The Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurological disorder of unknown etiology, characterized by progressive pontobulbar palsy associated with sensorineural deafness. It was first described by Brown in 1894 1, and later by Vialetto and Van Laere in 1936 2 and 1966 3 respectively.

Fifty-eight cases of BVVL have been reported in just over a century (Additional file 1). Around half of all cases are sporadic 4. The majority of familial cases demonstrate autosomal recessive inheritance, although autosomal dominant 56 or X-linked inheritance 5 has been suggested in a few families. The female to male ratio is approximately 3:1 in reported cases. This may be the result of reporting bias as males tend to be more severely affected and therefore die earlier in life 5678910.

It is difficult to map out accurately the clinical course of BVVL as most case reports do not give a detailed account of the development of symptoms and signs. However, in the vast majority of cases the first symptom is sensorineural deafness, which is usually progressive and severe. The time between the onset of deafness and the development of other symptoms has been reported to be shorter in males (mean of approximately five years) than in females (mean of almost 11 years) 11. Very rarely, affected cases do not appear to develop deafness, presumably because these individuals die before the hearing impairment develops 9. Other initial presenting features include limb weakness 12131415, respiratory compromise 89, slurring of speech 16, facial weakness 9, and neck and shoulder weakness 17. The age of onset of the initial symptom varies from infancy 2 to the third decade 1819. In a few cases, an intercurrent event, such as an infection, appears to have precipitated the initial symptom or worsened an existing symptom 278122021.

In BVVL, the lower cranial nerves VII to XII are commonly affected, while abnormalities of cranial nerves II to VI occur much less frequently. Cerebellar ataxia was reported in one case 22. Lower motor neuron (LMN) signs are common in the limbs. Upper motor neuron (UMN) involvement, for example brisk reflexes, clonus and extensor plantar responses, is less frequent 56789101113141920212223242526. Sensation is rarely affected, with only one reported case of subjective blunting of pinprick sensation below the knees 16.

Several other neurological features have been seen in patients with BVVL. Abnormalities of the fundi that have been reported include optic atrophy 513202127, retinitis pigmentosa 22 and macular hyperpigmentation 25. Autonomic dysfunction 2132829, epilepsy 218, mental retardation 1225, reduced horizontal eye movements 6 and tremor 925 have also been associated with BVVL.

Of the non-neurological features, respiratory compromise is the most common in BVVL 4567891011121315171920212427282930313233. Other non-neurological features that have been reported include auditory hallucinations 2, behavioral changes 27, color blindness 20, diabetes insipidus 1, delayed puberty and hypogonadism 16, dysmorphic features 25, gynecomastia 16 and hypertension 1133. In some cases, no other associated non-neurological features were reported 3435363738.

The etiopathogenesis of BVVL remains elusive. Two patients with BVVL have been screened for the mutations associated with common forms of spinal muscular atrophy (SMA), the survival motor neuron gene (SMA) and neuronal apoptosis inhibitory protein gene (NAIP), but these proved negative (4,39). There are no other published studies on the investigation of the genetic or molecular pathogenesis of BVVL.

The diagnosis of BVVL is based on the clinical description of the syndrome, as there is no confirmatory test for the condition. The major features of BVVL are the presence of sensorineural deafness, involvement of lower cranial nerves VII to XII and the presence of LMN, and to a lesser extent UMN, signs in the limbs. However, except for the sensorineural deafness, the presence of the other features can be variable. Respiratory compromise is the most common non-neurological feature in BVVL. The other neurological and non-neurological features seen in patients with BVVL described in the section 'Clinical description' are seen much less frequently.

Investigations are usually done to exclude other causes or confirm the clinical signs of the patients. Neurophysiological studies show changes consistent with chronic 57911121314162122252833 or active 6781519202426272933 denervation in muscles. Motor nerve conduction velocities are usually normal. Sensory action potentials are rarely reduced 467. Visual evoked potentials performed in 15 cases showed normal values in seven patients 91425283233 and prolonged latencies in the rest 5710121315192129. Brainstem auditory evoked potentials were abnormal when performed in 17 cases 45810121314152125273233. When carried out, audiometry universally showed sensorineural deafness. Electroencephalogram may show an excess of theta activity or slow waves 5202330. Electrocardiogram showed incomplete right bundle branch block in one case 4. Polysomnography demonstrated predominantly central sleep apnea with minimal obstructive sleep apnea in one case 32.

Magnetic resonance imaging of the brain may show atrophy of the brainstem 212527 and cerebellum 2125, or hyperintensity in the brainstem nuclei 1027, cerebellar peduncles 29, internal capsule 29 or subcortical white matter 29.

Muscle biopsy was carried out on eight patients. In four cases it showed normal muscle histology 691127, in one case it showed increased lipid content and myopathic changes (unspecified) 29, while in the remaining cases there was evidence of grouped atrophic fibres suggesting denervation 57121420222528. Sural nerve biopsies were undertaken in two patients, with one showing axonal depletion 22, while the other was normal 20.

Cerebrospinal fluid examination in BVVL may show mildly elevated protein content 512133033.

There are few pathological descriptions of BVVL available due to the rarity of the condition 712132030. There is usually neuronal injury and loss in the III, V, VI and lower cranial nerve nuclei (VII – XII). However, studies in a two-year old boy 7 and a 10-year old girl 30, revealed normal cranial nerve nuclei III, V and VI. Other neuropathological findings include depletion of spinal anterior horn cells 12132030, degeneration of spinocerebellar 132030 and pyramidal 1320 tracts, degeneration of cerebellar Purkinje cells 20, and abnormalities in the substantia nigra 1213, locus coeruleus 1220, olives 1213, cuneate nucleus 12, gracile nucleus 1220, ambiguous nucleus 71220, dorsal nucleus of Clarke 122030, fastigial nucleus 20, lateral lemnisci 1220, medial longitudinal fasciculus 12, trapezoid body 1213, optic pathways 12 and solitary tract 1220.

There are several conditions that closely resemble BVVL and that should always be considered in the differential diagnosis. It would be unrealistic to expect to make a diagnosis of BVVL in a patient who initially presents with just sensorineural deafness. The development of other cranial nerve and limb involvement in conjunction with sensorineural deafness is likely to be needed to secure the diagnosis with any degree of confidence. Figure 1 provides a diagnostic algorithm to aid in the diagnosis of this rare disorder.

Perhaps the most closely related condition is the progressive bulbar paralysis of Fazio-Londe 40, where the only distinguishing feature from BVVL is the absence of deafness. In fact, in the case reported by Voudris and colleagues 8, deafness was not clinically recognized and was only picked up by brainstem auditory evoked potential testing. In addition, in two of the four cases by Dipti and colleagues 9 who presented early in life, deafness was not thought to be present, possibly implying that the patients died before the deafness had developed.

Amyotrophic lateral sclerosis (ALS) is another alternative diagnosis. However, it does not usually present at a young age and sensorineural deafness is not a feature of this condition.

Another differential of BVVL is the Nathalie syndrome, which is a rare condition characterized by deafness in conjunction with spinal muscular atrophy, cataract, cardiac conduction defects and hypogonadism 41. Interestingly, one reported case of BVVL had a partial right bundle branch block on electrocardiography 4 and another had hypogonadism 16.

The Boltshauser syndrome, which is characterized by distal muscular atrophy with vocal cord paralysis and sensorineural hearing loss, is also very similar to BVVL 42. However, in the former, the brainstem signs are restricted to vocal cord paralysis and the inheritance is likely to be autosomal dominant. Autosomal dominant inheritance is very uncommon in BVVL, with only two possible families reported 56.

The Madras motor neuron disease (MMND) is another condition closely related to BVVL 43. MMND is characterized by wasting and weakness of limb muscles, sensorineural deafness and multiple cranial nerve palsies usually affecting cranial nerves VII, IX and XII. Dysfunction of cranial nerves III and VI has not been reported in MMND 44. Only about 15% of cases of MMND are familial 44, compared to 50% in BVVL 4.

There is no specific treatment for BVVL. Steroids and immunoglobulins have been tried in several cases. Temporary stabilization was reported two patients. In the first, steroids stabilized the condition temporarily for at least eight months 7. Stabilization of the condition for a year was seen in another patient who received intravenous immunoglobulin 11. However, two other patients who received intravenous immunoglobulin failed to show any improvement 2832.

Supportive care and symptomatic treatment are the mainstays of management for BVVL. In a rare condition like BVVL, evidence for the effectiveness of these measures is anecdotal as it would be impossible to carry out randomized controlled trials with the small numbers of patients available. However, the benefit from experience of using these methods in other similar conditions, in particular ALS, can be extrapolated for BVVL: for example, in ALS assisted ventilation and maintenance of nutrition have been proven to improve survival 45.

In BVVL, assisted ventilation has been shown to be useful when respiratory compromise is a major feature. Long-term nocturnal ventilatory support was beneficial in some cases 5691519. Tracheostomy and full ventilatory support was helpful in other cases 8910202428293132. In patients where dysphagia is a major problem, gastrostomy can alleviate its symptoms and maintain good nutritional status 689101328.

The clinical course of BVVL is variable in the 58 cases reported in the literature (Additional file 1). In 26 cases (45%), patients had gradual deterioration (GD), while in 19 cases (33%), there was gradual deterioration with stable periods in between (GDS). Ten patients (17%) had deterioration with abrupt periods of worsening (DW). The clinical course was not known in three cases (5%). At least 21 patients (36%) survived for 10 or more years after the initial symptom. Twenty three patients (40%) survived for five or less years after the onset of the first symptom.

The key unanswered question in BVVL is the molecular pathogenesis of the condition. Although the syndrome is very rare, advances in molecular biotechnology offer hope that the underlying pathogenesis of the disease will be unravelled in the near future.

It is likely that we still do not know the full clinical spectrum of BVVL. Thus, it is important that as more and more cases of BVVL are recognized, these cases continue to be reported in the literature to enhance our knowledge and understanding of this rare progressive neurological disorder. This will enable affected individuals and families to be provided with a better idea of the clinical course, prognosis and management of this debilitating condition.

The author(s) declare that they have no competing interests.

SS identified all the titles and abstracts for the review and wrote the review.