Table 1.

Prospective, multicenter studies of encephalitis conducted since 1990.

Study location & years (lead author)	Study population & case definition	Approach to testing	Number of patients enrolled	Major findings
California, 1998–2005 (Glaser) [5]	Hospitalized, immunocompetent patients ≥6 months of age. Encephalopathy (defined as depressed or altered level of consciousness lasting ≥24 h, lethargy, or personality change) plus ≥ 1 of the following: •fever •seizure •focal neurological findings •CSF pleocytosis •EEG or neuroimaging findings consistent with encephalitis	Core testing on all patient samples for 16 pathogens including HSV, enteroviruses, measles, West Nile virus, respiratory viruses, and Mycoplasma pneumoniae. Selective testing for additional pathogens based on exposure history, symptoms, or physician request.	1570	Despite extensive testing, a confirmed or probable agent was identified in only 16% of patients. Among those: •69% were viral – enteroviruses (17% of total patients), HSV-1 (16%), varicella zoster virus (9%) •20% were bacterial – Mycobacterium tuberculosis (8% of total patients), pyogenic bacteria (6%), Bartonella species (5%)
England, 2005–2007 (Granerod) [1]	Hospitalized patients of any age. Encephalopathy (defined as altered consciousness lasting ≥24 h, including lethargy, irritability, or a change in personality and behavior) plus ≥ 2 of the following: •fever or history of fever during the presenting illness •seizure •focal neurological findings (with evidence of brain parenchyma involvement) •CSF pleocytosis •EEG or neuroimaging findings consistent with encephalitis	Core testing on all patient samples for common causes of encephalitis, plus additional core testing for immunocompromised patients and those who had traveled abroad. Selective testing for additional pathogens as determined by expert panel review.	203	An infectious agent was identified in 42% of patients. Among those: •67% were viral – HSV (19% of total patients), varicella zoster virus (5%), enteroviruses (1%) •30% were bacterial – Mycobacterium tuberculosis (5% of total patients), Streptococci (2%), Neisseria meningitidis (1%) An immune-mediated cause was identified in an additional 21% of patients.
France, 2007 (Mailles) [3]	Hospitalized patients ≥28 days of age. Encephalitis defined as all of the following: •acute onset of illness •≥1 abnormality of the CSF (white blood cell count ≥4 cells/mm3 or protein level ≥ 40 mg/dL) •temperature ≥ 38 °C •decreased consciousness, seizures, altered mental status, or focal neurologic signs Patients with noninfectious CNS disease were excluded.	Diagnostic testing was performed in three successive steps according to the French Society of Infectious Diseases guidelines. Steps are determined by the frequency of infectious agents as a cause of encephalitis and the need to begin early treatment for some pathogens.	253	An infectious agent was identified in 52% of patients. •69% were viral – HSV (22% of total patients), varicella zoster virus (8%), cytomegalovirus (1%), Epstein-Barr virus (1%) •30% were bacterial – Mycobacterium tuberculosis (8% of total patients), Listeria monocytogenes (5%), Mycoplasma pneumoniae (1%), Borrelia burgdorferi (1%)
Finland, 1993–1994 (Koskiniemi) [4]	Hospitalized children aged 1 month – 15 years. Acute onset (≤4 weeks) of neurological signs lasting ≥24 h (including depressed consciousness, pareses, sensory symptoms, seizure, etc.)a	Core testing on all patient samples for common and less common pathogens.	175	An infectious agent was identified in 63% of patients. Among those: •94% were viral – varicella zoster virus (14% of total patients), respiratory viruses (13%), enteroviruses (12%), HSV (3%) •5% were bacterial – Chlamydia pneumoniae (3% of total patients), Mycoplasma pneumoniae (1%), Borrelia burgdorferi (1%)

HSV = herpes simplex virus, EEG = electroencephalography, CSF = cerebrospinal fluid.

^aIn cases where neurologic signs lasted <24 h, patients were included if they had EEG or CSF findings suggestive of encephalitis or depressed consciousness plus ≥1 additional characteristic neurologic sign.