Granerod MSc a , Helen E Ambrose DPhil a, Nicholas WS Davies PhD b, Jonathan P Clewley PhD a, Amanda L Walsh MSc a, Dilys Morgan MD a, Richard Cunningham FRCPath c, Mark Zuckerman FRCPath d, Ken J Mutton MBBS e, Prof Tom Solomon FRCP f g, Katherine N Ward PhD h, Michael PT Lunn FRCP i, Sarosh R Irani MRCP j, Prof Angela Vincent FRCPath j, Prof David WG Brown FRCPath a, Natasha S Crowcroft MD a k, on behalf of the UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. The Lancet Infectious Diseases, Early Online Publication, 18 October 2010

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.

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