Encephalitis

Encephalitis is an inflammation of the brain parenchyma, caused by viral (most common), bacterial, parasitic, or fungal infection (infectious encephalitis) or an antibody-mediated autoimmune response (autoimmune encephalitis). Prodromal symptoms include fever, headache, and nausea, with progression to neurological and psychiatric symptoms within hours to weeks, including altered mental status, seizures, focal neurological deficits, hallucinations, and psychosis. Diagnosis is based on laboratory studies (serology, CSF analysis), MRI of the head, and EEG. Epidemiologic clues (e.g., season of the year, geographic location, travel, and exposure history) and clinical features may guide the diagnostic process. Additional testing with antibody detection of specific pathogen antibodies or autoantibodies is not necessary for all patients and should be performed as directed by clinical suspicion. Brain biopsy is limited to idiopathic cases that do not respond to empiric treatment. Paraneoplastic encephalitis, mediated by autoantibodies targeted against intracellular antigens, may be the first manifestation of malignancy, which is why malignancy screening may be part of the diagnostic workup. Treatment is based on the etiology and may include antiinflammatory or immunomodulatory treatment. Acyclovir or empirical antibiotic treatment should be started immediately if viral or bacterial encephalitis is suspected, respectively.

Anatomical classification

• Encephalitis: inflammation of the brain parenchyma
  • Limbic encephalitis: inflammation of brain tissue that primarily affects the limbic system in the medial temporal lobes
  • Cerebellitis: inflammation of the cerebellum
  • Brainstem encephalitis: inflammation of the brain tissue that primarily affects the brainstem and adjacent regions
  • Meningoencephalitis: concurrent inflammation of meninges (meningitis) and brain parenchyma (encephalitis)
• Encephalomyelitis: concurrent inflammation of the brain (encephalitis) and spinal cord (myelitis)

Etiological classification

• Infectious encephalitis: inflammation of the brain parenchyma caused by pathogens
  • Viral encephalitis: inflammation of the brain parenchyma caused by viruses (most common type of infectious encephalitis) ^[1]
  • Bacterial encephalitis: inflammation of the brain parenchyma caused by bacteria
  • Other: fungal (e.g., Cryptococcus neoformans; ), parasitic (e.g., Naegleria fowleri)
• Autoimmune encephalitis: inflammation of brain tissue mediated by autoimmune antibodies ^[2]
  • According to its association with neoplasms
    • Paraneoplastic encephalitis: mediated by antibodies targeted against intracellular and extracellular neuronal proteins
    • Non-paraneoplastic: idiopathic, postinfectious (e.g., acute disseminated encephalomyelitis, anti-NMDAR encephalitis post herpes simplex encephalitis infection)
  • According to the targeted neuronal antigens
    • Intracellular antigens (commonly tumor-associated) ^[3]
    • Surface antigens

Infectious encephalitis

Causes of infectious encephalitis include viruses, bacteria, and, less frequently, fungi and protozoa.

Viral encephalitis

• Herpesviruses
  • Human herpesvirus 1 (herpes simplex virus type 1, HSV-1), Human herpesvirus 2 (herpes simplex virus type 2, HSV-2): herpes simplex encephalitis (HSE)
  • Human herpesvirus 3 (varicella-zoster virus, VZV): herpes zoster encephalitis
  • Cytomegalovirus (CMV): CMV encephalitis (most common in immunocompromised or HIV-positive individuals)
  • Human herpesvirus 4 (Ebstein-Barr virus): EBV encephalitis (most common in immunocompromised individuals)
• Mosquito-borne viruses
  • West Nile virus (WNV): West Nile encephalitis
  • Murray Valley encephalitis virus: Murray Valley encephalitis (MVE)
  • Japanese encephalitis virus (JEV): Japanese encephalitis
  • Saint Louis encephalitis virus: St. Louis encephalitis
  • Tick-borne encephalitis virus (TBEV): tick-borne encephalitis
  • California encephalitis orthobunyavirus: California encephalitis
  • Western equine encephalitis virus: Western equine encephalitis
  • Eastern equine encephalitis virus: Eastern equine encephalitis
  • La Crosse encephalitis virus: La Crosse encephalitis
• Other
  • Enteroviruses: enteroviral encephalitis (EVE)
  • Human immunodeficiency viruses (HIV): HIV-associated neurocognitive disorder (HAND)
  • Measles morbillivirus (measles virus): encephalitis, subacute sclerosing panencephalitis
  • Rabies lyssavirus (rabies virus): encephalitic rabies

Bacterial encephalitis

• Treponema pallidum: neurosyphilis
• Borrelia burgdorferi: neuroborreliosis
• Listeria monocytogenes: listeria encephalitis
• Rickettsia rickettsii: Rocky Mountain spotted fever (RMSF)
• Ehrlichia: ehrlichiosis

Autoimmune encephalitis

• Progression: acute (hours to days) or subacute (weeks to 3 months)
• Nonspecific prodromal symptoms (hours to weeks prior)
  • Fever
  • Headache
  • Nausea
• Neurological
  • Altered mental status
  • Memory loss
  • Seizures (focal or generalized)
  • Focal neurological deficit
    • Hemiparesis
    • Hyperreflexia
    • Cranial nerve palsies
    • Language dysfunction (e.g., aphasia, dysarthria)
    • Extrapyramidal symptoms
  • Dysautonomia
• Psychiatric
  • Behavioral changes (e.g., hypersexuality, hypomania, agitation)
  • Hallucinations
  • Anxiety
  • Psychosis

Subacute onset of psychiatric symptoms in combination with seizures and/or focal neurological deficits should raise clinical suspicion for encephalitis.

General

Management of encephalitis should focus on identifying and treating the underlying causes of encephalitis (see “Etiology” above).Diagnostic and treatment steps should be initiated simultaneously and empiric treatment should not be delayed for diagnostic steps.

• History and physical examination: detailed personal, travel, and exposure history
• All patients with suspected encephalitis require the following:
  • Neuroimaging (brain MRI with contrast)
  • Lumbar puncture
  • Electroencephalography

Neuroimaging

• Brain MRI with contrast: most sensitive and specific imaging modality
  • Indicated in all patients with suspected encephalitis
  • Limbic encephalitis: hyperintensity in the medial temporal lobes in T2/FLAIR sequence ^[5]
  • Herpes simplex encephalitis: hyperintense temporal lobe lesions and signal abnormalities in T2/FLAIR sequence (see “Neuroimaging” in “Herpes simplex encephalitis”)
  • Postinfectious encephalitis: multifocal white matter lesions in T2WI/FLAIR sequence ^[6]
• Brain CT (with or without contrast): indicated if MRI is not available or contraindicated
• Electroencephalography
  • Indicated in all patients with suspected encephalitis
  • Usually nonspecific findings
  • Used in cases of suspected viral encephalitis (see “Herpes simplex encephalitis EEG findings”) and inconclusive diagnosis of seizures (e.g., non-convulsive, subtle motor seizures)
• Brain FDG PET scan
  • Indicated in patients with negative neuroimaging and laboratory findings, but with high clinical suspicion for autoimmune encephalitis
  • Abnormal brain metabolism findings in autoimmune encephalitis ^[7]

A normal brain MRI does not exclude the diagnosis of encephalitis.

Always consider HSE when imaging suggests potential meningoencephalitis and temporal lobe involvement; bilateral temporal lobe abnormality is pathognomonic of HSE.

Laboratory studies

• Blood studies
  • CBC, CRP, ESR, and blood cultures
  • Renal function tests and liver function tests
  • Coagulation panel
  • HIV testing
• CSF analysis
  • Perform PCR, Gram stain, and cultures
  • Viral and autoimmune encephalitis CSF findings
    • May be normal in immunocompromised patients
    • ↑ Lymphocytes (lymphocytic pleocytosis)
    • Inflammatory markers: ↑ IgG index and/or oligoclonal bands

Other studies

• Serologic studies: autoantibodies in CSF and serum (e.g., anti-Hu antibodies, anti-NMDAR antibodies)
• Brain biopsy: last resort; consider in patients with encephalitis of unknown cause who continue to deteriorate despite empiric and supportive treatment
• Malignancy evaluation ^[2]
  • Consider if an autoantibody against an intracellular antigen has been detected and refine screening based on antibody results
  • E.g., CT or MRI scan of the chest, abdomen, and pelvis, mammography, serum prostate-specific antigen testing, ultrasound

• Encephalopathies (e.g., toxins, electrolyte disturbances, uremia)
• Meningitis
• Epilepsy
• Vascular (e.g., stroke, thrombosis)
• Degenerative disorders (e.g., Alzheimer disease, frontotemporal dementia)

The differential diagnoses listed here are not exhaustive.

General

• Initial stabilization for acute seizures.
• Seizure management: antiepileptic drugs ^[3]
• Empiric treatment should not be delayed. Once the responsible pathogen or autoantibody is identified, therapy should be tailored accordingly.
• Monitor intracranial pressure (see “ICP management”).

Infectious encephalitis

• Viral encephalitis
  • Start immediate antiviral therapy with acyclovir for all patients with suspected viral encephalitis (see “Antimicrobial treatment for herpes simplex encephalitis”).
  • CMV encephalitis: IV ganciclovir AND IV foscarnet
• Bacterial encephalitis ^[8]
  • Start immediate empiric antibiotic therapy for all patients with suspected bacterial encephalitis or meningitis (see also “Empiric antibiotic therapy for bacterial meningitis”).
  • Initiate definitive antibiotic treatment as soon as microbiological results become available
    • Neuroborreliosis: ceftriaxone, cefotaxime, or penicillin G
    • Neurosyphilis: penicillin G
    • Listeria encephalitis: ampicillin plus gentamycin
    • Rocky Mountain spotted fever: doxycycline
    • Ehrlichiosis: doxycycline

Immune-mediated encephalitis

• Paraneoplastic encephalitis: treatment of primary tumor and immunotherapy ^[9]
• Autoimmune encephalitis ^[2]
  • First-line: high-dose corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis
  • Second-line: rituximab, cyclophosphamide