Bilateral vestibular schwannomas in older patients: NF2 or chance?

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant condition with high spontaneous mutation rate which predisposes to the development of multiple nerve sheath tumours (schwannomas), meningiomas and ependymoma. The cardinal feature and main diagnostic criterion for the diagnosis of NF2 remains the development of bilateral vestibular schwannoma (BVS). With increasing use of MRI screening the possibility of a 'chance' diagnosis of BVS has been mooted with a potential frequency of one in two million people in their lifetime. Until now, however, no evidence for such an event has been published. We aimed to demonstrate that chance occurrence can occur and to estimate its frequency among those with just BVS late in life. METHODS: Two vestibular schwannomas from the same patient were DNA sequenced and underwent loss of heterozygosity analysis. RESULTS: We show that a man who developed BVS, at ages 52 and 67 years developed these tumours sporadically by demonstrating that there were no molecular events in common between the two tumours. Furthermore from a database of over 1200 patients with NF2, we have estimated that ~25% of cases of BVS over 50 years and 50% over 70 years of age where no other features of NF2 are present represent a chance occurrence rather than due to an underlying mosaic or constitutional NF2 mutation. CONCLUSIONS: Patients presenting with BVS later in life should be appraised of the potential likelihood they may not have NF2 and the resultant further reduction in risks of transmission to offspring.

Outcome of translabyrinthine surgery for vestibular schwannoma in neurofibromatosis type 2.

OBJECTIVES: To analyse the long-term outcome of translabyrinthine surgery for vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2). RESEARCH TYPE: Retrospective cohort study. SETTING: Two tertiary referral NF2 units. PATIENTS: One hundred and forty eight translabyrinthine operations for patients with VS were performed. Preoperative stereotactic radiotherapy had been performed on 12(9.4%) patients. RESULTS: Mean tumour size was 3.1 cm. Total tumour excision was achieved in 66% of cases, capsular remnants were left in 24% of cases, and subtotal excision was achieved in 5% and partial removal was achieved in 5%. The radiological residual/recurrence rate was 13.9%. The perioperative mortality was 1.6%. At 2 years postoperatively, facial function was expressed in terms of House-Brackmann score (HB): HB 1 in 53.4%, HB 1/2 in 61.3%, HB 1-3 in 83.2% and HB 4-6 in 16.8%. All nine patients who underwent surgery following failed stereotactic radiotherapy had HB 3 function or better. Among 9.5% of the cases, 14 facial nerves were lost during surgery and repaired using direct anastomosis or grafting. There was no tinnitus present preoperatively in 27% of the cases, and 22% of patients developed tinnitus postoperatively. In patients with preoperative tinnitus, 61% remained the same, 17% got it resolved and only in 21% it worsened. The preoperative hydrocephalus rate was 26%, and among 15% of the cases five ventriculo-peritoneal (VP) shunts were performed. The cerebrospinal fluid leak rate was 2.5%. Fifty-six patients underwent auditory brainstem implantation (ABI) and two patients had cochlear implant (CI) sleepers inserted. CONCLUSIONS: The management of patients with NF2 presents the clinician with a formidable challenge with many patients still presenting themselves late with the neurological compromise and a large tumour load. There is still an argument for the management by observation until the neurological compromise dictates interventional treatment particularly with the option of hearing rehabilitation with ABI or CI. The translabyrinthine approach provides a very satisfactory means of reducing the overall tumour volume.

The relationship between patients' perception of the effects of neurofibromatosis type 2 and the domains of the Short Form-36.

OBJECTIVES: To investigate the relationship between those issues concerning quality of life in patients with neurofibromatosis type 2 (NF2) as identified by the closed set NF2 questionnaire and the eight norm-based measures and the physical component summary (PCS) and mental component summary (MCS) scores of the Short Form-36 (SF-36) Questionnaire. DESIGN: Postal questionnaire study. SETTING: Questionnaires sent to subjects' home addresses. PARTICIPANTS: Eighty-seven adult subjects under the care of the Manchester Multidisciplinary NF2 Clinic were invited to participate. MAIN OUTCOME MEASURES: Sixty-two (71%) completed sets of closed set NF2 questionnaires and SF-36 questionnaires were returned. RESULTS: Subjects with NF2 scored less than the norm of 50 on both the physical component summary and mental component summary scores and the eight individual norm-based measures of the Short Form-36 questionnaire. Correlations (using Kendall's tau) were examined between patients' perceptions of their severity of difficulty with the following activities and the eight norm-based measures and the physical component summary and mental component summary scores of the Short Form-36 questionnaire: Communicating with spouse/significant other (N = 61). The correlation coefficients were significant at the 0.01 level for the mental component summary score, together with three of the norm-based scores [vitality (VT), social functioning and role emotional]. Social communication (N = 62). All 10 correlations were significant at the 0.01 or 0.001 level. Balance (N = 59). All 10 correlations were highly significant at the P < 0.001 level. Hearing difficulties (N = 61). All correlations were significant at either the 0.01 level or less apart from the mental component summary score and three of the norm-based scores (role physical, VT and mental health). Mood change (N = 61). All correlations were significant at the 0.01 level or less, apart from one norm-based score (role physical). CONCLUSIONS: The Short Form-36 questionnaire has allowed us to relate patients' perceptions of their difficulties, as identified by the closed set NF2 questionnaire, to the physical and mental domains measured by this validated and widely used scale, and has provided further insight into areas of functioning affected by NF2.

The role of nervus intermedius in side specific nasal responses.

BACKGROUND: Nervus intermedius (NI) dysfunction is common in patients who have had vestibular schwannoma (VS) surgery. Such patients have a unilateral parasympathetic-denervated nasal cavity. A number of side-specific nasal reflexes have been demonstrated in normal individuals, including hand cold-water immersion. It is not understood whether these reflexes have parasympathetic or sympathic efferent pathways. We aimed to evaluate the side specific nasal reflex to cold-water immersion in post-operative VS patients with NI dysfunction, in order to determine the nature of the efferent pathway of these reflexes. METHOD: Side specific responses to cold-water immersion were tested by acoustic rhinometry in 10 normal individuals and 18 patients with NI dysfunction (proven by Schirmer s test) after VS surgery. RESULTS: A consistent pattern of ipsilateral congestion and contralateral decongestion after the cold-water immersion was seen in normal individuals (p smaller than 0.001). We found no consistent response in VS patients both ipsilateral and contralateral to the side of NI dysfunction. CONCLUSIONS: We confirm the consistent side-specific nasal reflexes to cold-water hand immersion in normal individuals. This is disturbed in patients with NI dysfunction. We have also shown unexpectantly that the contralateral side-specific reflex is disturbed in these patients. These data suggest that the reflex is parasympathetic and crosses the midline.

Use of a closed set questionnaire to measure primary and secondary effects of neurofibromatosis type 2.

OBJECTIVES: To identify the greatest difficulties reported by people affected by neurofibromatosis type 2, and to determine the relationship between the primary and secondary effects of the disease. DESIGN: Postal questionnaire study. SETTING: Questionnaire sent to subjects' home addresses. PARTICIPANTS: Eighty-seven adult patients under the care of the Manchester multidisciplinary neurofibromatosis type 2 team were invited to take part. MAIN OUTCOME MEASURE: The response rate was 62 out of 87 (71 per cent). RESULTS: Respondents' answers emphasised that their greatest problem was deafness, which resulted in communication difficulties with social contacts, close partners, family and friends. Correlation coefficients indicated a relationship between general mood changes and hearing difficulties, social communication problems, balance difficulties and mobility problems. Self-confidence was significantly related only to social communication problems. CONCLUSIONS: The use of a closed set neurofibromatosis type 2 questionnaire identified hearing problems and subsequent communication difficulties as the main problems faced by people with this condition.

Further genotype--phenotype correlations in neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype-phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non-VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.

Vestibular schwannoma: role of conservative management.

OBJECTIVE: To assess the outcome of conservative management of vestibular schwannoma. STUDY DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: Four hundred and thirty-six patients with vestibular schwannoma (490 tumours), including 327 sporadic tumours and 163 tumours in 109 patients with neurofibromatosis type two. MAIN OUTCOME MEASURES: The relationship of tumour growth to tumour size at presentation, and to certain demographic features. RESULTS: The initial tumour size was significantly larger in the neurofibromatosis type two group (11 mm) than in the sporadic vestibular schwannoma group (5.1 mm). In both groups, 68 per cent of tumours did not grow during follow up (mean 3.6 years; range one to 14 years). The mean growth rate was 1.1 mm/year (range 0-15 mm/year) for sporadic tumours and 1.7 mm/year (range 0-18 mm/year) for neurofibromatosis type two tumours. The tumour growth rate correlated positively with tumour size in the sporadic tumour group, and correlated negatively with age in the neurofibromatosis type two group. CONCLUSION: Two-thirds of vestibular schwannomas did not grow. Radiological surveillance is an acceptable approach in carefully selected patients. Once a sporadic vestibular schwannoma reaches 2 cm in intracranial diameter, it is likely to continue growing. We do not recommend conservative management for sporadic tumours with an intracranial diameter of 1.5 cm or more. Vestibular schwannoma management is more complex in patients with neurofibromatosis type two.

Trigeminal schwannomas.

Trigeminal schwannomas are the second most common intracranial schwannoma. They may occur sporadically or in association with neurofibromatosis type 2. The vast majority are benign in nature although malignancies have been reported. They may present with a range of symptoms because of their variable locations in areas with multiple differing functional activities. There is little understanding of the natural history of these tumours, and the choice of treatment includes surgery, stereotactic radiosurgery and fractionated radiotherapy. This article reviews the management options and outcomes. The incidence of recurrence and the time interval following treatment to recurrence is unpredictable.

Imaging appearances of unusual conditions of the middle and inner ear.

Requests for imaging of patients complaining of deafness and other symptoms related to the petrous bone are becoming increasingly common. Although much of this work is related to the exclusion of vestibular schwannomas by MRI, high-resolution CT is available in most departments and is necessary for the evaluation of many conditions of the middle ear and bony labyrinth. In this pictorial review, some of the more unusual conditions that may be encountered in the middle and inner ear are presented, which might not be overly familiar to non-otological radiologists, illustrating the roles of CT and MRI.

Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma?

Early onset of vestibular schwannoma (VS) is associated with the inherited condition neurofibromatosis type 2 (NF2). However, the majority of NF2 presents bilaterally and the proportion of early-onset apparent sporadic unilateral VS because of NF2 remains to be determined. We have determined the risk by studying NF2 risk in a population-based set of VS, looking at the mode of presentation in a large NF2 data set and the outcome of NF2 mutation analysis in 148 sporadic unilateral VS. The risk of NF2 in an apparently sporadic case of unilateral VS is small apart from in the very youngest age group (<20 years). NF2 germ line mutation testing is unlikely to reveal a mutation except <20 years as a result of the low risk and high rates of mosaicism. Germ line mutation testing is probably only justified in sporadic unilateral VS <20 years unless other features of NF2 are present. Ideally mutation testing should start with the original tumour specimen.

Predictors of audiological outcome following cochlear implantation in adults.

The objective of this study was to examine variables that may predict open set speech discrimination following cochlear implantation. It consisted of a retrospective case review conducted in a tertiary referral centre with a cochlear implant programme. The patients were 117 postlingually deafened adult cochlear implant recipients. The main outcome measures were Bench, Kowal, Bamford (BKB) sentence scores recorded nine months following implant activation. The variables studied were age at the time of surgery, sex, duration of hearing loss, aetiology of hearing loss, residual hearing, implant type, speech processor strategy, number of active electrodes inserted. Variables found to have a significant effect on BKB following univariate analysis were entered into a multivariate analysis to determine independent predictors. Multivariate ordinal regression analysis gave an odds ration of 1.09 for each additional year of deafness prior to implantation (confidence interval 1.06-1.13; p < 0.001). Duration of deafness prior to implantation is an independent predictor of implant outcome. It accounted for 9% of the variability. Other factors must influence implant performance.

Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification.

BACKGROUND: Neurofibromatosis type 2 (NF2) is almost unique among inherited disorders in the frequency of mosaicism in the first affected generation. However, the implications of this on transmission risks have not been fully elucidated. METHODS: The expanded database of 460 families with NF2 and 704 affected individuals was analysed for mosaicism and transmission risks to offspring. RESULTS: 64 mosaic patients, with a projected mosaicism rate of 33% for sporadic classical NF2 with bilateral vestibular schwannoma at presentation and 60% for those presenting unilaterally, were identified. Offspring risks can be radically reduced on the basis of a sensitive mutation analysis of blood DNA including multiple ligation-dependent probe amplification (MLPA, which detects 15% of all mutations), but even MLPA cannot detect high levels of mosaicism. CONCLUSION: The chances of mosaicism in NF2 and the resultant risks of transmission of the mutation to offspring in a number of different clinical situations have been further delineated. The use of MLPA in this large NF2 series is also reported for the first time.

The genetics of otosclerosis: pedigree studies and linkage analysis.

Otosclerosis is one of the commonest causes of hearing loss in adults. The hereditary nature of the disease has been acknowledged for over a century but the precise genetic basis of the disorder has as yet not been characterised. It is currently recognised that familial otosclerosis exhibits autosomal dominant inheritance with variable penetrance and expression. More recently, family linkage studies have identified three chromosomal regions that can be ascribed to this disorder: otosclerosis 1 on chromosome 15, otosclerosis 2 on chromosome 7 and a third locus on chromosome 6. The genes responsible for the disease within these regions remain to be defined. The work presented in this paper firstly examined the familial nature of the disease in a cohort of individuals that had undergone surgery for otosclerosis. Following detailed ascertainment, pedigrees were constructed for subsequent genetic analysis. The laboratory analysis included linkage analysis of the candidate region on the long arm of chromosome 15, linkage analysis of the aggrecan protein gene within the 15q region and linkage analysis to chromosome 7q. The pedigree studies confirmed the hereditary nature of otosclerosis and the recognised mode of inheritance. Linkage to the chromosome 15 locus, the candidate aggrecan gene and the chromosome 7 locus was excluded, confirming that otosclerosis exhibits locus heterogeneity.

Cochlear implant outcomes and quality of life in the elderly: Manchester experience over 13 years.

OBJECTIVES: To objectively evaluate the clinical and functional outcomes of cochlear implantation in an elderly population. DESIGN: Retrospective comparative study. SETTING: Neurotology unit at Manchester Royal Infirmary, a supraregional tertiary referral centre in collaboration with Adult Cochlear Implant Programme at The University of Manchester. PARTICIPANTS: All cochlear implant procedures (38) undertaken on post-lingually deafened elderly patients (age range at the time of implantation 65-80 years, n = 34) in the period from 1989 to 2002. MAIN OUTCOME MEASURES: Medical and surgical outcomes. Audiological performance outcomes for isolated words, words in sentences in quiet and noise. Functional outcome measures used are self-reported measures of the social, psychological and emotional aspects of quality of life, and the differences between expectations for functional outcomes and the realization of functional outcomes. They included expectation profiles, Glasgow Benefit inventory (GBI) and Glasgow Health Status Inventory Questionnaire (GHSI). RESULTS: There was statistically significant improvement post-implantation of both open and closed set test scores (P < 0.01). Eighty-two percentage of patients were completely satisfied with their cochlear implants. Patients judged that implantation restored half the loss of quality of life that they had experienced as a result of severe-profound deafness with a highly significant (P < 0.001) improvement in overall quality of life after implantation. The commonest post-operative observation was transient mild pyrexia. CONCLUSIONS: The age of a cochlear implant candidate should not be a factor in the candidacy decision-making process. The quality of life of our elderly recipients was significantly improved after cochlear implant.

Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes.

In recent years the use of radiation treatment for benign tumours has increased with the advent of stereotactic delivery and, in particular, single high dose gamma knife therapy. This has been particularly true for benign CNS (central nervous system) tumours such as vestibular schwannoma, meningioma, pituitary adenoma, and haemangioblastoma. While short term follow up in patients with isolated tumours suggests this treatment is safe, there are particular concerns regarding its use in childhood and in tumour predisposing syndromes. We have reviewed the use of radiation treatment in these contexts with particular regard to malignant transformation and new tumour induction. This review indicates that much more caution is warranted regarding the use of radiation treatment for benign tumours in childhood and in tumour prone conditions such as the neurofibromatoses.

Cerebrospinal fluid leak rate after the use of BioGlue in translabyrinthine vestibular schwannoma surgery: a prospective study.

OBJECTIVE: To determine the effectiveness of BioGlue surgical adhesive in dural and middle ear closure after translabyrinthine vestibular schwannoma surgery. STUDY DESIGN: A prospective study. SETTING: Tertiary neurotological referral center. PATIENTS: There were 24 patients in the BioGlue series. BioGlue was used in the same manner in all cases. All patients received similar postoperative care. INTERVENTIONS: We studied the use of BioGlue and its possible effect on further reducing our department's cerebrospinal fluid leak rate for translabyrinthine vestibular schwannoma surgery. MAIN OUTCOME MEASURES: Postoperative events were documented that enabled us to determine the overall cerebrospinal fluid leak rate (including incidence of various leak routes and morbidity). RESULTS: The overall cerebrospinal fluid leak rate was 62.5% (15 of 24). Rhinorrhoea was the commonest route (80%), followed by postaural wound leak (33.3%) and external auditory canal otorrhoea (33.3%). Forty percent of cases had more than one cerebrospinal fluid leak route; 73.3% of leak cases required lumbar drain insertion, 40% needed pressure bandaging, and 66.7% had to undergo formal surgical repair. Forty percent had recurrent leaks after the initial episode had completely ceased. The mean extra stay in hospital as a result of the cerebrospinal fluid leak was 13.3 days. CONCLUSION: Our preliminary prospective study of the use of BioGlue for dural and middle ear closure in translabyrinthine vestibular schwannoma surgery demonstrated poor results. The high cerebrospinal fluid leak rate associated with the unusual presentations and ensuing management difficulties in controlling these leaks lead us to recommend that BioGlue not be used in translabyrinthine vestibular schwannoma surgery. The manufacturers have noted our results and have considered adding our recommendation to the product data sheet.

Epilepsy following middle-fossa extradural retraction: implications for driving.

New-onset epilepsy has several social and financial repercussions. Development of seizures after middle-fossa surgery is uncommon. We present two subjects who developed epilepsy following middle-fossa surgery, requiring treatment with anticonvulsants, and discuss the implications.

Stenosis of the internal auditory meatus masquerading as bilateral vestibular schwannomas: a cautionary tale.

Stenotic malformations of the internal auditory meatus (IAM) are rare. They are known to symptomatically mimic vestibular schwannomas leading to potential diagnostic error. We present a case (along with literature review) where a stenotic IAM was clinically and radiologically misdiagnosed as a vestibular schwannoma.

Metastatic carcinoma mimicking a facial nerve schwannoma: the role of computerized tomography in diagnosis.

Secondary deposits in the temporal bone are uncommon but well recognized. Such tumours may involve the facial nerve by direct extension of the destructive process into the fallopian canal. We present a rare case of metastasis from a breast carcinoma in the facial nerve itself, involving the nerve in the internal acoustic meatus with extension into the labyrinthine segment, the first genu and into the middle-ear segment. The rest of the temporal bone was not involved. The lesion resembled a facial schwannoma on a routine magnetic resonance (MR) image. The diagnosis was confirmed after a post-operative computed tomography (CT) scan showed another separate secondary deposit in the basisphenoid. Histology was consistent with secondary tumour from a breast carcinoma. The case highlights the importance of keeping a high degree of suspicion for metastatic tumours in patients with a previous history of malignancy and the usefulness of CT scan in the evaluation of such cases.