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BACKGROUND: Neuropsychiatric presentations of monkeypox (MPX) infection have not been well characterised, despite evidence of nervous system involvement associated with the related smallpox infection. METHODS: In this pre-registered (PROSPERO ID 336649) systematic review and meta-analysis, we searched MEDLINE, EMBASE, PsycINFO, AMED and the preprint server MedRxiv up to 31/05/2022. Any study design of humans infected with MPX that reported a neurological or psychiatric presentation was included. For eligible symptoms, we calculated a pooled prevalence using an inverse variance approach and corresponding 95% confidence intervals. The degree of variability that could be explained by between-study heterogeneity was assessed using the I 2 statistic. Risk of bias was assessed with the Newcastle Ottawa Scale and the Joanna Briggs Institute quality assessment tool. FINDINGS: From 1705 unique studies, we extracted data on 19 eligible studies (1512 participants, 1031 with confirmed infection using CDC criteria or PCR testing) most of which were cohort studies and case series with no control groups. Study quality was generally moderate. Three clinical features were eligible for meta-analysis: seizure 2.7% (95% CI 0.7-10.2%, I2 0%), confusion 2.4% (95% CI 1.1-5.2%, I2 0%) and encephalitis 2.0% (95% 0.5-8.2%, I2 55.8%). Other frequently reported symptoms included myalgia, headache and fatigue, where heterogeneity was too high for estimation of pooled prevalences, possibly as a result of differences in viral clades and study methodology. INTERPRETATION: There is preliminary evidence for a range of neuropsychiatric presentations including severe neurological complications (encephalitis and seizure) and nonspecific neurological features (confusion, headache and myalgia). There is less evidence regarding the psychiatric presentations or sequelae of MPX. This may warrant surveillance within the current MPX outbreak, with prospective longitudinal studies evaluating the mid- to long-term sequelae of the virus. Robust methods to evaluate the potential causality of MPX with these clinical features are required. More evidence is necessary to explain heterogeneity in prevalence estimates. FUNDING: UKRI/MRC (MR/V03605X/1), MRC-CSF (MR/V007181/1), MRC/AMED (MR/T028750/1) and the Wellcome Trust (102186/B/13/Z) and (102186/B/13/Z) and UCLH BRC.

Coronavirus disease 2019 (COVID-19) is a primarily respiratory disease with variable clinical courses for which animal models are needed to gather insights into the pathogenesis of its causative virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), in human patients. SARS-CoV-2 not only affects the respiratory tract but also the central nervous system (CNS), leading to neurological symptoms such as loss of smell and taste, headache, fatigue or severe complications like cerebrovascular diseases. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a well-known model of SARS-CoV-2 infection. In the present study, it served to investigate the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with relatively low SARS-CoV-2 doses and after prior influenza A virus infection. In K18-hACE2 mice, SARS-CoV-2 was found to frequently spread to and within the CNS during the later phase (day 7) of infection. Infection was restricted to neurons and appeared to first affect the olfactory bulb and spread from there mainly in basally orientated regions in the brain and into the spinal cord, in a dose dependent manner and independent of ACE2 expression. Neuronal infection was not associated with cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed. This was accompanied by apoptotic death of endothelial, microglial and immune cells, without evidence of viral infection of glial cells, endothelial cells and leukocytes. Taken together, microgliosis and immune cell apoptosis indicate a potential important role of microglial cells for the pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.

Background:The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents. Methods:We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age Findings:Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9–5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1–17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patientsvs1 [vssix [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patientsvs12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). Interpretation:This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes.

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB permeability, and morbidity, without influencing viral load. CXCL1 is produced by astrocytes in response to HSV-1 and by astrocytes and neurons in response to IL-1α, and it is the critical ligand required for neutrophil transendothelial migration, which correlates with BBB breakdown. Thus, the CXCL1-CXCR2 axis represents an attractive therapeutic target to limit neutrophil-mediated morbidity in HSV-1 encephalitis.

In recent years, autoimmunity has been increasingly recognised as an important cause of encephalitis. Many different antibodies are now known to target antigens on the neuronal surface, and some of these are associated with characteristic clinical presentations, although seronegative cases are also recognised. Autoimmune encephalitis may mimic other conditions, including primary psychiatric disorders, particularly early in the disease. Because early immune treatment of autoimmune encephalitis improves patient outcomes, and indeed many make a good recovery, it is important to recognise these syndromes promptly.

One hundred years ago, neurologists were faced with a surge of cases of uncertain cause manifesting a protean array of symptoms. Through careful semiological description, pattern recognition and histopathological analysis, von Economo and others unified these seemingly disparate cases, defining the epidemic of encephalitis lethargica. Several landmark papers in the Journal of Neurology and Psychopathology (now JNNP) helped to illuminate clinical and pathological aspects of this new disease. In the subsequent hundred years, there have been other infectious epidemics affecting the nervous system, with causative agents including flaviviruses, influenza, enteroviruses (eg, poliomyelitis) and coronaviruses (CoV). Neurologists seeing patients in the age of COVID-19 have much to gain from the historical lessons of the epidemics of the last 100 years in responding to these new challenges. A case of encephalitis lethargica involving chiefly the cerebral cortex Authors : Watson GA Year Published : 1920 Epidemic encephalitis: Clinical papers by various authors Authors : Horder T Year Published : 1920 The first systematic descriptions of encephalitis lethargica were those of von Economo in 1916–1917, who coined the term (figure 1),1 which is also known as ‘von Economo’s disease’.2 However, there were probable cases in 1915 predating the ‘influenza epidemic’, and von Economo and others suggested that earlier epidemics throughout modern history may also have been related.3 Figure 1 Constantin Freiherr Economo von San Serff (von Economo (1876–1931)) Austrian neurologist, psychiatrist, pilot and originator of the diagnosis encephalitis lethargica (https://commons.wikimedia.org/wiki/Category:Constantin\_von\_Economo). Encephalitis lethargica appears to have spread from Eastern Europe to Germany, France and Britain between 1916 and 1918 and and then to have affected much of the rest of the world in the following few years.1 4 It probably affected more than a million people during the first half of the twentieth century, before apparently disappearing, although some clinicians …

Purpose: Status epilepticus (SE) is a severe condition of unrelenting seizures requiring urgent identification and treatment. SE may be unprovoked, occurring in someone with epilepsy, or may be provoked by acute intracranial disease or metabolic derangement. Increasingly encephalitis, particularly autoimmune types, is reported to cause refractory seizures. Whilst convulsive SE is readily identified, non-convulsive SE (NCSE) can be difficult to identify clinically, and electroencephalography (EEG) is required. Therefore, it is critical to identify the key clinical features associated with NCSE on EEG to inform future use of EEG. Methods: We conducted a multicentre, retrospective analysis of EEG requests from four general and one specialist neurology hospital in the Northwest of England (2015-2018). Cases were identified from EEG requests for patients with suspected NCSE or other indications such as encephalopathy. We compared demographic and clinical characteristics between EEG-confirmed cases of NCSE and a randomly selected sample of negative controls. Results: 358 EEGs were reviewed, and 8 positive cases of NCSE were identified. Epilepsy was identified as the aetiology in 2 of these cases, and autoimmune encephalitis another 2 cases (one patient with N-methyl-d-aspartate receptor antibodies and another with voltage gated potassium channel antibodies). Previous alcohol excess (p = 0.005) and subtle motor signs (p = 0.047) on examination were observed more frequently in patients with NCSE compared to controls. Conclusion: Physicians should have a low threshold for urgent EEG in patients with suspected or previous encephalitis, especially if autoimmunity is suspected or subtle motor signs are present. info:eu-repo/semantics/publishedVersion

Herpes simplex virus (HSV) encephalitis affects 2–4 people per million/year. Immunocompomised patients can have atypical presentations of HSV encephalitis, including a lack of cerebrospinal fluid (CSF) pleocytosis. We present the case of a patient who was receiving ustekinumab therapy for psoriasis which inhibits interleukin (IL)-12 and IL-23 signalling pathways. The initial presentation was suggestive of encephalitis, but he was discharged prior to the reporting of HSV positivity due to the lack of CSF pleocytosis. On representation, he had worsening symptoms and imaging showed midline shift, indicating cerebral oedema despite the immunosupressant effects of ustekinumab. He required intensive care unit support and treatment with high dose aciclovir and dexamethasone; after a month of treatment he made a good recovery. This case is the first to report a link between ustekinumab and HSV encephalitis, and also emphasises that imunocompromised patients can lack CSF pleocytosis and develop significant cerebral oedema which responds to immune suppression.

Summary 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.

Background. Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood. Methods. We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging–based temporal lobe volume. Results. Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P = .004). Among patients infected with HSV, the ratio of CSF IL-1β to IL-1RA was associated with a worse outcome (P = .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%; P = .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P = .012) and a positive correlation with serum IL-1α level (P = .0003) and CSF IL-1β level (P = .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P = .007) and CSF specimens from all patients (P = .016); the IL-10 level correlated inversely with BBB permeability (P = .005). Conclusions. A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.

A wide range of infections of the central nervous system are responsible for both acute seizures and epilepsy. The pathogenesis and clinical semiology of the seizure disorders vary widely between the infective pathogens. The exact mechanisms underlying this are poorly understood, but appear, at least in part, to relate to the pathogen; the degree of cortical involvement; delays in treatment; and the host inflammatory response. The treatment of infective causes of seizures involves both symptomatic treatment with antiepileptic drugs and direct treatment of the underlying condition. In many cases, early treatment of the infection may affect the prognosis of the epilepsy syndrome. The greatest burden of acute and long-term infection-related seizures occurs in resource-poor settings, where both clinical and research facilities are often lacking to manage such patients adequately. Nevertheless, education programs may go a long way toward addressing the stigma, leading to improved diagnosis, management, and ultimately to better quality of life.

BACKGROUND:Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. METHODS:We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. RESULTS:Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p

Encephalitis is an inflammation and swelling of the brain, which is often caused by a viral infection; it is an important cause of acute symptomatic seizures as well as subsequent epilepsy. Herein we describe the definition, epidemiology, and etiology of encephalitis as a cause of seizures. We then focus on encephalitis due to herpes simplex virus (the most common sporadic viral cause of encephalitis) and Japanese encephalitis virus (the most common epidemic viral cause). We also discuss the evidence for seizures occurring in the context of antibody-associated encephalitis, an increasingly important condition. Finally, we describe the acute and longer-term management of encephalitis-related seizures and their potential pathophysiologic mechanisms, concluding with the emerging etiologic role of human herpesvirus 6.

In the 1980s the outcome of patients with herpes simplex encephalitis was shown to be dramatically improved with aciclovir treatment. Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis. Several comprehensive reviews of the investigation and management of encephalitis have been published. However, their impact on day-to day clinical practice appears to be limited. The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines.In February 2008 a group of clinicians met in Liverpool to begin the development process for clinical care guidelines based around a similar simple algorithm, supported by an evidence base, whose implementation is hoped would improve the management of patients with suspected encephalitis. © 2012.

This article provides an overview of encephalitis and addresses its diagnosis, some of the common presenting signs and symptoms, and the different aspects of nursing care required for these patients. In particular, it addresses how to explain encephalitis to the patient's relatives, the rehabilitation needs of these patients, and important aspects of discharge planning. Tests that are necessary for diagnosis in patients with suspected encephalitis and the importance of these are explained.

The acute central nervous system infections meningitis and encephalitis commonly require management on intensive care units. The clinical features often overlap and in the acute phase–altered consciousness and seizures may also need to be managed. In April 2012, the first UK national guideline for the management of suspected viral encephalitis was published by the British Infection Association and Association of British Neurologists, and other key stakeholders, and included a simple management algorithm. The new guideline results from evidence demonstrating a number of common oversights in the standard management of suspected viral encephalitis in many settings. In combination with British Infection Association meningitis guidelines, evidence-based approaches now exist to facilitate the non-expert managing patients with suspected central nervous system infections. Here we bring together these guidelines and the supporting evidence applicable for intensivists into a single resource.

Background Central nervous system infections can have devastating clinical outcomes if not diagnosed and treated promptly. There is a documented gap between recommended and actual practice and a limited understanding of its causes. We identified and explored the reasons for this gap, focusing on points in the patient pathway most amenable to change and the development of a tailored intervention strategy to improve diagnosis and treatment. Methods Using theoretically-informed semi-structured interviews, we explored barriers and enablers to diagnosing and managing patients with suspected encephalitis, specifically performing lumbar punctures and initiating antiviral therapy within 6 h. We purposively sampled hospitals and hospital staff in the UK. We audio recorded and transcribed all interviews prior to a framework analysis. We mapped identified barriers and enablers to the patient pathway. We matched behaviour change techniques targeting clinicians to the most salient barriers and enablers and embedded them within an intervention package. Results We interviewed 43 staff in six hospitals. Clinical staff expressed uncertainty when and how to perform lumbar punctures and highlighted practical difficulties in undertaking them within busy clinical settings. Once treatment need was triggered, clinicians generally felt able to take appropriate therapeutic action, albeit within organisational and resource constraints. Matched behaviour change techniques largely targeted antecedents of treatment. These included decision support to prompt recognition, highlighting the consequences of missed diagnoses for clinicians and patients, and practical support for lumbar punctures. We subsequently devised an evidence-informed package comprising ‘core’ interventions and, to allow for local flexibility, ‘optional’ interventions. Conclusions We identified several points in the patient pathway where practice could improve, the most critical being around clinical suspicion and initial investigation. Interventions targeting professional beliefs and behaviours whilst optimising their clinical environment were amongst the most promising approaches to improve the care of suspected encephalitis. Trial registration Randomised trial registered with Controlled Trials ISRCTN06886935. Electronic supplementary material The online version of this article (doi:10.1186/s13012-015-0224-2) contains supplementary material, which is available to authorized users.

Background Viral encephalitis is a devastating condition for which delayed treatment is associated with increased morbidity and mortality. Clinical audits indicate substantial scope for improved detection and treatment. Improvement strategies should ideally be tailored according to identified needs and barriers to change. The aim of the study is to evaluate the effectiveness and cost-effectiveness of a tailored intervention to improve the secondary care management of suspected encephalitis. Methods/Design The study is a two-arm cluster randomised controlled trial with allocation by postgraduate deanery. Participants were identified from 24 hospitals nested within 12 postgraduate deaneries in the United Kingdom (UK). We developed a multifaceted intervention package including core and flexible components with embedded behaviour change techniques selected on the basis of identified needs and barriers to change. The primary outcome will be a composite of the proportion of patients with suspected encephalitis receiving timely and appropriate diagnostic lumbar puncture within 12 h of hospital admission and aciclovir treatment within 6 h. We will gather outcome data pre-intervention and up to 12 months post-intervention from patient records. Statistical analysis at the cluster level will be blind to allocation. An economic evaluation will estimate intervention cost-effectiveness from the health service perspective. Trial registration Controlled Trials: ISRCTN06886935. Electronic supplementary material The online version of this article (doi:10.1186/s13012-014-0201-1) contains supplementary material, which is available to authorized users.

Background The emergence of influenza A(H1N1) 2009 was met with increased reports of associated neurological manifestations. We aimed to describe neurological manifestations of influenza in adults and children in the United Kingdom that presented at this time. Methods A 2-year surveillance study was undertaken through the British adult and pediatric neurological surveillance units from February 2011. Patients were included if they met clinical case definitions within 1 month of proven influenza infection. Results Twenty-five cases were identified: 21 (84%) in children and 4 (16%) in adults. Six (29%) children had preexisting neurological disorders. Polymerase chain reaction of respiratory secretions identified influenza A in 21 (81%; 20 of which [95%] were H1N1) and influenza B in 4 (15%). Twelve children had encephalopathy (1 with movement disorder), 8 had encephalitis, and 1 had meningoencephalitis. Two adults had encephalopathy with movement disorder, 1 had encephalitis, and 1 had Guillain-Barre syndrome. Seven individuals (6 children) had specific acute encephalopathy syndromes (4 acute necrotizing encephalopathy, 1 acute infantile encephalopathy predominantly affecting the frontal lobes, 1 hemorrhagic shock and encephalopathy, 1 acute hemorrhagic leukoencephalopathy). Twenty (80%) required intensive care, 17 (68%) had poor outcome, and 4 (16%) died. Conclusions This surveillance study described a cohort of adults and children with neurological manifestations of influenza. The majority were due to H1N1. More children than adults were identified; many children had specific encephalopathy syndromes with poor outcomes. None had been vaccinated, although 8 (32%) had indications for this. A modified classification system is proposed based on our data and the increasing spectrum of recognized acute encephalopathy syndromes.

Introduction The spectrum of encephalitis, a condition of brain inflammation and leucocyte infiltration, is expanding. Modern peripheral testing has resulted in fewer brain-biopsies. Consequently, our understanding of leucocyte-subsets driving inflammation is poorly understood. Methods The Walton Centre Brain-Bank was screened over 10 years, identifying all cases of biopsy and post-mortem tissue with encephalitis. Tissue underwent haemotoxylin/eosin stain, and immunohistochemical analysis for CD3, CD4, CD8, CD68, and CD79a. The immediate perivascular and surrounding parenchymal infiltrate quantitatively assessed. Results Of nine cases, two were herpes simplex virus (HSV), four immune-mediated, and three of unknown cause. In comparison to those of unknown cause, HSV had a greater proportion of CD4 and CD68 positive cells in the perivascular and immediate parenchyma respectively (p=0.007 and p=0.004). Neutrophils were only identified in HSV. Immune-mediated cases generally had a limited inflammatory infiltrate, similarly to unknown cases. Although one paraneoplastic case had a marked inflammatory infiltrate, including CD8 positive cells. Conclusions Our study describes potentially important differences in the relative leucocyte populations in the parenchyma of patients with encephalitis, which may have diagnostic and therapeutic implications. Further studies are planned to distinguish invading macrophage/monocytes from resident microglia in a transgenic murine model.

Encephalitis is an inflammation and swelling of the brain, which is often caused by a viral infection; it is an important cause of acute symptomatic seizures as well as subsequent epilepsy. Herein we describe the definition, epidemiology, and etiology of encephalitis as a cause of seizures. We then focus on encephalitis due to herpes simplex virus (the most common sporadic viral cause of encephalitis) and Japanese encephalitis virus (the most common epidemic viral cause). We also discuss the evidence for seizures occurring in the context of antibody-associated encephalitis, an increasingly important condition. Finally, we describe the acute and longer-term management of encephalitis-related seizures and their potential pathophysiologic mechanisms, concluding with the emerging etiologic role of human herpesvirus 6.

Background Acute central nervous system (CNS) infections, such as meningitis and encephalitis, are neurological emergencies for which accurate diagnosis and prompt treatment improve the outcome. Analysis of the cerebrospinal fluid (CSF) obtained at lumbar puncture (LP) is pivotal to establishing the diagnosis and guiding management. PCR analysis of the CSF is an important method to identify the pathogen. However, recent studies have demonstrated that many patients have inadequate CSF sample collection and analysis. Aims To increase the proportion of patients having an LP for a suspected CNS infection for whom the appropriate samples are taken. Secondary aims included to increase the proportion of patients for whom a pathogen was identified. Methods The authors developed an LP pack for patients with a suspected CNS infection. They also assessed its impact on diagnosis by comparing practice 6 months before and after its introduction to the medical admissions unit of a large inner city teaching hospital. Results The authors found that the LP pack reduced major errors in CSF sample collection and improved the diagnosis of acute CNS infections; among those patients who had a CSF pleocytosis, the proportion with a viral or bacterial pathogen identified by PCR was increased after introduction of the pack. Discussion This study has demonstrated that the introduction of a simple low-cost LP pack into a busy acute medical setting can improve the diagnosis of CNS infections and, thus, guide treatment. Further work is needed to see if these results are more widely reproducible, and to examine the clinical, health and economic impact on overall management of patients with suspected CNS infections.

The outcome of herpes simplex virus (HSV) encephalitis is improved with prompt initiation of aciclovir treatment. Delays are common, but there is little understanding of why they occur. The case notes of 21 adults admitted with suspected HSV encephalitis over one year were reviewed. The median (range) duration of illness was 2.5 (1-99) days. Seventeen (81%) patients had a lumbar puncture (LP) performed, at a median (range) time of 24 (2-114) hours after encephalitis was suspected. Lumbar puncture was delayed for a computed tomography (CT) scan in 15 patients, but only one of these had contraindications to an immediate LP. The median (range) time from presentation to starting aciclovir was 48 (2-432) hours. HSV-PCR (polymerase chain reaction) was requested on cerebrospinal fluid from 12 patients, one of whom was positive. Five (24%) patients were given the wrong dose of aciclovir. Overall the management of suspected HSV encephalitis was often sub-optimal, with delays in LP occurring due to unnecessary CT scans, and the wrong aciclovir dose administered. Guidelines for the management of suspected encephalitis are needed.

Viral encephalitis remains a major cause of neurodisability across the globe. Virus entry across the blood brain barrier (BBB) into the central nervous system is associated with marked inflammation, but whether this is amenable to treatment with corticosteroids is uncertain. In Asia, Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, despite recent successes with vaccination. Virus enters the brain across BBB, but how it does this is not known. We established a novel human BBB model using brain endothelial cells and primary astrocytes. We found that virus infected endothelial cells trigging an innate pro-inflammatory host mediator response, which opened up the BBB, facilitating further viral entry. Treatment with corticosteroid led to a significant reduction in the inflammatory response, and helped preserve BBB integrity. In the UK, herpes simplex virus (HSV) is the most commonly diagnosed viral encephalitis. To study brain swelling in humans with HSV encephalitis, we examined retrospectively, acute changes in temporal lobe volume and oedema on MRI brain scans. Temporal lobe volume and oedema increased for patients who did not received corticosteroid treatment, but decreased for patients who had received corticosteroids. The findings from the BBB model and imaging studies provide preliminary data supporting the “COrticosteroids in HErpes SImplex Virus Encephalitis” (COHESIVE) randomised controlled trial, due to start in 2014.

Introduction In recent years an increasing range of neurological syndromes has been associated with the emergence of novel influenza A:H1N1 (2009), and other influenza viruses. We aimed to describe the features of adults and children with neurological manifestations associated with influenza in the UK. Method A surveillance study was performed in conjunction with the BNSU and BPNSU* over a 24–month period (February 2011 to February 2013). Inclusion criteria specified acute neurological illness within 1 month of proven influenza infection and prospective case definitions were applied. Results Twenty–five cases were identified: 4 adults and 21 children [6 (23%) with pre–existing neurological disorders]. Four (16%) cases (all with encephalopathy syndromes) died. Twenty cases (80%) required admission to intensive care. Seventeen (68%) had Glasgow Outcome Scores of 2–5 indicating poor outcome. Polymerase chain reaction (PCR) of respiratory secretions identified: influenza A in 21 (20 H1N1) and influenza B in 4 cases. Two had co–infection with Streptococcus pneumoniae (one adult with septicaemia; one child with meningitis). Cerebrospinal fluid (CSF) revealed a pleocytosis in 3 out of 18 cases (median 184×106 cells/litre [range 16–900]). Influenza PCR was negative in all 10 CSF samples tested. Cerebral magnetic resonance imaging was performed in 3 cases, computerised tomography in 6, and 14 had both. Recognised acute encephalopathy syndromes were seen in 5, and non–specific changes including cerebral oedema and/or diffusion restriction in 5. For the 4 adults, 2 presented with acute extrapyramidal movement disorders, 1 with Guillain–Barre syndrome and 1 with acute encephalopathy. Of the 21 children, 17 presented with acute encephalopathy, 3 with encephalitis and 1 with acute dyskinesia. Encephalopathy syndromes were documented in 7 cases (6 children, 1 adult). They were characterised by their clinical presentation and neuroimaging and included 4 with Acute Necrotising Encephalopathy (ANE), 1 Acute Infantile Encephalopathy Predominantly Affecting the Frontal Lobes (AIEF), 1 Haemorrhagic Shock & Encephalopathy (HSE) syndrome and 1 Acute Haemorrhagic Leukoencephalopathy (AHL). Treatments included: systemic steroids in 4 cases, 1 had intravenous immunoglobulin, and 3 cases received both. None received plasma exchange. Influenza vaccination was indicated in eight cases, but none had received it. Conclusion This paediatric and adult UK cohort identified a severity of influenza related neurological manifestation not reported previously. Cases were more common in children, particularly those with underlying neurological conditions. Encephalopathy syndromes such as ANE, AIEF, HSE and AHL were seen more frequently in children and were associated with a worse outcome. Acute movement disorders and Guillain–Barre syndrome were identified more commonly in adults. Influenza related encephalopathy may be more common in those with abnormal genetically determined host inflammatory responses, but the virus itself is rarely detected in the CSF. Influenza should be considered a cause of acute neurological syndromes in the winter months, especially in children with unexplained encephalopathy. Encephalopathy may be more common with the H1N1 strain. Importantly none of the cases had been vaccinated although many had indications for this.

Background Over the last 15 years bacterial meningitis has received considerable attention; viral central nervous system (CNS) infections have been relatively neglected. Aim: Examine the relative incidence, clinical features and management of suspected adult CNS infections across the Region. Methods Multicentre (10 hospitals) cross-sectional retrospective cohort study over 3 months. All patients with cerebrospinal fluid analysis or acyclovir and/or third-generation cephalosporin; those with clinical features suspicious of a CNS infection were included. Management was compared with the national meningitis and regional encephalitis guidelines. Results 385 patients were screened; 217 had a suspected CNS infection; 44 (20%) had a CNS infection: 18 aseptic meningitis (one herpes simplex virus (HSV)-2), 13 purulent meningitis (four Streptococcus pneumoniae ), and 13 encephalitis (3 HSV-1). The median (range) time from admission to suspicion of CNS infection and to LP was longer for patients with encephalitis than meningitis (4 (0.3–312) vs 0.3 (0.1–12) h, p Conclusions Encephalitis was as common as purulent meningitis, and HSV as common as S pneumoniae . However, the management of patients with encephalitis was worse than meningitis. National encephalitis guidelines are needed.

Objective We aimed to audit the regional management of central nervous system (CNS) infection in children. Methods The study was undertaken in five district general hospitals and one tertiary paediatric hospital in the Mersey region of the UK. Children admitted to hospital with a suspected CNS infection over a three month period were identified. Children were aged between 4 weeks and 16 years old. Details were recorded from the case notes and electronic records. We measured the appropriateness of management pathways as outlined by national and local guidelines. Results Sixty-five children were identified with a median age of 6 months (range 1 month to 15 years). Ten had a CNS infection: 4 aseptic meningitis, 3 purulent meningitis, 3 encephalitis [2 with herpes simplex virus (HSV) type 1]. A lumbar puncture (LP) was attempted in 50 (77%) cases but only 43 had cerebrospinal fluid (CSF) available for analysis. Of these 24 (57%) had a complete standard set of tests performed. Fifty eight (89%) received a third generation cephalosporin. Seventeen (26%) also received aciclovir with no obvious indication in 9 (53%). Only 11 (65%) of those receiving aciclovir had CSF herpes virus PCR. Seventeen had cranial imaging and it was the first management step in 14. Treatment lengths of both antibiotics and aciclovir were highly variable: one child with HSV encephalitis was only treated with aciclovir for 7 days. Conclusions The clinical management of children with suspected CNS infections across the Mersey region is heterogeneous and often sub-optimal, particularly for the investigation and treatment of viral encephalitis. National guidelines for the management of viral encephalitis are needed.