Diagnostic markers of acute encephalitis syndrome and COVID-associated multisystem inflammatory syndrome in children from Southern India.

Acute encephalitis syndrome (AES) in children poses a significant public health challenge in India. This study aims to explore the utility of host inflammatory mediators and neurofilament (NfL) levels in distinguishing etiologies, assessing disease severity, and predicting outcomes in AES. We assessed 12 mediators in serum (n = 58) and 11 in cerebrospinal fluid (CSF) (n = 42) from 62 children with AES due to scrub typhus, viral etiologies, and COVID-associated multisystem inflammatory syndrome (MIS-C) in Southern India. Additionally, NfL levels in serum (n = 20) and CSF (n = 18) were examined. Clinical data, including Glasgow coma scale (GCS) and Liverpool outcome scores, were recorded. Examining serum and CSF markers in the three AES etiology groups revealed notable distinctions, with scrub typhus differing significantly from viral and MIS-C causes. Viral causes had elevated serum CCL11 and CCL2 compared with scrub typhus, while MIS-C cases showed higher HGF levels than scrub typhus. However, CSF analysis showed a distinct pattern with the scrub typhus group exhibiting elevated levels of IL-1RA, IL-1ß, and TNF compared with MIS-C, and lower CCL2 levels compared with the viral group. Modeling the characteristic features, we identified that age ≥3 years with serum CCL11 < 180 pg/mL effectively distinguished scrub typhus from other AES causes. Elevated serum CCL11, HGF, and IL-6:IL-10 ratio were associated with poor outcomes (p = 0.038, 0.005, 0.02). Positive CSF and serum NfL correlation, and negative GCS and serum NfL correlation were observed. Median NfL levels were higher in children with abnormal admission GCS and poor outcomes. Measuring immune mediators and brain injury markers in AES provides valuable diagnostic insights, with the potential to facilitate rapid diagnosis and prognosis. The correlation between CSF and serum NfL, along with distinctive serum cytokine profiles across various etiologies, indicates the adequacy of blood samples alone for assessment and monitoring. The association of elevated levels of CCL11, HGF, and an increased IL-6:IL-10 ratio with adverse outcomes suggests promising avenues for therapeutic exploration, warranting further investigation.

Fewer COVID-19 Neurological Complications with Dexamethasone and Remdesivir.

OBJECTIVE: The objective of this study was to assess the impact of treatment with dexamethasone, remdesivir or both on neurological complications in acute coronavirus diease 2019 (COVID-19). METHODS: We used observational data from the International Severe Acute and emerging Respiratory Infection Consortium World Health Organization (WHO) Clinical Characterization Protocol, United Kingdom. Hospital inpatients aged ≥18 years with laboratory-confirmed severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection admitted between January 31, 2020, and June 29, 2021, were included. Treatment allocation was non-blinded and performed by reporting clinicians. A propensity scoring methodology was used to minimize confounding. Treatment with remdesivir, dexamethasone, or both was assessed against the standard of care. The primary outcome was a neurological complication occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode. RESULTS: Out of 89,297 hospital inpatients, 64,088 had severe COVID-19 and 25,209 had non-hypoxic COVID-19. Neurological complications developed in 4.8% and 4.5%, respectively. In both groups, neurological complications were associated with increased mortality, intensive care unit (ICU) admission, worse self-care on discharge, and time to recovery. In patients with severe COVID-19, treatment with dexamethasone (n = 21,129), remdesivir (n = 1,428), and both combined (n = 10,846) were associated with a lower frequency of neurological complications: OR = 0.76 (95% confidence interval [CI] = 0.69-0.83), OR = 0.69 (95% CI = 0.51-0.90), and OR = 0.54 (95% CI = 0.47-0.61), respectively. In patients with non-hypoxic COVID-19, dexamethasone (n = 2,580) was associated with less neurological complications (OR = 0.78, 95% CI = 0.62-0.97), whereas the dexamethasone/remdesivir combination (n = 460) showed a similar trend (OR = 0.63, 95% CI = 0.31-1.15). INTERPRETATION: Treatment with dexamethasone, remdesivir, or both in patients hospitalized with COVID-19 was associated with a lower frequency of neurological complications in an additive manner, such that the greatest benefit was observed in patients who received both drugs together. ANN NEUROL 2023;93:88-102.

Mental health outcomes of encephalitis: An international web-based study.

BACKGROUND AND PURPOSE: Acute encephalitis is associated with psychiatric symptoms. Despite this, the extent of mental health problems following encephalitis has not been systematically reported. METHODS: We recruited adults who had been diagnosed with encephalitis of any aetiology to complete a web-based questionnaire. RESULTS: In total, 445 respondents from 31 countries (55.1% UK, 23.1% USA) responded. Infectious encephalitis constituted 65.4% of cases, autoimmune 29.7%. Mean age was 50.1 years, 65.8% were female, and median time since encephalitis diagnosis was 7 years. The most common self-reported psychiatric symptoms were anxiety (75.2%), sleep problems (64.4%), mood problems (62.2%), and unexpected crying (35.2%). Self-reported psychiatric diagnoses were common: anxiety (44.0%), depression (38.6%), panic disorder (15.7%), and posttraumatic stress disorder (PTSD; 21.3%). Severe mental illnesses such as psychosis (3.3%) and bipolar affective disorder (3.1%) were reported. Self-reported diagnosis rates were broadly consistent with results from the Psychiatric Diagnostic Screening Questionnaire. Many respondents also reported they had symptoms of anxiety (37.5%), depression (28.1%), PTSD (26.8%), or panic disorder (20.9%) that had not been diagnosed. Rates of psychiatric symptoms did not differ between autoimmune and infectious encephalitis. In total, 37.5% respondents had thought about suicide, and 4.4% had attempted suicide, since their encephalitis diagnosis. More than half of respondents (53.5%) reported they had no, or substandard, access to appropriate mental health care. High rates of sensory hypersensitivities (>75%) suggest a previously unreported association. CONCLUSIONS: This large international survey indicates that psychiatric symptoms following encephalitis are common and that mental health care provision may be inadequate. We highlight a need for proactive psychiatric input.

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation. METHODS: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders. RESULTS: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment. CONCLUSIONS: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

Global Landscape of Encephalitis: Key Priorities to Reduce Future Disease Burden.

Encephalitis affects people across the lifespan, has high rates of mortality and morbidity, and results in significant neurological sequelae with long-term consequences to quality of life and wider society. The true incidence is currently unknown due to inaccurate reporting systems. The disease burden of encephalitis is unequally distributed across the globe being highest in low- and middle-income countries where resources are limited. Here countries often lack diagnostic testing, with poor access to essential treatments and neurological services, and limited surveillance and vaccination programs. Many types of encephalitis are vaccine preventable, whereas others are treatable with early diagnosis and appropriate management. In this viewpoint, we provide a narrative review of key aspects of diagnosis, surveillance, treatment, and prevention of encephalitis and highlight priorities for public health, clinical management, and research, to reduce the disease burden.

Addressing vaccine-preventable encephalitis in vulnerable populations.

PURPOSE OF REVIEW: Vaccinations have been pivotal in lowering the global disease burden of vaccine-preventable encephalitides, including Japanese encephalitis, tick-borne encephalitis, measles encephalitis, and rabies encephalitis, among others. RECENT FINDINGS: Populations vulnerable to vaccine-preventable infections that may lead to encephalitis include those living in endemic and rural areas, military members, migrants, refugees, international travelers, younger and older persons, pregnant women, the immunocompromised, outdoor, healthcare and laboratory workers, and the homeless. There is scope for improving the availability and distribution of vaccinations, vaccine equity, surveillance of vaccine-preventable encephalitides, and public education and information. SUMMARY: Addressing these gaps in vaccination strategies will allow for improved vaccination coverage and lead to better health outcomes for those most at risk for vaccine-preventable encephalitis.

Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients.

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Encephalitis: diagnosis, management and recent advances in the field of encephalitides.

Encephalitis describes inflammation of the brain parenchyma, typically caused by either an infectious agent or through an autoimmune process which may be postinfectious, paraneoplastic or idiopathic. Patients can present with a combination of fever, alterations in behaviour, personality, cognition and consciousness. They may also exhibit focal neurological deficits, seizures, movement disorders and/or autonomic instability. However, it can sometimes present non-specifically, and this combined with its many causes make it a difficult to manage neurological syndrome. Despite improved treatments in some forms of encephalitides, encephalitis remains a global concern due to its high mortality and morbidity. Prompt diagnosis and administration of specific and supportive management options can lead to better outcomes. Over the last decade, research in encephalitis has led to marked developments in the understanding, diagnosis and management of encephalitis. In parallel, the number of autoimmune encephalitis syndromes has rapidly expanded and clinically characteristic syndromes in association with pathogenic autoantibodies have been defined. By focusing on findings presented at the Encephalitis Society's conference in December 2021, this article reviews the causes, clinical manifestations and management of encephalitis and integrate recent advances and challenges of research into encephalitis.

Encephalitis: diagnosis, management and recent advances in the field of encephalitides.

Encephalitis describes inflammation of the brain parenchyma, typically caused by either an infectious agent or through an autoimmune process which may be postinfectious, paraneoplastic or idiopathic. Patients can present with a combination of fever, alterations in behaviour, personality, cognition and consciousness. They may also exhibit focal neurological deficits, seizures, movement disorders and/or autonomic instability. However, it can sometimes present non-specifically, and this combined with its many causes make it a difficult to manage neurological syndrome. Despite improved treatments in some forms of encephalitides, encephalitis remains a global concern due to its high mortality and morbidity. Prompt diagnosis and administration of specific and supportive management options can lead to better outcomes. Over the last decade, research in encephalitis has led to marked developments in the understanding, diagnosis and management of encephalitis. In parallel, the number of autoimmune encephalitis syndromes has rapidly expanded and clinically characteristic syndromes in association with pathogenic autoantibodies have been defined. By focusing on findings presented at the Encephalitis Society's conference in December 2021, this article reviews the causes, clinical manifestations and management of encephalitis and integrate recent advances and challenges of research into encephalitis.

Approaches to understanding COVID-19 and its neurological associations.

There is an accumulating volume of research into neurological manifestations of COVID-19. However, inconsistent study designs, inadequate controls, poorly-validated tests, and differing settings, interventions, and cultural norms weaken study quality, comparability, and thus the understanding of the spectrum, burden and pathophysiology of these complications. Therefore, a global COVID-19 Neuro Research Coalition, together with the WHO, has reviewed reports of COVID-19 neurological complications and harmonised clinical measures for future research. This will facilitate well-designed studies using precise, consistent case definitions of SARS-CoV2 infection and neurological complications, with standardised forms for pooled data analyses that non-specialists can use, including in low-income settings. This article is protected by copyright. All rights reserved.

Increased volume of cerebral oedema is associated with risk of acute seizure activity and adverse neurological outcomes in encephalitis - regional and volumetric analysis in a multi-centre cohort.

BACKGROUND: Seizures can occur unpredictably in patients with acute encephalitis syndrome (AES), and many suffer from poor long-term neurological sequelae. Establishing factors associated with acute seizures risk and poor outcomes could support clinical care. We aimed to conduct regional and volumetric analysis of cerebral oedema on magnetic resonance imaging (MRI) in patients with AES. We assessed the relationship of brain oedema with acute seizure activity and long-term neurological outcome. METHODS: In a multi-centre cohort study, adults and children presenting with an AES were recruited in the UK. The clinical and brain MRI data were retrospectively reviewed. The outcomes variables were inpatient acute seizure activity and neurological disability at six-months post-discharge. A poor outcome was defined as a Glasgow outcome score (GOS) of 1-3. We quantified regional brain oedema on MRI through stereological examination of T2-weighted images using established methodology by independent and blinded assessors. Clinical and neuroimaging variables were analysed by multivariate logistic regression to assess for correlation with acute seizure activity and outcome. RESULTS: The study cohort comprised 69 patients (mean age 31.8 years; 53.6% female), of whom 41 (59.4%) had acute seizures as inpatients. A higher Glasgow coma scale (GCS) score on admission was a negative predictor of seizures (OR 0.61 [0.46-0.83], p = 0.001). Even correcting for GCS on admission, the presence of cortical oedema was a significant risk factor for acute seizure activity (OR 5.48 [1.62-18.51], p = 0.006) and greater volume of cerebral oedema in these cortical structures increased the risk of acute seizures (OR 1.90 [1.12-3.21], p = 0.017). At six-month post-discharge, 21 (30.4%) had a poor neurological outcome. Herpes simplex virus encephalitis was associated with higher risk of poor outcomes in univariate analysis (OR 3.92 [1.08-14.20], p = 0.038). When controlling for aetiology, increased volume of cerebral oedema was an independent risk factor for adverse neurological outcome at 6 months (OR 1.73 [1.06-2.83], p = 0.027). CONCLUSIONS: Both the presence and degree of cerebral oedema on MRIs of patients with AES may help identify patients at risk of acute seizure activity and subsequent long-term morbidity.

Lacosamide add-on therapy for focal epilepsy.

BACKGROUND: This is an updated version of the Cochrane review published in 2015. Around half of people with epilepsy will not achieve seizure freedom on their first antiepileptic drug; many will require add-on therapy. Around a third of people fail to achieve complete seizure freedom despite multiple antiepileptic drugs. Lacosamide has been licenced as an add-on therapy for drug-resistant focal epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of lacosamide as an add-on therapy for children and adults with drug-resistant focal epilepsy. SEARCH METHODS: We searched the following databases (22 August 2019): the Cochrane Register of Studies (CRS Web), including the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 20 August 2019), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP), with no language restrictions. We contacted UCB Pharma (sponsors of lacosamide). SELECTION CRITERIA: Randomised controlled trials of add-on lacosamide in people with drug-resistant focal epilepsy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology, assessing the following outcomes: 50% or greater reduction in seizure frequency; seizure freedom; treatment withdrawal; adverse events; quality of life; and cognitive changes. The primary analyses were intention-to-treat. We estimated summary risk ratios (RR) for each outcome presented with 99% confidence intervals (CI), except for 50% or greater seizure reduction, seizure freedom and treatment withdrawal which were presented with 95% CIs. We performed subgroup analyses according to lacosamide dose and sensitivity analyses according to population age, whereby data from children were excluded from the meta-analysis. MAIN RESULTS: We included five trials (2199 participants). The risk of bias for all studies was low to unclear. All studies were placebo-controlled and assessed doses from 200 mg to 600 mg per day. One study evaluated lacosamide in children; all other studies were in adults. Trial duration ranged from 24 to 26 weeks. All studies used adequate methods of randomisation and were double-blind. Overall, the certainty of the evidence for the outcomes was judged as moderate to high, with the exception of seizure freedom which was low. The RR for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.79 (95% CI 1.55 to 2.08; 5 studies; 2199 participants; high-certainty evidence). The RR for seizure freedom for all doses of lacosamide compared with placebo was 2.27 (95% CI 1.35 to 3.83; 5 studies; 2199 participants; low-certainty evidence). The RR for treatment withdrawal for all doses of lacosamide compared with placebo was 1.57 (95% CI 1.24 to 1.98; 5 studies; 2199 participants; moderate-certainty evidence). The estimated effect size for most outcomes did not change considerably following sensitivity analysis. For seizure freedom, however, the RR nearly doubled upon the exclusion of data from children (RR 4.04, 95% CI 1.52 to 10.73). Adverse events associated with lacosamide included: abnormal co-ordination (RR 6.12, 99% CI 1.35 to 27.77), blurred vision (RR 4.65, 99% CI 1.24 to 17.37), diplopia (RR 5.59, 99% CI 2.27 to 13.79), dizziness (RR 2.96, 99% CI 2.09 to 4.20), nausea (RR 2.35, 99% CI 1.37 to 4.02), somnolence (RR 2.04, 99% CI 1.22 to 3.41), vomiting (RR 2.94, 99% CI 1.54 to 5.64), and number of participants experiencing one or more adverse events (RR 1.12, 99% CI 1.01 to 1.24). Adverse events that were not significant were: vertigo (RR 3.71, 99% CI 0.86 to 15.95), rash (RR 0.58, 99% CI 0.17 to 1.89), nasopharyngitis (RR 1.41, 99% CI 0.87 to 2.28), headache (RR 1.34, 99% CI 0.90 to 1.98), fatigue (RR 2.11, 99% CI 0.92 to 4.85), nystagmus (RR 1.47, 99% CI 0.61 to 3.52), and upper respiratory tract infection (RR 0.70, 99% CI 0.43 to 1.15). AUTHORS' CONCLUSIONS: Lacosamide is effective and well-tolerated in the short term when used as add-on treatment for drug-resistant focal epilepsy. Lacosamide increases the number of people with 50% or greater reduction in seizure frequency and may increase seizure freedom, compared to placebo. Higher doses of lacosamide may be associated with higher rates of adverse events and treatment withdrawal. Additional evidence is required assessing the use of lacosamide in children and on longer-term efficacy and tolerability.

Transcranial magnetic stimulation for the treatment of epilepsy.

BACKGROUND: Epilepsy is a highly prevalent neurological condition characterised by repeated unprovoked seizures with various aetiologies. Although antiepileptic medications produce clinical improvement in many individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality, and even individuals who have clinical improvement from antiepileptic medications often report iatrogenic symptoms. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. This is an updated version of the original Cochrane Review published in 2016. OBJECTIVES: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side effects. SEARCH METHODS: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid 1946 to 2 June 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Epilepsy. SELECTION CRITERIA: We included randomised controlled trials that were double-blinded, single-blinded, or unblinded, and placebo controlled, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, coil, duration or intensity on participants with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. MAIN RESULTS: The original search revealed 274 records from the databases that after selection provided seven full-text relevant studies for inclusion. The latest search identified 179 new records from the databases that after evaluation against the inclusion and exclusion criteria provided one additional full-text relevant study. The eight included studies (241 participants) were all randomised trials; seven of the studies were blinded. Methodological and design information in the included studies was unclear, particularly relating to randomisation and allocation concealment methods. We were not able to combine the results of the trials in analysis due to differences in the studies' designs. For the current update, two of the eight studies analysed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively), whilst the other six studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls (low-certainty evidence). One study assessed quality of life and found that more participants showed improvement in quality of life scores with active treatments compared to the sham treatment, but this only involved seven participants (very low-certainty evidence). Four studies evaluated our secondary endpoint of mean number of epileptic discharges, three of which showed a statistically significant reduction in discharges after active rTMS treatment. Adverse effects were uncommon in the studies and typically involved headache, dizziness, and tinnitus; however increased seizure frequency did occur in a small number of individuals. The included trials reported no significant changes in medication use. Overall the risk of bias was either low or unclear, and the certainty of the evidence was low to very low. AUTHORS' CONCLUSIONS: Overall, we judged the certainty of evidence for the primary outcomes of this review to be low to very low. We found some evidence to suggest that rTMS is safe but some adverse events were experienced. The variability in technique and outcome reporting prevented meta-analysis, and the evidence for efficacy of rTMS for seizure reduction is still lacking, despite reasonable evidence that it is effective at reducing epileptiform discharges.

Antiepileptic drugs for seizure control in people with neurocysticercosis.

BACKGROUND: Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the most common clinical presentation, though people may also present with headache, symptoms of raised intracranial pressure, hydrocephalus, and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, antiepileptic drugs (AEDs), and anti-oedema drugs, such as steroids, form the mainstay of treatment. This is an updated version of the Cochrane Review previously published in 2019. OBJECTIVES: To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis. For the question of primary prevention, we examined whether AEDs reduce the likelihood of seizures in people who had neurocysticercosis but had not had a seizure. For the question of secondary prevention, we examined whether AEDs reduce the likelihood of further seizures in people who had had at least one seizure due to neurocysticercosis. As part of primary prevention studies, we also aimed to examine which AED was beneficial in people with neurocysticercosis in terms of duration, dose, and side-effect profile. SEARCH METHODS: For the 2021 update of this review, we searched the Cochrane Register of Studies (CRS Web), MEDLINE, and LILACS to January 2021. CRS Web includes randomised or quasi-randomised, controlled trials from CENTRAL, the Specialised Registers of Cochrane Review Groups, including Epilepsy, PubMed, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform. We also checked the reference lists of identified studies, and contacted experts and colleagues in the field to search for additional and ongoing studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials. Single-blind, double-blind, or unblinded studies were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures expected by Cochrane. Two review authors independently selected trials for inclusion and extracted the relevant data. The primary outcomes of interest were: proportion of individuals experiencing seizures, and time to first seizure post randomisation. Secondary outcomes included: seizure freedom, number of withdrawals, side effects, number of people seizure free with short or long durations of treatment, quality of life, therapy costs, hospitalisations, and mortality. We used an intention-to-treat analysis for the primary analysis. We calculated odds ratio (OR) for dichotomous data (proportion of individuals who experienced seizures, were seizure free for a specific time period (12 or 24 months), withdrew from treatment, developed drug-related side effects or complications, were seizure-free with each treatment policy, mortality), and planned to use mean difference (MD) for continuous data, if any continuous data were identified (quality of life, cost of treatment). We intended to evaluate time to first seizure after randomisation by calculating hazard ratios (HRs). We assessed precision using 95% confidence intervals (CIs). We stratified the analysis by treatment comparison. We also considered the duration of drug usage, co-medications, and the length of follow-up. MAIN RESULTS: We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures. We did not find any trials that directly compared individual AEDs for primary prevention in people with neurocysticercosis. We included four trials that evaluated the efficacy of short-term versus longer-term AED treatment for people with solitary neurocysticercosis (identified on computed tomography (CT) scan) who presented with seizures. In total, 466 people were enrolled. These studies compared AED treatment durations of 6, 12, and 24 months. The risk of seizure recurrence with six months of treatment compared with 12 to 24 months of treatment was inconclusive (odds ratio (OR) 1.34, 95% confidence interval (CI) 0.73 to 2.47; three studies, 360 participants; low-certainty evidence). The risk of seizure recurrence with six to 12 months of treatment compared with 24 months of treatment was inconclusive (OR 1.36, 95% CI 0.72 to 2.57; three studies, 385 participants; very low-certainty evidence). Two studies compared seizure recurrence with CT findings, and suggested that persistent and calcified lesions had a higher recurrence risk, and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of the drugs. None of the studies addressed the quality of life of the participants. These studies had methodological deficiencies, such as small sample sizes, and a possibility of bias due to lack of blinding, which affect the results of the review. AUTHORS' CONCLUSIONS: Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as seizure prophylaxis among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. Therefore, there is a need for large scale randomised controlled trials to address these questions.

Acute encephalitis in immunocompetent adults.

Encephalitis is a condition of inflammation of the brain parenchyma, occurs as a result of infectious or autoimmune causes, and can lead to encephalopathy, seizures, focal neurological deficits, neurological disability, and death. Viral causes account for the largest proportion, but in the last decade there has been growing recognition of anti-neuronal antibody syndromes. This Seminar focuses on the diagnosis and management of acute encephalitis in adults. Although viral and autoimmune causes are highlighted because of their prominent roles in encephalitis, other infectious pathogens are also considered. The role of cerebrospinal fluid studies, MRI, and novel diagnostic modalities (eg, next-generation sequencing) are discussed. Management approaches, including treatment of acute neurological complications and the use of immune suppressive and modulatory drugs for cases of suspected or confirmed autoimmune cause, are covered. Additionally, we discuss the remaining challenges in the diagnosis, management, and prognosis of encephalitis.

Antiepileptic drugs for seizure control in people with neurocysticercosis.

BACKGROUND: Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the most common clinical presentation, though it may also present with headache, symptoms of raised intracranial pressure, hydrocephalus and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, anti-oedema drugs, such as steroids, and antiepileptic drugs (AEDs) form the mainstay of treatment.This is an updated version of the original Cochrane Review published in 2015, Issue 10. OBJECTIVES: To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis.For the question of primary prevention, we examined whether AEDs reduce the likelihood of seizures in patients who have neurocysticercosis but have not had a seizure.For the question of secondary prevention, we examined whether AEDs reduce the likelihood of further seizures in patients who have had at least one seizure due to neurocysticercosis.As part of primary prevention studies, we also aimed to examine which AED has been found to be beneficial in people with neurocysticercosis in terms of duration, dose and side-effect profile. SEARCH METHODS: For the latest update of this review, we searched the following databases on 8 July 2019: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to July 05, 2019) and LILACS (1982- ). CRS Web includes the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised or quasi-randomised, controlled trials from Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We also checked the references lists of identified studies, and contacted experts in the field and colleagues to search for additional studies and for information about ongoing studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials.Single-blind, double-blind or unblinded studies were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors screened all citations for eligibility (MS screened the initially identified 180 citations, MF and BDM screened the 48 citations identified for the purpose of this update).Two review authors independently extracted data and evaluated each study for risk of bias. MAIN RESULTS: We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures.We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis.We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality.We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary neurocysticercosis (identified on computed tomography (CT) scan) presenting with seizures. In total, 466 people were enrolled. These studies compared various AED treatment durations, six, 12 and 24 months. The risk of seizure recurrence with six months treatment compared with 12 to 24 months treatment was not statistically significant (odds ratio (OR) 1.34 (95% confidence interval (CI) 0.73 to 2.47; three studies, 360 participants; low-certainty evidence)). The risk of seizure recurrence with six to 12 months compared with 24 months treatment was not statistically significant (OR 1.36 (95% CI 0.72 to 2.57; three studies, 385 participants; low-certainty evidence)).Two studies co-related seizure recurrence with CT findings and suggested that persistent and calcified lesions had a higher recurrence risk and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of drugs. None of the studies addressed the quality of life of the participants.These studies had certain methodological deficiencies such as a small sample size and a possibility of bias due to lack of blinding, which affect the results of this review. AUTHORS' CONCLUSIONS: Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as seizure prophylaxis among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. There is therefore a need for large scale randomised controlled trials to address these questions.

Clobazam add-on therapy for drug-resistant epilepsy.

BACKGROUND: Epilepsy affects approximately 1% of the population, with up to 30% of patients continuing to have seizures, despite antiepileptic drug treatment. Clobazam is a 1,5-benzodiazepine and is commonly used as an add-on treatment for drug-resistant epilepsy. This review is an updated version of the original Cochrane Review, first published in 2008, and examines the most current literature regarding clobazam as an add-on for drug-resistant epilepsy. OBJECTIVES: To assess the efficacy, effectiveness and tolerability of clobazam as an add-on therapy for drug-resistant generalised-onset and focal-onset seizures, with or without secondary generalisation, in adults and children. SEARCH METHODS: For the latest update, we searched the following databases on 9 October 2018: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (Ovid) 1946 to 8 October, 2018, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). For some previous updates we also searched SCOPUS, DARE, and BIOSIS Previews, but these are no longer needed. (SCOPUS was searched as a substitute for EMBASE, but randomised and quasi-randomised controlled trials in EMBASE are now included in CENTRAL; DARE ceased operation at the end of March 2015; BIOSIS Previews yielded no relevant items that were not found in the other databases). SELECTION CRITERIA: Randomised trials of add-on clobazam, with adequate methods of allocation concealment, recruiting patients with drug-resistant focal or generalised-onset seizures, with a minimum treatment period of eight weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: 50% or greater reduction in seizures, seizure freedom, treatment withdrawal and adverse events. MAIN RESULTS: Four double-blind, placebo-controlled, cross-over studies, representing 197 participants, were included in the review. All four studies were assessed as having unclear risk of bias due to the unavailability of methodological details. The studies demonstrated significant methodological heterogeneity and differences in outcome measures were noted. Consequently, it was not possible to summarise the data in a meta-analysis. Instead, findings were summarised in a narrative data synthesis, Only two of the studies reported 50% or greater seizure reduction. They respectively reported that 57.7% and 52.4% of participants receiving add-on clobazam experienced a 50% or greater reduction in seizure frequency, although publication bias needs to be considered (2 RCTs, n = 47, very low-quality evidence). Seizure freedom was reported by three of the included studies. Collectively, 27 out of 175 patients were seizure-free during treatment with clobazam (3 RCTs, n = 175, very low-quality evidence). Two studies specifically stated that seizure freedom was not observed in any of the participants receiving add-on placebo. Treatment withdrawal was reported by all four studies. There was a slightly higher incidence of treatment withdrawal associated with receiving clobazam, although the overall incidence was still fairly low (4 RCTs, n = 197, very low-quality evidence). Adverse events were only described in two of the studies, reportedly 36% and 85% of participants experienced one or more adverse events whilst receiving clobazam. The most commonly reported adverse event was drowsiness. AUTHORS' CONCLUSIONS: Clobazam as an add-on treatment may reduce seizure frequency and may be most effective in focal-onset seizures. It is important to recognise that this finding has been derived from very low-quality evidence and from studies judged to have an unclear risk of bias. It remains unclear which population demographic will best benefit from clobazam and over what time-frame. A large-scale, randomised controlled trial, conducted over a greater period of time, incorporating subgroups with differing seizure types, is required to effectively inform clinical practice.

Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model.

Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, globally, which continues to grow in importance despite the availability of vaccines. Viral entry into the brain can occur via the blood-brain barrier (BBB), and inflammation at the BBB is a common final pathway in many brain infections. However, the role of the BBB during JEV infection and the contribution of the endothelial and astrocytic cell inflammation in facilitating virus entry into the brain are incompletely understood. We established a BBB model using human brain endothelial cells (HBECs) and human astrocytes. HBECs are polarised, and therefore the model was inoculated by JEV from the apical side to simulate the in vivo situation. The effects of JEV on the BBB permeability and release of inflammatory mediators from both apical and basolateral sides, representing the blood and the brain side respectively were investigated. JEV infected HBECs with limited active virus production, before crossing the BBB and infecting astrocytes. Control of JEV production by HBECs was associated with a significant increase in permeability, and with elevation of many host mediators, including cytokines, chemokines, cellular adhesion molecules, and matrix metalloproteases. When compared to the controls, significantly higher amounts of mediators were released from the apical side as opposed to the basolateral side. The increased release of mediators over time also correlated with increased BBB permeability. Treatment with dexamethasone led to a significant reduction in the release of interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) from the apical side with a reduction in BBB disruption and no change in JEV production. The results are consistent with the hypothesis that JEV infection of the BBB triggers the production of a range of host mediators from both endothelial cells and astrocytes, which control JEV production but disrupt BBB integrity thus allowing virus entry into the brain. Dexamethasone treatment controlled the host response and limited BBB disruption in the model without increasing JEV production, supporting a re-investigation of its use therapeutically.