This study explores the natural history of vestibular, trigeminal and lower cranial nerve schwannomas (VS, TS, LCNS) in patients with Neurofibromatosis type 2 (NF2), to understand how pathogenic variants (PVs) of the NF2 gene affect tumour burden and growth rate, via a retrospective analysis of a UK NF2 centre database and imaging. VS, TS and LCNS location and size were measured in accordance with a standardised protocol. PVs were categorised in accordance with the UK NF2 Genetic Severity Score (GSS). 153 patients (age 5–82) had 458 schwannomas, of which 362 were previously untreated comprising: 204 VS, 93 TS, and 65 LCNS (IX, X, XI). 322 schwannomas had sequential imaging allowing growth rate analysis with a mean follow-up of 45 months. VS were universally present, and bilateral in 146/153 cases. 65% of tumours grew >2 mm during the study period at mean rate 2.0 mm/year. Significant association was found between increasing GSS and growth rate. TS occurred in 66/153 patients (bilateral in 27/153); 31% of tumours showed growth (mean 1.8 mm/yr). Significant increase in tumour prevalence was noted with increasing GSS. LCNS were found in 47/153 patients (bilateral in 19/153); 27% of tumours showed growth (mean 1.9 mm/yr). The trend for increased prevalence with increasing GSS did not reach significance. VS growth rate was significantly influenced by GSS and they were much more likely to grow than TS and LCNS. TS prevalence also correlated with increasing GSS.

Purpose To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). Methods Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation ( n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. Results The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. Conclusion This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Methods Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. Results Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). Conclusions Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Objectives/HypothesisUnilateral vestibular schwannoma (VS) occurs with a lifetime risk of around 1 in 1,000 and is due to inactivation of the NF2 gene, either somatically or from a constitutional mutation. It has been postulated that familial occurrence of unilateral VS occurs more frequently than by chance, but no causal mechanism has been confirmed. Study DesignRetrospective database analysis. MethodsThe likelihood of chance occurrence of unilateral VS, or occurring in the context of neurofibromatosis type 2 (NF2), was assessed using national UK audit data and data from the national NF2 database. Families with familial unilateral VS (occurrence in first- and second-degree relatives) were assessed for constitutional NF2 and LZTR1 genetic variants, and where possible the tumor was also analyzed. ResultsApproximately 1,000 cases of unilateral VS occurred annually in the United Kingdom between 2013 and 2016. Of these, 2.5 may be expected to have a first-degree relative who had previously developed a unilateral VS. The likelihood of this occurring in NF2 was considered to be as low as 0.05 annually. None of 28 families with familial unilateral VS had a constitutional NF2 intragenic variant, and in nine cases where the VS was analyzed, both mutational events in NF2 were identified and excluded from the germline. Only three variants of uncertain significance were found in LZTR1. ConclusionsFamilial occurrence of unilateral VS is very unlikely to be due to a constitutional NF2 or definitely pathogenic LZTR1 variant. The occurrence of unilateral VS in two or more first-degree relatives is likely due to chance. This phenomenon may well increase in clinical practice with increasing use of cranial magnetic resonance imaging in older patients. Level of Evidence2b Laryngoscope, 129:967-973, 2019

BACKGROUND The published literature suggests that malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in neurofibromatosis type 2 (NF2). A recent review based on incidence data in North America showed that 1 per 1000 cerebellopontine angle nerve sheath tumors were malignant. OBJECTIVE To determine whether MPNST occurred spontaneously in NF2 by reviewing our NF2 database. METHODS The prospective database consists of 1253 patients with NF2. One thousand and nine are known to be alive at last follow-up. The presence and laterality/pathology of vestibular schwannoma at diagnosis and last follow-up was sought. RESULTS There were no cases of spontaneous MPNST with 2114 proven (n = 1150) and presumed benign (n = 964) vestibular schwannomas found. Two patients had developed MPNST (1 presumed) after having previously undergone stereotactic radiosurgery for a vestibular schwannoma. CONCLUSION In this series, and from the literature, malignant transformation of a vestibular schwannoma was not a feature of NF2 in the unirradiated patient. NF2 patients should not be told that they have an increased risk of malignant change in a vestibular schwannoma unless they undergo radiation treatment. However, very much larger datasets are required before it can be determined whether there is any association between NF2 and MPNST in the unirradiated patient.

BACKGROUND:The Manchester criteria for neurofibromatosis type 2 (NF2) include a range of tumors, and gliomas were incorporated in the original description. The gliomas are now widely accepted to be predominantly spinal cord ependymomas. OBJECTIVE:To determine whether these gliomas include any cases of malignant glioma (WHO grade III and IV) through a database review. METHODS:The prospective database consists of 1253 patients with NF2. 1009 are known to be alive at last follow-up. RESULTS:There was a single case of glioblastoma multiforme (GBM; World Health Organization grade IV) in the series and no WHO grade III gliomas. The GBM was in a patient who had previously undergone stereotactic radiosurgery for a vestibular schwannoma. CONCLUSION:High-grade gliomas are not a feature of NF2 in the unirradiated patient and should be excluded from the diagnostic criteria.

Purpose We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods Two large databases of individuals fulfilling NF2 criteria ( n = 1361) and those tested for NF2 variants with criteria short of diagnosis ( n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. Results There was no evidence for usefulness of old criteria “glioma“ or “neurofibroma.” “Ependymoma” had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1- associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. Conclusions The present study confirms important deficiencies in NF2 diagnostic criteria. The term “glioma” should be dropped and replaced by “ependymoma.” Similarly “neurofibroma” should be removed. Dropping “sibling” from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

The management of spinal cord ependymomas in Neurofibromatosis Type 2 (NF2) has traditionally been conservative, in contrast to the management of sporadic cases; the assumption being that, in the context of NF2, they did not cause morbidity. With modern management and improved outcome of other NF2 tumours, this assumption, and therefore the lack of role for surgery, has been questioned. To compare the outcome of conservative treatment of spinal ependymomas in NF2 with surgical intervention in selected patients. Retrospective review at two NF2 centers, Manchester, UK and Paris/Lille, France. In Manchester patients were managed conservatively. In France surgery was a treatment option. Inclusion in the study was based on tumor length of greater than 1.5 cm. The primary parameter assessed was acquired neurological deficit measured by the Modified McCormick Outcome Score. 24 patients from Manchester and 46 patients from France were analyzed. From Manchester, 27% of these patients deteriorated during the course of follow-up. This effectively represents the natural history of ependymomas in NF2. Of the surgical cases, 23% deteriorated postoperatively, but only 2/18 (11%) of those operated on in the NF2 specialist centers. Comparison of the two specialist centers Manchester/France showed a significantly improved outcome (P = 0.012, χ2 test) in the actively surgical center. Spinal ependymomas produce morbidity. Surgery can prevent or improve this in selected cases but can itself can produce morbidity. Surgery should be considered in growing/symptomatic ependymomas, particularly in the absence of overwhelming tumor load where bevacizumab is the preferred option.

OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment.METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes.RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas.CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response.

A 36-year-old security officer presented with a 2.5-year history of left upper limb tremor, which worsened on pouring water. There was no slowing of movements, lower limb tremor, or improvement with alcohol. His four-year-old daughter was born prematurely and had been investigated for developmental delay in walking after her 2nd birthday, general clumsiness/dyspraxia and macrocephaly. Examination of the proband revealed relative macrocephaly (head circumference 98th centile), mild dystonic posturing and position-specific left upper limb action tremor. There was no evidence of Kayser-Fleischer rings, cervical dystonia, or bradykinesia. Neurological examination was otherwise normal.

A 36 year-old man presented with sudden onset of abnormal painful posturing of the left lower limb, worsening over seven years and exacerbated by walking. There were no obvious underlying psychological stressors. Aside from psoriasis, there was no other medical history. He described sudden exacerbations and remissions of the movements, which could last several months. Botulinum toxin injections to tibialis anterior and extensor hallucis were of limited and short-lived benefit. Examination revealed a fixed deformity of the left foot, which was held rigid at the ankle. This abnormality was fully reversible during examination under spinal anaesthesia. His symptoms further evolved over the following year, with ongoing painful movements of the left and right lower limbs, involving prolonged hip flexion movements, and fixed flexion of the left upper limb, with more subtle posturing of the right upper limb (video clip 1). The movements persisted on walking, with features of a “magnetic gait” and toe-walking (video clip 2). He was referred for neurophysiological studies to further examine his movement disorder and to exclude neurophysiological features of stiff person syndrome. Anti-GAD antibodies were negative.

Background: We aimed to characterize the clinical and electrophysiological features of patients with slow orthostatic tremor. Case Report: The clinical and neurophysiological data of patients referred for lower limb tremor on standing were reviewed. Patients with symptomatic or primary orthostatic tremor were excluded. Eight patients were identified with idiopathic slow 4–8 Hz orthostatic tremor, which was associated with tremor and dystonia in cervical and upper limb musculature. Coherence analysis in two patients showed findings different to those seen in primary orthostatic tremor. Discussion: Slow orthostatic tremor may be associated with dystonia and dystonic tremor.

BackgroundFrom June 2014, Greater Manchester, Lancashire and Cumbria neurology network implemented regional guidelines on management of CVT. Central to this was an agreement to transfer where appropriate all radiologically confirmed CVT to the regional neurosciences unit within 24 hr. Given this change in practice we assessed the impact on our service in Greater Manchester Neurosciences Centre.ResultsBetween June 2014 and November 2014, 14 patients were admitted; compared to 6 in 2012 and 6 in 2013.The wait for urgent beds did not vary compared to equivalent period in 2012 and 2013; median wait 1d. The wait for non-urgent beds increased slightly between 2013 and 2014 from 15.9d to 16.7d. Both were worse compared to 2012 (9.8d), likely reflecting overall pressure on acute services.There was no increase in the average LOS for the acute neurology wards. Average LOS was 15.3d between June and Nov 2014 compared to 22.3d in the equivalent period in 2013.ConclusionDespite a large change in practice for management of CVT there was a small increase in number of patients and no significant effect on admission waiting times, average LOS or critical care bed days was noted.

BackgroundFrom June 2014, regional guidelines to transfer within 24 hours all radiologically confirmed cases of cerebral venous thrombosis (CVT) were implemented across Greater Manchester. This service review assesses the impact on assessment, diagnosis and treatment.MethodsWe prospectively recorded all CVT cases transferred into our unit between June 1st and November 30th 2014 (14 patients), and retrospectively reviewed the casenotes of patients admitted in 2012, 2013 and early 2014 (13 patients).ResultsMean number of days from diagnosis to transfer after guideline introduction was 0.4. More patients underwent fundoscopy (86% vs 77%), visual acuity (50% vs 27%), visual field (79% vs 69%) and otoscopy (29% vs 8%). Patients admitted to SRFT previously had shorter symptom to diagnosis, imaging, transfer, and treatment times.ConclusionsAfter guideline introduction we found a high level of compliance with time to transfer, with improvements in several aspects of clinical assessments. We expect that patients previously admitted to our centre were more unwell or already admitted for other reasons (e.g. neurosurgical) and therefore time from symptoms to diagnosis appears longer. We aim to extend the current evaluation to all patients in the region who weren't transferred to our centre to allow a more valid comparison.

BACKGROUND & AIMS: Dysphagia in patients with Parkinson's disease, persisting despite dopaminergic treatment, affects intake of nutrients and medication, and reduces quality of life (QOL). We investigated the neurophysiologic mechanisms that contribute to dysphagia in these patients, on and off L-3,4-dihydroxyphenylalanine (levodopa), using transcranial magnetic stimulation.METHODS: We studied 26 patients with Parkinson's disease (age, 65 +/- 9 y; 10 men). Dysphagia and QOL were first assessed with qualitative questionnaires. Twelve hours after patients were taken off levodopa, they underwent cortical transcranial magnetic stimulation mapping of the pharyngeal musculature and trigeminal (bulbar) transcranial magnetic stimulation, as well as videofluoroscopy to examine swallowing. The analyses were repeated after administration of levodopa.RESULTS: Eleven patients initially reported dysphagia and reduced QOL scores. Videofluoroscopy identified 10 patients with swallowing impairments on and off levodopa, and 6 patients with swallowing impairments only on levodopa; the remaining 10 subjects showed no swallowing impairments, on or off the drug. While patients were on levodopa, those with swallowing impairments had bilateral increases in pharyngeal cortical excitability compared with those with no swallowing impairment (P < .05). By contrast, with medication, amplitudes of brainstem reflexes were altered only in patients with swallowing impairments on levodopa; these were decreased compared with when the patients were off levodopa.CONCLUSIONS: In patients with Parkinson's disease, dopaminergic medications such as levodopa can negatively affect swallowing. The increased cortical excitability observed in dysphagic patients after they begin taking levodopa likely results from compensatory mechanisms, perhaps secondary to subcortical disease, because we observed associated inhibition of brainstem reflexes in patients with affected swallowing on medication.

Background: The antiepileptic drug topiramate reduces levodopa-induced dyskinesia without exacerbating parkinsonism in animal models. We report a randomized, double-blind, placebo-controlled crossover trial in patients with Parkinson's disease and levodopa-induced dyskinesia.Methods: Fifteen patients with Parkinson's disease and stable levodopa-induced dyskinesia were enrolled into the study, of whom 13 were randomized to topiramate or placebo. The study medication was titrated to 100 mg/day over four weeks, and assessments were carried out after a further two weeks. Dyskinesia severity assessed by a blinded rater from video recordings was the primary outcome measure.Results: Seven patients (mean age 58.9 +/- 12.8 years) completed the study. Patients taking topiramate vs. placebo showed a significant increase in dyskinesia severity compared to baseline (Wilcoxon signed rank test, P = 0.043). Five patients withdrew from the study whilst taking topiramate due to adverse effects.Conclusions: Topiramate tended to worsen dyskinesia in patients with Parkinson's disease, and was poorly tolerated. (C) 2014 Elsevier Ltd. All rights reserved.

We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 × 10(6) imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as Pmeta < 5.0 × 10(-7)) with remission of seizures after starting treatment was observed at three loci: 6p12.2 (rs492146, Pmeta = 2.1 × 10(-7), OR[G] = 0.57), 9p23 (rs72700966, Pmeta = 3.1 × 10(-7), OR[C] = 2.70) and 15q13.2 (rs143536437, Pmeta = 3.2 × 10(-7), OR[C] = 1.92). Genes of biological interest at these loci include PTPRD and ARHGAP11B (encoding functions implicated in neuronal development) and GSTA4 (a phase II biotransformation enzyme). Pathway analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories 'calcium signaling pathway' and 'phosphatidylinositol signaling pathway'. Through a series of power curves, we conclude that it is unlikely any single common variant explains >4.4% of the variation in the outcome of newly treated epilepsy.