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.

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.

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.

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.

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.

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.

Cortical plasticity in the first year after cochlear implantation.

This study aimed to investigate changes in auditory and visual cortical activity over the first year following cochlear implantation using (18)F-fluorodeoxyglucose positron emission tomography. Subjects underwent scanning prior to the initial implant activation (control), after one to two months of implant use (early activation) and after one year of implant use (late activation). All subjects had activation of the auditory cortices. Group analysis using Statistical Parametric Mapping package SPM99 showed these became more focused over the first year of implant use. There was no evidence of left hemispheric dominance at any stage post implantation.Visual cortical activations were highly variable between patients and did not increase significantly between early and late activations. Taken together, our results lead us to suggest that the neural processes that occur during the first year of auditory rehabilitation following cochlear implantation vary between individuals to a greater extent than previously reported.

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.

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.

The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2.

Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1-5 had more severe disease than those with splice site mutations in exons 11-15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.

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.

Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas.

Neurofibromatosis type 2 (NF2) must be suspected in patients presenting with a unilateral vestibular schwannoma at a young age who are therefore at theoretical risk of developing bilateral disease. We identified 45 patients aged 30 years or less at the onset of symptoms of a unilateral vestibular schwannoma. Molecular genetic analysis of the NF2 gene was completed on peripheral blood samples in all 45 and on 28 tumour samples. No pathogenic NF2 mutations were identified in any of the blood samples. NF2 point mutations were identified in 21/28 (75%) tumour samples and loss of heterozygosity (LOH) in 21/28 (75%) tumour samples. Both mutational hits were identified in 18/28 (65%) tumour samples. In one multilobular tumour, one (presumably first hit) mutation was confirmed which was common to different foci of the tumour, while the second mutational event differed between foci. The molecular findings in this patient were consistent with somatic mosaicism for NF2 and the clinical diagnosis was confirmed with the presence of two meningiomas on a follow up MRI scan. A further patient developed a contralateral vestibular schwannoma on a follow up MRI scan in whom neither of the truncating mutations in the vestibular schwannoma were present in blood. It is important when counselling patients with unilateral vestibular schwannomas to identify (1) those at risk of bilateral disease, (2) those at risk of developing other tumours, and (3) other family members at risk of developing NF2. Comparing tumour and blood DNA cannot exclude mosaicism in the index case and cannot, therefore, be used to predict those at risk of developing further tumours. However, identification of both mutations or one mutation plus LOH in the tumour and exclusion of those mutations in the blood samples of the sibs or offspring of the affected case may be sufficient to render further screening unnecessary in these relatives.

Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation.

BACKGROUND: Schwannomas are benign tumours of the nervous system that are usually sporadic but also occur in the inherited disorder neurofibromatosis type 2 (NF2). The NF2 gene is a tumour suppressor on chromosome 22. Loss of expression of the NF2 protein product, merlin, is universal in both sporadic and NF2 related schwannomas. The GTPase signalling molecules RhoA and Rac1 regulate merlin function, but to date only mutation in the NF2 gene has been identified as a causal event in schwannoma formation. METHODS: Comparative genomic hybridisation (CGH) was used to screen 76 vestibular schwannomas from 76 patients (66 sporadic and 10 NF2 related) to identify other chromosome regions that may harbour genes involved in the tumorigenesis. RESULTS: The most common change was loss on chromosome 22, which was more frequent in sporadic than in NF2 related tumours. Importantly, eight tumours (10%) showed gain of copy number on chromosome 9q34. Each of the two NF2 patients who had received stereotactic radiotherapy had non-chromosome 22 changes, whereas only one of eight non-irradiated NF2 patients had any chromosome changes. Three tumours had gain on 17q, which has also been reported in malignant peripheral nerve sheath tumours that are associated with neurofibromatosis type 1. Other sites that were identified in three or fewer tumours were regions on chromosomes 10, 11, 13, 16, 19, 20, X, and Y. CONCLUSIONS: These findings should be verified using techniques that can detect smaller genetic changes, such as microarray-CGH.

Device nonuse among adult cochlear implant recipients.

OBJECTIVE: To examine the causes and prevalence of previous and current device nonuse among adults who have received cochlear implants. STUDY DESIGN: Retrospective case review. SETTING: Adult tertiary referral center for cochlear implantation. METHODS: Two hundred fourteen consecutively implanted adult patients. The length of implant use ranged from 1 month to 14 years. MAIN OUTCOME MEASURE: A period of 4 consecutive weeks of nonuse of cochlear implant, including both obligatory and elective nonuse. RESULTS: Twenty-nine adults (13.6% of implantees) were identified as having at some stage not used their device for a period of more than 4 consecutive weeks. The main reason was device failure (n = 11). Ten adults are current nonusers (4.7% of implantees). Reasons include surgical complication necessitating explantation (n = 3), comorbid illness (n = 3), elective nonuse (n = 2), audiologic complication (n = 1), and device failure (n = 1). CONCLUSION: The overall prevalence of device nonuse was noted to increase slowly with time. The role of psychologic factors in contributing to the decision of an individual to elect to opt out of device use remains unproven.

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.

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.

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.

Evaluation of clinical diagnostic criteria for neurofibromatosis 2.

BACKGROUND: Four sets of clinical diagnostic criteria for neurofibromatosis 2 (NF2) have been developed by groups of expert clinicians, but sensitivity has never been formally assessed. The sets of criteria differ for people without bilateral vestibular schwannomas, which are pathognomonic for NF2. OBJECTIVE: To empirically evaluate the four existing sets of clinical diagnostic criteria for NF2. METHODS: The study was based on 163 of 403 people in the United Kingdom NF2 registry (41%) who presented without bilateral vestibular schwannomas. The authors applied the sets of criteria to each person at initial assessment and at the most recent clinical evaluation (mean +/- SE length of follow-up, 13 +/- 1 years). RESULTS: In people with "definite NF2" and a negative family history of NF2, the 1987 US NIH and 1991 NIH criteria each identify 78% of people at the most recent clinical evaluation but 0% at initial assessment. The National Neurofibromatosis Foundation (NNFF) criteria and the Manchester criteria each identify higher proportions at both time points (NNFF criteria, 91% and 10%; Manchester criteria, 93% and 14%), but the proportions at initial assessment are still low. CONCLUSIONS: None of the existing sets of criteria are adequate at initial assessment for diagnosing people who present without bilateral vestibular schwannomas as having NF2, particularly people with a negative family history of NF2. The authors recommend that a single, revised set of diagnostic criteria be devised to replace all of the existing sets of criteria.

Comparison of three-dimensional visualization techniques for depicting the scala vestibuli and scala tympani of the cochlea by using high-resolution MR imaging.

BACKGROUND AND PURPOSE: Cochlear implantation requires introduction of a stimulating electrode array into the scala vestibuli or scala tympani. Although these structures can be separately identified on many high-resolution scans, it is often difficult to ascertain whether these channels are patent throughout their length. The aim of this study was to determine whether an optimized combination of an imaging protocol and a visualization technique allows routine 3D rendering of the scala vestibuli and scala tympani. METHODS: A submillimeter T2 fast spin-echo imaging sequence was designed to optimize the performance of 3D visualization methods. The spatial resolution was determined experimentally using primary images and 3D surface and volume renderings from eight healthy subjects. These data were used to develop the imaging sequence and to compare the quality and signal-to-noise dependency of four data visualization algorithms: maximum intensity projection, ray casting with transparent voxels, ray casting with opaque voxels, and isosurface rendering. The ability of these methods to produce 3D renderings of the scala tympani and scala vestibuli was also examined. The imaging technique was used in five patients with sensorineural deafness. RESULTS: Visualization techniques produced optimal results in combination with an isotropic volume imaging sequence. Clinicians preferred the isosurface-rendered images to other 3D visualizations. Both isosurface and ray casting displayed the scala vestibuli and scala tympani throughout their length. Abnormalities were shown in three patients, and in one of these, a focal occlusion of the scala tympani was confirmed at surgery. CONCLUSION: Three-dimensional images of the scala vestibuli and scala tympani can be routinely produced. The combination of an MR sequence optimized for use with isosurface rendering or ray-casting algorithms can produce 3D images with greater spatial resolution and anatomic detail than has been possible previously.