Samantha Mills

Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis

Objectives: We aimed to determine the proportion of individuals in our schwannomatosis cohort whose disease is associated with an LZTR1 mutation. Methods: We used exome sequencing, Sanger sequencing, and copy number analysis to screen 65 unrelated individuals with schwannomatosis who were negative for a germline NF2 or SMARCB1 mutation. We also screened samples from 39 patients with a unilateral vestibular schwannoma (UVS), plus at least one other schwannoma, but who did not have an identifiable germline or mosaic NF2 mutation. Results: We identified germline LZTR1 mutations in 6 of 16 patients (37.5%) with schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with UVS in our cohort. Three germline mutation–positive patients in total had developed a UVS. Mosaicism was excluded in 3 patients without germline mutation in NF2, SMARCB1, or LZTR1 by mutation screening in 2 tumors from each. Conclusions: Our data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and that further causative genes for schwannomatosis remain to be identified.

WHO grade 1 meningioma recurrence: Are location and Simpson grade still relevant?

OBJECTIVEnTo examine whether Simpson grade and pathology location are still predictors of recurrence/progression free survival (RPFS) in WHO grade 1 cranial meningiomas.nnnMETHODSnA retrospective case series of all WHO grade 1 cranial meningiomas undergoing surgical resection at our institution between 2002 to 2007 was performed. Demographic and outcome data included: Simpson grade, extent of resection [gross total (Simpson 1-3) and sub total (Simpson 4-5)], tumour location, timing of post-operative imaging and outpatient review, time to recurrence and subsequent management. Statistical analysis was by Kaplan-Meier survival curves.nnnRESULTSn145 cases were included of which 75% were female, with an overall median age of 55 years. 24% had parasagittal, 23% convexity and 53% skull base meningioma. 21% had a grade 1 Simpson resection, 43% grade 2, 35% grade 4 and 1% grade 5. The median follow up period was 60 months with a median 5.5 outpatient appointments and 5 post-operative imaging studies. 10 cases (6.9%) had recurrence/progression at a median period of 42 months. Of these, 4 remained under active surveillance, 3 received stereotactic radiosurgery and 3 were treated with fractionated radiotherapy. 5 year recurrence/progression free survival (RPFS) for Simpson grade 1 was 96.8%, 2: 100%, 4: 82.4% and 5: 0%. Simpson grade (p=0.01) and gross total/sub total resection (p=0.001) were significant predictors of RPFS. Meningioma location was not a significant predictor of RPFS (p-value 0.836).nnnCONCLUSIONnSimpson grade remains a significant predictor of RPFS in WHO grade 1 meningioma surgery. However, tumour location was not significant in this series. We advocate different post-operative imaging surveillance protocols depending on gross total or sub total surgical resection.

Multiple synchronous sites of origin of vestibular schwannomas in neurofibromatosis Type 2.

Background Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. Methods High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. Results Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. Discussion This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.

Postoperative seizures in meningioma patients: improving patient selection for antiepileptic drug therapy.

BackgroundEpilepsy is a major cause of morbidity and mortality in meningioma patients. The aims of this study were to determine which factors predispose meningioma patients to developing perioperative seizures and to understand the impact of antiepileptic drugs.MethodsPatients treated for a histologically-confirmed intracranial meningioma at the authors’ institution between 2010 and 2015 were retrospectively examined. Clinical and imaging data were assessed. Multivariate analysis was performed using binary logistic regression. The effect of antiepileptic treatment was assessed using survival analysis.ResultsTwo hundred and eighty-three patients met the selection criteria; seizures were present in 68 preoperatively (24%) and in 48 patients (17%) following surgery. Of the 68 with preoperative seizures, 19 continued to have them, whereas de-novo seizures arose postoperatively in 29 seizure-naïve patients. Risk factors of postoperative seizures were convexity location (OR 2.05 [95% CI 1.07–3.98], pu2009=u20090.030), fronto-parietal location (OR 4.42 [95% CI 1.49–13.16], pu2009=u20090.007) and preoperative seizures (OR 2.65 [95% CI 1.37–5.24], pu2009=u20090.005). The two locations, in addition to the presence of midline shift on preoperative imaging (OR 4.15 [95% CI 1.54–11.24], pu2009=u20090.005), were significantly correlated with postoperative seizures in seizure-naïve patients. Antiepileptic treatment in patients with those risk factors reduced the possibility of seizures at any time point within the 1st year postoperatively by approximately 40%, although this did not meet statistical significance.ConclusionProphylactic antiepileptic treatment might be warranted in seizure-naïve meningioma patients with ≥u20091 risk factor. High-quality randomised controlled trials are required to verify those factors and to define the role of antiepileptics in meningioma practice.

Health economic evaluation of a serum-based blood test for brain tumour diagnosis: exploration of two clinical scenarios

Objectives To determine the potential costs and health benefits of a serum-based spectroscopic triage tool for brain tumours, which could be developed to reduce diagnostic delays in the current clinical pathway. Design A model-based health pre-trial economic assessment. Decision tree models were constructed based on simplified diagnostic pathways. Models were populated with parameters identified from rapid reviews of the literature and clinical expert opinion. Setting Explored as a test in both primary and secondary care (neuroimaging) in the UK health service, as well as application to the USA. Participants Calculations based on an initial cohort of 10u2009000 patients. In primary care, it is estimated that the volume of tests would approach 75u2009000 per annum. The volume of tests in secondary care is estimated at 53u2009000 per annum. Main outcome measures The primary outcome measure was quality-adjusted life-years (QALY), which were employed to derive incremental cost-effectiveness ratios (ICER) in a cost-effectiveness analysis. Results Results indicate that using a blood-based spectroscopic test in both scenarios has the potential to be highly cost-effective in a health technology assessment agency decision-making process, as ICERs were well below standard threshold values of £20u2009000–£30 000 per QALY. This test may be cost-effective in both scenarios with test sensitivities and specificities as low as 80%; however, the price of the test would need to be lower (less than approximately £40). Conclusion Use of this test as triage tool in primary care has the potential to be both more effective and cost saving for the health service. In secondary care, this test would also be deemed more effective than the current diagnostic pathway.

Surgical management and long-term outcome of intracranial subependymoma

BackgroundIntracranial subependymomas account for 0.2–0.7% of central nervous system tumours and are classified as World Health Organization (WHO) grade 1 tumours. They are typically located within the ventricular system and are detected incidentally or with symptoms of hydrocephalus. Due to paucity of studies exploring this tumour type, the objective was to determine the medium- to long-term outcome of intracranial subependymoma treated by surgical resection.MethodsRetrospective case note review of adults with intracranial WHO grade 1 subependymoma diagnosed between 1990 and 2015 at the Walton Centre NHS Foundation Trust was undertaken. Tumour location, extent of resection (defined as gross total resection (GTR), sub-total resection (STR) or biopsy) and the WHO performance status at presentation and through follow-up were recorded.ResultsThirteen patients (7 males; 6 females) with a mean age of 47.6xa0years (range 33–58xa0years) and a median follow-up of 46xa0months (range 25–220xa0months) were studied. Eight patients had symptomatic tumours (headache, visual disturbance); five had incidental finding. Tumours were most commonly located in the fourth ventricle (nu2009=u20098). The performance status scores at diagnosis were 0 (nu2009=u20098) and 1 (nu2009=u20095). The early post-operative performance status scores at 6xa0months were 0 (nu2009=u20095) and 1 (nu2009=u20098) and at last follow-up were 0 (nu2009=u200911) and 1 (nu2009=u20092). There was no evidence of tumour re-growth following GTR or STR. The commonest complication was hydrocephalus (nu2009=u20093).ConclusionSubependymoma are indolent tumours. No patients exhibited a worsening of performance status at medium- to long-term follow-up and there were no tumour recurrence suggesting a shorter follow-up time may be sufficient. Surgical resection is indicated for symptomatic tumours or those without a clear imaging diagnosis. Incidental intraventricular subependymoma can be managed conservatively through MRI surveillance.

PO061 Spontaneous vertebral artery dissection presenting as hemicrania continua-like headache

Objective To report a patient who presented with acute symptoms resembling hemicrania continua, in whom further investigations demonstrated an acute ipsilateral vertebral artery dissection. Results A 30-year-old female patient presented with a seven-day history of worsening left sided headaches focused in the orbit, with ipsilateral ptosis and eyelid oedema. She also reported severe neck pain ongoing for two weeks, with no traumatic precipitant. A CT angiogram showed an extracranial left vertebral artery dissection with flow occlusion, and an MRI confirmed a mural thrombus. There was no evidence for acute brain ischaemia. The patient’s symptoms persisted for several months and partially responded to a left greater occipital nerve block. Conclusion The co-occurrence of vertebral artery dissection and trigeminal autonomic-type headache is very rare.We have not identified any previous reports of vertebral artery dissection presenting with features of hemicrania continua.