Familiar Meniere's disease restricted to 1.48 Mb on chromosome 12p12.3 by allelic and haplotype association.

Meniere's disease (MD) is a disorder of the inner ear characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. Most MD cases are sporadic, but 5-15% of patients are familial following an autosomal dominant mode of inheritance with incomplete penetrance. We have previously identified a candidate gene region for MD on chromosome 12p12.3 using linkage analysis. We genotyped 15 Swedish families segregating familial MD (FMD) to further clarify the role of chromosome 12p in a larger cohort of families. Highly polymorphic marker loci were analyzed over the 16-Mb candidate region in affected and healthy family members as well as in control subjects. The results revealed allelic association between FMD and several individual polymorphic marker alleles and single-nucleotide polymorphisms. Moreover, a common three-marker haplotype spanning 1.48 Mb co-segregates with FMD in 60% of the families investigated, forming the core of a possible ancestral haplotype associated with FMD in Sweden.

Effects of neurotrophic factors on growth and glial cell alignment of cultured adult spiral ganglion cells.

Adult spiral ganglion cells were cultured in chorus to assess the influence of the neurotrophins brain-derived neurotrophic factor, neurotrophin 3 and glial cell line-derived neurotrophic factor (GDNF) on neurite growth and Schwann cell alignment. Over 1500 measurements were collected using each factor at 10 ng/ml and all three in combination. Evaluation was made with GDNF at concentrations of up to 100 ng/ml. Neurite dimensions were assessed at days 5, 7, 9 and 11 using a computer-based program (Axon Analyzer). GDNF had a strong effect on spiral ganglion cell growth almost attaining the level of all three factors in combination. GDNF increased glial cell alignment and nerve bundle formation. Results show the potential of GDNF to maintain and possibly restore auditory nerve integrity.

Familial Ménière's disease in five generations.

OBJECTIVE: Clinical characterization of a Swedish family followed for five generations. Several members of each generation had Ménière's disease (MD). Possible modes of genetic transmission were assessed. STUDY DESIGN: Retrospective family survey. SETTING: University hospital. Tertiary referral center. PATIENTS: Members of a large family in which several members in each generation were affected by MD. INTERVENTIONS: Hearing levels were assessed, and the patients were asked to complete a questionnaire regarding age at onset, hearing loss, tinnitus, aural fullness, vertigo, and if MD was unilateral or bilateral. Glycerol tests were performed in a few cases. For deceased relatives, information was obtained from patient charts and interviews with relatives. Genetic studies with linkage analysis was performed for the loci DFNA 1, DFNA6/14, DFNA9, and DFNA15. RESULTS: One member of Generation I and, according to patient charts, two members of Generation II could have suffered from MD. In Generations III to V, 9 of 25 members developed inner ear dysfunction. Six of these individuals developed MD that was strictly in accordance with American Academy of Otolaryngology and Head and Neck Surgery, 1995 guidelines criteria, whereas three individuals had unilateral or bilateral hearing impairment, one in combination with benign paroxysmal positioning vertigo, which could represent an incomplete expression of the disease. The mean age at disease onset was 64.5 years in Generation III, 43 years in Generation IV, and 25 years in Generation V. In the genetic studies, none of the regions investigated showed linkage to the disease gene with a significant calculated log of odds ratio (LOD) score above three. CONCLUSION: The pattern of inheritance suggested that familial MD was autosomal dominant and exhibited incomplete expression of inner ear symptoms in some affected members. The decreasing age at onset of disease with succeeding generations could indicate anticipation. None of the hitherto-known DFNA loci, which has phenotypes bearing some resemblance to MD, had haplotypes in common with this large family affected by MD.

A Meniere's disease gene linked to chromosome 12p12.3.

Meniere's disease (MD) is characterized by spontaneous attacks of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. The majority of patients with MD appear sporadic but 5%-13% of the cases have a family history for the disease. The cause of both the sporadic and inherited forms of MD remains unclear despite a number of candidate genes defined from their association with hearing loss. We have performed a genome wide linkage scan on a large Swedish family segregating MD in five generations. Five candidate regions with a lod score of >1 were identified. Two additional families with autosomal dominant MD were analyzed for linkage to these regions and a cumulative Z(max) of 3.46 was obtained for a single region on chromosome 12p. In two of the three families, a shared haplotype was found to extend over 1.7 Mb which suggests a common ancestral origin. Within this region, a single recombination event restricts the candidate region to 463 kb.

Effects of intratympanic injection of latanoprost in Meniere's disease: a randomized, placebo-controlled, double-blind, pilot study.

OBJECTIVE: To determine the short-term effects of latanoprost, a selective FP prostanoid receptor agonist, in Meniere's disease. STUDY DESIGN AND METHODS: Latanoprost was administered by intratympanic injection once daily for 3 days. Before the first injection (day 1) and on days 5 and 15, hearing and tinnitus were determined. The patients assessed vertigo on a visual analogue scale on days 1-15. The study was randomized, double-blind, and placebo-controlled. RESULTS: Latanoprost reduced vertigo/dysequilibrium around 30% (P < 0.05), and improved speech discrimination around 15% (P < 0.05). Tinnitus loudness deteriorated after injection of placebo (P < 0.01) but not after latanoprost. Side effects were few. CONCLUSION AND SIGNIFICANCE: Latanoprost alleviated vertigo/dysequilibrium and improved hearing. The results indicate that the drug potentially could be useful for treatment of Meniere's disease.

Synaptophysin immunohistochemistry in the human cochlea.

Light microscopy and immunohistochemical analyses of a freshly prepared human cochlea, removed at meningioma skull base surgery, were performed with particular emphasis on synaptophysin (SY) reactivity. Synaptophysin, a 38-kDa glycoprotein, is one of the most abundant integral membrane proteins of small presynaptic vesicles and is a useful marker for sites of synaptic transmission of the efferent olivocochlear system in the cochlea. Following fixation and decalcification, cryosections of 30 microm were prepared. To introduce immunostaining, free-floating sections were exposed to monoclonal SY antibody. Positive SY immunostaining was solely restricted to the neural and sensory structures and did not include supporting cells of the organ of Corti. Dense reaction products were noted around the hair cells, especially at the basal portion of the inner and outer hair cells and their neural poles, as well as around the inner spiral bundle, tunnel spiral bundle, outer spiral bundle and upper tunnel crossing fibers. The majority of spiral ganglion cells stained positively. An intermingling network of thin unmyelinated nerve fibers stained densely, especially at the basal portions of the cochlea. The spiral limbus, inner and outer sulcus cells, basilar membrane, myelinated nerve fibers, spiral ligament and the stria vascularis were unstained. Human cochlea obtained during surgery offers excellent conditions for immunohistochemical analysis. In the basal cochlea in the organ of Corti, outer hair cell area, there may be alterations due to noise trauma from the drilling procedure.

Fourth branchial pouch sinus with recurrent deep cervical abscesses successfully treated with trichloroacetic acid cauterization.

A previously healthy 13-year-old girl presented with a left-sided deep cervical abscess. A CT scan demonstrated an abscess in the lower neck, anterior to the common carotid artery. Treatment with i.v. antibiotics and incision drainage resolved the condition. A recurrence of the abscess 7 months later was treated identically. Further investigations with MRI showed a 2-3-mm wide, 10-mm long structure in the lateral aspect of the left thyroid lobe. A barium radiograph depicted a narrow, 20-mm long fistula originating from the left pharynx. At endoscopy a 2-3-mm wide opening was found at the left pyriform sinus apex. This, together with the radiological findings, verified the diagnosis of a 4th branchial pouch sinus. The recurrence of the abscess may have been due to contamination by infectious pharyngeal secretions. Although radical surgical excision is traditionally recommended for this condition a non-invasive treatment, namely chemocauterization with 40% trichloroacetic acid (TCA), was chosen in this case. Three cauterizations were needed to close the pyriform sinus opening. To date (Month 14) there has been no recurrence of the cervical abscesses. TCA chemocauterization seems to be a safe first-line treatment for patients with a pyriform sinus fistula.

[A case report: anomaly of the fourth branchial pouch with recurring cervical abscesses. Cauterization with trichloroacetic acid closed the fistula opening and cured the patient]. / Fallbeskrivning: anomali i fjärde gälfickan med recidiverande halsabscesser. Etsning med triklorättiksyra tillslöt fistelmynning och botade patienten.

A fourth branchial pouch sinus is a rare congenital anomaly, which in a 13-year-old girl presented clinically as recurrent deep cervical abscesses. The location of the majority of these anomalies is the left side of the neck (90%). Radiological and endoscopic investigations verified the diagnosis. The internal orifice located at the apex of the pyriform sinus could facilitate contamination by infectious pharyngeal secretions and lead to abscess recurrence. Traditionally, the recommended treatment is radical surgery. It can, however, be technically difficult to excise the whole fistula tract. In this patient we used a non-invasive treatment modality; chemocauterization with 40% trichloroacetic acid (TCA). After three treatments the fistula was closed. To date (month no. 15) there has been no abscess recurrence. TCA chemocauterization seems to be a safe first-line treatment for patients with pyriform sinus fistulas.

Vascular occlusion in the endolymphatic sac in Meniere's disease.

In 2 patients with severe Meniere's disease (MD), there was histologic evidence of occlusion of the vein of the vestibular aqueduct (VVA). This finding coincided with total or partial occlusion of numerous small vessels around the endolymphatic sac (ES), flattening of epithelium, extensive perisaccular fibrosis, and signs of new bone formation. Ultrastructural analysis of the occluding material showed foci with dense connective tissue, calcification, lipid deposits, and layers of basement membrane, sometimes concentrically arranged. The exact nature of the occluding material was unknown. In another 2 MD patients, the VVA was not visualized, and the ES vessels showed no signs of occlusion. Seven controls with acoustic schwannoma or meningioma had normal vasculature. The presence of vascular impairment in the ES in MD patients indicated that altered hemodynamics may contribute to the pathogenesis of endolymphatic hydrops and MD.