Audiological and vestibular findings in a 2-year-old girl with OTOF mutation. (a) Audiogram. (b) Distortion product otoacoustic emission. (c) Auditory brainstem responses in response to 105 dBnHL clicks. (d) Results of dumped rotation test. (e) Cervical vestibular evoked myogenic potentials in response to 135 dBSPL tone bursts (5 ms). L left, R right
9.3 Vestibular Involvement in Other Neuropathic Diseases
Involvements of vestibular nerve in other neuropathic diseases have been reported in various neuropathic diseases (Table 9.1).
Vestibular involvement in other neuropathic diseases
Charcot-Marie-Tooth (CMT) disease
Dominant optic atrophy (DOA)
Chronic inflammatory demyelination polyneuropathy (CIDP)
9.3.1 Charcot-Marie-Tooth (CMT) Disease
CMT is a group of various inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation in various parts of the body . Patients with CMT have been clinically divided into two categories on the basis of nerve conduction velocity (NCV): slow conduction (CMT1) and normal conduction (CMT2). CMT is caused by mutations in neuronal proteins found in the myelin sheath and axon. The most common cause of CMT is the duplication of a large region on the short arm of chromosome 17 including the gene PMP22.
Jen et al.  reported that two patients with a point mutation in the PMP22 gene had a combination of vestibular dysfunction and peripheral neuropathy . Poretti et al.  performed two kinds of vestibular function tests, the cVEMP test and the head impulse test which assesses the high-acceleration vestibuloocular reflex of the semicircular canals, in 15 CMT patients. They reported that the cVEMPs and head impulse tests were impaired in 75 % and 60 % of the patients, respectively, suggesting that the neuropathic processes of CMT frequently involve the vestibular nerve .
9.3.2 Dominant Optic Atrophy (DOA)
DOA is among the most common inherited optic neuropathy, characterized by progressive bilateral visual loss in childhood . Retinal ganglion cell degeneration, affecting the small fibers of the papillomacular bundle, is characteristic of DOA. About 70 % of patients with DOA have pathogenic mutations in the nuclear gene (OPA1) encoding for the OPA1 protein. The most common extraocular manifestation in DOA is hearing loss in the form of auditory neuropathy .
Mizutari et al.  reported a patient with a mutation in OPA1 who had absent caloric responses in both ears and absent cVEMPs in one ear . Santarelli et al.  reported that two of the nine patients with the OPA-1 missense mutation reported vertigo . These patients might have had vestibular neuropathy as well as auditory neuropathy .
9.3.3 Guillain-Barre Syndrome (GBS)
GBS is a potentially life-threatening postinfectious neuropathy characterized by rapidly progressive, symmetrical weakness of the extremities . About 25 % of patients develop respiratory dysfunction, and most patients show signs of autonomic dysfunction. The pathogenesis of GBS is considered to be caused by cross-reactive antibodies against gangliosides generated by molecular mimicry of pathogen-borne antigens. Diagnosis can usually be made from the clinical symptoms: progressive weakness in legs and arms and areflexia in weak limbs, which continue to progress for up to 4 weeks. Lumbar puncture shows increased numbers of mononuclear or polymorphonuclear cells in the cerebrospinal fluid.
9.3.4 Chronic Inflammatory Demyelination Neuropathy (CIDP)
CIDP is defined by symmetric proximal and distal weakness with sensory signs and symptoms in both arms and legs in the presence of electrophysiological features consistent with demyelinating neuropathy. The symptoms of CIDP show a progressive course in 62 %, relapsing-remitting course in 26 %, and monophasic course in 12 % of patients . The pathogenesis of CIDP is still unclear, but an autoimmune etiology is presumed because of the similarity of CIDP to experimental autoimmune neuritis in rats .
CIDP is frequently associated with cranial neuropathies. Frohman et al.  reported a patient with CIDP who had oscillopsia, disequilibrium, and gait disturbance . Bilateral vestibulopathy of this patient was demonstrated by bithermal caloric tests, rotatory chair testing, and dynamic posturography. An MRI with gadolinium revealed enhancement of eight cranial nerves bilaterally. This patient’s gait disturbance and vestibulopathy were improved by immunotherapy, suggesting immune-mediated vestibulopathy .
Sarcoidosis is a systemic granulomatous disease whose origin is still unknown . The typical histopathologic feature of sarcoidosis is a granuloma composed of epithelioid cells surrounded by mature lymphocytes and Langerhans-type and foreign-body-type giant cells. Respiratory symptoms are most common, but other symptoms such as general fatigue, dry eyes, or skin lesions are also frequent.
Neurologic involvement occurs in about 5 % of patients with sarcoidosis, in which the facial nerve is most frequently involved. The eighth nerve is the fourth most commonly affected nerve in neurosarcoidosis. Babin et al.  reported a patient with neurosarcoidosis in which the cochlear, vestibular, and facial nerves were involved. Histopathological examination of the temporal bone revealed degeneration of the labyrinthine neuroepithelium . Agari et al.  reported a patient with neurosarcoidosis with hearing loss and unsteady gait . The patient showed moderate sensorineural hearing loss and absent caloric responses in both ears. Her hearing loss and vestibular dysfunction were significantly improved by administration of corticosteroids. Figure 9.2 shows results from a patient with neurosarcoidosis with bilateral involvement of the vestibular nerve.
Brain MRI and cVEMP responses in a 57-year-old man with neurosarcoidosis. This patient was referred to our clinic with a chief complaint of dizziness and instability while walking. (a) MRI of the brain. Neurosarcoidosis in the hypothalamus (arrow). (b) cVEMPs in response to 135 dB SPL tone burst showed no responses on both sides. EMG indicates background EMG (rectified). He showed no caloric nystagmus in both ears. Lt left, Rt right
9.3.6 Friedreich’s Ataxia (FRDA)
FRDA is the most common autosomal recessive hereditary ataxic disease, which affects the central and peripheral nervous systems, heart, skeleton, and pancreas. FRDA is caused by a mutation in a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 which leads to a transcriptional defect of the frataxin gene. Deficiency of frataxin, a small mitochondrial protein, is responsible for all manifestations of FRDA. Clinically, ataxia of gait is almost always the initial manifestation of FRDA. Subsequently, involvement of the upper and lower limbs, dysarthria, and loss of sensation occurs.
Vestibular dysfunction is common in FRDA. Spoendlin  reported two sisters with FRDA who showed no caloric responses. Examination of the temporal bone revealed degeneration of the cochlear nerve and the ampullary branch of the vestibular nerve . Fahey et al.  examined vestibular function in 20 FRDA patients using the head impulse test which measures high-frequency components of the vestibuloocular reflex and showed significantly reduced gain in both ears compared to controls .
9.3.7 Mitochondrial Encephalomyopathy
Mutations in mitochondrial DNA have a close association with sensorineural hearing loss . Deafness is observed in about 70 % of patients with mitochondrial syndromes such as Kearns-Sayre syndrome, myoclonus epilepsy associated with ragged-red fibers, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Iwasaki et al.  performed caloric tests and cVEMPs in 13 patients with mitochondrial A3243G mutations and showed that most of those patients had bilateral vestibular dysfunction (10 of 13 showed abnormal caloric responses; 12 of 13 showed abnormal cVEMPs), suggesting that vestibular dysfunction is common in patients with mitochondrial encephalomyopathy . However, results of galvanic cVEMPs, a test of retrolabyrinthine vestibular function, suggested that a labyrinthine lesion, not a retrolabyrinthine lesion, is responsible for vestibular dysfunction in these patients .
9.3.8 Wernicke’s Encephalopathy
Wernicke’s encephalopathy is an acute neuropsychiatric disorder resulting from deficiency in vitamin B1 (thiamine), which is associated with significant morbidity and mortality . It is characterized by gaze-evoked nystagmus, ophthalmoplegia, mental status changes, and unsteadiness of stance and gait, although only 16 % of patients manifest all of these symptoms. The presumptive diagnosis of Wernicke’s encephalopathy can be made by clinical symptoms and measurement of blood thiamine concentrations, but brain MRI is currently considered as the most valuable method to confirm a diagnosis. MRI studies typically show an increased T2 signal bilaterally and symmetrically in the paraventricular regions of the thalamus, hypothalamus, floor of the fourth ventricle, and midline cerebellum .
Furman and Becker  reported two patients with Wernicke’s encephalopathy who showed hypoactive vestibular responses to both caloric and rotational stimuli. Both patients showed improved vestibular function following treatment with thiamine . Choi et al.  performed head impulse tests in two patients with Wernicke’s encephalopathy and reported selective involvement of the horizontal semicircular canals, sparing function in the anterior and posterior semicircular canals . They suggested that this result might be due to selective vulnerability of neurons in the medial vestibular nucleus .
9.3.9 Diabetes Mellitus (DM)
DM is a metabolic disorder which causes hyperglycemia due to a lack of, or insensitivity to, insulin. Peripheral neuropathy is a major consequence of DM with up to 50 % of patients showing clinically significant neural injury during the disease course.
Several studies have demonstrated vestibular dysfunction in patient with DM on the basis of caloric responses [32, 33]. Klagenberg et al.  reported vestibular dysfunction in 60 % of patients with type 1 DM , suggesting peripheral involvement in the disease. On the other hand, Gawron et al. reported central vestibular involvement in patients with type I DM based on the results of electronystagmographic tests .