BACKGROUND:Non-traumatic coma in African children is a common life-threatening presentation often leading to hospital attendance. We aimed to estimate the distribution of non-traumatic coma causes and outcomes, including disease-specific outcomes, for which evidence is scarce. METHODS:We systematically reviewed MEDLINE, Embase, and Scopus databases from inception to Feb 6, 2024. We included studies recruiting children (aged 1 month to 16 years) with non-traumatic coma (Blantyre Coma Scale score ≤2, ie deep coma or comparable alternative) from any African country. Disease-specific studies were included if outcomes were reported. Primary data were requested where required. We used a DerSimonian-Laird random effects model to calculate pooled estimates for prevalence of causes, mortality, and morbidity (in-hospital and post-discharge), including analysis of mortality by temporality. This study was registered with PROSPERO (CRD4202014193). FINDINGS:We screened 16 666 articles. 138 studies were eligible for analysis, reporting causes, outcome data, or both from 35 027 children with non-traumatic coma in 30 African countries. 114 (89%) of 128 studies were determined to be high quality. Among the causes, cerebral malaria had highest pooled prevalence at 58% (95% CI 48-69), encephalopathy of unknown cause was associated with 23% (9-36) of cases, and acute bacterial meningitis was the cause of 10% (8-12) of cases, with all other causes representing lower proportions of cases. Pooled overall case-fatality rates were 17% (16-19) for cerebral malaria, 37% (20-55) for unknown encephalopathy, and 45% (34-55) for acute bacterial meningitis. By meta-regression, there was no significant difference in cerebral malaria (p=0·98), acute bacterial meningitis (p=0·99), or all-cause coma (p=0·081) mortality by year of study. There was no substantial difference in deaths associated with cerebral malaria in-hospital compared with post-discharge (17% [16-19] vs (18% [16-20]). Mortality was higher post-discharge than in-hospital in most non-malarial comas, including acute bacterial meningitis (39% [26-52]) vs 53% [38-69]). Disability associated with cerebral malaria was 11% (9-12). Pooled disability outcomes associated with other non-malarial diseases were largely absent. INTERPRETATION:The prevalence and outcomes of cerebral malaria and meningitis associated with non-traumatic coma were strikingly static across five decades. Enhanced molecular and radiological diagnostics, investment, policy making, community awareness, and health service provision are all required to facilitate earlier referral to specialist centres, to drive a step-change in diagnostic yield and treatment options to improve these outcomes. FUNDING:Wellcome Trust. TRANSLATIONS:For the Chichewa, French and Portuguese translations of the abstract see Supplementary Materials section.

PURPOSE OF REVIEW:Viral encephalitis is a potentially devastating condition of cerebral inflammation manifest as a combination of fever, altered mentation, and sometimes focal neurological signs and seizures. In this review we explore the new developments in understanding of the epidemiology, pathogenesis and treatment options. RECENT FINDINGS:The WHO technical brief is a landmark document which sets the stage for the advancement of the surveillance, prevention and management of viral encephalitis. Adjunctive dexamethasone given in herpes simplex virus encephalitis is not associated with a worse outcome or CSF viral persistence but may not significantly improve overall outcome. Simple interventions in resource limited settings can significantly increase the proportion of patients with a syndrome or aetiological diagnosis of viral encephalitis. SUMMARY OF IMPLICATIONS:This review highlights ongoing research further elucidating the underlying pathophysiological mechanisms of brain injury, paving the way for adjunctive targeted immunotherapy which can ameliorate those aspects of the inflammatory response contributing to brain injury. Nevertheless, large-scale networks are required to establish the prospective, adaptive platform trials necessary. Pending this, as laid out in the WHO Technical Brief on encephalitis, preventive measures have the potential to save lives, including surveillance, vector control, and uptake of established and emerging vaccines.

It is established that patients hospitalised with COVID-19 often have ongoing morbidity affecting activity of daily living (ADL), employment, and mental health. However, little is known about the relative outcomes in patients with COVID-19 neurological or psychiatric complications. We conducted a UK multicentre case-control study of patients hospitalised with COVID-19 (controls) and those who developed COVID-19 associated acute neurological or psychiatric complications (cases). Among the 651 patients, [362 (55%) cases and 289 (45%) controls], a higher proportion of cases had impairment in ADLs (199 [68.9%] vs 101 [51.8%], OR 2.06, p < 0.0002) and reported symptoms impacting employment (159 [58.2%] vs 69 [35.6%] OR 2.53, p < 0.0001). There was no significant difference in the proportion with depression or anxiety between case and control groups overall. For cases, impairment of ADLs was associated with increased risk in female sex, age > 50 years and hypertension (OR 5.43, p < 0.003, 3.11, p = 0.02, 3.66, p = 0.04). Those receiving either statins or angiotensin converting enzyme (ACE) inhibitors had a lower risk of impairment in ADLs (OR 0.09, p = 0.0006, 0.17, p = 0.03). Patients with neurological or psychiatric complications of COVID-19 had worse functional outcomes than those with respiratory COVID-19 alone in terms of ADLs and employment. Female sex, age > 50 years, and hypertension were associated with worse outcomes, and statins or ACE inhibitors with better outcomes.

The blood-brain barrier (BBB) protects the brain from pathogenic microorganisms. Neurologic complications from viral infections, including herpes simplex virus, varicella zoster virus, HIV, Japanese encephalitis virus, and SARS-CoV-2, are linked to BBB dysfunction and loss of barrier integrity. Increased BBB permeability associated with viral infections can occur through several mechanisms, such as direct neurotropism, Trojan horse mechanisms, or systemic infection and inflammation. Viruses cause direct and indirect immune-mediated damage. Understanding these neuroimmune mechanisms is critical to establish therapeutic strategies to protect BBB function. This review describes the effect of viral infection on the BBB, clinical methods to assess BBB integrity, and clinical management approaches to address viral-induced BBB damage.

OBJECTIVE:Thanks to the introduction of recent national guidelines for treating herpes simplex virus (HSV) encephalitis, health outcomes have improved. This paper evaluates the health system costs and the health-related quality of life implications of these guidelines. DESIGN AND SETTING:A sub-analysis of data from a prospective, multi-centre, observational cohort ENCEPH-UK study conducted across 29 hospitals in the UK from 2012 to 2015. STUDY PARTICIPANTS:Data for patients aged ≥16 years with a confirmed HSV encephalitis diagnosis admitted for treatment with aciclovir were collected at discharge, 3 and 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES:Patient health outcomes were measured by the Glasgow outcome score (GOS), modified ranking score (mRS) and the EuroQoL; healthcare costs were estimated per patient at discharge from hospital and at 12 months follow-up. In addition, Quality Adjusted Life Years (QALYs) were calculated from the EQ-5D utility scores. Cost-utility analysis was performed using the NHS and Social Care perspective. RESULTS:A total of 49 patients were included; 35 were treated within 48 hours, 'early' (median (IQR) 8.25 [3.7-20.5]) and 14 were treated after 48 hours 'delayed' (median (IQR) 93.9 [66.7-100.1]). At discharge, 30 (86%) in the early treatment group had a good mRS outcome score (0-3) compared with 4 (29%) in the delayed group. According to GOS, 10 (29%) had a good recovery in the early treatment group, but only 1 (7%) in the delayed group. EQ-5D-3L utility value at discharge was significantly higher for early treatment (0.609 vs 0.221, p<0.000). After adjusting for age and symptom duration at admission, early treatment incurred a lower average cost at discharge, £23,086 (95% CI: £15,186 to £30,987) vs £42,405 (95% CI: £25,457 to £59,354) [p<0.04]. A -£20,218 (95% CI: -£52,173 to £11,783) cost difference was observed at the 12- month follow-up post discharge. CONCLUSIONS:This study suggests that early treatment may be associated with better health outcomes and reduced patient healthcare costs, with a potential for savings to the NHS with faster treatment.

The blood-brain barrier is a physiological barrier that can prevent both small and complex drugs from reaching the brain to exert a pharmacological effect. For treatment of neurological diseases, drug concentrations at the target site are a fundamental parameter for therapeutic effect; thus, the blood-brain barrier is a major obstacle to overcome. Novel strategies have been developed to circumvent the blood-brain barrier, including CSF delivery, intracranial delivery, ultrasound-based methods, membrane transporters, receptor-mediated transcytosis, and nanotherapeutics. These approaches each have their advantages and disadvantages. CSF delivery and intracranial delivery are direct but invasive techniques that have not yet shown efficacy in clinical trials, although development of novel delivery devices might improve these approaches. Ultrasound-based disruption has shown some efficacy in clinical trials, but it can require invasive procedures. Approaches using membrane transporters and receptor-mediated transcytosis are less invasive than are other techniques, but they can have off-target effects. Nanotherapeutics have shown promise, but these strategies are in early stages of development. Advancements in drug delivery across the blood-brain barrier will require appropriately designed and powered clinical studies, with a focus on the timing of treatment, demographic and genetic considerations, head-to-head comparison with other treatment strategies (rather than a placebo), and relevant primary and secondary outcome measures.

Chikungunya virus (CHIKV) is an emerging cause of acute encephalitis syndrome (AES) in India, with limited data on its role in childhood AES in southern India. We systematically evaluated children with AES in southern India during a non-epidemic period for CHIKV. Serum and cerebrospinal fluid (CSF) samples were tested for CHIKV using IgM ELISA and real-time reverse transcriptase PCR. Amplicon sequencing was performed on PCR-positive samples. Clinical and laboratory features were compared between children with and without CSF CHIKV positivity (PCR/IgM antibodies). Of 376 children with AES, 20 (5.3%) had positive CHIKV tests. Co-infections were common, particularly with scrub typhus. Children presented with diverse symptoms affecting various organ systems. Neurological manifestations included meningism, seizures, cerebellar signs, behavioral abnormalities, cranial nerve involvement, involuntary movements, and hemiparesis/hemiplegia. Children with CSF CHIKV positivity showed more focal neurological deficits and transaminitis, and less musculoskeletal symptoms. Sequencing confirmation of CHIKV was made in all patients with positive CHIKV PCR, revealing a close relationship with 2016 Kenyan and Indian strains, albeit in a different clade within the East/Central/South African genotype. Along with important mutations known to impact CHIKV infectivity, four novel amino acid substitutions were detected in envelope protein coding regions. Our findings underscore the importance of routine and comprehensive CHIKV testing for children with AES, irrespective of season/outbreak. The high rate of co-infections warrants further research. Continued genomic surveillance is essential to monitor emerging mutations with epidemic potential, increased severity and the risk of neurological disease.

The COVID-19 Clinical Neuroscience Study (COVID-CNS) was a large UK research initiative investigating the clinical features, outcomes and biological mechanisms behind neurological and psychiatric complications from COVID-19. Through partnerships and patient enrolment, the study aimed to inform patient care and treatment selection to improve outcomes. Here, we evaluate the methodologies and results yielded from patient and public involvement (PPI) efforts within COVID-CNS, an important element of the research cycle which introduces patient perspectives and enhances research relevance. PPI involvement in the study heralded many accomplishments and contributed to the success of the study, in particular improving accessibility in study design and tools reducing patient burden; inclusivity and accessibility of the study in terms of recruitment; and in the plethora of assets to maximise dissemination of the study findings. Several challenges were identified, including barriers to diversify the PPI panel, difficulties faced by panel members to engage in PPI activities due to personal circumstances, as well as significant obstacles caused by the COVID-19 pandemic. Specific outcomes from this evaluation have included: identifying diversity gaps in the PPI panel, a deeper understanding of the impact of the PPI panel, including creating and adapting patient material, dissemination documents and raising awareness of the COVID-CNS study. Despite challenges, this evaluation has demonstrated the critical role of PPI within studies, particularly in this case, for strengthening understanding of how to alleviate the burden for patients of post-COVID-19 sequelae. Sufficient budget must be made available for PPI, and PPI panels must be accessible to a diverse range of people, whilst remaining adaptable to external circumstances.

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-1 beta, 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.