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Encephalitis is an inflammation of the brain parenchyma with clinical evidence of neurologic dysfunction, and associated cerebrospinal fluid (CSF) and electroencephalography (EEG) findings. Encephalopathy refers to global brain disease and dysfunction regardless of its etiology, while leukoencephalopathy is a group of diseases affecting the brain white matter.


Noninfectious causes such as autoimmune diseases, connective tissue diseases and paraneoplastic syndromes are not within the scope of this article.

Encephalitis can occur due to direct infection of the brain. Finding the causative agent in infectious encephalitis is a daunting task; despite extensive diagnostic workup 1/3 to 2/3 of the cases have an unknown etiology by the time of admission to rehabilitation.1Etiological agents differ between immunocompetent and immunocompromised patients. Among immunocompetent patients the major causes of encephalopathy are viral 40%, bacterial 30%, Lyme disease 7%, fungi 7%, syphilis 5%, Mycobacterium 5%, and prion diseases 3%. Among HIV patients, viruses are 46%, fungi in over 30%, and toxoplasmosis 10%.2,3Immunocompromised patients due to organ transplantation or cancer are also associated with certain infectious encephalitis. For example, Human Herpesvirus 6 (HHV-6) encephalitis is almost only found in immunocompromized patients after bone marrow transplantation,4whereas Cytomegalovirus (CMV) encephalitis infection can be seen in both HIV and transplant recipients.

In addition to direct infection, post-infectious encephalitis can occur as an immune reaction to infection anywhere in the body. Acute disseminated encephalomyelitis (ADEM), which can be considered a multiple sclerosis variant, is not an infection by itself but an autoimmune demyelination secondary to a systemic infection. It occurs mostly after viral infections, but is also seen after bacterial or parasitic infections and as a very rare complication after vaccination.

Epidemiology including risk factors and primary prevention

There are an estimated 20,000 new cases of infectious encephalitis in the United States annually, with incidence of 3 to 7 in every 100,000. Infants and elderly are the most severely involved. Homeless patients and those with HIV have highest rates of infections; a higher exposure to mosquitoes in the case of the homeless, and a higher prevalence of opportunistic infections in the immunocompromised population may be contributing factors.2,3Arboviruses are a family of viruses that are spread through arthropod vectors and are a common cause of encephalitis. Arboviral encephalitis epidemiology has geographic variations.5California encephalitis is commonest in the midwest. Eastern equine encephalitis is commonest on the East Coast. St. Louis encephalitis is common in both the midwest and East Coast. West Nile virus (WNV) fever and western equine encephalitis are found throughout the country.

ADEM is an uncommon illness, seen more in children than adults. Its incidence in children was 0.2/100,000 – 0.4/100,000 in the published studies.6


Pathophysiology of the disease depends on the infecting agent.

  1. Varicella-Zoster virus (VZV) can lead to vasculitis with subsequent hemorrhagic stroke.
  2. Herpes Simplex (HSV) has a predilection for involving the fronto-temporal cortical areas due to its retrograde transmission through olfactory nerve and/or the trigeminal ganglion.
  3. Japanese encephalitis and St. Louis encephalitis have a tendency to infect deep grey matter structures.7
  4. Epstein – Barr virus (EBV) central nervous system (CNS) involvement is widely variable, including: meningitis, encephalitis affecting variable areas of the brain–mostly subcortical white matter and deep gray matter, spinal cord involvement with transverse mellitus, or Guillain-Barre syndrome (GBS).8
  5. St. Louis encephalitis: The vast majority of elderly develop actual encephalitis, while infection in those younger than 20 years old varies equallybetween meningitis and encephalitis.9
  6. John Cunningham virus (JCV): Polyoma virus infects the oligodendrocytes causing sub-acute demyelinating disease.10It rarely affects neurons and spares astrocytes.
  7. WNV fever can cause meningitis and encephalitis and can also affect the anterior horn cells, leading to flaccid paralysis (sometimes involving the diaphragm) with picture of axonal loss with no evidence of demyelination.11,12
  8. Natalizumab for the treatment of multiple sclerosis (MS) was associated with more than 30 cases of progressive multifocal leukoencephalopathy (PML) and was almost pulled from the market by the FDA.13In a study, 100 cases of Non-Hodgkin’s lymphoma treated with rituximab also developed PML.14

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Disease Progression/Phases/Trajectory:

The natural course of the disease is variable depending on the infecting agent, age, and immune status of the patient. A 2-week viral prodrome/incubation state is common in many etiologies.

  1. Mortality without IV acyclovir treatment can be 70%; early treatment with IV acyclovir level (A-I) is the only parameter to lower morbidity and mortality in herpetic encephalitis.15
  2. HHV-6 has a predilection for the medial temporal lobe and the limbic system, leading to the clinical picture of short-term memory loss, seizures and sleep disturbance.
  3. CMV can lead to reversible encephalopathy and poly-radiculopathy.
  4. Only one out of 300 exposed to Japanese encephalitis or St. Louis encephalitis end up developing clinical manifestations.
  5. California encephalitis mostly affects children, with very low mortality and morbidity rates.
  6. Prion encephalitis is almost invariably fatal.

Specific secondary or associated conditions and complications

Different infectious etiologies lead to different secondary conditions.

  1. Seizure Disorder: Viruses that have predilection for cerebral cortex, especially involving the frontal-temporal and parietal lobes like HSV and HHV-6, are more likely to cause seizures, whereas those that involve white matter or deep brain structures such as WNV or PML are less likely to cause seizures.
  2. Movement Disorders: Parkinsonism, choreoathetosis, myoclonic jerks and dystonia are seen in infections of the basal ganglia and deep grey matter associated with St. Louis encephalitis and Japanese encephalitis.
  3. Cranial nerve involvement with facial weakness, paraesthesia, ptosis are very common with WNL16and Japanese encephalitis.
  4. Flaccid paralysis is usually due to axonal and anterior horn cells involvement in WNL, or with GBS demyelinating lesions in EBV.
  5. Visual disturbance – for example, alien hand phenomenon – is seen in cases of non-HIV PML which involves the subcortical occipital area.
  6. Communicating hydrocephalus: Patients need to be evaluated for the late development of communicating hydrocephalous, as noted by cognitive changes, ataxia and incontinence.
  7. Many of these patients will have problems with cognitive, behavioral and motor disorders, as noted in TBI patients. Similar management is recommended for these problems.
  8. Depression and anxiety are very common in HHV-6 due to involvement of the limbic system.



A comprehensive history should include assessment of premorbid functional, vocational, medical and social status, along with a detailed history of focal and generalized neurologic impairments, including seizures. Specific details pertaining to infectious encephalitis include:

  1. Exposure to mosquito or tick bites as seasonal risk factors.
  2. Underlining immune status of the affected individual, and in the case of HIV, documentated CD4 count trends (as Toxoplasmosis is a frequent pathogen with < 100 cells/mm while CMV is only seen with < 50 cells/mm).
  3. Duration of time between symptom onset and administration of IV Acyclovir treatment in the case of HSV encephalitis.
  4. Presence of documented increased intracranial pressure, seizures or hydrocephalus in the acute hospital stay.

Physical examination

The clinical picture ranges from obtunded encephalopathy to more specific focal neurological deficits. A detailed neurological examination should include assessment of mental status and overall orientation. In severely obtunded patients, one should rule out subclinical seizures with the use of EEG. Cranial nerve exam should be performed, including ophthalmologic exam evaluating for any signs of raised intracranial pressure. Manual muscle testing may reveal findings consistent with polyradiculopathy, axonal loss, or demyelinating lesions. Skin rash can raise suspicion for a bacterial cause of encephalitis/meningitis (neisseria meningitis), which is important to diagnose early since it is acutely life-threatening, requiring contact isolation and usually responding very well to intravenous (IV) third-generation cephalosporin.

Functional assessment

Functional independence measure (FIM), including all 18 components assessing cognitive and physical function, is helpful for monitoring functional status. In the early stages of confusion and disorientation, closed head injury scales such as the Rancho Los Amigos scale may be useful.

Laboratory studies

CSF analysis: Pleocytosis (10-2,000 cells/μL) with lymphocytic predominance, elevated protein and normal to mildly low glucose, with negative Gram stain and bacterial cultures indicates viral encephalitis. Any time infectious encephalitis is suspected, polymerase chained reaction (PCR) studies of the CSF should include viral DNA studies for: HSV, WNV, VZV, EBV, CMV, and HIV. These tests are highly specific when positive but they are not very sensitive.

Serums studies should include serology for WNV, EBV, mycoplasma, borellia, rickettsia coccidiodes, and histoplasma.

EEG: The common EEG picture with encephalitis is not very different from that of encephalopathy with generalized slowing, but in cases of HSV encephalitis focal abnormalities involving the temporal lobes are commonly found. EEG is valuable in evaluating an obtunded patient with encephalitis to rule out subclinical status epilepticus.


Acute assessment should include a head computerized tomography (CT) to rule out any space-occupying lesions and contraindications to lumbar puncture with elevated intracranial pressure. Magnetic resonance imaging (MRI) is a valuable diagnostic tool in patients with encephalitis. With variable T2 lesions corresponding to different etiologies, for example, HSV commonly involves the frontal-temporal lobes; it’s almost never seen outside the frontal-temporal areas alone. WNV fever does not usually have prominent MRI findings. VZV vasculitis presents multiple lesions of hemorrhagic infarction. Progressive multiple leukoencephalopathy (PML) causes primarily demyelinating lesions.

Supplemental assessment tools

Supplemental assessment tools for patients with impaired consciousness are often borrowed from traumatic brain injury. Two useful tools are the orientation log (which carries same clinical value as the Galveston Orientation and Amnesia Test),17the cognition-log,18as well as the Coma Recovery Scale-Revised. Specific assessment tools to infectious encephalitis can include CSF and serum viral load in cases like HSV, and VZV, and following the CD4 counts in HIV patients.

Early predictions of outcomes

The most significant early predictor of better outcome is the early administration of IV acyclovir in the case of HSV encephalitis.19The type of infectious agent can predict long-term complications and outcome. For example, encephalitis due to Japanese or St. Louis encephalitis has higher prevalence of long-term neurological dysfunction than that of California encephalitis. Cognitive impairment in patients with PML and low CD4 is progressive, irreversible, and ends with dementia.

Worst outcomes are expected with secondary complications such as intraparenchymal hemorrhage in cases of VSZ CNS vasculitis and severe intracranial edema in cases of Herpes encephalitis.


As with any patient with neurological impairment, accommodations have to be provided for patients, ranging from supervision and home care for those with cognitive impairments, to the utilization of assistive devices, orthotics and physical assistance for those with primarily motor weakness.

Of note for care-takers of these patients, viral etiologies of encephalitis are not contagious and patients don’t need to be under contact isolation. Care-takers need not worry about close physical contact with their dependent patients.

Social role and social support system

Etiologies like Japanese and California encephalitis mostly affect children; special accommodations at home/school and playground have to be considered. Some of the tick-mediated infections can affect otherwise healthy functioning and employed adults; issues pertaining to long-term loss of productivity and work should be addressed.

Professional Issues

Given the high rate of misdiagnosis in the acute setting (up to 2/3 as described above), subsequent diagnosis in the rehabilitation and sub-acute setting can lead to delayed diagnosis, with significant implications related to the potential therapeutic windows of antivirals. [acyclovir in the case of HSV and VZV, and gancyclovir with foscarnet in the case of HHV-620and CMV21encephalitis].


Available or current treatment guidelines

Given the relatively low incidence of encephalitis, rehabilitation studies are sparse, consisting mainly of case reports. Some of the medications used in traumatic brain injury have shown some anecdotal evidence of use. The utilization of dopamine agonists such levo-dopa and amantadine21can improve alertness and arousal, especially when deep grey matter structures are involved, as in the case of St. Louis and Japanese encephalitis. The utilization of donepezil is helpful for short-term memory loss and aphasia commonly seen in WNL, PML and HHV-6. Sertraline22for prevention of depression and potential improvement of motor recovery can be helpful, especially in those illnesses that involve the limibic system and deep white matter like HHV-6, PML and WNL. There is some evidence for benefits of cognitive rehabilitation for short-term memory and amnesia in post-viral encephalitis.23

Coordination of care

Close coordination of care with infectious disease specialist, primary care physician, local infection control agencies (as some cases have to be reported to the CDC), and neurologist, along with the rest of the rehabilitation team, is of great importance. Coordination with community integration (schools, vocational, geriatric) resources and support groups should be maximized.

Patient & family education

Patient and family should be educated about the prognosis and potential long-term complications and need for long-term assistance for the affected individual. The potential progressive nature of some diseases such as PML should be well discussed with families and care-givers.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Risk stratification for patients with MS, including serologic testing for JC virus, has been implemented for anyone to be treated with natalizumab, due to documented cases of PML (see pathophysiology section above). Those with positive JC serology are not good candidates for natalizumab.


Cutting edge concepts and practice

Nakayama vaccine was developed for Japanese encephalitis (the world’s most common infectious encephalitis, affecting 50.000 annually) with > 95% immunity rate,25despite Japanese encephalitis virus being very hybrid and with different lineages. Work is ongoing for vaccines in susceptible groups, for example, as against JC virus in HIV patients and arthropod viruses for campers and hikers.


Gaps in the evidence-based knowledge

Most data related to outcomes are either case reports or retrospective studies. Larger multicenter trials as well as clinical pathophysiologic correlates need to be prospectively obtained in each of these varied causes of encephalitis.


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Author Disclosure

Jay M. Meythaler, MD JD
Author indicated he/she has no relevant financial relationships to disclose.

Ayman Tarabishy, MD
Author indicated he/she has no relevant financial relationships to disclose.