Bilateral vestibulopathy …

Douglas J Lanska MD MS MSPH

Neuro-Ophthalmology & Neuro-Otology

Updated 05.21.2024
Released 08.11.2000
Expires For CME 05.21.2027

Bilateral vestibulopathy

Author: Douglas J Lanska MD MS MSPH

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Bilateral vestibulopathy

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Introduction

Overview

The author explains the clinical presentation, pathophysiology, prevention, diagnostic work-up, and management of bilateral vestibulopathy. Gait ataxia and oscillopsia are the key clinical features of bilateral vestibulopathy. Other clinical features of bilateral vestibulopathy include absence of spontaneous vertigo and nystagmus; inability to walk in the dark or on uneven or soft surfaces, unless by holding on to the wall or objects in the room (ie, use of contact cues); Romberg sign; no dysmetria or dysdiadochokinesis; insensitivity to motion sickness; a bilateral, usually symmetric, decreased sensitivity to caloric and rotational stimulation; and decreased or absent ocular counter-rolling. The most common causes of bilateral vestibulopathy are ototoxic aminoglycosides, Ménière disease, and meningitis. Clinicians should be particularly aware of risk factors for aminoglycoside-induced ototoxicity, including family history of ototoxicity, high serum levels, higher total dose, longer duration of therapy (beyond 7 to 10 days), intrathecal administration, previous exposure to ototoxins, concomitant use of other nephrotoxic or ototoxic drugs, renal impairment, fever, and older age. An imperceptible level of galvanic vestibular stimulation, delivered as “zero-mean current noise” (so-called “noisy galvanic vestibular stimulation”), may be effective in improving postural stability in patients with bilateral vestibular dysfunction.

Key points

	• Bilateral vestibulopathy has two primary modes of presentation: insidious (subacute) symmetric bilateral vestibulopathy and sequential unilateral vestibulopathy.
	• Gait ataxia and oscillopsia are the key clinical features of bilateral vestibulopathy.
	• Corrective saccades after rapid head turns to either side (ie, the “head-thrust test”) can be helpful in the diagnosis of bilateral vestibular dysfunction.
	• Risk factors for aminoglycoside-induced ototoxicity include: family history of ototoxicity, high serum levels, higher total dose, longer duration of therapy (beyond 7 to 10 days), intrathecal administration, previous exposure to ototoxins, concomitant use of other nephrotoxic or ototoxic drugs (eg, vancomycin, loop diuretics, cis-platinum, metronidazole), renal impairment, fever, and older age.
	• Prevention of aminoglycoside-induced vestibulotoxicity is essential because the hair cells do not regrow after vestibulotoxic insults; hence, vestibular function does not recover. Instead, the limited compensation that occurs after bilateral vestibulopathy is generally achieved by augmentation of visual and proprioceptive reflexes.
	• An imperceptible level of galvanic vestibular stimulation, delivered as “zero-mean current noise” (so-called “noisy galvanic vestibular stimulation”), may be effective in improving postural stability in patients with bilateral vestibular dysfunction.

Historical note and terminology

In the late 19th century, several investigators studied the manifestations of absent labyrinthine function in deaf-mute patients (91; 83). Observations made of such patients included dysequilibrium, ataxia, absence of vertigo during or after rotation, reduced caloric and rotation-induced nystagmus, and resistance to seasickness. In 1882, American psychologist and philosopher William James (1842-1910) reported that deaf-mutes were resistant to the development of seasickness, providing further evidence that the vestibular apparatus was somehow involved in the pathophysiology of this condition (91; 110; 111).

William James (1842-1910)

American psychologist and philosopher William James (1842-1910) found that deaf-mutes were resistant to the development of seasickness. (Courtesy of the U.S. National Library of Medicine. Contributed by Dr. Douglas J Lanska.)

Of 519 deaf-mutes tested, 186 were “totally insusceptible of being made dizzy by whirling rapidly round with the head in any position whatever.” In contrast, nearly 200 students and instructors at Harvard were similarly examined as controls, and “but a single one remained exempt from the vertigo.”

With the widespread use of streptomycin in the late 1940s, clinicians began to recognize the full clinical syndrome of acquired bilateral vestibulopathy. Some patients treated with streptomycin for tuberculosis developed severe ataxia and oscillopsia (06). The clinical features of these patients resembled those described earlier by neurosurgeon Walter Dandy in patients with Ménière disease who underwent bilateral vestibular nerve section.

Division of both vestibular nerves is attended by one rather surprising after-effect, jumbling of objects (visual) when the patient is in motion. As soon as the patient is at rest, the objects are again perfectly clear. The other disturbance is uncertainty when the patient is walking in the dark. Both of these effects persist, though with gradual lessening in severity (44).

Similar observations following bilateral vestibular nerve section had been reported even earlier by Ford and Walsh in a surgical patient of Dandy’s; therefore, it is not clear whether Dandy, or Ford and Walsh made the original observations (58; 106). Similar observations in nonsurgical patients were also made by Levin before Dandy's report (113).

Clinical manifestations

Presentation and course

	• Bilateral vestibulopathy has two primary modes of presentation: insidious (subacute) symmetric bilateral vestibulopathy and sequential unilateral vestibulopathy.
	• The insidious symmetrical presentation is characterized by gradually progressive persistent unsteadiness without episodes of vertigo.
	• In the sequential unilateral mode of presentation, the onset may be characterized by postural instability and severe vertigo with spontaneous nystagmus.
	• Gait ataxia and oscillopsia are the key clinical features of bilateral vestibulopathy.
	• Oscillopsia in patients with bilateral vestibulopathy is manifest by bidirectional, to-and-fro, and up-and-down illusory movements of the visual world that occur in the same axis (but in the opposite direction) as head movements, including head movements associated with ambulation.
	• Patients with bilateral vestibulopathy have an unsteady wide-based gait and a tendency to fall to either side; they do much worse on uneven or soft surfaces, such as foam cushions or mattresses.

Bilateral vestibulopathy is usually a chronic condition but may uncommonly be acute. Chronic bilateral vestibulopathy is a vestibular syndrome with two primary modes of presentation: insidious (subacute) symmetric bilateral vestibulopathy and sequential unilateral vestibulopathy (153; 210; 64). The insidious symmetrical presentation is characterized by gradually progressive persistent unsteadiness without episodes of vertigo. In contrast, in the sequential unilateral mode of presentation, the onset may be characterized by postural instability and severe vertigo with spontaneous nystagmus. Subsequently, there may be marked recovery of function over days or weeks so that the person functions normally until the opposite labyrinth is subsequently affected. As a result of the initial central compensation, the patient will likely again experience the symptoms of unilateral vestibulopathy with spontaneous nystagmus. These symptoms will occur, although there is now no input to the vestibular nuclei from either labyrinth (207). With recovery of the acute symptoms of involvement of the second labyrinth, the patient is left with persistent oscillopsia and gait ataxia, which may lessen somewhat over time (159).

Gait ataxia and oscillopsia are the key clinical features of bilateral vestibulopathy. Other clinical features of bilateral vestibulopathy include:

• Absence of spontaneous vertigo
• A sense of continuous turning in bed
• Absence of spontaneous nystagmus
• Inability to walk in the dark or on uneven or soft surfaces, unless by holding on to the wall or objects in the room (ie, use of contact cues)
• Romberg sign (and complaints of unsteadiness in darkness)
• No dysmetria or dysdiadochokinesis
• Nausea and sometimes vomiting
• Insensitivity to motion sickness
• A bilateral, usually symmetric, decreased sensitivity to caloric and rotational stimulation (59; 06; 77; 83).
• Decreased or absent ocular counter-rolling (136).

Occasionally, patients may have vertigo and illusions of tilt from asymmetric involvement (83), but this rapidly decreases over hours or days and leaves the patient with oscillopsia. Some patients with asymmetric vestibular involvement do not develop vertigo or nystagmus, either because of subacute development of vestibulopathy, which allows compensation to occur, or because of subacute but asymmetric recovery of vestibular function (195).

Oscillopsia in patients with bilateral vestibulopathy is manifest by bidirectional, to-and-fro, and up-and-down illusory movements of the visual world that occur in the same axis (but in the opposite direction) as head movements, including head movements associated with ambulation (30; 21; 22; 123; 148; 101; 69). There is no associated disorientation in space, illusion of self-motion, or autonomic system disturbance such as nausea or diaphoresis (83). Because the visual pursuit system can compensate for slow head movements (up to about 1 Hz), oscillopsia typically occurs with more rapid head movements. Oscillopsia is not universal in patients with bilateral vestibulopathy. Many patients do not report this symptom (15; 153), perhaps because of compensatory mechanisms in some patients (37).

The head impulse test (or head thrust test), in which corrective saccades are elicited after rapid head turns to either side, can be helpful in the diagnosis of bilateral vestibular dysfunction (73; 101; 118). In this test, the examiner turns the patient's head rapidly to one side while the patient attempts to maintain fixation on an object 6 or more feet away. The examiner then observes the patient for corrective saccades. Normally, a person makes smooth corrective eye movements and maintains fixation on the target. In contrast, the gaze of a patient with bilateral vestibulopathy shifts when the head is turned rapidly to either side. The gaze of a patient with unilateral labyrinthine dysfunction shifts only when the head moves quickly toward the dysfunctional side. In both cases, an oppositely directed compensatory saccade corrects the gaze error.

Patients with bilateral vestibulopathy also show a marked reduction in visual acuity with passive or active head oscillations in the horizontal or vertical planes, including during ambulation (101; 70). This can be evaluated clinically by assessing visual acuity before and during passive movements of the patient’s head at 0.5 to 2.0 Hz (116; 117; 206). Higher-frequency oscillations prevent visual following reflexes from stabilizing the eyes and facilitating target visualization (206). In any case, patients should not be allowed to stop at the turnaround point, or they will override the dynamic nature of the test. Visual acuity for normal individuals will decline by one line at most on the eye chart with this test. A decline of more than two lines is definitely abnormal (117; 206; 153). Patients with severe bilateral vestibulopathy may show a decline of five or more lines (206). Unpredictable head movements cause a greater visual acuity decrease than do predictable head movements (80). Other techniques to assess dynamic visual acuity are more complicated and may require specialized equipment (191).

There is a strong correlation between the clinical absence of dynamic ocular counter-rolling and bilateral caloric paresis (136).

Patients with bilateral vestibulopathy have an unsteady, wide-based gait and a tendency to fall to either side (81). They are typically asymptomatic while sitting or lying down under static conditions (170). Because they rely on vision as a compensatory strategy for maintaining balance, patients with bilateral vestibulopathy do worse in the dark (170; 81). They also do much worse on uneven or soft surfaces, such as foam cushions or mattresses (63; 170; 81). Patients with bilateral vestibulopathy are more susceptible to falls than are patients with unilateral vestibulopathy, particularly after several weeks following onset (158). Some of the increased falling risk in patients with bilateral vestibulopathy may be related to reduced activity and the use of assistive devices for ambulation (158). The most common patient-perceived causes of falls are loss of balance, darkness, and uneven ground (81).

Vestibulospinal and proprioceptive reflexes are gauged with the Romberg test. This test, however, is relatively insensitive for chronic bilateral vestibulopathy. The test’s sensitivity can be increased by narrowing the patient’s support base, which can be accomplished by performing the test in a tandem stance or on one foot (196; 109). The sensitivity can also be increased by having the patient stand on foam rubber to disrupt proprioceptive inputs (161; 109; 166). Foam posturography demonstrates high visual and somatosensory dependence levels in patients with bilateral vestibulopathy (62; 166). Examining patients standing on foam with the eyes closed is a good test of vestibular hypofunction (VOR gain), whereas postural control of patients with bilateral vestibulopathy is generally normal once visual and proprioceptive feedback is provided (166). Observing the patient walk or perform tandem gait, particularly with eyes closed, is also helpful.

Patients with bilateral vestibulopathy cannot maintain (or have reduced) balance during tasks with multisensory perturbations compared with healthy individuals and patients with unilateral vestibulopathy (82).

Dynamic vestibulospinal function is assessed by observing the patient’s gait, stability during rapid turns to either side, and ability to follow gentle perturbations imposed by the examiner (206). In research studies using quantitative measures, step length variability at slower speeds and step width variability at faster speeds were the most distinguishing parameters between healthy participants and people with bilateral vestibulopathy, and among people with bilateral vestibulopathy with different locomotor capacities; it is not clear, however, that this will be translatable to a clinical office environment (124).

The distribution of vestibular dysfunction in patients with idiopathic bilateral vestibulopathy is not uniform (146). It can preferentially affect lateral canal and utricular thresholds (ie, of yaw rotations and interaural translations, respectively) while relatively sparing vertical canal and saccular function (ie, roll tilt and superior-inferior translations) (146). A pattern of chronic bilateral posterior canal failure has also been identified among individuals older than 70 years, occurring in association with sensorineural hearing loss and positional downbeat nystagmus; idiopathic cases may contribute to the so-called "presbyastasis" (age-related gait impairment) (112) and "presbyvestibulopathy" (131). However, although approximately 5% of patients over 60 years of age meet the criteria for presbyvestibulopathy, most of these have relevant comorbidities in other systems, and "isolated" presbyvestibulopathy appears to be quite rare (occurring in only 1 of 707 patients or 0.14% in one study) (131).

Although episodic vertigo syndromes (eg, vestibular migraine and Ménière disease) are associated with a significant increase in psychiatric comorbidity, in particular anxiety/phobic disorders and depression, individuals with chronic bilateral vestibulopathy do not exhibit higher-than-normal frequency or severity of such psychiatric comorbidity (28). However, individuals with bilateral vestibulopathy do express various physical, cognitive, and emotional difficulties related to their impairments, which often result in a diminished quality of life (119).

CANVAS. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive disorder that is characterized by cerebellar ataxia, sensory neuropathy, and bilateral vestibulopathy (34; 39; 40; 16; 23; 26; 34; 08; 150; 152). The disorder affects adults, typically with onset between 30 and 60 years of age. Frequent presenting symptoms are gait ataxia and sensory disturbances, including neuropathic pain (50; 34; 43). Persistent coughing is a frequent feature and may precede other symptoms (50; 19; 34; 40). Some patients have autonomic impairment (50; 130; 19; 34). In some families, behavioral-psychiatric symptoms (eg, anxiety, panic attacks, alcohol abuse) may precede cerebellar ataxia, sensory neuropathy, and bilateral vestibulopathy (39). Ataxia and behavioral-cognitive aspects are the most disabling symptoms (39).

Prognosis and complications

Following vestibulotoxic insults (eg, from aminoglycosides) the hair cells do not regrow. In addition, vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes. Damage is usually complete by six months after aminoglycoside discontinuation.

Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function (77; 37; 31; 180; 138; 11; 79; 209; 210; 29), although some limited recovery of vestibular function may occur in a few cases (138; 29).

Over more than four years of follow-up on average, about half of patients with bilateral vestibulopathy subjectively rate the course of their disease as stable, about a quarter as worsened, and another quarter as improved, but in general mean peak slow phase velocity of nystagmus induced with bithermal caloric irrigation does not change (210).

Over a period of months, much of the initial disability can be compensated for (06; 77), but marked difficulty walking in the dark may persist (06). This is because patients have to rely strictly on proprioceptive reflexes rather than a combination of vestibular, visual, and proprioceptive reflexes for balance and ambulation. Recovery is inversely related to age, with children compensating more rapidly and more completely, whereas those over age 50 respond poorly or not at all (11). Gait instability and oscillopsia may improve more quickly and completely with vestibular rehabilitation therapy, but data supporting the use of such therapy are still limited and largely anecdotal (104; 135; 09).

Patients with bilateral vestibular failure (BVF) suffer from postural and gait unsteadiness and have an increased risk of falls (156; 166; 46; 201), leading to reduced ambulatory activity (201). In a study of 119 patients with bilateral vestibulopathy, 39% reported falls in the prior 12 months, and in a single-institution subset, 20% experienced three or more falls, and 4% suffered from severe fall-related injuries; residual vestibular function captured by single vestibular tests or by indices of overall vestibular were unable to distinguish fallers and non-fallers among individuals with bilateral vestibulopathy (46). The factors most strongly predictive of falls in patients with bilateral vestibulopathy are an increase in temporal gait variability, especially at slow walking speeds, and concomitant peripheral neuropathy (156).

In most patients, bilateral vestibulopathy has a strong negative impact on both physical and social functioning (69).

Clinical vignette

In 1948, shortly after streptomycin became available, a 30-year-old physician was treated with intramuscular and intraarticular streptomycin for presumptive tuberculous arthritis of the knee (06; 107; 108). After 2.5 months of treatment, the patient noted the dramatic onset and rapid progression of bilateral vestibular dysfunction over several days. Manifestations included postural instability in darkness (Romberg symptom), gait-ataxia, motion-induced vertigo and nausea, and oscillopsia.

Oscillopsia was initially severe. Even the cardioballistic effects of the pulse produced disturbing perceptions of motion. He was able to read by bracing his head between two metal bars on the bed and keeping his place with a finger or a pencil. He had to stand still to read the lettering on signs or to recognize familiar faces.

To ambulate, he initially had to rely on tactile cues and hold on to objects for support. Later, he was able to walk by focusing on distant objects. After 4 years, he had learned to walk fairly well in the light and had resumed most of his former recreational activities despite continued vestibular dysfunction. One partial benefit was a recognized resistance to seasickness. However, he was still severely impaired in the dark and sometimes had to move about on his hands and knees.

Forty years later he was still active and had little disability. He noted continued resistance to motion sickness. He continued to have difficulty on uneven or unstable surfaces and in the dark.

Biological basis

	• Bilateral vestibulopathy is typically due to dysfunction of the labyrinth on both sides, although it can uncommonly result from bilateral vestibular nerve or bilateral vestibular nuclei dysfunction.
	• The absence of vestibular function bilaterally produces impaired vestibulo-ocular and vestibulospinal reflexes, which result in oscillopsia, gait ataxia, and worsened ambulation in darkness.
	• Aminoglycosides are by far the most commonly implicated agents in permanent drug-induced vestibulotoxicity, whereas aspirin and loop diuretics typically cause reversible cochleotoxicity, and alkylating agents uncommonly cause mixed ototoxicity.
	• Aminoglycoside antibiotics can cause both auditory and vestibular toxicity, but gentamicin, streptomycin, and tobramycin are relatively specific toxins for the vestibular system.

Etiology and pathogenesis

Bilateral vestibulopathy is typically due to dysfunction of the labyrinth on both sides, although it can uncommonly result from bilateral vestibular nerve or bilateral vestibular nuclei dysfunction.

The absence of vestibular function bilaterally produces impaired vestibulo-ocular and vestibulospinal reflexes. These result in oscillopsia, gait ataxia, and worsened ambulation in darkness, as well as the other manifestations. Normal balance requires continuous monitoring of body sway and other orientation information, which are provided by the somatosensory, vestibular, and visual systems (109; 105). The functional ranges of these systems partially overlap, allowing partial compensation for deficits or distortions (133; 134). For example, a normal subject can maintain upright stance either with vision eliminated (with eye closure), proprioception disrupted (standing on a moving or tilting surface), or vestibular function distorted (as a result of rotationally induced vertigo) (109). However, loss or distortion of inputs from two or more systems is often associated with disequilibrium and falls. Thus, a patient with bilateral vestibular dysfunction may fall if vision is eliminated (with eyes closed) (109).

Vestibulotoxic drugs. The pathophysiology of vestibulotoxicity, particularly from aminoglycoside antibiotics, will be considered in some detail because of its frequency and importance as a cause of bilateral vestibulopathy. A few drugs are ototoxic, including aminoglycosides, aspirin, furosemide, and alkylating agents used in cancer chemotherapy. There is an anecdotal report of accidental hydroxychloroquine overdose resulting in permanent neurotoxic vestibulopathy (38).

Aminoglycosides are most commonly implicated in permanent drug-induced vestibulotoxicity, whereas aspirin and loop diuretics typically cause reversible cochleotoxicity, and alkylating agents uncommonly cause mixed ototoxicity (98). Moreover, aminoglycosides are the most commonly used antibiotics worldwide (154).

Aminoglycoside antibiotics can cause both auditory and vestibular toxicity (99), but gentamicin, streptomycin, and tobramycin are relatively specific toxins for the vestibular system (198; 47). Gentamicin is more vestibulotoxic than tobramycin (53). Kanamycin, neomycin, netilmicin, and amikacin are more cochleotoxic (193; 96; 198; 49; 83). Of the vestibulotoxic aminoglycoside antibiotics, gentamicin is in widest clinical use. It can selectively destroy vestibular hair cells and, thereby, impair vestibular function, including the vestibule-ocular reflex (10), without markedly affecting auditory function (47). It can do this with appropriate dosing and pharmacologic monitoring (122). Patients with gentamicin vestibulotoxicity rarely complain of hearing loss because gentamicin rarely affects hearing in the range of human speech (1 to 3 kHz) (33; 24; 35; 47). Cochleotoxicity from gentamicin initially results in a high-frequency hearing loss outside the human speech frequencies of 1 to 3 kHz and, hence, is often not monitored (33; 74; 164). Aminoglycoside-induced changes in the vestibular nerve and vestibular nuclei are secondary to damage to the vestibular hair cells (77; 86; 83) and variable direct damage to spiral ganglion cells (84). Damage to the vestibular system develops first in type I hair cells in the crista and later in type II hair cells (77). The otolith organs are relatively spared (49; 83).

Unlike other common antibiotics, aminoglycosides are concentrated in endolymph and perilymph. This undoubtedly explains their predilection for ototoxicity (77). Gentamicin therapy does not have to be administered systemically to be vestibulotoxic. Topical aminoglycoside-containing eardrops can produce vestibulotoxicity if they reach the middle ear through a tympanic membrane defect (perforation or tympanostomy tube), especially if therapy is prolonged beyond 7 days (18) or in burn patients (12; 18).

Aminoglycoside toxicity has been thought to result from an inhibition of mitochondrial protein synthesis because of a similarity between mitochondrial ribosomes and bacterial ribosomes (where aminoglycosides allow misreading of mRNA during translation). A highly conserved region of ribosomal RNA binds aminoglycosides, and mutations in this region may result in increased susceptibility to aminoglycoside-induced ototoxicity in humans and in bacterial resistance in prokaryotic bacteria (145; 87; 164). Other (not necessarily mutually exclusive) theories of aminoglycoside-induced toxicity include free radical formation via binding of iron and subsequent formation of oxidative compounds, reversible blockade of sensory transduction by blocking calcium-sensitive potassium channels, and excessive N-methyl-D-aspartate (NMDA) receptor activation and excitotoxicity due to aminoglycoside agonist activity at the NMDA subtype of glutamate receptor (17; 51; 154; 164).

A variety of candidate drugs have been identified with protective properties for vestibular hair cells and vestibular neurons in animal models of aminoglycoside ototoxicity (17; 51; 52; 154; 102; 164; 55; 100). These include various neurotrophic factors (eg, nerve growth factor, brain-derived neurotrophic factors, and neurotrophin 3), an inducer of nerve growth factor synthesis (ie, 4-methylcatechol), iron chelators, free radical scavengers (eg, alpha-tocopherol), and NMDA antagonists.

CANVAS. CANVAS is an autosomal recessive ganglionopathy involving specific cranial sensory ganglia as well as spinal dorsal root ganglia. The cranial sensory ganglionopathy neuronopathy (ganglionopathy) involves the vestibular, facial, and trigeminal ganglia but spares the auditory ganglia (88).

Clinical features include gait ataxia, unsteadiness, small fiber peripheral neuropathy, and autonomic dysfunction (173; 42; 179; 186).

Clinical features of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS)

Data presented as overall prevalence. All patients with CANVAS experienced more than one symptom. *Based on nerve conduction studies. (Source: Turner RD, Hirons B, Cortese A, Birring SS. Chronic cough as a genetic neurological ...

Chronic cough is a common feature of the syndrome, often preceding core neurologic symptoms by many years (126; 186; 137). Downbeat nystagmus may be present, and, indeed, biallelic RFC1 AAGGG expansions were identified in 15 of 65 patients with idiopathic downbeat nystagmus (23%), whereas none of 102 GAA-FGF14-positive patients had downbeat nystagmus (140). Atypical phenotypes have been recognized, including isolated sensory neuro(no)pathy without cerebellar ataxia or vestibular areflexia and immune‐mediated neuropathy (eg, Sjögren syndrome, Guillain‐Barré syndrome, idiopathic sensory ataxic neuropathy, and anti‐myelin‐associated glycoprotein [MAG] neuropathy (85; 179).

In a study of 127 cases meeting current diagnostic criteria of bilateral vestibulopathy (Bárány Society Classification), RFC1-related bilateral vestibulopathy manifested at a median age of 60 years (range 34 to 72 years) and co-occurred predominantly with mild polyneuropathy (184). Most cases had additional cerebellar involvement, but this was subtle and limited to oculomotor signs in the early stages before recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Dysarthria, appendicular ataxia, and cerebellar atrophy developed 6 to 8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive bilateral vestibulopathy from RFC1-negative bilateral vestibulopathy, whereas neither sensory symptoms nor fine motor problems discriminated between these groups. Video head impulse gains of cases with RFC1-positive bilateral vestibulopathy were lower than those of patients with RFC1-negative bilateral vestibulopathy and continued to decrease during the first decade of clinical disease.

In a study of seven patients with CANVAS, vestibular testing showed variable impairment: (1) rotatory chair testing showed reduced vestibulo-ocular reflex (VOR) gain in all patients; (2) caloric testing showed bilateral vestibular areflexia in three and unilateral hypofunction in two; and (3) only one patient had bilateral abnormal vHIT with gains under 0.6 in both ears (54).

Sural nerve biopsy in CANVAS with progressive sensory autonomic neuropathy shows marked loss of large and small myelinated fibers without amyloidosis or vasculitis (85).

Sural nerve biopsy showing marked loss of myelinated fibers, without amyloidosis or vasculitis

Light microscopic image of a sural nerve biopsy in a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and slowly progressive sensory autonomic neuropathy with mild motor deficit, moderate sensory impairment, and se...
Sural nerve biopsy showing marked loss of both large and small myelinated fibers

Light microscopic image of a sural nerve biopsy in a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and slowly progressive sensory autonomic neuropathy with mild motor deficit, moderate sensory impairment, and se...

In a study, electron microscopy showed many collagen pockets, reflecting unmyelinated fiber damage, Schwann cells with cytoplasmic dense material, cytoplasmic inclusions, and membranous material between myelin sheaths or between a myelin sheath and an axon, whereas cells that constitute vessels had no abnormality (85).

Sural nerve biopsy showing many collagen pockets, reflecting unmyelinated fiber damage

Electron microscopic image of a sural nerve biopsy shows many collagen pockets (black arrow), reflecting unmyelinated fiber damage. Biopsy findings are from a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and sl...
Sural nerve biopsy showing a Schwann cell with cytoplasmic dense material

Electron microscopic image of a sural nerve biopsy shows a Schwann cell with cytoplasmic dense material (blue arrow). Biopsy findings are from a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and slowly progressi...
Sural nerve biopsy showing a Schwann cell with a cytoplasmic inclusion (1)

Electron microscopic image of a sural nerve biopsy shows a Schwann cell with a cytoplasmic inclusion (yellow arrow). Biopsy findings are from a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and slowly progressiv...
Sural nerve biopsy showing a Schwann cell with a cytoplasmic inclusion (2)

Electron microscopic image of a sural nerve biopsy shows a Schwann cell with a cytoplasmic inclusion (yellow arrow). Biopsy findings are from a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and slowly progressiv...
Sural nerve biopsy showing membranous material between myelin sheaths or between a myelin sheath and an axon

Electron microscopic image of a sural nerve biopsy shows membranous material between myelin sheaths (white arrow) or between a myelin sheath and an axon (white arrowhead). Biopsy findings are from a woman in her late 70s with a...
Sural nerve biopsy showing cells that constitute vessels had no abnormality without aggregation

Electron microscopic image of sural nerve biopsy findings in a woman in her late 70s with an RFC1 mutation (biallelic ACAGG) and slowly progressive sensory autonomic neuropathy with mild motor deficit, moderate sensory impairme...

In 2019, CANVAS was found to be caused by an abnormal biallelic expansion in the replication factor C subunit 1 gene (RFC1) (41; 40), a finding that confirmed and improved understanding of the clinical spectrum of the disorder (48; 19; 43). Biallelic AAGGG or ACAGG repeat expansions in RFC1 have been identified as causative of this disease (128). Individuals with ACAGG/AAGGG compound heterozygous expansions have a later age of onset and slower clinical progression compared with either ACAGG or AAGGG homozygotes (128).

CANVAS is more common in offspring of consanguineous unions, as is common in Turkey (34).

The predominant MRI finding is cerebellar atrophy, but there may be other less common associated neuroimaging findings, including the (pseudo-)eye-of-the-tiger sign with bilateral and symmetrical changes in the globus pallidus, a central area of high signal, and peripheral low signal on T2-weighted MRI (01). The eye-of-the-tiger sign was previously considered pathognomonic of pantothenate kinase-associated neurodegeneration (PKAN); CANVAS and other neurodegenerative or genetic diseases may show similar findings (01).

Intronic FGF14 GAA repeat expansions. Intronic FGF14 GAA repeat expansions are another common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy (139).

In a group of 17 affected individuals, common clinical features in descending order of frequency included gait ataxia (100%), cerebellar oculomotor signs (94%), impaired vibration sense at the ankle (pallhypesthesia; 81%), falls (76%), and bilateral vestibulopathy (75%) (139).

Clinical features of GAA-FGF14-positive patients

Frequency of individual phenotypic features in 17 GAA-FGF14-positive patients. Numbers in brackets indicate the number of affected patients over the total number of patients assessed for this feature. FGF14, fibroblast growth f...

Among 45 patients negative for biallelic RFC1 repeat expansions (ie, CANVAS) with a combination of cerebellar ataxia plus peripheral neuropathy or bilateral vestibulopathy, the frequency of FGF14 GAA repeat expansions was 38% overall, 38% in the subgroup with cerebellar ataxia plus polyneuropathy, 43% in the subgroup with cerebellar ataxia plus bilateral vestibulopathy, and 27% in cases with all three features (139).

Frequency of the FGF14 GAA repeat expansion

Percentage of patients who carried an FGF14 (GAA) 250 or greater repeat expansion in the subgroups with (1) cerebellar ataxia plus polyneuropathy (CA+PN) (5 of 13 patients), (2) cerebellar ataxia plus bilateral vestibulopathy (...

Bilateral vestibulopathy was present in 75% of GAA-FGF14-positive cases (139). Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA-FGF14-positive patients. Family history of ataxia (59% vs 15%) was significantly more frequent and permanent cerebellar dysarthria (12% vs 54%) significantly less frequent in GAA-FGF14-positive than in GAA-FGF14-negative patients. Age at onset is inversely correlated with the size of the repeat expansion (139).

Negative correlation of age at onset with triplet repeat count in cases with FGF14 GAA repeat expansion

Negative correlation between the size of the FGF14 repeat expansion and age at disease onset in 17 patients (Pearson’s r, −0.67; R2=0.45; p=0.0031). The grey area displays the 95% confidence interval. Simple linear regression f...

Prevention

	• Prevention of bilateral vestibulopathy is often feasible with proper management of patients considered for, or receiving, aminoglycoside antibiotics.
	•There is a genetic tendency (due to mutations in the mitochondrial 12S rRNA gene) in one of every six patients with aminoglycoside-induced ototoxicity, which can now be detected by DNA screening.
	• Maternal relatives in families with known familial aminoglycoside-induced deafness or vestibular dysfunction should avoid aminoglycosides.
	• To avoid (or minimize) permanent impairment, aminoglycoside therapy should be stopped as soon as symptoms of either auditory or vestibular ototoxicity appear.

Prevention of bilateral vestibulopathy is often feasible with proper management of patients considered for, or receiving, aminoglycoside antibiotics (35; 122; 185):

	• document pre-existing hearing loss or vestibular dysfunction before prescribing vestibulotoxic or ototoxic medications
	• aminoglycosides should be administered for no longer than 1 week
	• aminoglycosides should be avoided in patients whose calculated creatinine clearance is less than 1.2 L/H
	• aminoglycosides should generally not be prescribed with other nephrotoxic (eg, vancomycin, nonsteroidal antiinflammatory drugs) or ototoxic drugs
	• extended dosing intervals should be used (ie, once daily, rather than multiple daily administration)
	• aminoglycosides should be discontinued when clinical vestibulotoxicity or ototoxicity is detected
	• monitor peak and trough aminoglycoside levels, and adjust dosing accordingly.

Mutations in the mitochondrial 12S rRNA gene have been identified in a significant proportion (17%) of patients with aminoglycoside-induced ototoxicity. This can now be detected by DNA screening (57). Most of these cases have a family history of aminoglycoside-induced ototoxicity, and bilateral vestibulopathy could have been prevented with an adequate clinical interview (57). Therefore, it is essential to obtain a family history of drug-induced ototoxicity in all patients before administering aminoglycosides. To prevent further cases within the family, sporadic patients with aminoglycoside-induced ototoxicity should be screened with molecular tests for the presence of known mutations (36).

Maternal relatives in families with known familial aminoglycoside-induced deafness or vestibular dysfunction should also certainly avoid aminoglycosides (145). Most familial cases received aminoglycoside antibiotics for a much shorter period and at a lower total dose than in sporadic cases. In identified families, the inheritance pattern of aminoglycoside-antibiotic susceptibility to ototoxicity has matched that of a mitochondrially inherited trait (ie, with maternal transmission) (145). Mutations in a highly conserved region of the mitochondrial 12S rRNA gene have been identified in families with aminoglycoside-induced deafness. The mutation occurs in the region known to bind aminoglycosides. Aminoglycoside-resistance mutations in this region have also been identified in other species (145).

To avoid (or minimize) permanent impairment, aminoglycoside therapy should be stopped as soon as symptoms of either auditory or vestibular ototoxicity appear (74). If identified early, much of the symptomatic toxicity is reversible (193; 53; 25). Unfortunately, vestibulotoxicity is often not recognized before discharge from the hospital (74). This lack of identification occurs because many clinicians mistakenly believe that vestibulotoxicity does not occur in the absence of cochleotoxicity. Furthermore, many patients who receive aminoglycoside antibiotics are severely ill and bedridden; vestibulotoxic symptoms are often not clinically evident in such patients.

Differential diagnosis

Confusing conditions

Chronic bilateral vestibulopathy resembles chronic cerebellar syndromes, such as alcoholic cerebellar degeneration affecting the anterior cerebellar vermis and late-onset sporadic cerebellar atrophy (Marie-Foix-Alajouanine syndrome). When cerebellar dysfunction occurs in isolation, there is no oscillopsia, and stance and gait do not commonly worsen in the dark as assessed with bedside evaluation. Some cerebellar degenerations, such as Friedreich ataxia, are associated with severe degeneration of dorsal columns and spinocerebellar tracts, further compounding the gait ataxia and, thus, producing a marked Romberg sign.

In addition, some cerebellar syndromes, such as paraneoplastic cerebellar degeneration, may be associated with vestibular involvement, producing so-called double-pathway balance impairment (144; 76).

Paraneoplastic cochleovestibulopathy commonly presents with rapidly progressive bilateral hearing loss or acute vertigo, sometimes concomitant with or following brainstem/cerebellar manifestations (76). Hearing loss is nearly universal and is bilateral in about two thirds of cases (76). Most affected individuals have cochleovestibular dysfunction as their initial presentation (ie, before manifestations of rhombencephalitis/encephalomyelitis) (76). The most commonly associated biomarker is KLHL11 IgG. The most common neoplastic association is seminoma (either testicular or extra-testicular), occurring in about half of the cases. Brain MRI may demonstrate internal auditory canal enhancement. Audiometry commonly reveals severe-to-profound bilateral sensorineural hearing loss. Most patients had a refractory course despite immunotherapy or cancer treatment.

Multisystem degeneration may have features of cerebellar ataxia in combination with bilateral vestibulopathy, possibly with impairment of the visually enhanced vestibulo-ocular reflex (doll’s head reflex), downbeat nystagmus, and sensory peripheral neuropathy or neuronopathy (127; 208; 210; 192; 103; 176; 177; 175; 56). In patients with a triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), the presenting features are mainly ataxia or ptosis, but these patients may also have cerebellar ataxia, limb-girdle weakness, and bilateral vestibulopathy (188). The "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" (CANVAS) is a recessive genetic disorder with a mean age of onset of 60 years (176; 142; 175; 181). In such cases, the sensory neuronopathy contributes significantly to the observed ataxia, and clinical and electrophysiological evidence of a sensory neuronopathy should be sought when the degree of ataxia is out of proportion to the clinically evident cerebellar and vestibular dysfunction (175).

The gait ataxia of bilateral posterior column dysfunction (as classically manifested by tabes dorsalis) can also be confused with that of bilateral vestibulopathy. The vestibulo-ocular reflexes are typically preserved with posterior column dysfunction, and oscillopsia is, therefore, absent.

Associated or underlying disorders

Identified causes of bilateral vestibulopathy include vestibulotoxic drugs (particularly aminoglycoside antibiotics, but also amiodarone), Ménière syndrome or disease, meningitis (bacterial or carcinomatous), aseptic meningoencephalitis, infectious labyrinthitis (bacterial including syphilitic, viral including measles, and fungal), bilateral vascular occlusion (eg, AICA), autoimmune disease (eg, Cogan syndrome, relapsing polychondritis), some neuropathies, neurofibromatosis, otosclerosis, head injury, bilateral cerebellopontine angle tumors, bilateral cochlear implantation, multisystem degeneration, superficial siderosis, cerebellar degenerations (including CANVAS), and aging ("presbyvestibulopathy") (20; 125; 14; 149; 27; 83; 114; 143; 160; 169; 93; 127; 03; 61; 47; 89; 208; 192; 92; 210; 118; 151; 71; 75). Rare causes include some congenital or hereditary conditions, idiosyncratic reactions to medications, delayed effects of heat exposure, late effects of recurrent vestibular migraine, cephalic tetanus, and neuroborreliosis (95; 94; 197; 05; 120).

Some inherited forms have been identified, such as CANVAS and a novel MPZ mutation (04).

In one series, 57 patients were identified of whom 41 had records available (97) (see Table 1). This series was relatively unique in including acute and correctable presentations of bilateral vestibulopathy (eg, Wernicke encephalopathy and phenytoin intoxication). Although the proportion of cases within each category will change in different series, this gives a rough idea of the distribution of causes that can be expected for patients with bilateral vestibulopathy.

Table 1. Etiology of Bilateral Vestibulopathy

Cause	N (%)
Wernicke encephalopathy	11 (27%)
Idiopathic	9 (22%)
Superficial siderosis	3 (7%)
Paraneoplastic syndrome	3 (7%)
Bilateral vestibular neuritis*	3 (7%)
Vestibulotoxicity**	2 (5%)
MELAS	2 (5%)
Spinocerebellar ataxia type***	2 (5%)
CANVAS	2 (5%)
Meniere disease	1 (2%)
Acute phenytoin intoxication	1 (2%)
Bilateral AICA stroke	1 (2%)
Mixed causes	1 (2%)
Note: Recurrent acute vestibular syndrome lasting days without cochlear symptoms; Combined aminoglycoside and chemotherapy toxicity; **Combined chronic unilateral tumor-related vestibulopathy and new contralateral vestibular neuritis [this patient presented with Bekhterev nystagmus] Contributed by (97)

Semicircular canal function in bilateral vestibular hypofunction shows disease-specific dissociations that may be related to either reduced vulnerability or increased recovery of the anterior canals (182). Overall, anterior canal hypofunction occurs significantly less often than horizontal and posterior hypofunction; preserved anterior canal function is specifically associated with aminoglycoside vestibulotoxicity, Meniere disease, and idiopathic bilateral vestibulopathy, whereas anterior canal function is not spared with inner-ear infections, the cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), and sensorineural hearing loss (182).

Associated hearing loss occurs particularly with otologic diseases (including Ménière syndrome), meningitis, and autoimmune disease (including Cogan syndrome) (208), but hearing can be normal in these conditions even in the presence of significant bilateral vestibulopathy (03). With most causes, the dysfunction occurs insidiously or in a subacute fashion, though Ménière syndrome, viral labyrinthitis, and vascular occlusion may produce acute bilateral sequential labyrinthine dysfunction.

A significant proportion of cases of bilateral vestibulopathy remain undiagnosed after evaluation, as many as 20% to 50% in several series (92; 210; 67; 118; 97). Idiopathic cases typically manifest in young or middle-aged men, although they may occur in childhood (115). Some report previous episodes of vertigo consistent with the diagnosis of sequential bilateral vestibulopathy, whereas some others have unsteadiness without episodes of vertigo and without even a history suggestive of bilateral vestibulopathy (15; 60; 118). Hearing loss seldom occurs in conjunction with idiopathic bilateral vestibulopathy (149; 190; 67). The role of autoantibodies in the production of “idiopathic” bilateral vestibulopathy is not clear (07; 03; 67). Most antilabyrinthine autoantibodies are likely an epiphenomenon, but a small subgroup may be etiologically implicated in the development of vestibular lesions (67).

Acute simultaneous hypofunction of both vestibular organs or their afferents is uncommon and is most often due to toxic (eg, aminoglycosides), traumatic (eg, bilateral temporal bone fracture), infectious (eg, basal meningitis), or metabolic (eg, Wernicke encephalopathy) causes (97; 45).

Chronic bilateral vestibulopathy resembles chronic cerebellar syndromes, such as alcoholic cerebellar degeneration affecting the anterior cerebellar vermis, and late-onset sporadic cerebellar atrophy (Marie-Foix-Alajouanine syndrome). When cerebellar dysfunction occurs in isolation, there is no oscillopsia, and stance and gait do not commonly worsen in the dark as assessed with bedside evaluation. Some cerebellar degenerations, such as Friedreich ataxia, are associated with severe degeneration of dorsal columns and spinocerebellar tracts, further compounding the gait ataxia and, thus, producing a marked Romberg sign. In addition, some cerebellar syndromes, such as paraneoplastic cerebellar degeneration, may be associated with vestibular involvement, producing so-called double-pathway balance impairment (144).

Multisystem degeneration may have features of cerebellar ataxia in combination with bilateral vestibulopathy, possibly with impairment of the visually enhanced vestibulo-ocular reflex (doll’s head reflex), downbeat nystagmus, and sensory peripheral neuropathy or neuronopathy (127; 208; 210; 192; 103; 176; 177; 175; 56). In patients with a triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), the presenting features are mainly ataxia or ptosis, but these patients may also have cerebellar ataxia, limb-girdle weakness, and bilateral vestibulopathy (188). The "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" (CANVAS) is thought to be a recessive genetic disorder with a mean age of onset of 60 years (176; 142; 175; 181). In such cases, the sensory neuronopathy contributes significantly to the observed ataxia, and, indeed, clinical and electrophysiological evidence of a sensory neuronopathy should be sought when the degree of ataxia is out of proportion to the clinically evident cerebellar and vestibular dysfunction (175).

The clinical course of bilateral vestibulopathy helps suggest a differential diagnosis (118). Bilateral vestibulopathy following recurrent episodes of vertigo is most often seen with Ménière syndrome, genetic disorders, or idiopathic vestibulopathy, whereas rapidly progressive bilateral vestibulopathy is typically a result of ototoxicity, especially with aminoglycoside antibiotics. Slowly progressive bilateral vestibulopathy without other neurologic deficits is most often seen with genetic disorders or idiopathic vestibulopathy, and slowly progressive bilateral vestibulopathy with other neurologic deficits is most often associated with cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) (118).

Although isolated age-associated bilateral vestibulopathy, or presbyvestibulopathy, is rare, presbyvestibulopathy is regularly accompanied by other multisensory dysfunction (131).

Diagnostic workup

	• Laboratory testing should be directed at supporting and quantifying the clinical diagnosis, evaluating associated dysfunction, such as hearing, and identifying suspected etiologies.
	• Testing can include electronystagmography with bithermal caloric testing, the video head impulse test, rotational testing of the horizontal semicircular ducts, and posturography.
	• The Classification Committee of the Bárány Society has proposed diagnostic criteria for bilateral vestibulopathy.

Elderly patients with bilateral vestibulopathy are generally more impaired by the symptoms but may not report typical diagnosis-defining symptoms (194).

Laboratory testing should be directed at supporting and quantifying the clinical diagnosis, evaluating associated dysfunction, such as hearing, and identifying suspected etiologies. Testing can include electronystagmography with bithermal caloric testing, the video head impulse test, rotational testing of the horizontal semicircular ducts, and posturography (12; 101; 129). In addition, tests of vertical semicircular ducts and otolith function are available in some vestibular laboratories (12).

Caloric testing evaluates vestibulo-ocular reflexes corresponding to a low-frequency angular acceleration stimulus; therefore, results of caloric testing correlate most closely with low-frequency sinusoidal rotatory stimuli (13). Diminished or absent caloric responses do not alone establish a diagnosis of bilateral vestibulopathy; such responses can be impaired for physical reasons (impacted cerumen, narrow external auditory canals, and highly pneumatized temporal bones).

Positive bilateral video head impulse test results do not always correlate with caloric or rotatory chair test results, which may reflect a wide spectrum of vestibulopathies that are variably evident as a function of stimulation frequency (129).

Rotary chair testing at several frequencies helps confirm and quantify bilateral vestibular dysfunction and should include stimuli corresponding to the higher frequency rotational head perturbations experienced during locomotion (0.5 Hz and higher) (68; 183). Even when caloric responses are absent, responses to rotary stimuli may be normal or near normal with higher frequency rotatory testing (above 0.4 Hz) (13; 183). Both gain and time constant are reduced or absent in patients with bilateral vestibulopathy with impulsive rotatory testing. This can be better quantified with sinusoidal rotatory testing, which allows measurement of gain and phase of per rotatory eye movements at different frequencies. Partial bilateral vestibulopathy produces symmetrically decreased vestibulo-ocular reflex gain and increased phase lead at low frequencies (below 0.2 Hz) but normal gain and phase lead at higher frequencies (13). Patients with more severe bilateral vestibular impairment have dysfunction at all measured frequencies. With recovery of function, vestibulo-ocular high-frequency gains may recover to within normal limits, but time constants show only limited recovery and remain below the normal range (25). The early ocular response to random, high-acceleration yaw rotation of the whole body (ie, peak acceleration of 2800°/sec) may demonstrate profound deficits of semicircular canal and otolith function in patients with relatively mild abnormalities on standard sinusoidal rotation testing (200).

Posturography is abnormal in most patients with bilateral vestibulopathy and typically shows vestibular or severe dysfunction patterns (183).

Many patients with bilateral vestibulopathy have some degree of sensorineural hearing loss that can be demonstrated with audiography.

The Classification Committee of the Bárány Society has proposed diagnostic criteria for bilateral vestibulopathy (170):

Table 2. Diagnostic Criteria for Bilateral Vestibulopathy

	A. Chronic vestibular syndrome with at least three of the following symptoms:
		1. Postural imbalance 2. Unsteady gait 3. Postural imbalance or gait unsteadiness worsens in darkness or on uneven ground 4. Movement-induced blurred vision or oscillopsia during walking or quick head/body movements
	B. No symptoms while sitting or lying down under static conditions (except cardioballistic oscillopsia induced by heartbeats)
	C. Bilaterally reduced or absent angular VOR function documented by any of the following:
		1. Bilaterally pathological horizontal angular VOR gain < 0.6, measured by the video-HIT or scleral-coil technique 2. Reduced caloric response (ie, sum of bithermal maximum peak slow-phase velocity on each side < 6°/sec) 3. Reduced horizontal angular VOR gain < 0.1 on sinusoidal stimulation on a rotatory chair (0.1 Hz, Vmax = 50°/sec).
	D. Not better accounted for by another disease

Table 3. Diagnostic Criteria for Probably Bilateral Vestibulopathy

	A. Chronic vestibular syndrome with at least three of the following symptoms:
		1. Postural imbalance 2. Unsteady gait 3. Postural imbalance or gait unsteadiness worsens in darkness or on uneven ground 4. Movement-induced blurred vision or oscillopsia during walking or quick head/body movements
	B. No symptoms while sitting or lying down under static conditions (except cardioballistic oscillopsia induced by heartbeats)
	C. Bilaterally pathological horizontal bedside head impulse test
	D. Not better accounted for by another disease
Modified from Consensus document of the Classification Committee of the Bárány Society.

Unfortunately, there continues to be a wide variation in reference values and pathological cutoff values used in clinical practice in different vestibular laboratories worldwide (168).

Presbyvestibulopathy. The Classification Committee of the Bárány Society has also proposed diagnostic criteria for “presbyvestibulopathy,” a “chronic vestibular syndrome [of older adults] characterized by unsteadiness, gait disturbance, or recurrent falls in the presence of mild bilateral vestibular deficits, with findings on laboratory tests that are between normal values and thresholds established for bilateral vestibulopathy” (02). Presbyvestibulopathy typically occurs with other age-related deficits of vision, proprioception, and cortical, cerebellar, and extrapyramidal function, and "isolated" presbyvestibulopathy appears to be quite rare (131). The diagnosis of presbyvestibulopathy requires demonstration of bilaterally reduced function of the vestibulo-ocular reflex, which can be diagnosed for the high-frequency range of the vestibulo-ocular reflex with video-head-impulse testing, for the middle-frequency range with rotary chair testing, and for the low-frequency range with caloric testing. At least one of the following should be met for this diagnosis: (1) the horizontal angular vestibulo-ocular reflex gain on both sides should be between 0.6 and 0.8; (2) the sum of the maximal peak velocities of the slow phase caloric-induced nystagmus on each side should be less than 25°/s for stimulation with warm and greater than 6°/s for stimulation with cold water; and (3) the horizontal angular vestibulo-ocular reflex gain should be between 0.1 and 0.3 for sinusoidal stimulation on a rotatory chair.

CANVAS. Patients with CANVAS typically have absent sensory nerve action potentials in all limbs, abnormal blink reflexes, absent tibial H-reflexes, and abnormal somatosensory evoked potentials (175). Many are apparently misdiagnosed as chronic idiopathic axonal polyneuropathy (178). They may also have abnormal masseter reflexes and abnormal brainstem auditory evoked responses (175). Reduced vestibulo-ocular reflex gain on video head impulse test is common and may precede clinically evident cerebellar ataxia (26).

Diagnostic criteria for CANVAS have been proposed (174). More information can be found in Table 2.

For all of the diagnostic categories of CANVAS, genetic ataxias for which genetic tests are available (especially spinocerebellar ataxia type 3 and Friedreich ataxia) must be excluded.

Table 4. Diagnostic Criteria for CANVAS

Possible CANVAS (All are required)
	• Clinical evidence of bilateral vestibular hypofunction
	• Clinical evidence of cerebellar impairment
	• Abnormal nerve conduction testing that is consistent with a sensory deficit but that excludes other pathology (eg, nerve entrapment neuropathies)
Clinically probable CANVAS (All are required)
	• Clinical evidence of an abnormal visually enhanced vestibulo-ocular reflex
	• Cerebellar atrophy on MRI or signs of cerebellar impairment on examination
	• Abnormal nerve conduction testing that is consistent with predominantly sensory impairment and that demonstrates little or no motor abnormality
Clinically definite CANVAS (All are required)
	• Abnormal visually enhanced vestibulo-ocular reflex on video-oculography, video-nystagmography, or rotational chair testing
	• Cerebellar atrophy on MRI
		- anterior and dorsal vermis atrophy (vermal lobules VI, VIIa, and VII)
		- lateral hemispheric atrophy predominantly affecting crus I (corresponding to vermal lobule VII)
	• Neurophysiologic evidence of a neuronopathy (ganglionopathy)
Pathologically definite CANVAS (All are required)
	• Temporal bone pathology findings of a vestibular neuronopathy (ganglionopathy)
	• Autopsy demonstration of typical pathologic features
	• Macroscopic cerebellar atrophy
		- anterior and dorsal vermis atrophy (vermal lobules VI, VIIa, and VII)
		- lateral hemispheric atrophy predominantly affecting crus I (corresponding to vermal lobule VII)
	• Microscopic evidence of neuronal loss in the Purkinje cell layer of the cerebellum
	• Microscopic evidence of significant dorsal root ganglia neuron loss (usually accompanied by loss of myelinated neurons in the posterior columns)

Management

	• Management of bilateral vestibulopathy depends in part on the underlying etiology.
	• Patients with bilateral vestibulopathy should avoid situations that exacerbate their dysfunction, such as walking in the dark.
	• Clinicians should offer vestibular rehabilitation to persons with impairments and functional limitations related to bilateral vestibular hypofunction.

Management of bilateral vestibulopathy depends in part on the underlying etiology. All such patients should avoid situations that exacerbate their dysfunction, such as walking in the dark or attempting to read while walking (06; 83). Patients should attempt to fixate on distant stable points when walking in the light and use contact cues in the dark (06; 83). Furthermore, oscillopsia can be reduced if high-frequency oscillations are minimized or dampened during ambulation (83).

Steroids have been used to treat presumptive cases of idiopathic cases of bilateral vestibulopathy on the assumption that these cases are or may be due to autoimmune disease (67). This is complicated, as most autoantibodies are apparently epiphenomena in such cases, even if a small minority may have an etiologic role (67). Early initiation of steroid therapy in presumptive autoimmune cases has been claimed to impact therapeutic success (67).

An emerging professional consensus, and a preponderance of benefit over harm, suggests that clinicians should offer vestibular rehabilitation to persons with impairments and functional limitations related to bilateral vestibular hypofunction (72; 199). Such individuals may benefit from supervised once-a-week sessions for 8 to 12 weeks in addition to a daily home exercise program (72). Potential benefits from an individualized vestibular exercise program for bilateral vestibular hypofunction include improved oscillopsia, postural stability, strategies for maintaining posture, and dynamic stability during locomotion, as well as improved physical function and less self-perceived handicap, but no change has been demonstrated in the number of falls or the use of assistive devices (104; 135; 09; 32). Poor results with vestibular rehabilitation (and in general with bilateral vestibulopathy) may result from more severe vestibular dysfunction, progressive vestibular dysfunction, and multiple medical problems (66). Further controlled studies of such therapy are needed in this group of patients.

Given the frequent failure of standard approaches in patients with bilateral vestibular hypofunction, vestibular research has shifted to development of a system capable of artificially restoring vestibular function, using three different approaches: (1) vestibular co-stimulation with a cochlear implant; (2) electrical vestibular stimulation with a vestibular implant; and (3) and galvanic vestibular stimulation (121; 78; 147; 162; 163; 165; 167; 172; 171; 187; 157). Anecdotal evidence suggests that vestibular implantation and prosthetic electrical stimulation of semicircular canal afferent nerves can drive canal-specific eye movement responses more than 20 years after the onset of ototoxic vestibular hypofunction (157). Patient expectations regarding a vestibular implant focus on three key themes: symptom reduction, functions and activities, and quality of life (189). Many technical hurdles must be overcome, including optimizing the electrical stimulation profile; refining the surgical implantation procedure to minimize damage to vestibular structures; preserving residual labyrinthine functions, including hearing, gaining regulatory approval; and establishing a clinical care infrastructure similar to what exists for cochlear implants (171).

Vestibular implant and a cochlear lead in relation to the bony and membranous labyrinth of the inner ear

Vestibular implant, combined with a cochlear lead (ie, a vestibulocochlear implant), in relation to the bony and membranous labyrinth of the inner ear. The electrodes implanted through fenestrations in the bony semicircular can...
Ossified metal artifact implanted in a human inner ear (micro-CT)

The xy, yz, and xz planes are resolved at 20 μm/voxel. Lateral, anterior, and posterior semicircular canals are shown with metal wires of vestibular electrodes colored blue. The crosshair intersection represents the tip of the ...
Vibratome section through a lateral semicircular canal with the electrode position preserved as an empty space in the gelatin matrix

The endolymphatic compartment (E) is completely preserved. A vibratome is an instrument used to cut thin slices of material. It is similar to a microtome but uses a vibrating blade to cut through tissue. (Source: Stultiens JJ, ...
Histological section of an over‐inserted electrode in the posterior canal close to an ampullar organ

Retraction (double arrow) of the electrode ending is evident (E‐endolymph). (Source: Stultiens JJ, Lewis RF, Phillips JO, et al. The next challenges of vestibular implantation in humans. J Assoc Res Otolaryngol 2023;24[4]:401-1...
Over‐inserted electrode showed severe damage of the crista ampullaris sensorineural epithelium exposing ruptures and compressions

CA, crista ampullaris. (Source: Stultiens JJ, Lewis RF, Phillips JO, et al. The next challenges of vestibular implantation in humans. J Assoc Res Otolaryngol 2023;24[4]:401-12. Creative Commons Attribution 4.0 International [CC...

An imperceptible level of galvanic vestibular stimulation, delivered as “zero-mean current noise” (so-called “noisy vestibular stimulation” or “vestibular noise stimulation”), transiently improves postural stability in patients with bilateral vestibular dysfunction (90; 65; 205; 202; 203; 155; 204). Postural stability is improved for more than two hours after the cessation of the stimulus and tends to decrease thereafter (65). Walking stability, particularly during slower walking speeds, is moderately improved (205). Noisy galvanic vestibular stimulation lowers the vestibular threshold to elicit balance-related reflexes that are required to adequately regulate postural equilibrium, so this intervention is only effective if there is some residual vestibular function (155).

Media

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Patient Profile

Age range of presentation: 2 years to 65+ years
Sex preponderance: female>male,>1:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Bilateral vestibulopathy

Associated Disorders

Insidious symmetric bilateral vestibulopathy
Sequential unilateral vestibulopathy

Differential Diagnosis

vestibulotoxic drugs
Ménière disease
meningitis
infectious labyrinthitis
bilateral vascular occlusion
- autoimmune disease (Cogan syndrome)
- neuropathies
- neurofibromatosis
- otosclerosis
- head injury
- bilateral cerebellopontine angle tumors
- bilateral cochlear implantation
- multisystem degeneration
- rare hereditary conditions
- cerebellar degenerations
- otologic disease
- alcoholic cerebellar degeneration
- late-onset sporadic cerebellar atrophy (Marie-Foix-Alajouanine syndrome)
- Friedreich ataxia
- paraneoplastic cerebellar degeneration
- multisystem degeneration
- bilateral posterior column dysfunction
- genetic disorders
- idiopathic vestibulopathy
- ototoxicity
- cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

Also Relevant

Dizziness
Gait disorders
Labyrinthine infarction
Meniere syndrome
Vertigo

Clinical Categories

Neuro-Ophthalmology & Neuro-Otology

Patient Handouts

Web References

Testing

MTRNR1-Related Hearing Loss and Deafness

Bilateral vestibulopathy …

Bilateral vestibulopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Table 1. Etiology of Bilateral Vestibulopathy

Diagnostic workup

Table 2. Diagnostic Criteria for Bilateral Vestibulopathy

Table 3. Diagnostic Criteria for Probably Bilateral Vestibulopathy

Table 4. Diagnostic Criteria for CANVAS

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

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Also in This Category

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

Von Hippel-Lindau disease

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

Vestibular schwannoma

Bilateral vestibulopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Table 1. Etiology of Bilateral Vestibulopathy

Diagnostic workup

Table 2. Diagnostic Criteria for Bilateral Vestibulopathy

Table 3. Diagnostic Criteria for Probably Bilateral Vestibulopathy

Table 4. Diagnostic Criteria for CANVAS

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

Von Hippel-Lindau disease

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

Vestibular schwannoma

This is an article preview.
Start a Free Account
to access the full version.