Major Criterion (required):

Patients presenting to medical attention with altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) lasting ≥24 h with no alternative cause identified.

Minor Criteria (2 required for possible encephalitis; ≥3 required for probable or confirmed^a encephalitis):

Documented fever ≥38° C (100.4°F) within the 72 h before or after presentation^b

Generalized or partial seizures not fully attributable to a preexisting seizure disorder^c

New onset of focal neurologic findings

CSF WBC count ≥5/cubic mm^d

Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onset^e

Abnormality on electroencephalography that is consistent with encephalitis and not attributable to another cause.^f

• Abbreviations: CNS, central nervous system; CSF, cerebral spinal fluid; EEG, electroencephalogram; RBC, red blood cell; WBC, white blood cell.
• ^a Confirmed encephalitis requires one of the following: (1) Pathologic confirmation of brain inflammation consistent with encephalitis; (2) Defined pathologic, microbiologic, or serologic evidence of acute infection with a microorganism strongly associated with encephalitis from an appropriate clinical specimen (for examples, see references [1, 2]); or (3) Laboratory evidence of an autoimmune condition strongly associated with encephalitis.
• ^b Fever is a common finding in patients with acute encephalitis but is nonspecific. The requirement for objective documentation of fever within a restricted time frame of ≤72 h after hospitalization was chosen to exclude secondary health-care associated infections. It is recognized that fevers can occur as a result of a number of infections outside of the central nervous system that can cause encephalopathy, as well as with noninfectious entities that mimic encephalitis. It is also recognized that fever may fluctuate and, as such, objective fever may be lacking in patients with infectious encephalitis at the time of clinical assessment. Furthermore, immunosuppressed patients with encephalitis may not mount a fever.
• ^c Seizures associated with encephalitis may be generalized, suggestive of global CNS dysfunction, or focal, indicating a localized process. Subclinical seizures may also occur and can be a cause of altered sensorium. Seizures associated with high temperatures are relatively common in young children and, if occurring in isolation, do not mandate evaluation for encephalitis. The major requirement for at least 24 h of altered mentation was selected to exclude the post-ictal state seen in patients with febrile seizures.
• ^d CSF pleocytosis is suggestive of an inflammatory process of the brain parenchyma, meninges, or both (meningoencephalitis). The absence of CSF pleocytosis, however, does not exclude encephalitis. In particular, it is recognized that the CSF may be devoid of cells in immunocompromised patients (Fodor et al., Neurology 1998 51:554–59) or early in the course of infection (Weil et al, Clin Infect Dis 2002 34:1154–57; Mook-Kanamori et al., J Am Geriatr Soc 57:1514–15; Jakob et al., Crit Care Med 2012 40:1304–8). Conversely, the CSF profile with inflammation limited to the meninges may be indistinguishable from that in patients with encephalitis. In the majority of cases of encephalitis, however, the absolute number of leukocytes is < 1000/mm³ and lymphocytes typically predominate. To ensure adequate sensitivity of the definition, the group defined CSF pleocytosis as ≥5 WBC/mm³. In cases where there are large numbers of red blood cells in the CSF, such as with a traumatic lumbar puncture, the following formula may allow correction of the WBC count: True CSF WBC = actual CSF WBC—(WBC in blood X RBC in CSF)/RBC in blood (Tunkel A. In Mandel ed., Principles and Practice of Infectious Diseases, 7th ed., 2010:1183–88; Bonadio Pediatr Infect Dis J 1992 11:423–31). Notably, rules for adjusting leukocytes in blood-contaminated CSF have not been well validated (Bonsu and Harper, Pediatr Infect Dis J 2006 25:8–11).
• ^e Neuroimaging plays a crucial role in the evaluation of patients with suspected encephalitis, as it may support the diagnosis of a specific etiology or identify alternate conditions that mimic encephalitis. Magnetic resonance imaging (MRI) is the radiologic modality of choice for evaluation of patients with suspected encephalitis. Multiple studies have confirmed MRI to be superior to computed tomographic (CT) scanning for demonstration of CNS abnormalities (Tunkel et al. Clin Infect Dis 2008 47:303–27; Glaser et al. Clin Infect Dis 2006 43:1565–77). MRI may aid in defining an etiology, as localization of inflammation may be suggestive of particular pathogens (eg, temporal lobe involvement in patients with herpes simplex virus encephalitis) or of an autoimmune phenomenon (eg, demyelination in patients with acute disseminated encephalomyelitis). A noncontrast CT scan is most useful in evaluating safety in the performance of a lumbar puncture and in excluding alternative diagnoses such as subarachnoid hemorrhage. We recognize that MRI or CT may not be available in resource-limited settings, in which case the diagnosis of encephalitis will need to rely on clinical and laboratory criteria.
• ^f EEG abnormalities reported in cases of encephalitis range from nonspecific generalized slowing to distinctive patterns suggestive of specific entities, including repetitive sharp wave complexes over the temporal lobes or periodic lateralizing epileptiform discharges in HSV-1 (Lai and Gragasin J Clin Neurophysiol 1988 5:87–103) and bilateral synchronous periodic sharp and slow waves associated with subacute sclerosing panencephalitis (Gutierrez et al. Dev Med Child Neurol 2010 52:901–7). EEG abnormalities are frequently nonspecific and may be attributable to medications or metabolic abnormalities. The EEG may identify epileptiform discharges in the absence of clinical evidence of seizure activity (subclinical or nonconvulsive status epilepticus) as a cause of obtundation.

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