Familial Ménière's disease: clinical and genetic aspects.

BACKGROUND AND PURPOSE: Ménière's disease is not uncommon, with an incidence in Caucasians of about one in 2000. The incidence peaks in the fifth decade. Cases are usually isolated or sporadic, but in perhaps five per cent other family members are affected. We report here the clinical and genetic characteristics of a comprehensive set of familial Ménière's disease cases from the UK. METHODS: Forty-six affected families were studied. All cases were diagnosed using the American Academy of Otolaryngology-Head and Neck Surgery committee on hearing and equilibrium 1995, or more stringent, criteria. OUTCOMES AND RESULTS: Autosomal dominant inheritance with reduced penetrance was the most likely mode of inheritance overall. Apparent genetic anticipation was observed, but may also be a result of ascertainment bias given the collection strategy. There was also a slight tendency for cases to result from maternal transmission within the families in this set. The family pedigrees are presented, and the authors have also set up a website at which all the pedigrees may be viewed in greater detail.

Anticipation in Menière's disease.

The aetiology of Menière's disease (MD) remains obscure, but is likely to be multifactorial, one of the factors being a genetic predisposition. Forty-one families with more than one living member with MD were ascertained and affected and normal relations examined. Blood was collected and DNA extracted and stored. In these families the mode of inheritance is autosomal dominant, the penetrance of the mutation being about 60 per cent. Some of the family members exhibit a partial syndrome, vestibular symptoms predominating. Sporadic and familial cases exhibit the same clinical features. The striking finding is the phenomenon of anticipation, whereby with successive generations there is an earlier age of onset and a tendency to more severe manifestation. The inference, considering that the cells which regulate endolymph are of neuroectodermal origin, is that, like other neurodegenerative disorders which show anticipation, MD manifestation is likely to be related to trinucloetide expansion within a gene.

On genetic and environmental factors in Menière's disease.

The etiology of Menière's disease (MD) remains obscure. Previous studies have shown a highly significant association between sporadic MD and one of the human leukocyte antigen, HLA-C genotypes, whereas disease activity has been related to the detection of enterovirus-specific viral protein (VP1) in the peripheral circulation. This present research extends the HLA association of sporadic cases to the study of families with more than one living member with unequivocal MD. Since the sporadic HLA associations point to chromosome 6 being a candidate region of a possible MD mutation, this area of the human genome has been investigated first; DNA suitable for study by other markers has been stored. The presence or absence of VP1 in the familial MD patients has been measured and related to disease activity at the time of sample collection. The association, in both sporadic and familial cases, of MD and partial HLA class I haplotypes points to a likely MD locus lying between the HLA-C and HLA-A loci on the short arm of chromosome 6. The significant relation between disease activity and circulating VP1 has been confirmed. It is likely that the predisposition to familial MD is attributable to a mutation on chromosome 6, which has been designated M1.

Bilateral cerebellopontine angle tumors in neurofibromatosis type 2.

In a series of over 500 cases of cerebellopontine angle tumors, 19 patients had bilateral neurinomas. Four of these tumors arose from the facial rather than the acoustic nerve. A conservative policy regarding surgery had been adopted in an effort to prevent hearing loss for as long as possible. Nevertheless, all patients operated on in this series are now totally deaf. The results of managing these patients surgically and conservatively are discussed.

Hearing conservation in acoustic neuroma surgery via the posterior fossa.

An increasing number of patients with an acoustic neuroma present with useful hearing in the tumour ear. Surgical removal of these tumours via the posterior fossa route may enable preservation of the cochlear nerve and otic capsule without increasing the morbidity to the facial nerve. The results of treating 51 cases of acoustic neuroma via the posterior fossa is presented. Forty four tumours measured less than 20 mm in diameter in the cerebellopontine angle and surgery was undertaken with hearing preservation as a principle objective. In 26 cases, the cochlear nerve was preserved anatomically and post-operative hearing at levels better than mean pure tone threshold of 50 dB or 50 per cent speech discrimination was recorded in 14 patients. The preservation of hearing represents a worthwhile surgical goal in selected patients with an acoustic neuroma without increasing the operative morbidity.

Primary facial nerve tumors within the skull.

In a series of 527 cerebellopontine angle tumors, there were 416 cases of acoustic nerve tumors and 14 cases of primary tumor of the facial nerve in the petrous bone or intracranial cavity. Six additional patients were presumed to have facial tumors, although they were not operated on. Of the 14 verified facial nerve tumors, all but two were neurinomas and 11 had important intracranial extensions into the middle and/or the posterior fossa. In most of these 14 cases, surgical removal was performed via the translabyrinthine route, which is advantageous in that it displays the characteristic relationship of the tumor to the facial nerve, and facilitates nerve repair. The clinical and radiological features of these facial nerve lesions are discussed and also the indications for surgical treatment which, as the unoperated cases illustrate, is not always necessary.

Epidermoid and cholesterol cysts in the apex of the petrous bone.

Cystic lesions in the petrous apex are nearly always either epidermoid cysts, with a soft but solid content, or cholesterol cysts, containing brown fluid. They may be symptomless, produce progressive cranial nerve palsies or, occasionally, reach the CSF pathways thus leading either to meningitis or a CSF leak. Thirteen cases and four unverified cases have been encountered amongst a series of more than 500 cerebellopontine angle tumours. Their clinical features, radiological diagnosis and difficulties of surgical approach are discussed.

'Otology at the crossroads' (the second Morell MacKenzie address).

It is an honour for an otological surgeon to be asked to deliver the second Sir Morell MacKenzie address. Thank you for the invitation and for that honour. Exactly 100 years ago MacKenzie, with Norris Wolfenden, founded 'The Journal of Laryngology and Rhinology'. 'Otology' was not added to the title until 1892, the year MacKenzie died. I shall return to this theme later. It is also exactly 100 years since, in 1887, MacKenzie was asked by Queen Victoria to examine her son-in-law, Frederick, Crown Prince of Germany. The controversy and subsequent recrimination which flowed from the management of Frederick's laryngeal lesion I shall leave to future lecturers to assess. It is as the founder of British laryngology that he should be remembered. As early as 1863 he had started the Metropolitan Free Dispensary for Diseases of the Throat and Loss of Voice, the first institution of its kind in the world. He wrote authoritatively on diseases of the throat and invented many instruments for the difficult art of indirect laryngeal and pharyngeal surgery. He received his Knighthood, also in 1887.

Immune status in patients with Menière's disease.

Sera of 164 patients with classical Meniere's disease were screened for autoantibodies, immune complexes and HLA status. Increased thyroid microsomal antibodies were significant in those patients in the 40- to 60-year age range. Raised IgM complexes and C1q component of complement were significant in all age groups. Low levels of IgA complexes were a consistent finding and were significantly lower in the HLA Cw7 group. Patients with migraine had no increased incidence of immune disturbances.

Predictive tests for Meniere's disease.

The prognostic value of electrocochleography and of the glycerol dehydration test in Meniere's disease is well recognized. Abnormal electrocochleographic waveforms carry a poorer prognosis. After adequate dehydration, significant threshold changes for better or worse predict the likely course of events following endolymphatic sac surgery. Meniere's disease frequently becomes bilateral. Vestibular aqueduct tomography in patients with Meniere's disease gives very different results, in both ears, compared with those in control patients. The acetazolamide cochlear hydration test can help detect latent hydrops. Plasma osmolality studies are an essential part of all these tests. Otoadmittance investigations show significantly higher baseline values in fluctuant endolymphatic hydrops compared with nonfluctuant Meniere's disease or control subjects. When the hearing improves after dehydration there is a paradoxical increased resistance to the flow of sound energy through the inner ear. Reduced hearing after glycerol is associated with an increase in maximum conductance or a decreased cochlear resistance. Otoadmittance studies on the "normal" ear of patients with "unilateral" Meniere's disease show similar abnormalities and changes. A study of serum levels of immune complexes and complement in patients with Meniere's disease shows elevated levels compared with controls. As yet the significance of this finding is unclear, though it may be related to disease activity.

HLA antigens in the pathogenesis of Menière's disease.

In the Department of Otolaryngology of the London Hospital many clinical and laboratory investigations have been conducted over the past fifteen years in an attempt to unravel some of the mysteries of Menière's disease. Many of these have been directed towards diagnosis, prognosis or therapy. Some have had a bearing on the aetiology of the idiopathic disease--these were summarised by Morrison (1981), including the finding of an hereditary predisposition, of an association with migraine in a significant proportion, also familial, of a 'personality type' of patient with Menière's disease and of typical radiological changes in the skull base in the majority of sufferers. More recently Brookes (1985), writing from this department, drew attention to both the occasional finding of an association between endolymphatic hydrops and elevated levels of circulating immune complexes, and also to the immunological studies in progress in patients with Menière's disease. These latter early results were reported by Morrison (1984) and are summarised in Table I. There was a highly significant difference between the levels of circulating complement and of immune complexes in patients with Menière's disease compared with control patients. There was, however, no difference in the results of autoantibody screening nor in the levels of serum immunoglobulins between the groups.

Unilateral Meniere's disease: is the contralateral ear normal?

Certain investigations in patients with unilateral Meniere's disease may on occasion show abnormalities in the completely symptomless contralateral ear. These tests include transtympanic electrocochleography, the acetazolamide cochlear hydration test, vestibular aqueduct tomography, and caloric testing. Eventually these ears may well become symptomatic. Previous studies have shown that otoadmittance changes are a sensitive indicator of glycerol-induced intracochlear pressure alterations in hydropic ears, but do not occur in patients without Meniere's disease. Otoadmittance parameters were evaluated in the asymptomatic ears of 73 consecutive patients with unilateral Meniere's disease. Satisfactory traces and adequate dehydration were achieved in fifty-nine. A significant change in the maximum conductance, similar to that often seen in symptomatic hydropic ears, was found in twenty-four cases (40.7%). The presence of functional abnormalities in well over one-third of asymptomatic ears means that they cannot be used as controls in clinical research studies. Furthermore, recognition of contralateral latent hydrops at the initial otologic assessment may modify the subsequent treatment strategy.

Acoustic Neuroma Suspicion Index: an aid to investigation and diagnosis.

A clinical scale, the Acoustic Neuroma Suspicion Index (ANSI) is presented. It was based initially on the retrospective analysis of 397 patients suspected of having an acoustic neuroma of whom, following full investigation, 263 (66%) were found to have space occupying lesions. After minor modifications, the Index was re-tested on 98 patients of whom 56 proved to have tumors while 47, who did not, formed a control group. All tumor cases were confirmed surgically. Neuro-otological investigations can be expensive, time consuming and occasionally unpleasant for patients; furthermore they are not always readily available. Though the diagnosis of an acoustic tumor or other cerebellopontine angle lesion is often straightforward, atypicality of presentation occurs often. The ANSI uses simple selected data from the history and clinical examination, with routine audiological, vestibular and radiological investigations to calculate a score. If this score exceeds the predetermined threshold, further investigations should be undertaken.

Otoadmittance changes following glycerol dehydration in Meniere's disease.

Otoadmittance studies were undertaken in 76 patients with Meniere's disease and 8 control subjects undergoing glycerol dehydration. Baseline otoadmittance values were significantly higher in ears with fluctuant hydrops compared to the non-fluctuant ears (p less than 0.01), suggesting that there is a pathophysiological difference between these clinical Meniere's groups. Significant maximum conductance changes were seen in 53.4% of hydroptic ears, and were associated with subjective audiometric threshold shifts in 23.2%. Similar changes were not seen in the control ears. These findings provide further clinical evidence to support an underlying physical basis for the auditory symptoms of endolymphatic hydrops and the effects of glycerol dehydration on the inner ear. Objective otoadmittance changes appear to be a more sensitive indicator of reversible hydrops than conventional audiometry. Possible mechanisms to explain the somewhat paradoxical increase in the resistance to the flow of sound energy through the cochlea following reduction of the endolymphatic hydrops by glycerol dehydration are discussed.