At a Glance

Encephalitis is defined as inflammation of the brain, but, regardless whether the cause is directly infectious or postinfectious, there is commonly concomitant meningitis. In fact, many of the attributes of encephalitis are also seen in cases of meningitis (see Meningitis Module), and encephalitis is considered a progression of meningitis disease in many situations. Symptoms of meningeal irritation are commonly present, including headache and meningismus. However, encephalitis (or meningoencephalitis) is more likely to present with altered mental status. Fever is also present in most cases but can be absent with both infectious and noninfectious causes.

The differential diagnosis for causes of encephalitis should include both infectious and postinfectious etiologies, as these can be difficult to distinguish clinically. The differential should be formed based on the progression of disease, other affected organ systems/sites, known comorbidities, time of the year, and any other clues from the patient’s history.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Encephalitis is most commonly caused by one of a number of viral agents, and a viral agent should be near the top of the differential in most cases. However, bacterial, fungal, rickettsial, and amoebic causes are also possibilities. As mentioned, the differential diagnosis should also include postinfectious causes. As peripheral blood studies are rarely helpful in diagnosis and management of encephalitis, cerebrospinal fluid (CSF) studies are essential.

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In patients with suspected encephalitis:

Obtain 3-4 sets of blood cultures from at least 2 different sites.

Send a serum glucose.

If cerebral malaria is suspected, send blood smears for malarial detection and identification.

Perform a STAT lumbar puncture to obtain CSF for analysis:

Measure opening pressure.

At least 3 (preferably 4) sterile tubes should be collected, numbered, and placed on wet ice:

Tube 1 for chemistries (glucose and protein levels):

Glucose levels are reduced in bacterial meningoencephalitis(<40mg/dL with CSF-to-serum glucose ratio < 0.3 in 60-70% ofcases).

Protein levels are typically elevated in bacterial meningoencephalitis (>100mg/dL).

CSF Glucose can be slightly low and protein slightly high in viral encephalitis, but both can be normal.

Tube 2 for microbiology/cultures (gram stain and aerobic culture):

Other secondary tests can be ordered, depending on suspicion. Theseinclude cryptococcal antigen, fungal culture, mycobacterial smears andculture, viral culture, Venereal Disease Research Laboratory test (VDRL), specific polymerase chain reaction (PCR) assays for herpes simplex virus (HSV), enterovirus, HIV or arboviruses, and specific antibodies to certain pathogens, such as B. burgdorferi.Enterovirus, tick-borne and mosquito-borne causes of encephalitis aremost common in the late spring to early fall. PCR assays on CSF areavailable in many reference labs to identify these pathogens.

The list of possible causes of encephalitis, especially possible viralcauses, is very long, and it will not be possible to order all tests on every suspected case of encephalitis. So, it is imperative that the differential diagnosis based on patient history be a guide to prioritizing test selection. Consultation with Infectious Disease experts is recommended.

Anaerobic culture is not routinely performed, as anaerobic bacterial encephalitis is quite rare. However, this might be suspected if the gram stain is positive, but there is no growth in the aerobic cultures.

Tube 3 for cellular analysis (white blood cell [WBC] with differential, red blood cell [RBC]):

Cytology and flow cytometry can also be ordered if malignancy is suspected.

WBC count is usually 1,000-5,000/mm3with a neutrophil predominance in bacterial encephalitis and alymphocytic predominance in viral encephalitis. However, the differential can be misleading in some cases.

Tube 4 for additional add-on testing after the results from Tubes 1-3 are completed.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

There are a number of factors that can affect CSF analysis, most preanalytical in nature.

  • Blood in CSF due to a traumatic lumbar puncture:

    This complicates interpretation of both chemistry and cellular analysis.

  • Presence of skin flora in CSF secondary to improper preparation of the skin prior to performing the lumbar puncture:

    Coagulase negative Staphylococcusis a common contaminant in CSF cultures, and, unless it is present insignificant amounts, is not typically fully worked up in most microbiology laboratories.

    The exception to this is if the patient has a cerebral shunt or any foreign material that might be in contact with the CSF.

  • Administration of antimicrobials prior to obtaining CSF:

    Administration of antimicrobials appropriate for the organism present can inhibit the growth of the organism in as little as 2-4 hours after administration.

    This is why a STAT CT scan and lumbar puncture are crucial in patients with neurological deficits.

  • Delayed CSF testing or failure to place tubes on ice:

    Especially if blood is present, ongoing glycolysis can artificially lower glucose levels.

    Some more fastidious organisms may lose viability.

    Some contaminating organisms could overgrow, suppressing growth of a true pathogen.

  • PCR for viral causes performed early during the course of disease maybe negative, and it is recommended that these are repeated, possibly multiple times, on new samples 24-72 hours later.

What Lab Results Are Absolutely Confirmatory?

What lab results are absolutely confirmatory can be a complex question for any microbiological analysis, as the presence of a microorganism (or viral nucleic acid) in a clinical sample is not 100% confirmatory, but rather the presence of that organism (or viral nucleic acid) must be determined to be the clinically relevant pathogen based on the clinical scenario.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A discussion of encephalitis/meningoencephalitis is not complete without a short reminder of the most common causative pathogens. The most common causes are viral, especially enterovirus, HSV and arboviruses. However, the list of viruses that are capable of causing is very long and include Cytomegalovirus (CMV), Epstein-Barr virus (EBV), influenza, mumps, measles, human herpesvirus 6 (HHV6), human herpesvirus 7 (HHV7), and varicella zoster virus (VZV). For a full list of viruses, consult an infectious disease text.

For nonviral causes, the list is also quite long. Most common nonviral causes include bacterial pathogens and Cryptococcus neoformans. However, there are many other causes, including malaria, tick-borne diseases (e.g., Rocky Mountain Spotted Fever), syphilis, Lyme disease, tuberculosis, toxoplasma, histoplasma, and amoebic causes.