Viral Encephalitis Workup

  • Author: Francisco de Assis Aquino Gondim, MD, MSc, PhD, FAAN; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Feb 18, 2016
 

Approach Considerations

Usually, general laboratory studies are not helpful, except for identifying a viral infectious process (eg, a lymphocytic predominance in the complete blood count [CBC], rather than the polymorphonuclear predominance indicative of bacterial infection). The diagnostic evaluation should include a CBC, tests of renal and hepatic function, coagulation studies, and chest radiography.

During epidemics, viral encephalitis is diagnosed readily on clinical grounds. However, sporadic cases of viral encephalitis are often difficult to distinguish from other febrile illnesses (eg, gastroenteritis with dehydration and convulsions) or from intoxication. Although specific treatment for most causes of viral encephalitis is still not available, establishing the final diagnosis is important to avoid unnecessary treatments with potential side effects.[39]

In most instances, the currently available specific laboratory tests only help provide a retrospective diagnosis. Serologic tests depend on the occurrence of a rise in antibody titer. However, the early detection of specific immunoglobulin M (IgM) antibody may assist early diagnosis.

Analysis of cerebrospinal fluid (CSF), including polymerase chain reaction (PCR) testing, plays an important role. Reliance on magnetic resonance imaging (MRI) findings to make the diagnosis of encephalitis or to distinguish among the different viral etiologies is usually not advisable.

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Blood and Skin Cultures

All patients with encephalitis should have blood cultures to rule out bacterial and fungal infections. Specific clinical findings should also guide the evaluation of other sites for culture (scraping of vesicles, sputum, nasopharynx, and stool). For most arboviral infections, the viremia is usually of low magnitude and short duration, so blood viral cultures are low yield tests most of the time.

Skin biopsies may be useful for diagnosis conditions such as Rocky Mountain spotted fever, and full-thickness skin biopsy from the neck with staining of sensory axons may be useful for the diagnosis of rabies. Viral cultures from throat, stool samples, and antigen detection for herpes and respiratory viruses are recommended during the first week.

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Serologic Tests

Some causes of encephalitis can be diagnosed by detecting serum IgM antibodies (varicella and arboviruses).

Currently, IgM and immunoglobulin G (IgG) capture enzyme linked immunosorbent assays (ELISAs) are the most useful and most widely used tests for the diagnosis of arboviral encephalitis. However, there is significant cross-reactivity among flaviviruses (Japanese encephalitis virus, St Louis encephalitis virus, and West Nile virus). Anti-West Nile virus IgM is detectable in CS) and serum 10 days after infection onset.

A PCR-based test for rapid detection of West Nile virus has been developed in California. A diagnosis of Japanese encephalitis (JE) can be confirmed serologically with demonstration of IgM in the CSF (sensitivity and specificity >95%). The PCR test may detect the virus within 2 days, but its reliability is uncertain.

ELISAs for detection of dengue virus IgM and IgG are available for serum and CSF.[40] Antibodies to Borrelia burgdorferi and serologic testing for Rickettsia, Ehrlichia, and Anaplasma species should be checked in all patients coming from endemic areas. Blood from the acute phase should be saved for future comparisons with the titers from the convalescent phase.

Despite all major efforts, in a recent study from Spain, a significant number of cases of aseptic CNS infection (42.9% meningitis, 59.3% meningoencephalitis, 72.4% encephalitis) may still have no etiological diagnosis.[41]

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Analysis of Cerebrospinal Fluid

Lumbar puncture

Lumbar puncture should be performed immediately once a space-occupying lesion is ruled out. CSF examination is critical to establish the diagnosis and reveals, acutely, a typical viral profile: mildly to moderately elevated protein (60-80 mg/dL), normal glucose, and a moderate pleocytosis (up to 1000 leukocytes/µL). Mononuclear cells usually predominate, though early in fulminant encephalitis, polymorphonuclear leukocytes predominate. Persistent neutrophilic pleocytosis can occur in patients with West Nile encephalitis (WNE).

Viral cultures are rarely helpful for acute management. Findings from CSF cultures for enteroviruses, mumps, and certain arboviruses may be positive. Low CSF glucose is unusual with viral encephalitis and suggests infection by bacteria, fungal agents, or tuberculosis.

Herpes simplex encephalitis (HSE), as well as other forms of hemorrhagic encephalitis, may be associated with increased red blood cells (RBCs) and xanthochromia in the CSF. The fluid should be sent for PCR evaluation to detect herpes simplex virus (HSV) DNA; PCR is highly specific and remains positive for as long as 5 days after initiation of treatment (see below). Intrathecal antibodies can also be quantified.

Eosinophils can be present in infections with helminths, Treponema pallidum, Mycoplasma pneumoniae, Rickettsia rickettsii, Coccidioides immitis, and Toxoplasma gondii. They can be mistaken for neutrophils if cell count is done in automated cell counters or can be easily destroyed or distorted during processing.

Up to 10% of the patients with viral encephalitis may have completely normal CSF studies.

CSF findings in patients with acute disseminated encephalomyelitis (ADEM) are similar to those in patients with viral encephalitis, but pleocytosis is less marked or absent, and markers of intrathecal immunoglobulin synthesis may be present (less than in multiple sclerosis).

Polymerase chain reaction

PCR testing should be performed to detect viral nucleic acid in CSF. In undiagnosed cases, PCR should be repeated after 3-7 days, and blood tests should be performed after 2-4 weeks to show possible seroconversion or diagnostic increase in antibody levels.

PCR is especially useful for infections caused by herpesviruses and enteroviruses. In infants and neonates, the sensitivity and specificity for CSF PCR for HSV are more variable. In adults, the test may initially yield negative results, especially if the white blood cell (WBC) count in the CSF is lower than 10/µL. Results may turn positive 1-3 days after initiation of treatment.

PCR can also detect varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), JC virus, and West Nile virus (positive in < 60% serologically confirmed cases). Molecular testing of the saliva may establish the diagnosis of rabies.

PCR testing may also be important for the diagnosis of nonviral encephalitis (as in ehrlichiosis and Bartonella henselae infection).

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Computed Tomography and Positron Emission Tomography

In HSV encephalitis, computed tomography (CT) scanning may show low-density lesions in the temporal lobes, which may not be present until 3-4 days after onset. Edema and hemorrhages may be found, and, after 1 week, contrast enhancement may be observed.

CT findings are usually not helpful in differentiating the different viral encephalitides. However, given its low cost and its ready availability in most institutions, CT scanning may be a good choice for evaluating acute disease progression and following up on complications. It scan can readily reveal important complications (eg, hemorrhage, hydrocephalus, and herniation) and can help guide neurosurgical interventions.

Positron emission tomography (PET) scanning may be useful for the evaluation of possible paraneoplastic disorders.

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Magnetic Resonance Imaging

Relying on MRI findings to make the diagnosis of encephalitis or to distinguish among the different viral etiologies is usually not advisable.

MRI is more sensitive and specific than CT for identifying viral encephalitides, especially in the early phase. Diffusion-weighted imaging may be useful for the early diagnosis of HSV, enterovirus 71, and West Nile virus infections.

In HSE, MRI typically shows temporal lobe lesions, which may be hemorrhagic and unilateral or bilateral. Inferomedial temporal lobe and cingulate gyrus are the areas most commonly detected by MRI. In children and infants, a more widespread pattern may be observed.

MRI may help in differentiating Japanese encephalitis (JE) from Nipah virus encephalitis. JE is characterized by gray matter involvement, whereas Nipah virus encephalitis is associated with multiple, small, white matter lesions.

With flavivirus encephalitis and eastern equine encephalitis (EEE), MRI may show mixed intense or hypointense lesions in the thalamus, basal ganglia, and midbrain, being hyperintense on fluid attenuated inversion recovery (FLAIR) and T2.

The rhombencephalitis caused by enterovirus 71 can be visualized by T2-weighted MRI, which shows hyperintense signals in the brainstem.

A peculiar MRI pattern on diffusion-weighted imaging and magnetic resonance spectroscopy has been described in an acute and rapid form of subacute sclerosing panencephalitis (SSPE).[42]

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Electroencephalography

In HSE, electroencephalography (EEG) shows abnormalities in four fifths of biopsy-proven cases. Focal temporal changes, diffuse slowing, and periodic complexes and periodic lateralizing epileptiform discharges (PLEDs) are commonly described. Frontal slowing and occasional frontal spikes have been described in encephalitis associated with influenza virus.

JE is commonly associated with 3 EEG patterns: (1) diffuse continuous delta activity, (2) diffuse delta activity with spikes, and (3) alpha coma pattern. In 1 study, the EEG pattern did not correlate with the Glasgow Coma Scale score and outcome.[43]

In St Louis encephalitis, EEG is characterized by diffuse delta activity, and spike and waves are not prominent in the acute stage.

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Brain Biopsy

Brain biopsies can yield definitive diagnosis of encephalitis, but at present they are rarely performed. A biopsy may be considered when a lumbar puncture is precluded or when the diagnosis is uncertain (eg, to rule out other conditions, such as vasculitis) and the patient’s condition is deteriorating despite treatment with acyclovir. If considered, it should be performed earlier in the course, rather than later, so that a potentially treatable condition can be identified.

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Histologic Findings

In acute viral encephalitis, capillary and endothelial inflammation of cortical vessels is a pathologic hallmark occurring in the gray matter or at the junction of the gray matter and white matter. Lymphocytic infiltration of the gray matter and neuronophagia may also occur. Astrocytosis and gliosis become prominent with disease progression.

Some histopathologic features, such as Cowdry type A inclusion bodies in HSV infection and Negri bodies in rabies, are unique to viral infections. Arboviruses cause little histopathologic change outside the nervous system, with the possible exception of renal involvement in St Louis encephalitis.

Gross examination reveals varying degrees of meningitis, cerebral edema, congestion, and hemorrhage in the brain.

Microscopic examination confirms a leptomeningitis with round-cell infiltration, small hemorrhages with perivascular cuffing, and nodules of leukocytes or microglial cells. Demyelination may follow the destruction of oligodendroglias, and involvement of ependymal cells may lead to hydranencephaly. Neuronal damage is seen as chromatolysis and neuronophagia. Areas of necrosis may be extensive, especially in EEE, JE, and the Far East form of tick-borne encephalitis.

In patients who survive the initial illness, varying degrees of repair are observed, which may include calcification. The pattern of distribution of lesions in the brain is rarely sufficiently specific to enable identification of the infecting virus. Generally, in EEE, the lesions are concentrated in the cortex; in western equine encephalitis (WEE), they are concentrated in the basal nuclei; and in St Louis encephalitis, they are concentrated in the substantia nigra, thalamus, pons, cerebellum, cortex, bulb, and anterior horn cells.

HSE in infants is usually part of a widespread infection that produces focal necrotic lesions with typical intranuclear inclusions in many organs. In adults and in some children, lesions are confined to the brain. Necrotic foci may be macroscopically evident as softening. Hemorrhage and Cowdry type A inclusions bodies are found readily in the margins of areas of necrosis.

Herpesviruses have tropism for the temporal cortex and pons, but the lesions may be widespread. Rabies virus tends to exhibit a tropism for the temporal lobes, affecting the Ammon horns. Autopsy studies in individuals with West Nile virus have shown particular brainstem involvement, especially the medulla, with endoneural mononuclear inflammation of cranial nerve roots.

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Contributor Information and Disclosures
Author

Francisco de Assis Aquino Gondim, MD, MSc, PhD, FAAN Professor Adjunto of Neurology and Clinical Skills, Department of Internal Medicine, Universidade Federal do Ceará, Brazil

Francisco de Assis Aquino Gondim, MD, MSc, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, International Parkinson and Movement Disorder Society

Disclosure: Received travel grants from for: Aché, Biogen, Genzyme, Ipsen, Novartis.

Coauthor(s)

Florian P Thomas, MD, PhD, Drmed, MA, MS Director, National MS Society Multiple Sclerosis Center; Professor and Director, Clinical Research Unit, Department of Neurology, Adjunct Professor of Physical Therapy, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Florian P Thomas, MD, PhD, Drmed, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi

Disclosure: Nothing to disclose.

Gisele Oliveira, MD Resident Physician, Department of Neurology, St Louis University School of Medicine

Gisele Oliveira, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Additional Contributors

J Stephen Huff, MD, FACEP Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD, FACEP is a member of the following medical societies: American Academy of Neurology, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

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Table 1. Examples of Physiologic Roles of Known Viral Receptors
Virus Receptor Abbreviation/Synonym Function
Measles virus Membrane cofactor protein CD46 Regulates complement and prevents activation of complement on autologous cells
Poliovirus CD155 hPVR/CD155 Expressed on primary human monocytes; supports poliovirus replication in vivo
HSV Heparan sulfate None Cell surface proteoglycans
Herpesvirus entry mediator A Hve A, HVEM TNF receptor superfamily
Herpesvirus entry mediator B Hve B, Human nectin-2, or Prr2alpha-Hve B Participate in organization of epithelial and endothelial junctions
Herpesvirus entry mediator C Hve C, nectin1delta, or Prr1-Hve C Immunoglobulin superfamily
TNFSF14 hTNFSF14/HVEM-L TNF receptor superfamily
Rabies virus Nicotinic AChR (a-bungarotoxin binding site) AChR Nicotinic AChR
NCAM NCAM, CD56, D2CAM, Leu19, or NKH-1 Cell adhesion glycoprotein of immunoglobulin superfamily
NGFR NGFR NGFR
p75 neurotrophin receptor (p75NTR) p75NTR  
HIV-1 CD4 CD4 T lymphocyte protein with helper or inducer function in immune system
CCR3 CCR3 Chemotactic activity
CCR5 CCR5 Coreceptor for macrophage-tropic strain
CCR6 CCR65 Chemotactic activity
CXCR4 CXCR4 Coreceptor for CD4
JC virus N-linked glycoprotein with alpha 2-6 sialic acid N-linked glycoprotein Unknown
Japanese B virus[6] Protein GRP78 --- ER-stress response protein
AChR—acetylcetylcholine receptor; CCR—chemokine receptor; HSV—herpes simplex virus; NCAM—neural cell adhesion molecule; NGFR—nerve growth factor receptor; TNF—tumor necrosis factor.
Table 2. Common Viral Encephalitides: Part 1
Virus (Family) Viral Structure Transmission Mortality Specific Clinical Patterns Sequelae Season
HSV (herpesvirus) ds DNA Unknown 70% if untreated Rare forms: subacute, psychiatric, opercular, recurrent meningitis



HSV-1: brainstem; HSV-2: myelitis



Common All year
VZV (herpesvirus) ds DNA Direct contact (air), highly contagious Variable; low in children Rash, encephalitis in 0.1-0.2% of children with chickenpox; cerebellar ataxia (cerebellitis) Adults worse; cerebellitis good Late winter, spring
Influenza virus (orthomyxovirus) ss RNA Direct contact (air), highly contagious Unknown Reversible frontal syndrome in children; Guillain-Barré, myelitis Parkinsonism (encephalitis lethargica) Usually winter
Enteroviruses (picornavirus) ss RNA Fecal-oral route Low; high for enterovirus 71 Herpangina; hand, foot, mouth disease; enterovirus 71 causes rhombencephalitis Mild, except for enterovirus 71 Summer, fall; tropics: no season
Rabies virus (rhabdovirus) ss RNA Dogs, wild animals (eg, fox, wolf, skunk) Virtually 100% Paresthesias; confusion, spasms, hydrophobia; brainstem features Mortality virtually 100% All year
ds—double strand; HSV—herpes simplex virus; ss—single strand; VZV—varicella-zoster virus.
Table 3. Common Viral Encephalitides: Part 2
Virus (Family) Viral Structure Transmission Mortality Specific Clinical Patterns Sequelae Season
Lymphocytic choriomeningitis virus (arenavirus) ss RNA Rodents Low (< 1%) Progressive fever and myalgia; orchitis; aseptic meningitis; leukopenia, thrombocytopenia Rare More in winter
Lassa virus (arenavirus) ss RNA Rodents 15% Multisystem disease; proteinuria Deafness (one third) All year
Mumps virus (paramyxovirus) ss RNA Direct contact (air), highly contagious Low Parotitis, pancreatitis, orchitis, aseptic meningitis Frequent sequelae Winter and spring
Measles virus (paramyxovirus) ss RNA Direct contact (air), highly contagious 10% Characteristic rash; frequent EEG changes; myelitis Frequent: mental retardation, seizures, SSPE Winter and spring
Nipah virus (paramyxovirus) ss RNA Pigs; bats 40-75% Brainstem or cerebellar signs; segmental myoclonus, dysautonomia SSPE-like syndrome? All year
ds—double strand; EEG—electroencephalographic; ss—single strand; SSPE—subacute sclerosing panencephalitis.
Table 4. Common Arboviral Encephalitides
Virus (Family) Vector Reservoir Mortality Specific Clinical Patterns Sequelae Season
Eastern equine virus (alphavirus) Aedes sollicitans Birds 35% Severe, rapid progression Common, especially in children June to



October



Western equine virus (alphavirus) Culex tarsalis Birds 10% Classic encephalitis Moderate in infants; low in others July to



October



Venezuelan equine encephalitis virus (alphavirus) Mosquito species Horses, small mammals ~ 0.4 % Low rate (4%) of CNS involvement Mild Rainy season
St Louis encephalitis virus (flavivirus) Culex pipiens,C tarsalis Birds 2% in young people; 20% in elderly people SIADH More in elderly people August to October
Japanese encephalitis virus (flavivirus) Culex taeniorhynchus Birds 33% (50% in elderly people) Extrapyramidal features 50% neuro psychiatric; parkinsonism Summer
West Nile virus (flavivirus) Culex,Aedes spp Birds In US: 12% (elderly people only) Motor or brainstem involvement Usually not prominent Summer
Far East encephalitis virus (flavivirus) Ixodes persulcatus (tick) Small mammals, birds 20% Epilepsia partialis continua Frequent; residual weakness Spring to early summer
Central European encephalitis virus (flavivirus) Ixodes ricinus (tick) Small mammals, birds Less common than in Far East Limb-girdle paralysis (spine/medulla) Less common than in Far East April to October
Powassan virus (flavivirus) Ixodes cookei (tick) Small mammals, birds High Severe encephalitis Common (50%) May to December
Dengue virus (flavivirus) Aedes spp Mosquitoes Low, except hemorrhagic Flulike syndrome; possible CNS involvement Mild, except for hemorrhagic Rainy season
La Crosse virus (bunyavirus) Aedes triseriatus Small mammals Low (< 1%) Mild, primarily in children Mild; seizures Summer
Colorado tick fever virus (orbivirus) Dermacentor andersoni (tick) Small mammals Low   Mild  
CNS—central nervous system; SIADH—syndrome of inappropriate antidiuretic hormone secretion.
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