibular function.

All patients received a complete neurological, neuroph-thalmological, and neurootological examination. The neuro-logical examination included a sensory examination (touch,temperature, pain, and proprioception) and evaluation oftendon reflexes. Pain sense, touch sense, and muscle strengthwere tested at the feet, lower legs, hands, and lower arms.Position sense was tested at the big toes, index finger, ormiddle fingers. Vibration sense was tested with a 128Hz tun-ing fork at the big toes, ankles, knees, or index/middle fin-gers. The criteria for establishing a peripheral polyneurop-athy were as follows. Touch sense, joint sense, pain sense,and manual muscle strength testing were dichotomized innormal and abnormal/decreased. Vibration sense and tendonreflexes (biceps, triceps, supinator, knee, ankle) were dichot-omized in normal, reduced (ie, �4/8 for vibration sense),respectively decreased, and absent. Thirty-five of the patientswho fulfilled the above-mentioned criteria of a polyneurop-athy underwent nerve conduction studies, electromyographicrecordings, or both.

The neurophthalmological and neurootological examinationincluded head-thrust test, evaluation for spontaneous nystag-mus with Frenzel’s goggles in primary position and duringgaze deviations, gaze-evoked nystagmus, smooth pursuit, sac-

cades, optokinetic nystagmus, visual fixation suppression ofthe VOR, rebound nystagmus, head-shaking nystagmus, anddetermination of the subjective visual vertical. Dynamic vi-sual acuity was determined in 143 patients; a decrease of 0.2or more was defined as pathological. The eye position in rollwas measured with a scanning laser ophthalmoscope in allincluded patients (for general neurophthalmological and neu-rootological testing, see Brandt and Strupp7).

All patients underwent the following bedside clinical ma-neuvers for diagnosing hearing impairment. First, the patientswere asked if they subjectively had hearing impairment.Then the whispered-voice test and the Weber and Rinnetuning fork tests were performed. A pure-tone audiogramwas made in those patients who acknowledged they had ahearing impairment and/or had a pathological whispered-voice test (n � 80).

ENG with bithermal caloric testing (30 and 44°C) wasperformed in all patients to determine mean peak slow-phasevelocity using Igor Pro Wave Metric software (version 3.13,Wave Metrics, Inc., Lake Oswego).

Cranial magnetic resonance imaging or computed tomog-raphy was obtained for 214 patients. Specific laboratory testswere initiated according to the suspected specific causativeagents (autoantibodies against inner ear structures, vitaminB12 and folate, antinuclear antibodies, complement factorsC3 and C4, and cerebrospinal fluid test). Autoantibodiesagainst inner ear structures were determined as previouslypublished by our group.8

Data were collected and evaluated by means of Excel (Mi-crosoft, Redmond, WA) spreadsheet software. Categoricalvalues were compared using a �2 test; metric values werecompared by a t test for two samples with unequal variances.Significance was defined as an � level of 0.05.

ResultsThe mean age of the patients was 61.9 � 15.9 (range,12–98) years at the time of assessment of diagnosis.The majority were male (62%; n � 157) patients witha mean age of 59.4 � 16.1 years as compared withfemale (38%; n � 98) patients with a mean age of65.9 � 14.7 years. The Figure shows the age distribu-tion of the 255 BV patients in comparison with a totalof 2,314 patients (the latter group was patients seenbetween 1995 and 2005) who were referred to our diz-ziness unit with various vestibular and ocular motordisorders. Diagnosis of BV was made at all ages, butmost were made between 61 and 70 years of age, andthe frequency increased in elderly patients.

Severe Impairment or Loss of Vestibular FunctionAccording to the criteria listed earlier, 27% of all pa-tients (n � 70; mean age, 60 � 18 years) sufferedfrom complete bilateral vestibular loss. The remainingpatients (n � 185; 62 �16 years) exhibited incompleteBV. In these two small subgroups, patients with bilat-eral normal head-thrust tests, but pathological caloricresponses (n � 9), and patients with preserved caloricresponses (mean peak slow-phase velocity � 5 degrees/

Zingler et al: Bilateral Vestibulopathy 525

sec), but pathological head-thrust tests on both sides(n � 13), were identified. Thus, in the 255 patients,the head-thrust test was pathological on both sides in93%, and the ENG showed absent or severely dimin-ished caloric responses in 95%.

Time Course of the Disease ManifestationEpisodes of vertigo or dizziness preceded the manifes-tation of BV in 36% of the patients (n � 91); theywere said to have a “sequential course.” BV developedsimultaneously, most often slowly progressively in 64%of all patients (n � 164), as indicated by a patienthistory of progressive unsteadiness of gait and oscillop-sia. There was a difference between female and malepatients as to the sequential disease manifestation (p �0.0159): more male (71%) than female (29%) patientshad a sequential course. In the group with a slowlyprogressive course, the ratio was 56% male to 44% fe-male patients. The patients with a sequential coursewere younger (54.9 � 15.2 years) than those with aslowly progressive manifestation (65.8 � 14.9 years)(p � 0.0001). Most patients with a sequential coursedescribed subsequent attacks of rotatory vertigo (n �66), and fewer suffered from recurrent postural imbal-ance (n � 24) lasting seconds to days. The neurolog-ical examination demonstrated gait unsteadiness in99% (n � 253) at the time that BV was diagnosed.Oscillopsia during head and body movements was re-ported spontaneously by 112 of all patients (n � 44%of total). Particularly those with a sequential course de-veloped oscillopsia more frequently (63% of thisgroup) than the slowly progressive group (34% of thisgroup). Oscillopsia occurred in 54% of the patientswith complete BV and less frequently (ie, in 40%) inpatients with incomplete BV.

Time Until the Diagnosis Was EstablishedThe diagnosis was made, on average, 65.3 � 101.6months (median, 35 months) after onset of the firstsymptoms. Overall BV was diagnosed slightly earlier inwomen (60.6 � 108.6; median, 28 months) than inmen (68.3 � 97.3; median, 37 months). The time un-til the diagnosis was established was longer in thegroup with a sequential course (86.5 � 125.6; median,47 months) than in the group with a slowly progressivecourse (53.6 � 83.7; median, 30.5 months).

Cause of Bilateral VestibulopathyOverall, the definite cause of BV was defined in 24%and the probable cause in 25% of all included patients(49% of total; n � 125, 74 male and 51 female pa-tients). Subgroup analysis demonstrated that the defi-nite or probable cause of BV was determined in thepatients with a slowly progressive or a sequential formin similar percentages (48 and 50%, respectively). Ta-ble 1 gives an overview of the different causes of BV.The most frequent cause (13% of total; n � 32) wasadverse effects of aminoglycosides: gentamycin only in15 of 32 patients, gentamycin or streptomycin plusother antibiotics (vancomycin, penicillin, cephalospo-rins) in 11 of 32 patients, and gentamycin (or genta-mycin combined with other antibiotics) plus diuretics(furosemide, torasemide) in 6 of 32 patients. Renal in-sufficiency, described as an additional toxicity risk fac-tor of antibiotics, coexisted in 4 of 32 patients. Themean age of the patients with BV due to antibiotics(65 � 13 years) did not differ much from the averageage of the total study population (61.9 � 15.9 years).The second largest group (7% of total; n � 17) con-sisted of patients with Meniere’s disease, and the thirdlargest group (5%; n � 13) of patients who had suf-fered from meningoencephalitis. The patients with BVcaused by Meniere’s disease (mean age, 56 � 17 years)and meningoencephalitis (mean age, 55 � 19 years)were, on average, slightly younger compared with thetotal study population. In 5% (n � 12), two differentcauses (eg, vestibular neuritis and antibiotics) led toBV. In 4% (n � 9), there was an association with aneurodegenerative disorder or ion channel disorder,such as spinocerebellar ataxia types 6 (n � 2) and 3(n � 2), episodic ataxia type 2 (n � 2), and multiplesystem atrophy (n � 3). Systemic autoimmune diseaseswere associated with BV in 3% (n � 8; sarcoidosis:n � 1; Sjogren’s syndrome: n � 2; giant cell arteritis:n � 1; Crohn’s disease: n � 2; ulcerative colitis: n �1; autoimmune hepatitis: n � 1). Rarer causes of BVwere deficits of vitamin B12 and folate 2% (n � 4),Creutzfeldt–Jakob disease (CJD) 1% (n � 3), andCogan’s syndrome 1% (n � 3). (Cogan’s syndrome isprimarily a clinical diagnosis based on a typical triad offindings: inflammatory eye disease; rapidly progressive,usually sequential bilateral hypoacusis; and peripheral

Fig 1. Age distribution of the patients with bilateral vestibu-lopathy (seen between 1988 and 2005) and patients examinedin our dizziness unit (seen between 1995 and 2005) for dif-ferent vestibular disorders. One hundred percent equals thetotal number of patients with bilateral vestibulopathy (n �255; black bars) and of all patients seen in our dizziness unit(gray bars).

526 Annals of Neurology Vol 61 No 6 June 2007

vestibular hypofunction. There are still no specific testsfor Cogan’s syndrome.9,10) There was also a group (8%of total; n � 21) with different “miscellaneous” causes,such as hemosiderosis, neurofibromatosis type 2 withbilateral acoustic neuroma, side effects of a high-dosetherapy with aspirin or furosemide, head trauma, oto-sclerosis, and alcohol. There was a positive family his-tory for inner ear disease in 1% (n � 3). The under-lying cause of BV remained unclear in 51% (n � 130;83 male and 47 female patients). The disease had aslowly progressive manifestation in 65% and a sequen-tial manifestation in 35% of these patients with so-called idiopathic BV.

Clinical Features and Associated DiseasesNEUROPHTHALMOLOGICAL FINDINGS. A detailed over-view of the neurophthalmological findings in all in-cluded patients is given in Table 2. In about one thirdof the patients, a smooth pursuit deficit (35% of total)and a horizontal gaze-evoked nystagmus (29% of total)were assessed. A cerebellar ocular motor disorder fre-quently occurred, which was characterized by eitherone or a combination of the following ocular motordysfunctions: rebound nystagmus, downbeat nystag-mus, pathological saccades, and pathological visual fix-ation suppression of the VOR. The latter two abnor-malities were detected most often, that is, pathologicalvisual fixation suppression of the VOR in 13% andpathological saccades in 12% of the patients (n � 31;saccades were too slow in 39%, hypometric in 34%,and hypermetric in 27%). An additional subgroupanalysis demonstrated that all BV patients with multi-ple system atrophy, spinocerebellar ataxia, episodicataxia, or CJD had a cerebellar ocular motor disorder(Table 3). Cerebellar ocular motor abnormalities were

also common in patients with idiopathic BV or withhereditary inner ear disease and in patients who hadsuffered from meningoencephalitis in the past. Dy-namic visual acuity was determined in 143 patients,and it was pathological in 101; a decrease of 0.2 ormore was defined as pathological. A pathological oculartorsion to the right was found in 14, and one to theleft in 10 patients.

Bilateral Vestibulopathy and Its Association withCerebellar Symptoms and PolyneuropathyTwenty-five percent of all patients with BV (n � 65;age, 62 � 15 years) were also diagnosed with a cere-bellar syndrome; there was no sex difference. BV de-

Table 2. Overview of the Different Ocular MotorDisorders in All Patients with BilateralVestibulopathy (N � 255)

Ocular Motor Disorder n % ofTotal

Smooth pursuit deficit 89 35

Horizontal gaze-evoked nystagmus 74 29

Pathological vestibuloocular reflexfixation suppression

33 13

Pathological saccades 31 12

Downbeat nystagmus 17 7

Vertical gaze-evoked nystagmus 16 6

Head-shaking nystagmus 15 6

Rebound nystagmus 6 2

Upbeat nystagmus 3 1

Table 1. Patients with a Bilateral Vestibulopathy of Definite or Probable Cause (n � 125; 49% of Total)

Cause of Bilateral Vestibulopathy Definite Cause Probable Cause �

n %a n %a n %a

Antibiotics 27 11 5 2 32 13Meniere’s disease 4 2 13 5 17 7Meningitis/encephalitis/cerebellitis 12 5 1 0 13 5Two different causes 1 0 11 4 12 5Spinocerebellar ataxia type 3 and 6/episodic ataxia

type II/multiple system atrophy0 0 9 4 9 4

Systemic autoimmune disease 2 1 6 3 8 3Deficit of vitamin B12/folic acid 3 1 1 0 4 2Creutzfeldt–Jakob disease 3 1 0 0 3 1Cogan’s syndrome 3 1 0 0 3 1Positive family history for inner ear diseases 0 0 3 1 3 1Miscellaneous 7 3 14 5 21 8

aFrequency of each cause is given as percentage of all included patients (N � 255); some of the percentages have been rounded up,others rounded down.


veloped slowly progressively in 83% of the patients andsequentially with episodes of vertigo in 17%. The fol-lowing cerebellar signs were found: ocular motor dis-orders in 86% (n � 56), ataxia of the limbs in 55%(n � 36), and a dysarthrophonia in 23% (n � 15).The magnetic resonance imaging of 10 patients showeda cerebellar atrophy. Cerebellar dysfunction was associ-ated with a peripheral polyneuropathy in 32% of thesepatients, and thus more often than in the BV patientswithout any cerebellar signs (18%).

Further findings of the subgroup analysis were as fol-lows. In the patients with idiopathic BV, cerebellarsymptoms developed in 49% compared with 26% inthe group with nonidiopathic BV. A polyneuropathywas diagnosed in 26% of the patients with idiopathicBV and again less frequently in the patients with non-idiopathic BV (17%).

The features of the polyneuropathy were as follows:75% of the patients suffered from a neuropathy withsensory abnormalities, and 25% showed sensory andmotor disturbances; 85% had an axonal polyneurop-athy, and 15% a mixed demyelinating and axonal poly-neuropathy.

EAR SYMPTOMS. Hypoacusis occurred bilaterally in25% and unilaterally in 6% of all patients. The meanage of these patients was 55.0 � 18.6 years, and 60%of this subgroup was male patients. In the majority of

the patients (64%), BV developed sequentially with ep-isodes of vertigo, dizziness, and hearing symptoms.Fourteen percent of these patients were also diagnosedto have a peripheral polyneuropathy, and only 5% ofthese patients showed cerebellar signs. Of the 80 pa-tients who had a pure-tone audiogram, 98% sufferedfrom sensorineural hypoacusis. There was a predomi-nant deficit for the high frequencies in 65%, for thehigh and low frequencies in 20%, and for only the lowfrequencies in the rest of the patients. Bilateral persis-tent or recurrent tinnitus was reported in 9% and uni-lateral tinnitus in 6% of all patients. Tables 4 and 5show the relative frequency of hypoacusis and tinnitusin the different patient groups according to the causeof BV.

In contrast, disease manifestation in the BV patientswith normal hearing began at an older age (mean age,64 � 11.6 years) and showed a slowly progressive de-velopment in 68%. There was a male preponderance of65%, which was similar to the group with hearing loss.The patients with BV and normal hearing sufferedmore often from ataxia (17%) and a polyneuropathy(24%).

MAGNETIC RESONANCE IMAGING AND COMPUTED TO-

MOGRAPHY FINDINGS. Cranial imaging studies wereperformed in the majority of the BV patients (mag-netic resonance imaging: n � 210; computed tomog-raphy: n � 4). The following abnormalities werefound: cerebellar atrophy (n � 10), other cerebellar le-

Table 3. Frequency of Cerebellar Ocular MotorDisorders in the Different Patient Groups withKnown and Unknown Causes of BilateralVestibulopathy

Causative Factor n/ta % ofSubgroup

Spinocerebellar ataxia type 3 and6/episodic ataxia type II/multiplesystem atrophy

9/9 100

Creutzfeldt–Jakob disease 3/3 100

Positive family history for inner eardiseases

2/3 67

Miscellaneous 6/21 29

Meningitis/encephalitis/cerebellitis 3/13 23

Unknown cause 29/130 22

Systemic autoimmune disease 1/8 13

Antibiotics 2/32 6

Meniere’s disease 1/17 6

Deficit of vitamin B12/folic acid 0/4 0

Cogan’s syndrome 0/3 0

Two different causes 0/2 0

n/ta � number of patients with cerebellar ocular motordisorders; A � total number of patients in each subgroup.

Table 4. Frequency of Hypoacusis in the DifferentPatient Groups According to the Cause of BilateralVestibulopathy

Causative Factor Hypoacusis(%)

Cogan’s syndrome 100

Meningitis/encephalitis/cerebellitis 69

Meniere’s disease 59

Deficit of vitamin B12/folic acid 50

Systemic autoimmune disease 38

Miscellaneous 38


33

Antibiotics 28

Unknown cause 24

Two different causes 17


0

Creutzfeldt–Jakob disease 0


sions (eg, cerebellar infarction, n � 6), bilateral acous-tic neuroma (n � 1), Cogan’s syndrome (n � 1), andsupratentorial or infratentorial vascular lesions (n �36).

ANTIBODIES AGAINST INNER EAR STRUCTURES. In 44patients (of 77 tested), antibodies against inner earstructures were pathological. However, in 9 of these 44patients, another definite cause of BV was established(antibiotics: n � 4; deficit of vitamin B12: n � 2; sideeffects of aspirin: n � 1; CJD: n � 1; Meniere’s dis-ease: n � 1).

As described earlier, systemic autoimmune diseaseswere associated with BV in eight patients. Autoanti-bodies against inner ear structures were determined infour of them; one had a titer of 1:100. Fluctuatingvertigo and hearing symptoms were reported by threeof the eight patients. A permanent bilateral hypoacusisoccurred in three patients during the course of theirdisease.

Table 6 gives a survey of the other diseases diag-nosed in the past and present medical histories of ourpatients.

DiscussionAlthough this large retrospective study confirms certainaspects of earlier investigations, it also discloses newfacts, for instance, certain epidemiological parametersand the association between BV and peripheral nervedisorders.

Cause of Bilateral VestibulopathyThe definite or probable cause of BV was determinedin approximately 50% of our study population (n �255). This finding confirms that of the review of 52BV patients by Vibert and colleagues,3 but contradictsthat of the study by Rinne and coworkers,4 who re-ported that the probable cause of BV could be deter-mined in about 80% of all patients (n � 53). OtotoxicBV caused by antibiotic treatment with gentamycinalone or in combination with other ototoxic agents (eg,diuretics) was the most frequent cause in our and pre-vious studies.3,4,11,12 We found Meniere’s disease to bethe second-most and meningoencephalitis the third-most frequent cause. Postmeningitic BV has been at-tributed mainly to bacterial, but also to viralagents.3,4,11,13,14 Another inflammatory disorder thatmay also cause BV and has so far been presumably un-derestimated is CJD, which was found in three of ourpatients. An association of BV with this prion diseasehas not yet been described but is known from bovinespongiform encephalopathy.15 The frequency of theother causes (see Table 1) was similar to that reportedin previous reviews.3,4

Table 5. Frequency of Tinnitus in the DifferentPatient Groups According to the Cause of BilateralVestibulopathy

Causative Factor Tinnitus(%)

Cogan’s syndrome 67

Meniere’s disease 35

Miscellaneous 29

Two different causes 25

Meningitis/encephalitis/cerebellitis 15

Unknown cause 14

Antibiotics 9

Deficit of vitamin B12/folic acid 0

Systemic autoimmune disease 0


0

Creutzfeldt–Jakob disease 0


0

Table 6. Other Associated Diseases in the Patientswith Bilateral Vestibulopathy

Diseasea n % ofTotalb

Peripheral polyneuropathy 55 22

Cardiovascular disorders 51 20

Arterial hypertension 43 17

Otolaryngological disorders 26 10

Ophthalmological disorders 22 9

Cancer 20 8

Tension-type headache 16 6

Migraine 10 4

Diabetes type II 11 4aThe subgroups comprise the following diseases: cardiovasculardisorders—coronary artery disease, peripheral arterial occlusivedisease, stenosis, occlusion or aneurysm of the intracranial orextracranial vessels, cardiac arrhythmia, cardiomyopathy,endocarditis, mitral or aortic valvular heart disease or valvereplacement or myocardial infarction in medical history,orthostatic dysregulation; otolaryngological disorders—acutehearing loss, hereditary hearing loss, otosclerosis, otitis media,cholesteatoma, perilymph fistula, mastoiditis, benign peripheralparoxysmal vertigo; ophthalmological disorders—glaucoma,cataract, macular diseases, iritis, uveitis, retinitis pigmentosa,surgery due to strabismus, central retinal vein occlusion;cancer—lymphoma, plasmocytoma, myeloproliferative disorders,and breast, cervical, gastric, colon, renal cell, bladder, prostate,laryngeal, and head and neck cancers. bThe frequency of eachdisease is given as a percentage of total study population (N �255).


Idiopathic Bilateral VestibulopathyHalf of our patients suffered from BV of unknowncause. It manifested more often as slowly progressivethan as sequentially progressive. In the past, severalsuggestions have been made about possible causes, forexample, recurrent vestibular neuritis caused by acuteor prior viral infection.16 A recent long-term follow-upof 103 patients with definite vestibular neuritis over amean duration of almost 10 years did not support aviral cause of BV, because there were only two recur-rences in the contralateral ear and neither caused BV.17

Other potential pathomechanisms or risk factors dis-cussed included autoimmune diseases, exposure totoxic substances (with familial susceptibility), vestibularaging, ischemia of the labyrinth, arterial hypertension,or diabetes mellitus.3,18 Idiopathic and nonidiopathicpatients with BV showed no difference with respect tothe cooccurrence of cardiovascular diseases and arterialhypertension.

Only three of our patients had a positive family his-tory for inner ear diseases. Although such a history wassuggestive for inherited BV, this was not proved by ge-netic testing. Only 2 of the more than 40 geneticallydefined, dominantly inherited hearing loss syndromesare associated with BV.19,20 More recently, dominantlyinherited vestibulopathy and normal hearing were re-ported to be linked to chromosome 6q.21 Genetic het-erogeneity is likely in inherited vestibulopathy.

Autoantibodies against Inner Ear StructuresTo investigate the possibility of an autoimmune mech-anism in idiopathic BV, Arbusow and colleagues8

screened sera for antibodies against inner ear structuresusing immunofluorescence on cryosections of rat innerear. IgG antibodies against membranous labyrinth weredetected in 8 of 12 patients; all but 1 serum of 22healthy control subjects showed only background stain-ing. In our study, autoantibodies were pathological in44 of 77 patients tested; however, a different definitecause of BV was established in 9 (eg, side effect of as-pirin22 or antibiotics, CJD). Thus, it is still not clearwhich role organ-specific antibodies play in BV. Thedata suggest that the bulk of anti-labyrinthine autoan-tibodies may be an epiphenomenon, but a small sub-group of organ-specific autoantibodies may synergizewith a cellular response to develop vestibular le-sions.8,23 Furthermore, it was recently reported thatsystemic autoimmune diseases coexist in 15 to 30% ofpatients with autoimmune inner ear diseases.24

OscillopsiaOnly 44% of all patients and more frequently youngpatients described oscillopsia during head or bodymovements. This is in agreement with other studies.3,5

New aspects of our study are that oscillopsia occurred

more often in patients with a sequential course andwith complete loss of peripheral vestibular function.

EpidemiologyThe age distribution of our BV patients ranged fromyouth to old age. The mean age at which the diagnosiswas established was around 60 years. This agrees withprevious studies.3,6,25 We found a preponderance ofmale patients with a male/female ratio of 3:2. Diseasemanifestation of sequential BV begins significantly at ayounger age and affects men much more than women.An almost equal sex ratio was found for the slowly pro-gressive form, which begins comparatively later in life.Our data also showed that BV is diagnosed later in itscourse, if the patient is male, or if the disease developssequentially. This was surprising, because one wouldexpect that repetitive neurootological investigations inpatients with recurrent vertigo attacks should lead tothe diagnosis.

Association of Bilateral Vestibulopathy withCerebellar Disorders and Peripheral PolyneuropathyThe combination of cerebellar ataxia (CA) and BV, theso-called CABV syndrome, has been previously de-scribed in only a few patients with CA, mostly of un-known cause.4,26,27 It was therefore also thought thatthe relation between CA and BV might be purely co-incidental. However, 25% of all BV patients in ourstudy had a cerebellar syndrome (which was slowlyprogressive in 83% without any sex preponderance).This indicates that a pure coincidental occurrence ofboth syndromes is unlikely. As in previous reports,4,27

the cause of CABV often remained unclear. However,case reports have also described BV in patients withdifferent cerebellar disorders, namely, spinocerebellarataxia type 3,28 Friedreich’s ataxia,29 olivoponto CA,and cerebellar-olivary atrophy.30

More patients with idiopathic BV suffered from cer-ebellar dysfunction than patients with nonidiopathicBV. Because relatively more patients with idiopathicBV had a cerebellar dysfunction plus a peripheral poly-neuropathy, one could speculate about an unrevealedsyndrome characterized by a combined (slowly progres-sive) development of BV and cerebellar as well as pe-ripheral nerve dysfunction. This may be due to a neu-rodegenerative or autoimmune process.

Association of Bilateral Vestibulopathy withHearing LossHearing was affected in various degrees bilaterally in aquarter of all included BV patients. As found in a pre-vious study,4 hearing was most often affected in pa-tients with BV caused by primary otological disease(eg, Meniere’s disease,31,32 meningitis,4,33 and Cogan’ssyndrome9,10). In these patients, BV developed mostfrequently at a younger age and sequentially with pre-


ceding attacks of vertigo or hearing symptoms. Cere-bellar dysfunction and a peripheral polyneuropathywere rarely detected (see Results). Thus, the subgroupof patients with BV and associated hearing loss differedfrom the patients without hearing loss, in whom BVgenerally developed slowly progressively and far moreoften in combination with a cerebellar syndrome or aperipheral polyneuropathy, or both.

In patients with BV caused by meningitis, aminogly-cosides, Meniere’s disease, Cogan’s syndrome, and au-toimmune disorders, BV and hearing loss are assumedto have the same cause.

Sensitivity of Investigation MethodsIt was essential to apply both methods, that is, ENGand the head-thrust test, to establish a diagnosis, espe-cially for the patient group with incomplete BV. More-over, we identified a few patients in whom only one ofthe methods indicated BV. A low-frequency deficit ofthe VOR can be measured by ENG with caloric irri-gation,6 whereas a high-frequency deficit can be de-tected only by applying the head-thrust test.2 Overall,both investigation methods reached a high and similarsensitivity of about 95%.

Cranial ImagingThe main role of imaging was to exclude cranial pa-thology or to assess rare pathologies such as Cogan’ssyndrome10 or bilateral acoustic neuroma. Likewise,cerebellar atrophy was found in only 10 patients.

Clinical Consequences (for Diagnosis andPatient Management)There are several clinical consequences (for diagnosisand patient management) of BV. First, when BV issuspected, the diagnosis should be confirmed by com-bining the caloric irrigation test for a low-frequencydeficit of the VOR and the head-thrust test for a high-frequency VOR deficit. Second, the risk of overlookingBV is high, especially in patients with recurrent attacksof vertigo, additional cerebellar symptoms, or a periph-eral polyneuropathy. BV should also be considered inpatients who do not spontaneously describe oscillopsia.Third, cranial imaging should be performed despite thelow frequency of acoustic neuroma and Cogan’s syn-drome. Laboratory tests may be helpful if an autoim-mune disease or vitamin deficiency is suspected.Fourth, ototoxic aminoglycosides and Meniere’s diseasewere the most common of the various causes of BV.Therefore, the use of aminoglycosides should be re-stricted: They should be given as single dosages perday, their serum concentrations should be monitored,and they should not be combined with other ototoxicsubstances, such as furosemide.34 The major aim oftreatment of Meniere’s disease is to prevent attacks.7,35

By preventing the attacks, one can also most likely pre-

vent a progression of the audiological and vestibulardeficits. This, however, has to be proved in a long-termstudy.

Perspectives with Respect to IdiopathicBilateral VestibulopathyCurrently, the cause of BV remains unclear in half ofall affected patients despite intensive medical workups.Future research is imperative, including postmortemhistopathological examination of the inner ear and thecerebellum to differentiate between inflammatory, au-toimmune, and degenerative causes. Furthermore, ge-netic heterogeneity is likely in cases of inherited BV.Additional investigations have to be done on BV withand without hearing loss. Precise family histories of pa-tients with BV will be essential.

We thank J. Benson for copyediting the manuscript.

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causative factors and epidemiology of bilateral vestibulopathy in 255 patients

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