Diagnostic Approach and Update on Rncephalitis

Adarsh Bhimraj; Rodrigo Hasbun


Curr Opin Infect Dis. 2022;35(3):231-237. 

In This Article

Abstract and Introduction


Purpose of Review: The present article gives an update and outlines the fundamental principles of clinical reasoning and a diagnostic approach to a patient suspected to have acute encephalitis.

Recent Findings: Encephalitis remains to be associated with significant mortality and neurological morbidity. Unfortunately, the etiologic diagnosis remains elusive for the majority of the patients with encephalitis preventing targeted therapies. Clinicians could utilize clues such as duration of symptoms, exposure history, cerebrospinal fluid profile, neuroimaging findings and locations, and entertain certain opportunistic infections in immunosuppressed individuals. A comprehensive diagnostic for the most common viral and autoimmune etiologies should be systematically done and prompt empiric antiviral therapy should be started. Evaluation and therapy for autoimmune etiologies should be done for patients with a negative viral work up. Brain biopsy and metagenomic sequencing should be considered for patients with unknown etiologies that are clinically worsening.

Summary: Encephalitis remains with unacceptable mortality and morbidity with the most common etiologies being idiopathic. A comprehensive diagnostic work up and prompt antiviral and autoimmune therapies are of paramount importance to improve the outcomes of this devastating disease.


Acute encephalitis is inflammation in the brain parenchyma and can be a debilitating disorder associated with high rates of mortality and neurological sequelae. The incidence of encephalitis is 1.5–10 cases/100 000 per year in high income countries.[1–3] The known etiologies include a wide spectrum of infectious and noninfectious etiologies. Often the etiology is elusive, with the incidence of unknown cause up to 50% or higher in some series.[1,4,5] In recent decades, autoimmune encephalitis has been increasingly being recognized as an etiology.[1,4,5] The cause of encephalitis depends on geographic location, time of the year, season, age, exposure and other epidemiologic factors. In a multicenter prospective population-based study in England 42% had infectious causes, with herpes simplex virus (HSV) being the most common infectious encephalitis (19%). In that series, 21% had acute immune mediated encephalitis and 37% had unknown causes.[1]

Encephalitis remains a diagnostic and management challenge as the differential diagnosis is broad and many patients do not undergo a thorough diagnostic evaluation as recommended by international guidelines.[6] Even after performing a CT (computerized tomography) brain and routine CSF (cerebrospinal fluid) studies, nonmolecular CSF microbiology studies a large proportion of patients do not have a clearly identified etiology. The advent of newer rapid diagnostic tests like specific organism PCR's especially multiplex-PCR's which incorporate targets for several organisms have improved timely diagnosis of infectious encephalitis. Even when CSF testing is not diagnostic, patterns of involvement on the MRI brain especially using sensitive sequences like DWI (diffusion weighted imaging) provide clues to possible etiologies. Testing for autoantibodies for autoimmune mediated encephalitis in the serum and CSF should be done once viral causes have been ruled out but unfortunately the turnaround of these tests can cause a delay in diagnosis. Furthermore, imaging of non-CNS sites for tumors as a cause of paraneoplastic encephalitis have further increased our ability to identify a cause. In patients where initial testing does not give a clear diagnosis, pathogen agnostic testing like unbiased meta-genomic sequencing from the CSF may be of utility but recent studies have shown that they only modestly improve the detection of pathogens.[7] Despite thorough initial testing a cause might be elusive needing close follow-up, re-testing and need for empiric therapeutic trial for infectious and/or autoimmune encephalitis. Invasive testing like brain biopsies, even with special stains for infectious and noninfectious etiologies, may only identify inflammation in the brain parenchyma without providing an etiologic diagnosis, so should be used as a last resort.

A diagnostic approach to a patient with suspected acute encephalitis must localize inflammation to the brain parenchyma, identify the specific pattern or parts of the brain involved and identify a microbiologic, autoimmune or alternative etiology. An accurate anatomic and especially an etiologic hypothesis requires a very detailed history (including localizing symptoms, duration, age, underlying comorbidities including immunocompromised states, time of the year, season, exposure and epidemiologic risk factors specific to the encephalitis etiology being entertained). A complete physical exam including a thorough neurologic exam, and an appropriate diagnostic work-up including imaging and CSF (cerebrospinal fluid) labs. Prognosis and management depend on an accurate diagnostic hypothesis.

A practical approach to the patient with suspected acute encephalitis would be to answer the following questions, to make a diagnostic and prognostic hypothesis:

  1. Where specifically in the brain parenchyma is the 'itis' or inflammation (anatomic pattern based on clinical history and imaging)? (see ).

  2. How long has it been going on (duration of illness)?

  3. What is the exposure or epidemiological history?

  4. Is the patient a 'normal host' or an 'immuno-compromised host'?

  5. What is the type of CSF inflammatory response on routine CSF analysis?

Two examples to illustrate the outlined diagnostic approach would be:

Clinical Scenario-1

A 33-year-old female presents acutely with symptom onset a few days ago of high fever, seizures, amnesia, olfactory hallucinations one would localize it to the mesial temporal lobe and orbito-frontal cortex. The most probable cause is HSV regardless of the time of the year, season or geographic location. If the patient has an MRI brain which shows T2/FLAIR hyperintensities with edema, restricted diffusion and gadolinium enhancement in the right medial temporal lobe that further strengthens the diagnosis. A CSF HSV PCR will be diagnostic, but even if the CSF HSV PCR is initially negative, the pretest probability of HSV for acute temporal lobe encephalitis is high and warrants a repeat CSF HSV PCR in 3–5 days[6] and treatment with IV acyclovir given the poor prognosis without antiviral treatment.

Clinical Scenario-2

A 35-year-old male presents with extreme forgetfulness for weeks with the MRI brain showing bilateral symmetric T/2 FLAIR hyperintensities with restricted diffusion, but no gadolinium enhancement. He had two separate CSF analyses with CSF HSV PCR's done a week apart that were negative, and a testicular mass was palpable on scrotal exam and seen on ultrasound. This would most likely have anti-Ma2 paraneoplastic limbic encephalitis associated with testicular cancer.