Julia Granerod

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.

Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium

BACKGROUND Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. METHODS In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. RESULTS We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. CONCLUSIONS We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Causality in acute encephalitis: defining aetiologies

Defining the causal relationship between a microbe and encephalitis is complex. Over 100 different infectious agents may cause encephalitis, often as one of the rarer manifestations of infection. The gold-standard techniques to detect causative infectious agents in encephalitis in life depend on the study of brain biopsy material; however, in most cases this is not possible. We present the UK perspective on aetiological case definitions for acute encephalitis and extend them to include immune-mediated causes. Expert opinion was primarily used and was supplemented by literature-based methods. Wide usage of these definitions will facilitate comparison between studies and result in a better understanding of the causes of this devastating condition. They provide a framework for regular review and updating as the knowledge base increases both clinically and through improvements in diagnostic methods. The importance of new and emerging pathogens as causes of encephalitis can be assessed against the principles laid out here.

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.

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.

Diagnostic Strategy Used To Establish Etiologies of Encephalitis in a Prospective Cohort of Patients in England

ABSTRACT The laboratory diagnostic strategy used to determine the etiology of encephalitis in 203 patients is reported. An etiological diagnosis was made by first-line laboratory testing for 111 (55%) patients. Subsequent testing, based on individual case reviews, resulted in 17 (8%) further diagnoses, of which 12 (71%) were immune-mediated and 5 (29%) were due to infection. Seventy-five cases were of unknown etiology. Sixteen (8%) of 203 samples were found to be associated with either N-methyl-d-aspartate receptor or voltage-gated potassium channel complex antibodies. The most common viral causes identified were herpes simplex virus (HSV) (19%) and varicella-zoster virus (5%), while the most important bacterial cause was Mycobacterium tuberculosis (5%). The diagnostic value of testing cerebrospinal fluid (CSF) for antibody was assessed using 139 samples from 99 patients, and antibody was detected in 46 samples from 37 patients. Samples collected at 14 to 28 days were more likely to be positive than samples taken 0 to 6 days postadmission. Three PCR-negative HSV cases were diagnosed by the presence of virus-specific antibody in the central nervous system (CNS). It was not possible to make an etiological diagnosis for one-third of the cases; these were therefore considered to be due to unknown causes. Delayed sampling did not contribute to these cases. Twenty percent of the patients with infections with an unknown etiology showed evidence of localized immune activation within the CNS, but no novel viral DNA or RNA sequences were found. We conclude that a good standard of clinical investigation and thorough first-line laboratory testing allows the diagnosis of most cases of infectious encephalitis; testing for CSF antibodies allows further cases to be diagnosed. It is important that testing for immune-mediated causes also be included in a diagnostic algorithm.

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. J. Med. Virol. 80: 1181–1188, 2008.

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-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.

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

BackgroundEncephalitis 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.MethodsWe 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.ResultsOur 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.ConclusionsIt 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.

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.