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In this issue of Neurologic Clinics, guest editors Drs. Joseph S. Kass and Michael A. Rubin bring their considerable expertise to the topic of medicolegal issues in neurology. Top experts in the field provide up-to-date, focused guidance on how to identify and approach the major medicolegal and ethical issues that neurologists confront in today's clinical practice.

Summary Background Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. Methods 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABAB1 or GABAB2 receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. Findings All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABAB receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABAB receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0·005). Low levels of GABAB1 receptor antibodies were identified in two of 104 controls (p<0·0001). Interpretation GABAB receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. Funding National Institutes of Health.

To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at high imminent risk of developing symptoms due to Alzheimer's disease. This 5–8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30–60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1Glu280Ala autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test–Cueing Index (FCSRT–CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed. 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab–carrier, n=85; placebo–carrier, n=84; placebo–non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was –1·10 (SE 0·29) in the crenezumab group and –1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI –0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT–CI was –0·03 (0·00) in the crenezumab group and –0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5–8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.

This survey assessed the current exposure and training in cognitive neurology among UK neurology registrars and trainees. Participants rated their prior exposure to cognitive neurology, identified challenges, and proposed improvements.Of the respondents, 33 were neurology registrars or trainees. Only 5 participants (14%) rated their prior exposure as high (score 5), while the majority (48%) rated it as moderate (score 3). A significant number reported inadequate exposure to cognitive neurology clinics due to heavy inpatient workloads, limited specialist clinics, and insufficient teaching opportunities. Training was often restricted to acute care, with few chances to attend specialized cognitive clinics.Key challenges included lack of formal access to cognitive clinics, inadequate supervision, and competing service provision demands. Suggestions for improvement included organizing trainee-friendly sessions, such as case-based clinical talks, trainee-led presentations, and practical workshops. Many participants highlighted the need for regular cognitive clinics in training programs and teaching sessions led by cognitive neurologists.Nearly 90% of respondents expressed interest in attending workshops on cognitive neurology, emphasizing the need for enhanced training opportunities. This survey underscores the importance of structured, accessible training programs to improve competency and confidence in managing cognitive neurology cases.b.shao@nhs.net

\"Multiple sclerosis is the most common debilitating neurological disease in people under the age of forty in the developed world. Many publications cover medical and clinical approaches to the disease; however, The Biology of Multiple Sclerosis provides a clear and concise up-to-date overview of the scientific literature on the various theories of MS pathogenesis. Covering the main elements of scientific research into multiple sclerosis, the book contains chapters on the neuropathology of the disease as well as an account of the most extensively used animal model experimental autoimmune encephalomyelitis. The book contains chapters regarding the role of viruses in the development of multiple sclerosis. Viruses have long been implicated and chapters on animal models based on virus infection, as well as their possible role in the etiology of MS, are included. Of interest to MS researchers, the book is written to also be of value to postgraduate and medical students\"-- Provided by publisher.

BackgroundIn the acute setting, performance of a targeted neurological examination by non-neurologists prior to referral is an expected standard of care.AimsThe aims were to characterise the reasons for acute neurology service referral and determine the percentage of neurological examinations including fundoscopy performed by non-neurologists prior to acute neurology input.MethodsConsecutive referrals to the acute neurology service at two hospital sites over a four-month period in 2024 were analysed. An expected standard of documented neurological examination prior to specialist referral was created and independently verified by a panel of neurology consultants.ResultsOf 232 referrals across two hospital sites, 39.3% had a targeted neurological examination documented, 10% had no documented neurological examination and 9% had only GCS or pupillary reflexes documented. For lower limb examinations, deep tendon reflexes were the least commonly performed component, documented in 35% of referrals. Of the referrals that qualified for fundoscopy assessment (n=43), an examination was documented in 16%. Seizures were the most common reason for referral (19.8%).DiscussionThis audit highlights that the majority of acute neurology referrals lacked a documented neurological examination. Future efforts will include identifying and overcoming real and perceived barriers to performing a neurological examination amongst non-neurologists.a.aojula@nhs.net