European Journal of Neurology

BackgroundChildren with epilepsy are rarely included in clinical drug trials, delaying approval and introduction of new antiseizure medications (ASMs). To circumvent this we used population-wide register data to study retention, an intergrated meassure of effect and tolerability, of newer ASMs used in children in Sweden; brivaracetam, cenobamate, lacosamide, and perampanel. MethodsAll cases of incident epilepsy and subsequent ASM treatment 2007-2021 were identified using national registers. Retention rates of newer ASMs were calculated using Kaplan-Meier analyses. Cox regression was used to investigate how factors associated with therapy-resistant epilepsy affected risk of discontinuing each drug and to compare the risk of discontinuing each of the newer ASMs to levetiracetam, the most common ASM, in patients matched for age at epilepsy onset and number of previously tried ASMs. ResultsOut of 16431 included 54% were male, median age 7 years [Q1-Q3:3-12]. Developmental or intellectual disorders, followed by neurological malformations, were the most common comorbidities. In 2023 [~]10% of all ongoing treatments started <18years were brivaracetam, cenobamate, lacosamide, or perampanel. Brivaracetam, cenobamate, and lacosamide were all used off-label before authorization in children. Brivaracetam had the highest three-year retention of all antiseizure medications, 67%(95%CI:60-76) for the whole cohort, lacosamide and lamotrigine the highest five-year retentions: 40%(95%CI:36-45) and 45%(95%CI:43-46). perampanel had the lowest four-year retention. Retentions in the youngest were modest. In those 1-5years brivaracetam had among the highest three-year retention: 64%(95%CI:52-79), followed by lamotrigine and valproate. Lacosamide and lamotrigine had the highest five-year retentions: 40%(95%CI:33-49) and 42%(95%CI:39-44). Brivaracetam had the highest of all three-year retentions in those 6-11: 74%(95%CI:63-87) and lacosamide among the highest five-year retentions: 48%(95%CI:40-57), together with lamotrigine. In the eldest brivaracetam and lamotrigine had the highest retentions: 68%(95%CI:51-91) and 62%(95%CI:60-64), lacosamide had lower five-year retention than levetiracetam and lamotrigine. In Cox regression users of newer antiseizure medications, age-matched to levetiracetam-users with equal number previous antiseizure medications, the hazard ratio for discontinuing brivaracetam was 0.5(95%CI:0.4-0.8), perampanel 2.0(95%CI:1.2-3.2), and lacosamide 1.0(95%CI:0.8-1.2). ConclusionBrivaracetam show higher or similar retention and lacosamide similar retention as levetiracetam and lamotrigine, suggesting these could be treatment options in early epilepsy. Off-label use is common stressing the need for pediatric clinical trials.

ImportanceSeveral preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet. Objectiveto describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment. DesignThe ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. ResultsOut of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions and relevanceWe found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations. Questionwhat are the phenotypes of encephalitis associated to SARS-CoV-2 infection? Findings25 cases of encephalitis in SARS-CoV-2 infection were included in a prospective observational multi-centre study. Encephalitis cases in COVID-19 exhibited a wide heterogeneity in terms of clinical features, CSF, MRI findings, response to treatment and outcomes with 13 cases with normal MRI, 7 with heterogeneous MRI alterations and rarer ADEM/limbic encephalitis cases. Meaningheterogeneity of presentation, response to treatment and outcomes of encephalitis of COVID-19 underlines different pathophysiological mechanisms

ObjectivesCOVID-19 is spreading in long-term care facilities with devastating outcomes worldwide, especially for people with chronic health conditions. There is a pressing need to adopt effective measures prevention and containment of in such settings. DesignRetrospective cohort study assessing the effect of enhanced surveillance and early preventative strategies and comparing outcomes for people with severe epilepsy and other comorbidities SettingThree long-term care facilities: Chalfont Centre for Epilepsy (CCE), St. Elisabeth (STE), and The Meath (TM) with different models of primary and specialist care involvement, in the United Kingdom Participants286 long-term residents (age range 19-91 years), 740 carers who had been in contact with the residents during the observation period between 16 March and 05 June 2020. InterventionsEarly preventative and infection control measures with identification and isolation of symptomatic cases, with additional enhanced surveillance and isolation of asymptomatic residents and carers at one site (CCE) Main outcome measuresInfection rate for SARS-CoV-2 among residents and carers, asymptomatic rate and case fatality rate, if available. ResultsDuring a 12-week observation period, we identified 29 people (13 residents) who were SARS-CoV-2 positive with confirmed outbreaks amongst residents in two long-term care facilities (CCE, STE). At CCE, two out of 98 residents were symptomatic and tested positive, one of whom died. A further seven individuals testing positive on weekly enhanced surveillance had a completely asymptomatic course. One asymptomatic carer tested positive after contact with confirmed COVID-19 patients in another institution. Since 30 April 2020, during on-site weekly enhanced surveillance all 275 caregivers tested repeatedly negative. At STE, three out of 146 residents were symptomatic and tested positive, a fourth tested positive during hospital admission for symptoms not related to COVID-19. Since April 6, 2020, 105/215 carers presenting with typical symptoms for COVID-19 were tested, of whom 15 tested positive. At TM, testing of symptomatic carers only started from early/mid-April, whilst on-site testing, even of symptomatic residents, was not available until recently. During the observation period, eight of 80 residents were symptomatic but none was tested. Twenty-six of 250 carers were symptomatic and were tested, of whom two tested positive. ConclusionsInfection outbreaks in long-term care facilities for vulnerable people with epilepsy can be quickly contained, but only if asymptomatic cases are identified through enhanced surveillance at individual and care staff level. We observed a low rate of morbidity and mortality which confirmed that preventative measures with isolation of suspected and confirmed cases of COVID-19 can reduce resident-to-resident and reverse resident-to-carer transmission.

ObjectiveSeizure following immunization, especially in persons with epilepsy (PwE), has long been a concern, and seizure aggravation followed by Coronavirus Disease 2019 (COVID-19) vaccines is a serious issue for PwE. The immunization rate in PwE has been lower compared to same-age controls due to vaccine hesitancy and concerns about seizure control. Herein, we systematically reviewed the seizure activity-related events in PwE following COVID-19 vaccination. MethodsFour search engines were searched from inception until January 31, 2023, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was followed. Random- and fixed-effect models using the logit transformation method were used for meta-analysis. The quality of the studies was evaluated by the Newcastle-Ottawa scale. Outcomes of interest included (a) pooled proportion of increased seizure frequency and (b) pooled incidence proportion of status epilepticus (SE) in PwE receiving COVID-19 vaccines. ResultsOf the 2207 studies identified, 18 met eligibility criteria, of which 16 entered the meta-analysis. The pooled proportion of increased seizure frequency (16 studies-4197 PwE) was 5% (95CI: 3%-6%, I2 =57%), further subcategorized into viral vector (3%, 95CI: 2%-7%, I2 =0%), mRNA (5%, 95CI: 4%-7%, I2 =48%), and inactivated (4%, 95CI: 2%-8%, I2 =77%) vaccines. The pooled incidence proportion of SE (15 studies-2480 PwE) was 0.08% (95CI: 0.02%-0.32%, I2 =0%), further subcategorized into the viral vector (0.00%, 95CI: 0.00%-1.00%, I2 =0%), mRNA (0.09%, 95CI: 0.01%-0.62%, I2 =0%), and inactivated (0.00%, 95CI: 0.00%-1.00%, I2 =0%) vaccines. No significant difference was observed between mRNA and viral vector vaccines (5 studies, 1122 vs. 198 PwE, respectively) regarding increased seizure frequency (OR: 1.10, 95CI: 0.49-2.50, p-value=0.81, I2 =0%). SignificanceThe meta-analysis proposed a 5% increased seizure frequency following COVID-19 vaccination in PwE, with no difference between mRNA and viral vector vaccines. Furthermore, we found a 0.08% incidence proportion for SE. While this safety evidence is noteworthy, this cost should be weighed against vaccination benefits.

Transient loss of consciousness (TLoC) is a leading cause of referrals to acute neurological services. A witness account is often lacking and ancillary investigations are a critical diagnostic adjunct. Hypophosphataemia was recently identified as a potential maker of epileptic seizures in ward and emergency department presentations. We evaluated the real-world utility of checking phosphate in an unselected cohort of people presenting with TLoC. We retrospectively reviewed 182 episodes (91 referrals to first seizure clinic and 91 consults) from 173 patients. We assessed nine pre-specified serological markers frequently measured in people presenting with TLoC. Raw P-values comparing mean levels showed significant difference between epileptic seizures and non-epileptic episodes only for phosphate (0.98 vs. 1.19 mmol/L, P=0.006) and lactate (2.82 vs. 1.82 mmol/L, P=0.007). No blood biomarkers were significant after multiple comparison correction, although a phosphate below 0.8mmol/L was significantly more likely to associate with epileptic seizures than non-epileptic episodes (17/64, 26.5% vs. 7.4%, 2/27, P=0.049). Logistic regression showed that a model including lactate and phosphate was most accurate to predict epileptic seizures with an area-under-the ROC curve of 0.728 (96% CI 0.607-0.848). Checking serum phosphate may be valuable in helping to determine the aetiology of an episode of TLoC. Plain language summaryWe studied blood test results of 173 people suspected of having had an epileptic seizure who presented to a UK hospital neurology service. Although blood phosphate tests were infrequently requested, our results suggest a low phosphate level could be useful to help distinguish between epileptic and non-epileptic attacks.

Objective To estimate the prevalence of epilepsy-associated malformations of cortical development (MCDs) in Eastern Denmark, and to validate whether epilepsy prevalence in the same population is consistent with national estimates. Methods A retrospective cohort study of people registered with ICD-10 code DG40* and/or DZ033A from 1998 up to 1 July 2023 was conducted. The study population was defined as all living residents in Eastern Denmark with at least one recorded hospital-patient contact within the year preceding 1 July 2023. Magnetic resonance imaging (MRI) availability was required to assess presence of any MCD. MRI radiology reports were manually reviewed or evaluated using a language model to identify MCDs, including encephalocele, focal cortical dysplasia (FCD), hemimegalencephaly, heterotopia, hypothalamic hamartoma, lissencephaly, polymicrogyria and schizencephaly. Prevalence estimates were calculated for each MCD subtype and for epilepsy overall, and compared with the available literature. Results On 1 July 2023, 28,739 people met inclusion criteria, and 14,434 had an available brain MRI, including radiological description of possible MCDs. The prevalence per 100,000 population was 1044.6 (95\% CI 1032.6 to 1056.6) for epilepsy and 32.1 (95\% CI 30.1 to 34.3) for any MCD associated with seizures. Reported MCD prevalence in the literature, when existent, was derived from pediatric age-ranged selected cohorts, except for FCD. No prevalence estimates for hemimegalencephaly and heterotopia were identified. Signifiance We presented the first population-based estimates of seizure-associated MCD prevalence in a large all-age cohort. Direct comparison with prior literature was prevented due to differences in study design and population structure, but epilepsy prevalence was consistent with previously reported national estimates.

Nusinersen was the first disease modifying treatment approved for 5q spinal muscular atrophy (SMA). Long-term results of broad populations, particularly for adolescents and adults, remain limited. We conducted a population-based, ambispective observational study of all SMA patients living in the Valencian Community (Spain) between September 2017 and December 2022 and follow-up until December 2025. Demographic, clinical and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. The risk for nusinersen discontinuation was assessed with a Bayesian model, and SMA-FCR trajectories with mixed linear regression. Of 72 patients included, 18 were <12 years old (all treated with nusinersen) and 54 were [&ge;]12 years (28 treated; 26 untreated) at the baseline visit. After a median of 7 years, all patients <12 years were classified as responders versus 68% of patients [&ge;]12 years. Discontinuation rates were 11% in children compared to75% in the older cohort. In patients [&ge;]12 years, reasons for discontinuation included: treatment burden (71%), and loss(53%) or lack of benefit (43 %). Lower baseline SMA-FCR (expEstimate= 0.84 [0.718,0.93], prob:1) and older age (expEstimate=1.028 [1.011,1.055], prob:1) independently predicted higher discontinuation risk. Sustained nusinersen treatment was independently associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration over time. In this long-term population-based study, nusinersen use and persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy. However, a proportion of adolescents and adults (those younger and with higher baseline function) experienced sustained benefit.

BackgroundAntipsychotic drugs have been associated with increased mortality, stroke and myocardial infarction in people with dementia. Concerns have been raised that antipsychotic prescribing may have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of the virus. We used multisource, routinely-collected healthcare data from Wales, UK, to investigate prescribing and mortality trends in people with dementia before and during the COVID-19 pandemic. MethodsWe used individual-level, anonymised, population-scale linked health data to identify adults aged [&ge;]60 years with a diagnosis of dementia in Wales, UK. We explored antipsychotic prescribing trends over 67 months between 1st January 2016 and 1st August 2021, overall and stratified by age and dementia subtype. We used time series analyses to examine all-cause, myocardial infarction (MI) and stroke mortality over the study period and identified the leading causes of death in people with dementia. FindingsOf 57,396 people with dementia, 11,929 (21%) were prescribed an antipsychotic at any point during follow-up. Accounting for seasonality, antipsychotic prescribing increased during the second half of 2019 and throughout 2020. However, the absolute difference in prescribing rates was small, ranging from 1253 to 1305 per 10,000 person-months. Prescribing in the 60-64 age group and those with Alzheimers disease increased throughout the 5-year period. All-cause and stroke mortality increased in the second half of 2019 and throughout 2020 but MI mortality declined. From January 2020, COVID-19 was the second commonest underlying cause of death in people with dementia. InterpretationDuring the COVID-19 pandemic there was a small increase in antipsychotic prescribing in people with dementia. The long-term increase in antipsychotic prescribing in younger people and in those with Alzheimers disease warrants further investigation. FundingBritish Heart Foundation (BHF) (SP/19/3/34678) via the BHF Data Science Centre led by HDR UK, and the Scottish Neurological Research Fund. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Ovid MEDLINE for studies describing antipsychotic prescribing trends in people with dementia during the COVID-19 pandemic, published between 1st January 2020 and 22nd March 2022. The following search terms were used: (exp Antipsychotic Agents/ OR antipsychotic.mp OR neuroleptic.mp OR risperidone.mp OR exp Risperidone/ OR quetiapine.mp OR exp Quetiapine Fumarate/ OR olanzapine.mp OR exp Olanzapine/ OR exp Psychotropic Drugs/ or psychotropic.mp) AND (exp Dementia/ OR exp Alzheimer Disease/ or alzheimer.mp) AND (prescri*.mp OR exp Prescriptions/ OR exp Electronic Prescribing/ OR trend*.mp OR time series.mp). The search identified 128 published studies, of which three were eligible for inclusion. Two studies, based on data from England and the USA, compared antipsychotic prescribing in people with dementia before and during the COVID-19 pandemic. Both reported an increase in the proportion of patients prescribed an antipsychotic after the onset of the pandemic. A third study, based in the Netherlands, reported antipsychotic prescription trends in nursing home residents with dementia during the first four months of the pandemic, comparing prescribing rates to the timings of lifting of social restrictions, showing that antipsychotic prescribing rates remained constant throughout this period. Added value of this studyWe conducted age-standardised time series analyses using comprehensive, linked, anonymised, individual-level routinely-collected, population-scale health data for the population of Wales, UK. By accounting for seasonal variations in prescribing and mortality, we demonstrated that the absolute increase in antipsychotic prescribing in people with dementia of any cause during the COVID-19 pandemic was small. In contrast, antipsychotic prescribing in the youngest age group (60-64 years) and in people with a subtype diagnosis of Alzheimers disease increased throughout the five-year study period. Accounting for seasonal variation, all-cause mortality rates in people with dementia began to increase in late 2019 and increased sharply during the first few months of the pandemic. COVID-19 became the leading non-dementia cause of death in people with dementia from 2020 to 2021. Stroke mortality increased during the pandemic, following a similar pattern to that of all-cause mortality, whereas myocardial infarction rates decreased. Implications of all the available evidenceDuring COVID-19 we observed a large increase in all-cause and stroke mortality in people with dementia. When seasonal variations are accounted for, antipsychotic prescribing rates in all-cause dementia increased by a small amount before and during the pandemic in the UK. The increased prescribing rates in younger age groups and in people with Alzheimers disease warrants further investigation.

Introductionseveral cases of Guillain-Barre Syndrome (GBS) associated with SARS-CoV-2 infection have been described. This study illustrated the demographic, clinical, and neurophysiological characteristics of patients with GBS and COVID-19, as well as associated factors with disability at discharge. MethodsA retrospective analytical observational study was conducted. It included patients diagnosed with GBS admitted in a national reference center in Peru between 2019 and 2021. Epidemiological, clinical, neurophysiological and cerebrospinal fluid data were analyzed. A multivariate analysis, using the generalized linear model, was performed, considering the presence of disability at discharge as the dependent variable. Results81 subjects diagnosed with GBS were included. The mean age was 46.8 years (SD: 15.2), with a predominance of males (61.73%). The most frequent clinical presentation was the classic sensory-motor form in 74 cases (91.36%) with AIDP (82.35%) as the most frequent neurophysiological pattern in the group with COVID-19, while AMAN pattern predominated (59.26%) in those without COVID-19 (p=<0.000). The disability prevalence ratio at discharge between subjects with COVID-19 and those without COVID-19 was 1.89 (CI 1.06-3.34), p=0.030, adjusted for age, sex, and neurophysiological subtype. ConclusionsThe neurophysiologic subtype AIDP, and a higher disability were associated with the presence of COVID-19.

Background and purposeTo test the hypothesis that the incidence of Creutzfeldt-Jakob disease (CJD) has remained constant, we calculated the rate of hospitalizations for CJD in the United States using the National Inpatient Sample (NIS) from 2000 to 2019. MethodsWe used ICD-9 and ICD-10 codes to identify people hospitalized with presumed CJD in the National Inpatient Sample (NIS) from 2000 to 2019. Survey weights were used to calculate nationally representative estimates. We used 2000 census data to calculate age-adjusted standardized rates of CJD hospitalizations by sex and race-ethnicity and then used Joinpoint regression to evaluate changes in those rates. ResultsFrom 2000 to 2019, there were 11,064 admissions for CJD across the U.S. Across this period, the age-adjusted rate of CJD-related hospitalizations increased significantly from 1.25 (95% CI, 1.25-1.26) to 1.98 (95% CI, 1.98-1.99) per million U.S. adults per year, with a significant annual percentage change between 2004 and 2013 of 7.6% (95% CI, 4.4%-10.9%). ConclusionsThe incidence of CJD increased in the United States from 2000 to 2019, with a significant increase specifically between 2004 and 2013, though the overall case rate remains low.

BackgroundHigh-income countries studies show unfavorable trends in stroke incidence (SI) in younger populations. We aimed to estimate temporal change in SI disaggregated by age and sex in Latin America and the Caribbean region (LAC). MethodsA search strategy was used in MEDLINE, WOS, and LILACS databases from 1997 to 2021, including prospective observational studies with age and sex-disaggregated data of first-ever stroke (FES) incidence. Risk of bias was assessed with The Joanna Briggs Institutes guide. The main outcomes were incidence rate ratio (IRR) and relative temporal trend ratio (RTTR) of SI, comparing time periods [&ge;]2010 with <2010. Pooled RTTR (pRTTR) only considering studies with two periods in the same population were calculated by random-effects meta-analysis. ResultsFrom 9,242 records identified, six studies were selected including 4,483 FES in 4,101,084 individuals. Crude IRR in younger subjects (<55 years) comparing [&ge;]2010:<2010 periods showed an increase in SI in the last decade (IRR 1.37;95%CI 1.23-1.50), in contrast to a decrease in older people during the same period (IRR 0.83; 95%CI 0.76-0.89). Overall RTTR (<55:[&ge;]55 years) was 1.65 (95CI% 1.50-1.80), with higher increase in young women (pRTTR 3.08; 95%CI 1.18-4.97; p for heterogeneity <0.001). ConclusionsAn unfavorable change in SI in young people - especially in women - was detected in the last decade in LAC. Further investigation of the explanatory variables is required to ameliorate stroke prevention and inform local decision-makers. Registration of protocolCRD42022332563 (PROSPERO).

BackgroundThe lack of specific guidelines for seizure treatment after acute ischemic stroke (AIS), makes the choice of an appropriate anti-seizure medication choice a challenge for providers because each drug may have different adverse effects and outcomes. MethodsIn this retrospective matched cohort study, we analyzed a 20% sample of U.S. Medicare beneficiaries aged 65 and over hospitalized for a first acute ischemic stroke (AIS) between 2009-2021 who were discharged home. We included individuals who were enrolled in Medicare hospital, medical and prescription drug insurance for 12 months prior to hospitalization and were not taking epilepsy-specific anti-seizure medication (ESM) prior to hospitalization. We matched individuals on days from discharge to ESM initiation. Individuals who initiated ESMs other than Levetiracetam, i.e. Lamotrigine, Carbamazepine, Oxcarbazepine within 30 days of discharge (N = 229) were matched to Levetiracetam initiators (N =687). We investigated the time to seizure-like events, emergency department (ED) visits, and re-hospitalizations with a follow-up of 180 days after initiation using a semi-competing risk framework. We estimated the average treatment effect among the treated i.e. those who received other ESMs. ResultsThe matched cohort of 916 ESM initiators had a median age of 74 (IQR 69, 82) and was 57% female and 71% Non-Hispanic White. Using the semi-competing risk framework, those who received other ESM had a 37% lower hazard of seizure-like events compared to receiving LEV, given that death had not occurred, hazard ratio 0.63 (95% CI: 0.43, 0.91). Among those who initiated ESMs other than Levetiracetam, the hazard of ED visits and hospitalizations, given that death had not occurred, did not different significantly from initiating Levetiracetam; hazard ratios 1.00 (95% CI: 0.80, 1.25) and 0.98 (95% CI: 0.75, 1.28), respectively. ConclusionIn a sample of Medicare beneficiaries hospitalized for acute ischemic stroke and discharged home, initiating Levetiracetam in the outpatient setting was associated with a higher risk of seizure-like events compared to other ESMs. However, no significant differences were observed in the incidence of ED visits or hospitalizations, suggesting comparable safety profiles in these broader clinical outcomes.

OBJECTIVENeurological complications can worsen outcomes in COVID-19. We defined the prevalence of a wide range of neurological conditions among patients hospitalized with COVID-19 in geographically diverse multinational populations. METHODSUsing electronic health record (EHR) data from 348 participating hospitals across 6 countries and 3 continents between January and September 2020, we performed a cross-sectional study of hospitalized adult and pediatric patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test, both with and without severe COVID-19. We assessed the frequency of each disease category and 3-character International Classification of Disease (ICD) code of neurological diseases by countries, sites, time before and after admission for COVID-19, and COVID-19 severity. RESULTSAmong the 35,177 hospitalized patients with SARS-CoV-2 infection, there was increased prevalence of disorders of consciousness (5.8%, 95% confidence interval [CI]: 3.7%-7.8%, pFDR<.001) and unspecified disorders of the brain (8.1%, 95%CI: 5.7%-10.5%, pFDR<.001), compared to pre-admission prevalence. During hospitalization, patients who experienced severe COVID-19 status had 22% (95%CI: 19%-25%) increase in the relative risk (RR) of disorders of consciousness, 24% (95%CI: 13%-35%) increase in other cerebrovascular diseases, 34% (95%CI: 20%-50%) increase in nontraumatic intracranial hemorrhage, 37% (95%CI: 17%-60%) increase in encephalitis and/or myelitis, and 72% (95%CI: 67%-77%) increase in myopathy compared to those who never experienced severe disease. INTERPRETATIONUsing an international network and common EHR data elements, we highlight an increase in the prevalence of central and peripheral neurological phenotypes in patients hospitalized with SARS-CoV-2 infection, particularly among those with severe disease.

ObjectiveTo describe the safety and efficacy of risdiplam in non-sitter adult patients with 5q spinal muscular atrophy (SMA). MethodsType 2 SMA adult patients, who were not eligible for nusinersen, were offered risdiplam through the expanded access program. Patients were followed up with a battery of scales and clinical measures. ResultsSix non-sitter patients (17 - 46 years old) were treated with risdiplam. One patient reported mild adverse events (dyspepsia and headache). After one year of treatment, all patients showed clinically meaningful improvements in at least one scale and none of them showed any clinically meaningful deterioration. Two patients showed a clinically significant increase in the body mass index and other two in the revised upper limb module. Moreover, clinically meaningful improvements were found in motor (axial and upper limbs), bulbar (speech and swallowing) and respiratory (coughing) domains of functional scales, in five patients. Four subjects achieved at least one of the goals set with the goal attainment scale (GAS). DiscussionThis series suggests the safety and efficacy of risdiplam in non-sitter adult SMA patients. In these patients, functional scales and GAS are more appropriate than motor scales to detect changes, because they include axial, bulbar and respiratory domains.

BackgroundGiven the increasing diversity among neurological patients, standardized protocols are essential for evaluating the severity and complexity of the variety of conditions. Aim of the present work was to standardize the assessment of the severity and complexity of neurological impairment in an acute setting by using a modified version of the Neurological Impairment Scale (mNIS). Methodsconsecutively hospitalized neurological inpatients underwent a multidimensional standardized assessment of multimorbidity, frailty, functional dependency, and neurological impairment using mNIS and other validated scales. Inter-rater reliability of the mNIS total and sub-scores was evaluated. Construct validity was assessed separately in patients with Cerebrovascular disease performing correlations between corresponding sub-scores of mNIS, original NIS, and National Institutes of Health Stroke Scale (NIHSS). mNIS Complexity Index (mNIS-CI) for neurological severity was used to classify patients into subtle, mild, moderate, and severe impairment. Resultsone thousand eighty-one neurological patients admitted to a neurological ward from the emergency setting were enrolled. The inter-rater reliability was remarkable for mNIS total and sub-scores (ICC 0.90, 95% CI 0.82-0.95). The mNIS showed strong construct validity for total and sub-scores compared to other clinical scales (r 0.47-0.97, p<0.001) and 52.7% of patients scored at least one in one of the four newly listed items. The stratification of patients according to mNIS-CI exhibited high construct validity distinguishing the extent of impairment and involved domains. ConclusionsThe mNIS is valuable for measuring neurologic severity and complexity in acute inpatients and holds significant potential for application in different settings. What is already known on this topicStandardization of neurological assessment and development of functional rating scales of global impairment are pivotal to characterize and follow up patients both in the clinical practice and in the research setting. What this study addsmNIS is a valuable tool to measure neurologic severity and complexity in acute inpatients: the four added items are useful for capturing a broader spectrum of signs and symptoms; the severity and complexity scores provide different information about neurological status and domain imapired at individual level. How this study might affect research, practice, or policymNIS can be instrumental in grading the severity of neurological conditions, tracking clinical progress, and gauging response to treatments in the acute setting.

ImportanceSevere COVID-19 infection has been associated with neurological complications, but its role in accelerating cognitive decline remains unclear. ObjectiveTo determine whether individuals hospitalized for severe COVID-19 exhibit a higher incidence of new onset cognitive impairment compared to those hospitalized for other conditions. DesignA retrospective study emulating a target trial using Mass General Brigham electronic health records (March 2020-August 2024). The causal effect of COVID-19 hospitalization was estimated via cumulative incidence functions accounting for the competing risk of death. SettingMulticenter hospital-based study across the Mass General Brigham healthcare system. ParticipantsA total of 221613 hospitalized patients met the eligibility criteria, including 6454 (2.0%) admitted due to COVID-19 and 215159 (98.0%) for all other conditions. Patients were excluded if they had less than three months of follow-up (due to censoring, cognitive impairment, or death), were younger than 55 years at baseline, or had no prior visit to Mass General Brigham in the year before baseline. Main Outcomes and MeasuresThe primary outcome was new-onset cognitive impairment, identified via ICD codes and dementia medication prescriptions. The primary analysis estimated the hazard ratio for cognitive impairment with COVID-19 hospitalization relative to other hospitalizations, along with the risk difference at 4.5 years estimated via cumulative incidence functions. Inverse propensity score weighting was used to balance covariates (age, sex, comorbidities, hospitalization period). ResultsAmong eligible patients (mean [SD] age, 69.55 [9.42] years, 55% female), those hospitalized for COVID-19 were significantly older and had more comorbidities (p < 0.05). COVID-19 hospitalization was associated with a higher risk of developing cognitive impairment (Hazard Ratio: 1.14 [95% CI: 1.02-1.30], P = 0.018). At 4.5 years, the cumulative incidence of cognitive impairment was 12.5% [95% CI: 11.3-13.5] in the COVID-19 group, compared to 11.6% [95% CI: 11.1-12.1] in the non-COVID-19 group. Conclusions and RelevanceSevere COVID-19 infection was associated with an elevated risk of developing clinically recognized cognitive impairment. Future studies are needed to validate findings in other health care settings. Early screening and intervention for cognitive decline may help optimize long-term outcomes for COVID-19 patients. Key pointsO_ST_ABSQuestionC_ST_ABSDo individuals hospitalized for severe COVID-19 have a higher incidence of new-onset cognitive impairment compared to those hospitalized for other conditions? FindingsIn this retrospective study of 221613 hospitalized patients, including 6454 hospitalized due to COVID-19, a higher incidence of new-onset cognitive impairment was observed among COVID-19 patients. MeaningEarly recognition and diagnosis of dementia in individuals with severe COVID-19 are crucial for optimizing long-term patient outcomes.

BackgroundCerebral small vessel disease (cSVD) is a major cause of stroke and dementia but patients often report a lack of specialist care. We aimed to identify the availability and type of care, current management practices and areas of unmet need for patients with cSVD. MethodsWe performed a literature review to identify clinical practices towards cSVD and an online international survey of health-care centres (one clinician per hospital/clinic) treating individuals with cSVD between September/2022-May/2023. All answers were anonymised (with an option to sign). We compared the clinical workup between cSVD-dedicated and non-cSVD-dedicated health-care services, regions and country-income-class groups using descriptive statistics. ResultsOur review found five clinical cSVD-services. We distributed 264 survey requests and received 137 responses (response rate=52%); 130 responses representing 45 different countries contained analysable data; 63% responses were from High-Income countries (HIC). Fourteen centres/130 responses (11%) had cSVD-services, nine in HIC, seeing a median of 150 (IQR 64.5,290) individuals with cSVD/year. 79% (91/115) physicians reported cognitive decline as the primary concern for patients. Follow-up was more likely in cSVD-services (cSVD-centres vs not: 85% 11/13 vs 45% 49/109; 2(df)=1, p=0.007) for main outcomes stroke and dementia. 77% (84/109) centres without a cSVD-service believed there is an unmet clinical need for cSVD. 21% did not assess cognition, and 21% (25/117) applied diagnostic cognitive tools. For covert-cSVD, antiplatelet use was more likely in Latin-America & the Caribbean (Fisher-exact, p<0.001) and statins in Europe & Central Asia (Fisher-exact, p=0.01). 61 services evaluated long-term outcomes, of which 8 reported patient-reported-outcome measures. ConclusionsThis survey has identified very few cSVD specialist services, a large, physician-acknowledged unmet clinical need, and serious mismatch between clinical management and patient-reported priorities for people with cSVD. Our results indicate a need for improved person-centred care for cSVD. Standardisation of practices and services could significantly improve health-care for people with cSVD.

BackgroundPathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. MethodsWe leveraged a large, multicentre international cohort comprising 282 individuals with KCNQ2 pathogenic variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed. ResultsSCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, early SCB initiation within the first month of life was associated with significantly more favourable neurodevelopmental trajectories, including higher rates of achievement of major motor milestones. Early seizure freedom itself was a strong predictor of improved neurodevelopment, with the positive effect of SCBs likely mediated by their ability to control seizures. However, considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation. Variant severity and possible genetic modifiers likely contribute to this heterogeneity, underscoring the need for precision therapies beyond nonspecific ASM approaches. ConclusionOur results strongly support the use of SCBs as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE due to their high effectiveness. Moreover, SCBs appear most beneficial when initiated during the neonatal period, with earlier treatment linked to earlier seizure offset and better developmental outcomes. These results highlight the importance of early genetic diagnosis and timely SCB therapy, and support CBZ or OXC as first-line agents. We however emphasise that early treatment is not universally transformative, and further work, including exploration of targeted therapies but also standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.

ObjectiveTo analyze postsurgical outcomes in relation to epilepsy characteristics and genetic etiology in pediatric patients with isolated low-grade epilepsy associated tumors (LEAT) and LEAT plus focal cortical dysplasia type IIIb (FCD IIIb) who underwent epilepsy surgery. MethodsPatients younger than 19 years at the time of epilepsy surgery, with isolated LEAT or LEAT plus FCD IIIb and a minimum follow-up of 2 years were included. Clinical data, neuroimaging, EEG, neuropsychological findings, surgical variables, histopathological and molecular-genetic findings were evaluated. Surgical outcomes were assessed in four domains: seizures, antiseizure medication (ASM) use, cognitive performance changes and complications, including predictor analysis. ResultsSeventy-three children fulfilled the inclusion criteria, with 53 (72.6%) having drug-resistant epilepsy. LEAT plus FCD IIIb were more frequent than isolated LEAT (44/73, 60.3% vs. 29/73, 39.7%) and gangliogliomas were the most common tumor type (43/73, 58.9%), followed by dysembryoplastic neuroepithelial tumor (19/73, 26.0 %). Genetic testing was more frequently positive in isolated LEAT (20/28) than LEAT plus FCD IIIb (18/43, p = 0.02). At the end of follow-up (median 5.7 years), 66 patients (90.4%) were seizure-free, and 57 (78.1%) had discontinued ASM. Younger age at seizure onset, longer epilepsy duration, and a higher number of ASM were correlated to lower pre- and postoperative IQ. An IQ gain of > 10 pts. postoperatively was present in 8 patients (15.1%). Two patients (2.7%) had an unexpected permanent deficit, while 10 (13.7%) had minor temporary deficit. No additional predictive outcome factors were identified. SignificanceEpilepsy surgery yields high chances of freedom from seizures and ASM discontinuation. Early surgical intervention in terms of shorter duration of epilepsy and fewer used ASM can be associated to a higher pre- and postoperative IQ. Molecular-genetic differences between isolated LEAT and LEAT plus FCD IIIb suggest distinct neoplastic and dysplastic entities, respectively. Key pointsO_LIA majority of patients with LEAT achieved freedom from seizures and ASM post-surgically. C_LIO_LIChildren with younger age at seizure onset, longer duration of epilepsy and a higher number of ASM used before surgery had lower pre- and postoperative IQ. C_LIO_LIGenetic cause was detected more often in patients with isolated LEAT vs. LEAT + FCD IIIb implying their neoplastic respectively dysplastic origin. C_LI

Background/objectiveVarious studies have demonstrated, European data regarding ethnic disparities in health-related quality of life (HRQOL) after stroke is scarce and none used patient reported outcomes measurements (PROMs). This study explores whether ethnicity predict HRQOL using PROMs and cognitive function after stroke in the Netherlands. Patients and methodsPatients admitted to the hospital with a first ever stroke were included. Outcome assessments included the Patient Reported Outcomes Measurement Information System (PROMIS) Profile and EuroQoL-5D (EQ-5D index and EQ-5D-L Visual Analogue Scale, VAS) for HRQOL and the PROMIS Cognitive Function for cognitive functioning. Measurements were done at hospital admission and after 3 and 12 months (EQ-5D-3L and EQ-VAS only at 12 months). Ethnicity (migration background yes/no), other demographics and stroke characteristics were collected at admission. Outcomes were compared between patients with and without a migration background by a multivariate linear mixed-effects model, adjusted for age, sex, education level and severity of stroke (NIHSS at admission). Results262 patients were included, of whom 74 (28.2%) did and 188 (71.8%) did not have a migration background. A significant difference was observed at admission for the physical function score (estimate=3.30, SE=1.25, p=0.01), at three months for anxiety score (estimate=-2.95, SE=1.48, p=0.05) and twelve months for sleep disturbance score (estimate=-5.43, SE=1.61, p<0.01). These results are all to the disadvantage of patients with a migration background. The EQ-5D index and EQ-5D VAS at twelve months follow-up was significantly lower in patients with a migration background compared to patients without a migration background (respectively adjusted B -0.09 (95% CI -0.17; -0.01)) and adjusted B -7.27 (95% CI (-13.99; -0.56)). ConclusionUp to twelve months after hospital admission, stroke patients with a migration background had significantly worse scores regarding several domains of HRQOL compared to patients without a migration background.