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.

How does research activity align with research need in chronic subdural haematoma: a gap analysis of systematic reviews with end-user selected knowledge gaps.

BACKGROUND: Chronic subdural haematoma (CSDH) is increasingly common. Although treatment is triaged and provided by neurosurgery, the role of non-operative care, alongside observed peri-operative morbidity and patient complexity, suggests that optimum care requires a multi-disciplinary approach. A UK consortium (Improving Care in Elderly Neurosurgery Initiative [ICENI]) has been formed to develop the first comprehensive clinical practice guideline. This starts by identifying critical questions to ask of the literature. The aim of this review was to consider whether existing systematic reviews had suitably addressed these questions. METHODS: Critical research questions to inform CSDH care were identified using multi-stakeholder workshops, including patient and public representation. A CSDH umbrella review of full-text systematic reviews and meta-analysis was conducted in accordance with the PRISMA statement (CRD42022328562). Four databases were searched from inception up to 30 April 2022. Review quality was assessed using AMSTAR-2 criteria, mapped to critical research questions. RESULTS: Forty-four critical research questions were identified, across 12 themes. Seventy-three articles were included in the umbrella review, comprising 206,369 patients. Most reviews (86.3%, n=63) assessed complications and recurrence after surgery. ICENI themes were not addressed in current literature, and duplication of reviews was common (54.8%, n=40). AMSTAR-2 confidence rating was high in 7 (9.6%) reviews, moderate in 8 (11.0%), low in 10 (13.7%) and critically low in 48 (65.8%). CONCLUSIONS: The ICENI themes have yet to be examined in existing secondary CSDH literature, and a series of new reviews is now required to address these questions for a clinical practice guideline. There is a need to broaden and redirect research efforts to meet the organisation of services and clinical needs of individual patients.

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.

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study.

BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.

Genomic Alterations and the Incidence of Brain Metastases in Advanced and Metastatic NSCLC: A Systematic Review and Meta-Analysis.

INTRODUCTION: Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could influence screening and determine targeted treatment. We aimed to establish prevalence and incidence in these groups, stratified by genomic alterations. METHODS: A systematic review and meta-analysis compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were conducted (PROSPERO identification CRD42022315915). Articles published in MEDLINE, EMBASE, and Cochrane Library between January 2000 and May 2022 were included. Prevalence at diagnosis and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models. RESULTS: A total of 64 unique articles were included (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC having incidence data from 40 studies). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% confidence interval [CI]: 26.1-31.0), and highest in patients that are ALK-positive (34.9%) or with RET-translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 0.13 in the wild-type group (14 studies, 95% CI: 0.11-0.16). Incidence was 0.16 in the EGFR group (16 studies, 95% CI: 0.11-0.21), 0.17 in the ALK group (five studies, 95% CI: 0.10-0.27), 0.10 in the KRAS group (four studies, 95% CI: 0.06-0.17), 0.13 in the ROS1 group (three studies, 95% CI: 0.06-0.28), and 0.12 in the RET group (two studies, 95% CI: 0.08-0.17). CONCLUSIONS: Comprehensive meta-analysis indicates a higher prevalence and incidence of BM in patients with certain targetable genomic alterations. This supports brain imaging at staging and follow-up, and the need for targeted therapies with brain penetrance.

Long-Standing Overt Ventriculomegaly in Adults: A Systematic Review and Meta-Analysis of Endoscopic Third Ventriculostomy Versus Ventriculoperitoneal Shunt as First-Line Treatment.

BACKGROUND: Long-standing overt ventriculomegaly in adults (LOVA) is a heterogeneous term describing forms of adult hydrocephalus. LOVA incidence is increasing, yet the optimal treatment strategy for symptomatic cases remains unclear. We compared success rates and complication rates between endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) as first-line treatment for LOVA. METHODS: A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Three databases were searched, and articles published from 2000 to October 2022 were included (last search date October 24, 2022). Success rates and complications of both ETV and VPS were compared using random-effects models. RESULTS: Of 895 articles identified, 22 studies were included in the analysis (556 patients: 346 in ETV group, 210 in VPS group). Mean age was 44.8 years. The most common presenting symptoms were gait disturbance (n = 178), headache (n = 156), and cognitive decline (n = 134). Combined success rates were 81.8% (n = 283/346) in the ETV group and 86.7% (n = 182/210) in the VPS group (median follow-up 41 months). There was no difference in success rates between ETV and VPS groups (odds ratio 0.94, 95% confidence interval 0.86-1.03, I2 = 0%). Combined complication rates were 4.6% (n = 16/346) in the ETV group and 27.1% (n = 57/210) in the VPS group. ETV had a lower rate of postoperative complications (odds ratio 0.22, 95% confidence interval 0.11-0.33, I2 = 0%). CONCLUSIONS: Symptomatic LOVA can be successfully managed with surgical intervention. ETV and VPS have similar success rates when used as first-line treatment. VPS has a higher complication rate.

Nipah virus, an emerging zoonotic disease causing fatal encephalitis.

Nipah virus is an acute febrile illness that can cause fatal encephalitis. It is an emerging zoonotic paramyxovirus endemic to south-east Asia and the western Pacific, and can be transmitted by its primary reservoir of fruit bats, through intermediate animal vectors and by human-to-human spread. Outbreaks of Nipah virus encephalitis have occurred in Malaysia, Singapore, Philippines, India and Bangladesh, with the most recent outbreak occurring in Kerala, India in late 2021. Extremely high case fatality rates have been reported from these outbreaks, and to date no vaccines or therapeutic management options are available. Combining this with its propensity to present non-specifically, Nipah virus encephalitis presents a challenging diagnosis that should not be missed in patients returning from endemic regions. Raising awareness of the epidemiology, clinical presentation and risk factors of contracting Nipah virus is vital to recognise and manage potential outbreaks of this disease in the UK.

Increasing anti-S antibody testing: a quality improvement initiative with evolving COVID-19 guidelines.

BACKGROUND: COVID-19 management guidelines are constantly evolving, making them difficult to implement practically. Ronapreve was a neutralising monoclonal antibody introduced into UK COVID-19 guidelines in 2021. It reduces mortality in seronegative patients infected with non-omicron variants. Antibody testing on admission is therefore vital in ensuring patients could be considered for Ronapreve as inpatients. LOCAL PROBLEM: We found that on our COVID-19 ward, 31.4% of patients were not having anti-S tests despite fulfilling the other criteria to be eligible for Ronapreve. This was identified as an important target to improve; by not requesting anti-S tests, we were forgoing the opportunity to use an intervention that could improve outcomes. METHODS: We analysed patient records for patients with COVID-19 admitted to our ward over 4 months to observe if awareness of the need to request anti-S increased through conducting plan-do-study-act (PDSA) cycles. INTERVENTIONS: Our first intervention was an multidisciplinary team (MDT) discussion at our departmental audit meeting highlighting our baseline findings and the importance of anti-S requesting. Our second intervention was to hang printed posters in both the doctors' room and the ward as a visual reminder to staff. Our final intervention was trust-wide communications of updated local COVID-19 guidance that included instructions for anti-S requesting on admission. RESULTS: Our baseline data showed that only 68.6% of patients with symptomatic COVID-19 were having anti-S antibody tests requested. This increased to 95.0% following our three interventions. There was also a reduction in the amount of anti-S requests being 'added on', from 57.1% to 15.8%. CONCLUSIONS: COVID-19 guidelines are constantly evolving and require interventions that can be quickly and easily implemented to improve adherence. Sustained reminders through different approaches allowed a continued increase in requesting. This agrees with research that suggests a mixture of educational sessions and visual reminders of guidelines increase their application in clinical practice.

Neurological manifestations of scrub typhus infection: A systematic review and meta-analysis of clinical features and case fatality.

BACKGROUND: Scrub typhus has become a leading cause of central nervous system (CNS) infection in endemic regions. As a treatable condition, prompt recognition is vital. However, few studies have focused on describing the symptomology and outcomes of neurological scrub typhus infection. We conducted a systematic review and meta-analysis to report the clinical features and case fatality ratio (CFR) in patients with CNS scrub typhus infection. METHODS: A search and analysis plan was published in PROSPERO [ID 328732]. A systematic search of PubMed and Scopus was performed and studies describing patients with CNS manifestations of proven scrub typhus infection were included. The outcomes studied were weighted pooled prevalence (WPP) of clinical features during illness and weighted CFR. RESULTS: Nineteen studies with 1,221 (656 adults and 565 paediatric) patients were included. The most common clinical features in CNS scrub typhus were those consistent with non-specific acute encephalitis syndromes (AES), such as fever (WPP 100.0% [99.5%-100.0%, I2 = 47.8%]), altered sensorium (67.4% [54.9-78.8%, I2 = 93.3%]), headache (65.0% [51.5-77.6%, I2 = 95.1%]) and neck stiffness 56.6% (29.4-80.4%, I2 = 96.3%). Classical features of scrub typhus were infrequently identified; an eschar was found in only 20.8% (9.8%-34.3%, I2 = 95.4%) and lymphadenopathy in 24.1% (95% CI 11.8% - 38.9%, I2 = 87.8%). The pooled CFR (95% CI) was 3.6% (1.5%- 6.4%, I2 = 67.3%). Paediatric cohorts had a CFR of 6.1% (1.9-12.1%, I2 = 77%) whilst adult cohorts reported 2.6% (0.7-5.3%, I2 = 43%). CONCLUSION: Our meta-analyses illustrate that 3.6% of patients with CNS manifestations of scrub typhus die. Clinicians should have a high index of suspicion for scrub typhus in patients presenting with AES in endemic regions and consider starting empiric treatment whilst awaiting results of investigations, even in the absence of classical signs such as an eschar or lymphadenopathy.

Acute seizure risk in patients with encephalitis: development and validation of clinical prediction models from two independent prospective multicentre cohorts.

Objective: In patients with encephalitis, the development of acute symptomatic seizures is highly variable, but when present is associated with a worse outcome. We aimed to determine the factors associated with seizures in encephalitis and develop a clinical prediction model. Methods: We analysed 203 patients from 24 English hospitals (2005-2008) (Cohort 1). Outcome measures were seizures prior to and during admission, inpatient seizures and status epilepticus. A binary logistic regression risk model was converted to a clinical score and independently validated on an additional 233 patients from 31 UK hospitals (2013-2016) (Cohort 2). Results: In Cohort 1, 121 (60%) patients had a seizure including 103 (51%) with inpatient seizures. Admission Glasgow Coma Scale (GCS) ≤8/15 was predictive of subsequent inpatient seizures (OR (95% CI) 5.55 (2.10 to 14.64), p<0.001), including in those without a history of prior seizures at presentation (OR 6.57 (95% CI 1.37 to 31.5), p=0.025).A clinical model of overall seizure risk identified admission GCS along with aetiology (autoantibody-associated OR 11.99 (95% CI 2.09 to 68.86) and Herpes simplex virus 3.58 (95% CI 1.06 to 12.12)) (area under receiver operating characteristics curve (AUROC) =0.75 (95% CI 0.701 to 0.848), p<0.001). The same model was externally validated in Cohort 2 (AUROC=0.744 (95% CI 0.677 to 0.811), p<0.001). A clinical scoring system for stratifying inpatient seizure risk by decile demonstrated good discrimination using variables available on admission; age, GCS and fever (AUROC=0.716 (95% CI 0.634 to 0.798), p<0.001) and once probable aetiology established (AUROC=0.761 (95% CI 0.6840.839), p<0.001). Conclusion: Age, GCS, fever and aetiology can effectively stratify acute seizure risk in patients with encephalitis. These findings can support the development of targeted interventions and aid clinical trial design for antiseizure medication prophylaxis.