The Clinical Spectrum of Encephalitis

By Joseph E. Safdieh, MD

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Safdieh reports no financial relationships relevant to this field of study.

Synopsis: The majority of cases of encephalitis are viral or autoimmune, and factors associated with a poor prognosis include coma and need for mechanical ventilation.

Sources:Singh TD, et al. The spectrum of acute encephalitis: Causes, management and predictors of Outcome. Neurology 2015;84:1-8.
Sonneville R, et al. Clinical spectrum and outcomes of patients with encephalitis requiring intensive care. Eur J Neurol 2015;22:6-16.

Encephalitis is a serious neurologic condition caused by acute inflammation of the brain. Patients typically present acutely with any combination of confusion, fever, seizures, headache, focal neurologic deficits, and abnormal involuntary movements. Diagnosis is typically made by cerebrospinal fluid (CSF) analysis and serologic studies on CSF and blood. Neuroimaging and electroencephalogram can sometimes assist in making the diagnosis. The acute treatment of suspected encephalitis includes antiviral therapy and aggressive supportive care, including management of intracranial hypertension, if significant cerebral edema is present. The most common cause of encephalitis is viral infection, but over the past decade there has been a rapidly increasing recognition of immune-mediated causes, including both paraneoplastic and non-paraneoplastic antibodies.

Neurologists are often called to assist in the diagnosis of encephalitis, especially when the etiology is not readily apparent on standard workup. Because encephalitis is relatively rare (0.07-12.6 cases per 100,000), large case series, accumulated over a number of years, are necessary to recognize causes and outcomes. The two studies summarized here are both rigorous, detailed, retrospective reviews of patients diagnosed with encephalitis over the prior 10 or more years. Both papers assessed the causes of encephalitis, demographic factors, outcomes, and prognostic factors. The American study, performed at the Mayo Clinic, reviewed all cases of encephalitis from 2000-2012, and the European study, performed at a Parisian hospital, reviewed all cases of encephalitis requiring ICU care from 1991-2012.

In the American study, the authors identified 198 patients over a decade. There was no clear gender predilection and the median age was 58 years. Forty-eight percent of the patients were determined to have viral encephalitis, 22% autoimmune, and 30% unknown or other etiology. Within the viral encephalitis group, 38.9% were caused by herpes simplex virus, 23% by varicella zoster virus, 19% by West Nile virus, 6% by Epstein-Barr virus, and 3% by HIV. Within the autoimmune group, the most common autoantibodies identified were NMDA (24.4%) and voltage-gated potassium channel (24.4%). Good outcomes (modified Rankin score 0-2) occurred in 50% of the viral encephalitis group, 40% of the autoimmune encephalitis group, and 54% of the group with undetermined etiologies. Prognostic factors that were associated with poor outcome included coma (odds ratio [OR], 5.06), mechanical ventilation (OR, 3.44), immune-compromised state (OR, 2.79), acute thrombocytopenia (OR, 2.36), and older age (OR, 2.28). Overall mortality rate was 9%.

In the European study, 279 patients were identified over 20 years. Causes included infectious/viral in 53%, immune mediated in 15%, and undetermined in 32%. Of note, there was a higher incidence of cases of autoimmune encephalitis in the 2002-2012 patients compared to the 1991-2001 patients. Good outcomes (modified Rankin scale) occurred in 75% of patients. Mortality rate was 17%. The authors performed a multivariate analysis and determined that prognostic factors for poor outcome included coma (OR, 7) and aspiration pneumonia (OR, 4). Other significant but less robust prognostic factors included lower body temperature, elevated CSF protein levels, and delayed ICU admission. The most common causes of infectious encephalitis in this cohort included tuberculosis and herpes simplex virus.

Commentary

Despite being done on different continents, these studies share some striking similarities that allow for more significant generalizability of the findings. In both studies, infectious causes accounted for about half of the cases of encephalitis, with autoimmune causes accounting for 15-22% of cases. Both studies also clearly demonstrated that coma is a very poor prognostic factor in encephalitis cases. Of note, only the American study found an association of poor prognosis with older age. Also, tuberculosis was a common cause of encephalitis in the European cohort (23% overall), but was not noted in the American cohort. It is interesting to note as well that delayed ICU admission was an independent predictor of poor prognosis, suggesting that early ICU care may improve the prognosis of encephalitis. One caveat to note is that retrospective prognostic data must always be applied cautiously in the clinical setting so as to avoid the problem of the “self-fulfilling prophecy” in which a patient with presumed poor prognostic factors is not treated aggressively, resulting in a bad outcome.

Encephalitis is an important diagnosis to recognize and treat in a rapid and efficient manner. These studies are important because they summarize recent large cohorts of patients with encephalitis, allowing the clinician to use these data to more accurately diagnose and care for patients with encephalitis.