Walton Centre

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Abstract Objective To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19). Design Prospective observational cohort study. Setting International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium—ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020 . Participants Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction. Main outcome measure In-hospital mortality. Results 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73). Conclusions An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations. Study registration ISRCTN66726260

Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration : an update

BACKGROUND: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

An international consensus group of clinician-researchers in epilepsy, neurology, neuropsychology, and neuropsychiatry collaborated with the aim of developing clear guidance on standards for the diagnosis of psychogenic nonepileptic seizures (PNES). Because the gold standard of video electroencephalography (vEEG) is not available worldwide, or for every patient, the group delineated a staged approach to PNES diagnosis. Using a consensus review of the literature, this group evaluated key diagnostic approaches. These included: history, EEG, ambulatory EEG, vEEG/monitoring, neurophysiologic, neurohumoral, neuroimaging, neuropsychological testing, hypnosis, and conversation analysis. Levels of diagnostic certainty were developed including possible, probable, clinically established, and documented diagnosis, based on the availability of history, witnessed event, and investigations, including vEEG. The aim and hope of this report is to provide greater clarity about the process and certainty of the diagnosis of PNES, with the intent to improve the care for people with epilepsy and nonepileptic seizures.

STUDY DESIGN: A retrospective analysis of the outcome of lumbar microdiscectomy, with independent assessment of outcome. OBJECTIVES: To explore whether the initial positive outcome after microdiscectomy is maintained at long-term follow-up. SUMMARY OF BACKGROUND DATA: Previous reports on long-term outcome after lumbar disc surgery give conflicting messages about whether an initially positive surgical outcome is maintained throughout a 10-year period. This is partly due to differing methods and the failure to include initial outcome, thereby permitting assessment of possible deterioration in the quality of outcome. METHODS: This study presents the initial and long-term outcome after lumbar microdiscectomy, with an independent assessment of outcome. Eighty-eight consecutive patients undergoing lumbar microdiscectomy were identified. Assessment at 10 years after surgery was obtained in 79 (90%) of the cases. The initial outcome was assessed retrospectively by an independent observer at 6 months after surgery using the Macnab classification. The final outcome Macnab classification was completed by postal questionnaire by the patients themselves, who also completed a modified Roland-Morris disability questionnaire. RESULTS: A successful outcome at 6 months was achieved in 91% of the cases. At 10-year follow-up, this result declined slightly to an 83% success rate. However, there was no statistically significant difference between these outcome results. The long-term Macnab classification results correlated well with disability, as measured by the Roland-Morris score. Patient satisfaction with the results of microdiscectomy 10 years later was high. CONCLUSIONS: Lumbar microdiscectomy achieves a high level of initial success, and this positive outcome is maintained at a 10-year follow-up.

PURPOSE: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. METHODS: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, >or=48-week treatment duration without forced exit criteria, information on >or=24-week seizure freedom data (efficacy) or >or=48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a <or=20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21-30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. RESULTS: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic-clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. CONCLUSIONS: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ("red flags") that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.

BACKGROUND: Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. METHODS: The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222. FINDINGS: 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5.0 points in the surgery group and 0.3 points in the medical therapy group (difference -4.7, 95% CI -7.6 to -1.8; p=0.001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was -8.9 (95% CI -13.8 to -4.0; p=0.0004), in the activities of daily living domain was -12.4 (-17.3 to -7.5; p<0.0001), and in the bodily discomfort domain was -7.5 (-12.6 to -2.4; p=0.004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson's disease and drug treatment. INTERPRETATION: At 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted.

See de Seze (doi:10.1093/brain/awx292) for a scientific commentary on this article. A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.

Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type, and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.

BACKGROUND: Central pain in multiple sclerosis (MS) is common and often refractory to treatment. METHODS: We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours. RESULTS: Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale. CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change -2.7, 95% CI: -3.4 to -2.0, placebo -1.4 95% CI: -2.0 to -0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change -2.5, 95% CI: -3.4 to -1.7, placebo -0.8, 95% CI: -1.5 to -0.1, comparison between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage. CONCLUSIONS: Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.

BACKGROUND AND PURPOSE: Trigeminal neuralgia (TN) is an extremely painful condition which can be difficult to diagnose and treat. In Europe, TN patients are managed by many different specialities. Therefore, there is a great need for comprehensive European guidelines for the management of TN. The European Academy of Neurology asked an expert panel to develop recommendations for a series of questions that are essential for daily clinical management of patients with TN. METHODS: A systematic review of the literature was performed and recommendations was developed based on GRADE, where feasible; if not, a good practice statement was given. RESULTS: The use of the most recent classification system is recommended, which diagnoses TN as primary TN, either classical or idiopathic depending on the degree of neurovascular contact, or as secondary TN caused by pathology other than neurovascular contact. Magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN. If MRI is not possible, trigeminal reflexes can be used. Neurovascular contact plays an important role in primary TN, but demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression. In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used. For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice. Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy. It is recommended that patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated. Microvascular decompression is recommended as first-line surgery in patients with classical TN. No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN. Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact. Treatment for patients with secondary TN should in general follow the same principles as for primary TN. In addition to medical and surgical management, it is recommended that patients are offered psychological and nursing support. CONCLUSIONS: Compared with previous TN guidelines, there are important changes regarding diagnosis and imaging. These allow better characterization of patients and help in decision making regarding the planning of medical and surgical management. Recommendations on pharmacological and surgical management have been updated. There is a great need for future research on all aspects of TN, including pathophysiology and management.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

The aim was to capture interdisciplinary expertise from a large group of clinicians, reflecting practice from across the UK and further, to inform subsequent development of a national consensus guidance for optimal management of idiopathic intracranial hypertension (IIH). METHODS: Between September 2015 and October 2017, a specialist interest group including neurology, neurosurgery, neuroradiology, ophthalmology, nursing, primary care doctors and patient representatives met. An initial UK survey of attitudes and practice in IIH was sent to a wide group of physicians and surgeons who investigate and manage IIH regularly. A comprehensive systematic literature review was performed to assemble the foundations of the statements. An international panel along with four national professional bodies, namely the Association of British Neurologists, British Association for the Study of Headache, the Society of British Neurological Surgeons and the Royal College of Ophthalmologists critically reviewed the statements. RESULTS: Over 20 questions were constructed: one based on the diagnostic principles for optimal investigation of papilloedema and 21 for the management of IIH. Three main principles were identified: (1) to treat the underlying disease; (2) to protect the vision; and (3) to minimise the headache morbidity. Statements presented provide insight to uncertainties in IIH where research opportunities exist. CONCLUSIONS: In collaboration with many different specialists, professions and patient representatives, we have developed guidance statements for the investigation and management of adult IIH.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

OBJECTIVES: To establish the prevalence of spasticity 12 months after stroke and examine its relationship with functional ability. DESIGN: A cohort study of prevalence of spasticity at 12 months post stroke. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, UK. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Muscle tone measured at the elbow using the Modified Ashworth Scale and at several joints, in the arms and legs, using the Tone Assessment Scale; functional ability using the modified Barthel Index. RESULTS: Increased muscle tone (spasticity) was present in 29 (27%) and 38 (36%) of the 106 patients when measured using the Modified Ashworth Scale and Tone Assessment Scale respectively. Combining the results from both scales produced a prevalence of 40 (38%). Those with spasticity had significantly lower Barthel scores at 12 months (p < 0.0001). CONCLUSION: When estimating the prevalence of spasticity it is essential to assess both arms and legs, using both scales. Despite measuring tone at several joints, spasticity was demonstrated in only 40 (38%) patients, lower than previous estimates.