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.

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.

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.

Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study.

The true extent of sequelae in encephalitis survivors relative to rates within the general population is not known. This study aimed to quantify increased risks of epilepsy, depressive disorders, anxiety disorders, psychotic disorders, bipolar disorder, cognitive problems, dementia, headache, and alcohol abuse among encephalitis cases. 2460 exposed individuals diagnosed with incident encephalitis in the Clinical Practice Research Datalink and 47,914 unexposed individuals without a history of encephalitis were included. Multivariable Poisson regression was used to estimate adjusted rate ratios in individuals with encephalitis compared to the general population and to estimate whether the effect of these outcomes varied over time. Individuals with encephalitis had an increased risk of all investigated outcomes. The highest RR was seen for epilepsy (adjusted RR 31.9; 95 % confidence interval 25.38-40.08), whereas the lowest was seen for anxiety disorders (1.46, 1.27-1.68). The second highest RRs were for particular psychiatric illnesses, including bipolar disorder (6.34, 3.34-12.04) and psychotic disorders (3.48, 2.18-5.57). The RR was highest in the first year of follow-up for all outcomes except headache; this was particularly true for epilepsy (adjusted RR in first year of follow-up 139.6, 90.62-215.03). This study shows that sequelae are common in survivors of encephalitis. We confirm the presence of outcomes more commonly linked to encephalitis and describe those less commonly identified as being associated with encephalitis. The results of this study have important implications for the management of encephalitis patients and for the design of tertiary prevention strategies, as many of these sequelae are treatable.

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology.

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<0.0001). CONCLUSIONS: Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

The Interleukin-1 Balance During Encephalitis Is Associated With Clinical Severity, Blood-Brain Barrier Permeability, Neuroimaging Changes, and Disease Outcome.

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-1ß 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-1ß 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.

Quality of life and associated socio-clinical factors after encephalitis in children and adults in England: a population-based, prospective cohort study.

OBJECTIVE: We sought to measure HRQoL in all-cause encephalitis survivors and assess the impact of various socio-clinical factors on outcome. METHODS: We used a prospective cohort study design, using the short-form 36 (SF-36) to measure the HRQoL in patients 15 years and older, and the short-form 10 (SF-10) for patients less than 15 years old. We posted questionnaires to individuals six months after discharge from hospital. All scores were normalised to the age- and sex-matched general population. We used multivariate statistical analysis to assess the relative association of clinical and socio-demographic variables on HRQoL in adults. RESULTS: Of 109 individuals followed-up, we received 61 SF-36 and twenty SF-10 questionnaires (response rate 74%). Patients scored consistently worse than the general population in all domains of the SF-36 and SF-10, although there was variation in individual scores. Infectious encephalitis was associated with the worst HRQoL in those aged 15 years and over, scoring on average 5.64 points less than immune-mediated encephalitis (95% CI -8.77- -2.89). In those aged less than 15 years the worst quality of life followed encephalitis of unknown cause. Immuno compromise, unemployment, and the 35-44 age group all had an independent negative association with HRQoL. A poor Glasgow Outcome Score was most strongly associated with a poor HRQoL. Less than half of those who had made a 'good' recovery on the score reported a HRQoL equivalent to the general population. CONCLUSIONS: Encephalitis has adverse effects on the majority of survivors' wellbeing and quality of life. Many of these adverse consequences could be minimised by prompt identification and treatment, and with better rehabilitation and support for survivors.

New estimates of incidence of encephalitis in England.

Encephalitis causes high rates of illness and death, yet its epidemiology remains poorly understood. To improve incidence estimates in England and inform priority setting and treatment and prevention strategies, we used hospitalization data to estimate incidence of infectious and noninfectious encephalitis during 2005-2009. Hospitalization data were linked to a dataset of extensively investigated cases of encephalitis from a prospective study, and capture-recapture models were applied. Incidence was estimated from unlinked hospitalization data as 4.32 cases/100,000 population/year. Capture-recapture models gave a best estimate of encephalitis incidence of 5.23 cases/100,000/year, although the models' indicated incidence could be as high as 8.66 cases/100,000/year. This analysis indicates that the incidence of encephalitis in England is considerably higher than previously estimated. Therefore, encephalitis should be a greater priority for clinicians, researchers, and public health officials.

Potential risk factors associated with human encephalitis: application of canonical correlation analysis.

BACKGROUND: Infection of the CNS is considered to be the major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. Despite being identified worldwide as an important public health concern, studies on encephalitis are very few and often focus on particular types (with respect to causative agents) of encephalitis (e.g. West Nile, Japanese, etc.). Moreover, a number of other infectious and non-infectious conditions present with similar symptoms, and distinguishing encephalitis from other disguising conditions continues to a challenging task. METHODS: We used canonical correlation analysis (CCA) to assess associations between set of exposure variable and set of symptom and diagnostic variables in human encephalitis. Data consists of 208 confirmed cases of encephalitis from a prospective multicenter study conducted in the United Kingdom. We used a covariance matrix based on Gini's measure of similarity and used permutation based approaches to test significance of canonical variates. RESULTS: Results show that weak pair-wise correlation exists between the risk factor (exposure and demographic) and symptom/laboratory variables. However, the first canonical variate from CCA revealed strong multivariate correlation (ρ = 0.71, se = 0.03, p = 0.013) between the two sets. We found a moderate correlation (ρ = 0.54, se = 0.02) between the variables in the second canonical variate, however, the value is not statistically significant (p = 0.68). Our results also show that a very small amount of the variation in the symptom sets is explained by the exposure variables. This indicates that host factors, rather than environmental factors might be important towards understanding the etiology of encephalitis and facilitate early diagnosis and treatment of encephalitis patients. CONCLUSIONS: There is no standard laboratory diagnostic strategy for investigation of encephalitis and even experienced physicians are often uncertain about the cause, appropriate therapy and prognosis of encephalitis. Exploration of human encephalitis data using advanced multivariate statistical modelling approaches that can capture the inherent complexity in the data is, therefore, crucial in understanding the causes of human encephalitis. Moreover, application of multivariate exploratory techniques will generate clinically important hypotheses and offer useful insight into the number and nature of variables worthy of further consideration in a confirmatory statistical analysis.

Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.

BACKGROUND: Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS: Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS: We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). INTERPRETATION: Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING: The Policy Research Programme, Department of Health, UK.

Cluster analysis for identifying sub-groups and selecting potential discriminatory variables in human encephalitis.

BACKGROUND: Encephalitis is an acute clinical syndrome of the central nervous system (CNS), often associated with fatal outcome or permanent damage, including cognitive and behavioural impairment, affective disorders and epileptic seizures. Infection of the central nervous system is considered to be a major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. However, a large proportion of cases have unknown disease etiology. METHODS: We perform hierarchical cluster analysis on a multicenter England encephalitis data set with the aim of identifying sub-groups in human encephalitis. We use the simple matching similarity measure which is appropriate for binary data sets and performed variable selection using cluster heatmaps. We also use heatmaps to visually assess underlying patterns in the data, identify the main clinical and laboratory features and identify potential risk factors associated with encephalitis. RESULTS: Our results identified fever, personality and behavioural change, headache and lethargy as the main characteristics of encephalitis. Diagnostic variables such as brain scan and measurements from cerebrospinal fluids are also identified as main indicators of encephalitis. Our analysis revealed six major clusters in the England encephalitis data set. However, marked within-cluster heterogeneity is observed in some of the big clusters indicating possible sub-groups. Overall, the results show that patients are clustered according to symptom and diagnostic variables rather than causal agents. Exposure variables such as recent infection, sick person contact and animal contact have been identified as potential risk factors. CONCLUSIONS: It is in general assumed and is a common practice to group encephalitis cases according to disease etiology. However, our results indicate that patients are clustered with respect to mainly symptom and diagnostic variables rather than causal agents. These similarities and/or differences with respect to symptom and diagnostic measurements might be attributed to host factors. The idea that characteristics of the host may be more important than the pathogen is also consistent with the observation that for some causes, such as herpes simplex virus (HSV), encephalitis is a rare outcome of a common infection.

Outbreaks of hepatitis A in England and Wales associated with two co-circulating hepatitis A virus strains.

During 2002, an upsurge in frequency of hepatitis A outbreaks among injecting drug users was observed in England and Wales. As lack of risk factor information and the high mobility of the cases made linkage of outbreaks difficult, the relationship of nucleotide sequences in the VP1/2PA junction of the hepatitis A virus (HAV) genome amplified from serum of case-patients was investigated. A total of 204 HAV RNA positive sera obtained from a network of 23 laboratories were studied. Comparison of the sequences identified two principal strains: ES1 (n=95) belonging to type IB, and ES2 (n=72) to type IIIA. Of the remaining samples, 15 were type IA, 11 were type IB and 11 were type IIIA. ES1 predominated in Doncaster and other towns in Trent and northern England, and ES2 in the Midlands and southern England; the difference in geographical distribution between these two strains was significant (P<0.0001). In comparison to the sporadic cases, cases infected by either ES1 or ES2 tended to be younger, injecting drug users, people in contact with injecting drug users, or those with a history of incarceration in prisons or homelessness (P<0.0001). Cases infected by ES1 tended to be younger than those by ES2 (P<0.0001). The association of the outbreaks to two geographically restricted strains implicates two principal transmission pathways associated with injecting behavior. Identifying these routes may be conducive to preventing further outbreaks.

The epidemiology of acute encephalitis.

Encephalitis means inflammation of the brain matter. Despite being a rare condition, encephalitis is of public health importance worldwide because it has high morbidity and mortality. Yet, many details about its epidemiology have yet to be elucidated. This review attempts to summarise what is known about the epidemiology of the infective causes of encephalitis and is based on a literature search of the Medline archives. Infection is the most common cause identified, with viruses being the most important known aetiological agents. Incidence varies between studies but is generally between 3.5 and 7.4 per 100,000 patient-years. Encephalitis affects peoples of all ages; however, incidence is higher in the paediatric population. Although both sexes are affected, most studies have shown a slight predominance in males. Encephalitis occurs worldwide; some aetiologies have a global distribution (herpesviruses) while others are geographically restricted (arboviruses). Although definite epidemiological trends are evident, it is difficult to make generalisations as few population-based studies exist, most cases are not reported to health authorities, and many possible pathogens are implicated but in most cases a cause is never found. A better understanding of the epidemiology of this devastating disease will pave the way for better prevention and control strategies.