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Encephalitis

OVERVIEW

  • Highlights & Basics
  • Images

DIAGNOSIS

  • Diagnostic Approach
  • Risk Factors
  • History & Exam
  • Tests
  • Differential Diagnosis

TREATMENT

  • Tx Approach
  • Tx Options
  • Emerging Tx
  • Prevention

FOLLOW-UP

  • Overview
  • Complications

REFERENCES

  • Citations
  • Guidelines
  • Credits

PATIENT RESOURCES

  • Patient Instructions

Highlights & Basics

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Key Highlights

  • Encephalitis is a pathologic state of brain parenchymal dysfunction leading to an altered state of consciousness or focal neurologic signs.

  • Serious, complex, and potentially fatal disorder with noninfectious and infectious causes.

  • Presents with acute onset of a febrile illness and altered mental status; typical features include headache, seizures, and focal neurologic signs.

  • Investigations should include blood cultures, neuroimaging (preferably magnetic resonance imaging), and cerebrospinal fluid analysis.

  • Acyclovir should be administered as soon as possible in all cases of suspected viral encephalitis.

  • Complications include seizures, hydrocephalus, and neurologic sequelae (e.g., behavioral disturbances, motor problems).

Noncontrast head CT of a patient with HSV encephalitis: shows subtle hypodensities involving the lef
Noncontrast head CT of a patient with HSV encephalitis: shows subtle hypodensities involving the left insular region. Some blurring of gray-white margins and sulcal effacement over the left temporal region is discernible
From the personal collection of Catalina C. Ionita, MD; used with permission

Quick Reference

  • History & Exam

    • Key Factors

      • fever

      • rash

      • altered mental state

      • focal neurologic deficit

      • meningismus

      • parotitis

      • lymphadenopathy

      • optic neuritis

      • acute flaccid paralysis

      • movement disorder

    • Other Factors

      • cough

      • gastrointestinal infection

      • seizures

      • biphasic illness

      • autonomic and hypothalamic disturbances

      • myocarditis/pericarditis

      • jaundice

      • arthritis

      • retinitis

      • parkinsonism

    More information...

  • Diagnostics Tests

    • 1st Tests to Order

      • CBC

      • peripheral blood smear

      • serum electrolytes

      • liver function tests

      • blood cultures

      • throat swab

      • nasopharyngeal aspirate

      • sputum culture

      • chest radiography

      • CT brain

      • MRI brain

      • electroencephalogram (EEG)

      • cerebrospinal fluid (CSF) analysis

      • CSF culture

      • CSF serology

      • CSF polymerase chain reaction (PCR)

    • Other Tests to consider

      • stool enteroviral culture

      • IgG and IgM antibodies (blood)

      • PCR (blood)

      • HIV serology/RNA test

      • CSF biomarkers/prion protein assay

      • paraneoplastic antibodies (blood and CSF)

      • abdominal/pelvic ultrasound

      • whole-body CT

      • whole-body PET scans

      • magnetic resonance spectroscopy

      • next-generation sequencing of CSF

      • brain biopsy

    More information...

  • Treatment Options

    • presumptive

      • immunocompetent host: suspected viral etiology

        • acyclovir

        • supportive care

      • immunocompromised host: suspected viral etiology

        • combination antiviral therapy

        • supportive care

    More information...

Definition

Encephalitis is defined as inflammation of the brain parenchyma associated with neurologic dysfunction, such as altered state of consciousness, seizures, personality changes, cranial nerve palsies, speech problems, and motor and sensory deficits.[1] It is the result of direct inflammation of the brain tissue, as opposed to the inflammation of the meninges (meningitis), and can be the result of infectious or noninfectious causes. An etiologic agent is only identified in around 50% of cases.[2] [3]

Classifications

Diagnostic definition

Diagnostic criteria for encephalitis and encephalopathy of presumed infectious or autoimmune etiology

  • Major criterion (required):

    • Patients presenting to medical attention with altered mental status (defined as decreased or altered level of consciousness, lethargy, or personality change) lasting ≥24 hours with no alternative cause identified.

  • Minor criteria (2 required for possible encephalitis; ≥3 required for probable or confirmed encephalitis):

    • Documented fever ≥100.4°F (38°C) within the 72 hours before or after presentation

    • Generalized or partial seizures not fully attributable to a preexisting seizure disorder

    • New onset of focal neurologic findings

    • Cerebrospinal fluid WBC count ≥5/mm³

    • Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onset

    • Abnormality on electroencephalography that is consistent with encephalitis and not attributable to another cause.

Confirmed encephalitis requires one of the following:

  • Pathologic confirmation of brain inflammation consistent with encephalitis

  • Defined pathologic, microbiologic, or serologic evidence of acute infection with a microorganism strongly associated with encephalitis from an appropriate clinical specimen

  • Laboratory evidence of an autoimmune condition strongly associated with encephalitis.

Vignette

Common Vignette 1

A 56-year-old man presents to the emergency department with headache, fever, blurred vision, and somnolence followed shortly by unresponsiveness to verbal commands. For the last 2 weeks he had been feeling ill, and had decreased appetite and myalgias. Three days prior to presentation he experienced intermittent confusion, severe headache, and fever. Examination was limited by a generalized tonic-clonic seizure, for which he received lorazepam.

Common Vignette 2

A 19-year-old man presents to the emergency department with a witnessed generalized tonic-clonic seizure episode. One month previously he had an upper respiratory tract infection. Over the last 2 weeks he developed headaches, blurred vision, generalized weakness, and progressive difficulty walking. Examination revealed pain on eye movement as well as limb and gait ataxia.

Epidemiology

Globally, the incidence of encephalitis is around 7 per 100,000 population per year.[4] Approximately 20,000 cases occur each year in the US.[5] True incidence is difficult to determine (due to the wide spectrum of clinical presentation, under-diagnosis, and under-reporting), and may be higher than hospital discharge data suggest in England, France, Italy, Canada, and Australia.[6] [7] [8] [9] [10] [11] There is no specific predominance in either sex, but frequently a bimodal age distribution is seen with highest incidence in those under one year and over 65 years.
Seasonal and geographic variations occur in some cases of viral encephalitis in the US and other parts of the world. There is increased incidence in summer and early fall (peaking July to October) for enteroviruses and most arboviruses, reflecting seasonal variations in pathogen and/or vector activity. Certain arboviruses show marked geographic variation. In Europe, tick-borne encephalitis (TBE) is increasing due to broadening of endemic areas and prolongation of the tick activity season.[12] TBE virus is endemic in rural and forested areas of central, eastern, and northern Europe.[13] In 2019, there were 3246 cases of TBE across twenty-five EU/EEA countries. The highest number of confirmed cases were seen in Czechia, Lithuania, and Germany.[14]
Incidence of encephalitis associated with HIV infections has decreased and stabilized since the late 1990s with the advent of antiretroviral therapies.[5] In contrast, encephalitis associated with immunocompromised states induced in the setting of transplant or immune-mediated diseases has steadily increased.

Etiology

An etiologic agent is only identified in around 50% of cases.[5] [6] [15] [16] [17] [18] [19]
Viruses are the main cause of encephalitis, with herpes virus being the most common group of viruses identified. In the US, West Nile virus emerged as a significant cause of encephalitis in the late 2000s; the incidence has decreased, but this may be cyclical.[5] Other arboviruses (ARthropod-BOrne viruses) with ticks and mosquitoes as vectors are a main contributor to encephalitic etiologies worldwide.CDC: Division of vector-borne diseases (DVBD)
The incidence of encephalitis in patients with HIV has improved since the advent of highly active antiretroviral therapy, mainly manifested by a decrease in incidence of toxoplasma encephalitis. Neisseria meningitides is the main bacterial cause of meningoencephalitis and disproportionately affects the young (<1 year old) and old (>65 years old).[6]
Immune-mediated or autoimmune encephalitis remains rare and accounts for approximately one third of cases with identified etiology. Incidence is increasing likely due to the increased availability of diagnostic testing and increased awareness among clinical practitioners.[5] [20] Acute disseminated encephalomyelitis (ADEM) is a common cause of autoimmune encephalitis in children.
The following is a list of the main etiologic agents in encephalitis.
Viral infections:

  • Herpes viruses: herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, herpes B virus

  • Picornaviridae/enteroviruses: enterovirus-71, coxsackievirus, poliovirus

  • Parechovirus

  • Flaviviruses: West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, Powassan virus, dengue virus

  • Bunyavirus: La Crosse virus, Jamestown Canyon virus, Toscana virus

  • Togavirus: chikungunya virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, Eastern equine encephalitis virus

  • Paramyxovirus: Nipah virus, Hendra virus

  • Others: coronaviruses, snowshoe hare virus, lymphocytic choriomeningitis virus, mumps virus, HIV, rabies virus, measles virus, adenovirus, influenza virus, parainfluenza virus, hepatitis C virus, rotavirus, parvovirus B19, BK virus, JC virus, cycloviruses, and Zika.

Bacterial infections:

  • Neisseria meningitidis

  • Tuberculosis

  • Syphilis

  • Listeria

  • Bartonella (cat-scratch disease)

  • Borrelia burgdorferi (Lyme disease)

  • Rickettsia and ehrlichiosis (Rocky Mountain spotted fever, Ehrlichia, Coxiella burnetii)

  • Mycoplasma

  • Typhoid fever

  • Brucellosis

  • Leptospirosis

  • Tropheryma whipplei (Whipple disease)

  • Actinomyces

  • Streptococcus agalactiae

  • Klebsiella

  • Streptococcus pneumoniae

  • Staphylococcus aureus

  • Streptococcus viridans

  • Group C beta-hemolytic streptococci

  • Treponema pallidum

  • Nocardia.

Fungal infections:

  • Cryptococcus

  • Coccidioides

  • Histoplasma

  • Blastomycosis

  • Candida.

Parasitic infections:

  • Toxoplasma gondii

  • Cysticercosis

  • Amoebic

  • Naegleria

  • Entamoeba histolytica

  • Plasmodium falciparum

  • Balamuthia mandrillaris

  • Baylisascaris procyonis

  • Echinococcus granulosis

  • Human African trypanosomiasis

  • Schistosomiasis.

Parainfectious:

  • ADEM

  • Acute hemorrhagic leukoencephalitis

  • Bickerstaff encephalitis

  • Rasmussen encephalitis.

Prion diseases:

  • Creutzfeldt-Jakob disease.

Paraneoplastic syndromes:

  • "Classical" antibodies against intracellular onconeuronal antigens (e.g., anti-Hu)

  • Surface antibodies targeting neuronal surface or synaptic antigens (e.g., N-methyl-D-aspartate receptor-antibody and leucine-rich glioma inactivated-antibody).

Pathophysiology

Encephalitis is an inflammatory process in the brain parenchyma. It is associated with clinical evidence of brain dysfunction due to infectious (usually viral) or noninfectious (usually autoimmune) processes. The pattern of brain involvement depends on the specific pathogen, the immunologic state of the host, and a range of environmental factors. In viral encephalitis the virus initially gains entry and replicates in local or regional tissue, such as the gastrointestinal tract, skin, urogenital system, or respiratory system. Subsequent dissemination to the central nervous system occurs by hematogenous routes (enterovirus, arboviruses, herpes simplex virus, HIV, mumps) or via retrograde axonal transport as with the herpes virus, the rabies virus, or variant scrapie-isoform prion proteins.
Depending on the interactions between the neurotropic properties of the virus and the host immune response (mediated by humoral antibodies, cytotoxic T cells, cytokines, innate immunity of each neuronal subtype), infection and inflammation of brain parenchyma occur.[21] In these cases, neuronal involvement occurs along with evidence of a productive viral infection. In contrast, autoimmune etiologies are thought to result from antibodies directed against normal brain components (e.g., myelin), which play a role in anti-N-methyl-D-aspartate receptor encephalitis and other paraneoplastic syndromes. Given the immune-mediated pathophysiology of autoimmune encephalitis, these conditions are amenable to immunosuppressive therapy.
Authors
  • Payal B. Patel, MD
  • Acknowledgements
Peer Reviewers
  • Russel Dale, MBChB, MRCPCH, MSc, PhD
  • Arun Venkatesan, MD, PhD
content by BMJ Group
Last updated Fri Nov 18 2022

Images

  • Noncontrast head CT of a patient with HSV encephalitis: shows subtle hypodensities involving the lef

    Noncontrast head CT of a patient with HSV encephalitis: shows subtle hypodensities involving the left insular region. Some blurring of gray-white margins and sulcal effacement over the left temporal region is discernible

  • The first 5 images are FLAIR images of patient with varicella zoster virus meningoencephalitis showi

    The first 5 images are FLAIR images of patient with varicella zoster virus meningoencephalitis showing white and gray matter hyperintensities. The last image is T1 image with contrast showing parenchymal and diffuse leptomeningeal enhancement

  • Series of MRI images of brain of patient with acute disseminated encephalomyelitis: hyperintense les

    Series of MRI images of brain of patient with acute disseminated encephalomyelitis: hyperintense lesions of fluid attenuated inversion recovery (FLAIR) involving the left cerebellar peduncle

  • Series of MRI images of brain of patient with acute disseminated encephalomyelitis: asymmetric "fluf

    Series of MRI images of brain of patient with acute disseminated encephalomyelitis: asymmetric "fluffy" lesions over the bilateral ventricular horns and thalami

  • Series of MRI images of brain of patient with acute disseminated encephalomyelitis: periventricular

    Series of MRI images of brain of patient with acute disseminated encephalomyelitis: periventricular regions

  • Series of MRI images of brain of patient with acute disseminated encephalomyelitis: centrum semioval

    Series of MRI images of brain of patient with acute disseminated encephalomyelitis: centrum semiovale

  • Series of MRI images of brain of patient with acute disseminated encephalomyelitis: T1 post-gadolini

    Series of MRI images of brain of patient with acute disseminated encephalomyelitis: T1 post-gadolinium enhanced image shows ring enhancement around a lesion in the right centrum semiovale region and faint diffuse enhancement just above this area

  • Series of MRI images of brain of patient with acute disseminated encephalomyelitis: diffusion-weight

    Series of MRI images of brain of patient with acute disseminated encephalomyelitis: diffusion-weighted image from the same patient shows high signal intensity in the same area, and this correlates with increased (bright on ADC maps) diffusion

  • MRI brain: the pulvinar sign (a term referencing bilateral pulvinar hyperintensity) in a patient wit

    MRI brain: the pulvinar sign (a term referencing bilateral pulvinar hyperintensity) in a patient with Creutzfeldt-Jakob disease on diffusion-weighted images

  • MRI brain: cortical ribboning in a patient with Creutzfeldt-Jakob disease on diffusion-weighted imag

    MRI brain: cortical ribboning in a patient with Creutzfeldt-Jakob disease on diffusion-weighted images

  • Biopsy of brain from right temporal lobe: the classic H&E stain shows evidence of patchy but extensi

    Biopsy of brain from right temporal lobe: the classic H&E stain shows evidence of patchy but extensive inflammatory infiltrate of small mononuclear cells (lymphocytes) in the brain parenchyma, predominantly around the blood vessel walls. PCR studies of the biopsy sample were positive for EBV infection

  • Biopsy of brain from right temporal lobe: a close-up view of a blood vessel with its surrounding mar

    Biopsy of brain from right temporal lobe: a close-up view of a blood vessel with its surrounding marked inflammatory infiltrate is also seen. PCR studies of the biopsy sample were positive for EBV infection.

  • Biopsy from hippocampus of patient with rabies showing 2 neurons with eosinophilic Negri bodies (red

    Biopsy from hippocampus of patient with rabies showing 2 neurons with eosinophilic Negri bodies (red arrows). These are found in areas, often with little inflammatory reaction. The blue arrows highlight microglial cells

  • Biopsy from hippocampus of patient with rabies showing neurons with eosinophilic Negri bodies (red a

    Biopsy from hippocampus of patient with rabies showing neurons with eosinophilic Negri bodies (red arrow). The blue arrow highlights a collection of satelliting oligodendrocytes

  • Biopsy from hippocampus of patient with rabies showing a neuron with an eosinophilic cytoplasmic Neg

    Biopsy from hippocampus of patient with rabies showing a neuron with an eosinophilic cytoplasmic Negri body (red arrow). The blue arrow highlights a collection of microglial cells next to a blood vessel

  • Biopsy from the brainstem of HIV patient with CMV encephalitis. The ependymal lining shows enlarged

    Biopsy from the brainstem of HIV patient with CMV encephalitis. The ependymal lining shows enlarged cells (arrows) with intranuclear inclusions

  • Biopsy from cortex of neonate with CMV encephalitis showing enlarged cells (arrows) with intranuclea

    Biopsy from cortex of neonate with CMV encephalitis showing enlarged cells (arrows) with intranuclear inclusions. The top arrow points to a neuron with two nuclei each with a nuclear inclusion

  • Biopsy from brain of immunocompromised patient with cryptococcal meningitis at low magnification. Th

    Biopsy from brain of immunocompromised patient with cryptococcal meningitis at low magnification. The meninges are expanded (arrow), but the cortex is histologically relatively uninvolved

  • Biopsy from brain of immunocompromised patient with cryptococcal meningitis showing the meninges wit

    Biopsy from brain of immunocompromised patient with cryptococcal meningitis showing the meninges with round translucent cryptococcal organism (red arrow) as well as a budding yeast (blue arrow)

  • Biopsy from brain of an immunocompetent patient with cryptococcal meningitis at low magnification sh

    Biopsy from brain of an immunocompetent patient with cryptococcal meningitis at low magnification showing the meninges with inflammation (red arrow)

  • Biopsy from brain of immunocompetent patient with cryptococcal meningitis showing the meninges with

    Biopsy from brain of immunocompetent patient with cryptococcal meningitis showing the meninges with inflammatory cells and Cryptococcus

  • Biopsy from meninges of patient with cryptococcal meningitis stained with mucicarmine, demonstrating

    Biopsy from meninges of patient with cryptococcal meningitis stained with mucicarmine, demonstrating fungal organisms, particularly in giant cells

  • Coronal slice of the brain of patient with cryptococcal meningoencephalitis showing classical appear

    Coronal slice of the brain of patient with cryptococcal meningoencephalitis showing classical appearance of "soap bubble" structures in the basal ganglia (arrows) resulting from the cryptococcal expansion of Virchow-Robbin spaces around the lenticulostriate vessels

  • Biopsy from basal ganglia of patient with cryptococcal meningoencephalitis showing cryptococcal (blu

    Biopsy from basal ganglia of patient with cryptococcal meningoencephalitis showing cryptococcal (blue arrow) expansion of Virchow-Robbin spaces around a lenticulostriate vessel (red arrow)

  • Gross autopsy of brain of patient with cryptococcal meningitis showing the surface with a "glazed" l

    Gross autopsy of brain of patient with cryptococcal meningitis showing the surface with a "glazed" look. There is also a shunt present

  • Biopsy from brain of patient with subacute HIV leukoencephalitis showing the distinctive multinuclea

    Biopsy from brain of patient with subacute HIV leukoencephalitis showing the distinctive multinucleated cell (red arrow) in the white matter next to inflammatory cells in the Virchow-Robin space

  • Biopsy from brain of patient with subacute HIV leukoencephalitis showing the distinctive multinuclea

    Biopsy from brain of patient with subacute HIV leukoencephalitis showing the distinctive multinucleated cell (red arrow) in the white matter

  • Biopsy from brain of patient with subacute HIV encephalitis showing the distinctive multinucleated g

    Biopsy from brain of patient with subacute HIV encephalitis showing the distinctive multinucleated giant cell (red arrow), which contains the HIV virus. The multinucleated giant cells are from histiocyte/macrophage lineage. There is also associated astrocytosis

  • Coronal slice of the brain of HIV patient in his 30s. He had subacute HIV encephalitis involving bot

    Coronal slice of the brain of HIV patient in his 30s. He had subacute HIV encephalitis involving both the white matter and gray matter diffusely. The ventricles were enlarged reflecting white matter and cortical loss

  • Coronal slice of the brain of HIV patient with toxoplasmosis, showing infection of the periventricul

    Coronal slice of the brain of HIV patient with toxoplasmosis, showing infection of the periventricular superior part of the left thalamus

  • Biopsy of the brain of an HIV patient with toxoplasmosis, showing encysted bradyzoites (red arrow) a

    Biopsy of the brain of an HIV patient with toxoplasmosis, showing encysted bradyzoites (red arrow) and tachyzoites (blue arrow)

  • Biopsy of HIV patient with toxoplasmosis, showing both pieces of cellular debris and tachyzoites. Th

    Biopsy of HIV patient with toxoplasmosis, showing both pieces of cellular debris and tachyzoites. The tachyzoites are round, smooth, and hard to identify without antibody staining (see next image)

  • Biopsy of HIV patient with toxoplasmosis, with the tachyzoites identified using immunohistochemistry

    Biopsy of HIV patient with toxoplasmosis, with the tachyzoites identified using immunohistochemistry

  • Biopsy of the posterior thalamus of patient with Creutzfeldt-Jakob disease showing the spongiform ch

    Biopsy of the posterior thalamus of patient with Creutzfeldt-Jakob disease showing the spongiform changes

Diagnostic Approach

Encephalitis is a medical emergency.[24] An acute or subacute onset of a febrile illness, altered mental status, focal neurologic abnormalities, and seizures raises suspicion for this condition. The main differential to distinguish is encephalopathy secondary to metabolic or toxic disturbances. Once a primary central nervous system disease is diagnosed, the diagnostic approach is geared toward determining the etiology and appropriate therapy (i.e., finding the appropriate antiviral or antibacterial agents versus immunotherapy).

Clinical evaluation

History may provide differentiation factors. Age (extremes of age), chronicity of disease, and immune status (HIV, organ transplantation, immunosuppressive medication) are important aspects to review. The time of year (summer), geographic location, travel history, and unusual exposures (including occupational, vector, animal, ill contacts) are additional considerations. Other factors to consider are a recent viral illness or vaccination, or a history of autoimmune disorders or malignancies.
General examination features such as skin rashes, parotitis, or upper respiratory tract involvement may suggest a specific etiologic agent. Altered mental state, ranging from subtle alterations in level of arousal and behavioral abnormalities to coma, is typical. Focal neurologic findings are common and include hemiparesis, ataxia, pyramidal signs (brisk tendon reflexes, extensor plantar responses), cranial nerve deficits, involuntary movements (myoclonus and tremors), and seizures.
Encephalitis is caused by a heterogeneous group of pathogens, but presents with a near-uniform neurologic dysfunction. Altered mental status ranging from mild lethargy to profound coma can be seen. Cognitive behavioral issues frequently occur, and these include: altered personality, withdrawal, inability to make decisions, akinetic mutism, bizarre behavior, memory problems, and an amnestic state. Seizures of all varieties occur; complex partial seizures are most commonly seen. Focal neurologic signs (e.g., aphasia, visual disturbances, cranial nerve deficits, lateralized motor weakness, ataxia, tremors, myoclonus, paraplegia, and generalized weakness) are also presenting features. Signs of meningoencephalitis (e.g., headache, photophobia, neck stiffness) are present in patients with meningeal inflammation. Symptoms and signs of a systemic illness, such as fever or upper respiratory or gastrointestinal symptoms, may precede or occur concurrently with the other presenting features. Other less common signs and symptoms include autonomic and hypothalamic disturbances, pericarditis/myocarditis, arthritis, retinitis, and acute flaccid paralysis, depending on the causative pathogen.
Autoimmune encephalitis associated with surface antibodies targeting neuronal surface or synaptic antigens presents with a broad range of features, but well-recognized clinical syndromes do occur. Limbic encephalitis associated with leucine-rich glioma-inactivated 1 (LGI1) antibodies usually affects older patients, and is associated with faciobrachial dystonic seizures (e.g., rapid jerks of the face and/or ipsilateral arm and shoulder) before the development of frank seizures, behavioral changes, and cognitive impairment.[34] [35] Limbic encephalitis associated with contactin-associated protein-like 2 (CASPR2) antibodies is associated with peripheral nervous system involvement, including neuromyotonia and neuropathic pain syndromes. Anti-N-methyl-D-aspartate receptor (Anti-NMDA-R) encephalitis is marked by rapid onset (less than three months) and primarily affects young patients, with a female predominance.[36] Its features include early abnormal behavior and cognition, memory deficit, speech disorder, seizures, abnormal movements (e.g., orofacial, limb, or trunk dyskinesias), reduced consciousness level, and autonomic dysfunction or central hypoventilation.[37] Psychiatric symptoms including agitation, hallucinations, delusions, and catatonia may lead to hospital admission for psychosis are common presenting symptoms.[38]

Investigations required for all patients

A lumbar puncture is always recommended as long as there is no contraindication, and 2 out of the following 4 symptoms are present: fever, headaches, altered mental status of unknown etiology, meningismus. Contraindications to lumbar puncture include mass effect causing potential herniation, coagulopathy, or open skin lesion at the site of entry.
Routine investigations in all patients should include:[24] [39]

  • Cerebrospinal fluid (CSF):

    • Opening pressure

    • Cell count

    • Protein

    • Glucose

    • Gram stain

    • Bacterial culture

    • Herpes simplex virus-1/2 polymerase chain reaction (PCR)

    • Enterovirus PCR

    • Measles, mumps (if unvaccinated)

    • Erythrovirus B19

    • Influenza (depending on the season)

    • Hold residual sample for further testing.

  • Serum:

    • CBC

    • Serum electrolytes/liver function test

    • Blood cultures

    • Hold for further testing.

  • Imaging:

    • Chest x-ray

    • Neuroimaging (MRI is the study of choice).

  • Electroencephalogram (all patients with a persistent altered mental status or seizures).

Further investigations required for specific groups

Adults

  • CSF

    • Varicella zoster virus (VZV) PCR, VZV IgG/IgM

    • Cryptococcal antigen and/or India ink staining

    • Oligoclonal bands and IgG Index

    • Venereal Disease Research Laboratory (VDRL), fluorescent treponemal antibody absorption (FTA-ABS) test.

  • Serum

    • HIV serology (consider RNA)

    • Nontreponemal testing (VDRL, rapid plasma reagin, ICE Syphilis recombinant antigen test), with treponemal testing for positive/equivocal results (FTA-ABS, enzyme immunoassay, or microhemagglutination assay).

Children

  • CSF

    • Rotavirus (if unvaccinated)

    Serum

    • Epstein-Barr virus (EBV) serology (viral-capsid antigen IgG and IgM and EBV nuclear antigen IgG)

    • Mycoplasma pneumoniae IgM and IgG

  • Nasopharyngeal/respiratory tract aspirate

    • Influenza/adenovirus PCR.

Immunosuppressed patients

  • CSF

    • Cytomegalovirus PCR

    • Epstein-Barr virus PCR

    • Human herpesvirus-6/7 PCR

    • HIV PCR

    • JC virus PCR

  • Toxoplasma gondii serology and/or PCR

  • Mycobacterium tuberculosis testing

  • Fungal testing

  • West Nile virus testing.

Other tests to consider

  • CSF viral-specific IgG/IgM antibodies and serum PCR (if a viral etiology is suspected).[39]

  • Serum 16S ribosomal RNA gene (rRNA) sequencing for bacteria, acid-fast bacilli, fungus.

  • Serum for LGI1 or CASPR2 antibodies and NMDA receptor antibodies. Voltage-gated potassium channel positivity, in the absence of LGI1 or CASPR2 antibodies, may not be a true marker of disease.[1] [40]

  • CSF paraneoplastic antibody testing if there is a high clinical suspicion with a negative serum test. Up to 14% of patients with anti-NMDA-R encephalitis have antibodies in the CSF, but not serum. The clinical course seems to correlate better with CSF antibodies than serum antibodies.[41]

  • CSF analysis for NMDA receptor antibodies may be useful in patients with relapsing symptoms after herpes simplex encephalitis (HSE), if clinical suspicion for autoimmune encephalitis supports this. In 20% of patients with HSE, antibodies may be triggered against the NMDA receptor.[42] [43] [44] These patients may respond to immunotherapy.[45]

  • Stool culture (obtained more frequently in children when gastrointestinal symptoms precede encephalitis, or when enterovirus is suspected).

  • Sputum PCR (in children, for Mycoplasma pneumoniae and enterovirus).

  • Arbovirus testing: if an arbovirus infection is suspected, specific guidance on testing, such as from the Centers for Disease Control and Prevention, should be sought.CDC: Division of vector-borne diseases (DVBD)

  • Brain biopsy: although it is the most specific diagnostic test, brain biopsy is not performed routinely due to its invasive nature, lack of widespread availability, and because DNA amplification techniques are now widely available to identify virologic causes. Where diagnosis is uncertain and prognosis remains poor, brain biopsy may be essential. Important for diagnosis and treatment, the brain biopsy may also provide an etiologic clue.[46]

  • Whole-body CT and whole-body PET scans (performed if an underlying cancer is suspected).

  • Abdominal/pelvic ultrasound may be useful if anti-NMDA-R encephalitis is suspected; up to 58% of affected young female patients have an ovarian teratoma.[38]

  • If malignancy screening is negative, repeating the assessment 3 to 6 months later should be considered in cases where the autoantibody found is strongly associated with malignancy.[1] [38]

Additional tests (typically restricted to academic centers)

Magnetic resonance spectroscopy

  • Advanced imaging techniques provide metabolic data that can be used to clarify abnormal brain areas and identify the etiology. They are obtained in patients with a clinical diagnosis of encephalitis but in whom etiology is unknown, or if diagnosis of encephalitis is suspected but cannot be differentiated from brain tumors (e.g., by first-line tests).

Next-generation sequencing of CSF

  • As opposed to directed PCR amplification of a selected number of targets, technology is now available to detect organisms in an unbiased manner. Genetic material is isolated from organisms, and select DNA and RNA sequences can be amplified with universal primers. The sequence is then compared with publicly available sequences to identify the organism. Furthermore, unbiased next-generation sequencing will provide a powerful tool to potentially identify new and/or potentially treatable infectious agents.

View diagnostic guideline references

Risk Factors

strong Factors
Expand All

age <1 or >65 years

    • Increased risk of developing more extensive and prominent symptoms and signs of infective (viral) encephalitis.

    • Neonates are especially susceptible to infectious encephalitis.

immunodeficiency

    • Etiologic agent and clinical severity varies with host immune status.

    • Immunocompromised patients (e.g., patients with HIV infection and those receiving chemotherapy or immunosuppressive medications) tend to have more extensive and florid manifestations. They are susceptible to pathogens that usually do not cause encephalitis in immunocompetent hosts (e.g., cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, toxoplasmosis, JC virus, Candida, and Nocardia). Agammaglobulinemic patients are particularly susceptible to enteroviral meningoencephalitis.[5]

postinfection

    • Bickerstaff encephalitis, Rasmussen encephalitis, anti-N-methyl-D-aspartate receptor encephalitis, and acute disseminated encephalomyelitis can be seen after the resolution of a viral illness (e.g., varicella, herpes virus, nonspecific upper respiratory viral infections, mumps, rubella, enterovirus, Epstein-Barr virus, influenza viruses, adenovirus) and may be due to an autoimmune process.

blood/body fluid exposure

    • HIV and West Nile virus can be transmitted by contaminated blood products, needle sticks, and body fluid exposure.

organ transplantation

    • Rabies, West Nile virus, and cytomegalovirus infections have occurred in transplant patients who received organs from infected donors.[23]

animal or insect bites

    • Mosquitoes can transmit West Nile virus, St. Louis encephalitis virus, Eastern equine, Western equine, Venezuelan equine, Japanese B, Murray Valley, Ilheus, and Rocio viruses.

    • Tick bites are associated with tick-borne encephalitis, Colorado tick fever, Powassan virus, Far Eastern, Central European, Kyasanur Forest disease virus, Louping Ill, Negishi, Russian spring-summer, Lyme disease, Rocky Mountain spotted fever, and Ehrlichia.

    • Animal bite/exposure is associated with rabies, brucellosis, Bartonella (cats), Toxoplasma, Q fever, and herpes B (primates). It is important to note that lack of a known bite or other exposure history does not exclude the diagnosis of rabies.

location

    • Etiologic agents are endemic to certain locales.[24] Consider recent travel history.

    • Africa: malaria, trypanosomiasis, dengue, Ebola virus.

    • Asia: Japanese encephalitis virus, dengue, malaria, Nipah virus.

    • Australia: Murray Valley encephalitis, Kunjin virus, Australian bat lyssavirus.[25]

    • Europe: tick-borne encephalitis virus, West Nile virus, Toscana virus.

    • Central and South America: dengue, malaria, West Nile virus, Venezuelan equine encephalitis.

    • North America: West Nile virus and St. Louis encephalitis virus are common throughout the US. Coccidioides and blastomycosis are common in the southwestern and midwestern US, respectively. Lyme disease in northcentral and northeastern US.

season

    • Spring: Powassan virus, Colorado tick fever.

    • Summer: enterovirus, arboviruses, Colorado tick fever, Lyme disease (but may occur year-round).

    • Fall: enterovirus, arboviruses, lymphocytic choriomeningitis virus (LCMV).

    • Winter: LCMV, influenza.

    • July-November: West Nile virus.

    • Rainy season: Venezuelan equine (May through December).

swimming or diving in warm freshwater or nasal/sinus irrigation

    • Associated with Naegleria.

weak Factors
Expand All

vaccination

    • Vaccination may be associated with a minimal increased risk of developing acute disseminated encephalomyelitis.

    • Children not vaccinated against mumps and measles are at risk of developing measles or mumps encephalitis.

    • Rarely, unvaccinated children suffering with measles infection can develop subacute sclerosing panencephalitis, a progressive neurologic deterioration typically leading to death within 4 years.[22]

occupation

    • Forestry worker: Lyme disease, Kyasanur Forest disease virus, rabies.

    • Farm workers: Nipah, avian influenza, brucellosis.

    • Abattoir workers: Q fever.

    • Laboratory workers: Ebola, Marburg, herpes B.

hunting/trekking in woods

    • Associated with Lyme disease and rabies (through exposure to a rabid animal).

spelunking (cave-exploring)

    • Associated with rabies.

death in animals

    • Epidemic outbreaks of certain viral encephalitides in humans are frequently preceded by large-scale illnesses and death in animals (horses for equine encephalitides) and birds (West Nile virus).

cancer

    • Paraneoplastic encephalitis may be related to classical antibodies against intracellular onconeuronal antigens (e.g., anti-Hu), or antibodies targeting neuronal surface or synaptic antigens (e.g., N-methyl-D-aspartate receptor-antibody and leucine-rich glioma inactivated-antibody).[26]

History & Exam

Key Factors

Frequency

Expand All

fever

common

  • Frequently seen in infectious causes of encephalitis. Important exceptions are individuals with measles causing subacute sclerosing panencephalitis, varicella zoster virus infection, and hepatitis C.

common

rash

common

  • Vesicular eruption - enterovirus, herpes simplex virus (HSV), varicella zoster virus.

  • Maculopapular eruption - Epstein-Barr virus (after treatment with ampicillin), measles, human herpesvirus-6, Colorado tick fever, West Nile virus.

  • Malar rash - systemic lupus erythematosus.

  • Petechial rash - rickettsial fever.

  • Erythema migrans - Lyme disease.

  • Erythema nodosum - tuberculosis and histoplasmosis, sarcoidosis.

  • Erythema multiforme - HSV, Mycoplasma.

  • Mucous membrane lesions - herpes virus, Behcet.

  • Pharyngitis - enterovirus, adenovirus.

  • Conjunctivitis - St. Louis encephalitis virus, adenovirus, leptospirosis (conjunctival suffusion).

  • Gumma - syphilis.

  • Kaposi sarcoma - HIV/AIDS.

  • Nonhealing skin lesions - Balamuthia mandrillaris, Acanthamoeba.

  • Genital lesions - HSV-2, Behcet.

common

altered mental state

common

  • A frequent component. Ranges from mild somnolence to coma.

  • Cognitive dysfunction with acute memory disturbances and psychiatric and behavioral manifestations (e.g., withdrawal, apathy, abulia, akinetic mutism, personality changes, psychotic behavior, disorientation, and hallucinations) can be seen.

common

focal neurologic deficit

common

  • Include aphasia, hemianopia, hemiparesis, ataxia, brisk tendon reflexes, Babinski sign, cranial nerve deficits (seen in human herpesvirus-6, tuberculosis, syphilis, brucellosis, acute disseminated encephalomyelitis, West Nile virus, St. Louis encephalitis virus, varicella zoster virus, herpes B virus, rabies); tremors (arboviruses); myoclonus (subacute sclerosing panencephalitis); paresthesias (Colorado tick fever, rabies); generalized weakness (West Nile virus, rabies).

common

meningismus

common

  • Some patients have evidence of meningeal inflammation with headache, photophobia, and neck stiffness.

common

parotitis

uncommon

  • Seen in mumps.

uncommon

lymphadenopathy

uncommon

  • Seen in Bartonella.

uncommon

optic neuritis

uncommon

  • Seen in acute disseminated encephalomyelitis.

uncommon

acute flaccid paralysis

uncommon

  • West Nile virus and other arboviruses, rabies.

uncommon

movement disorder

uncommon

  • Creutzfeldt-Jakob disease (myoclonus), anti-N-methyl-D-aspartate receptor encephalitis (orofacial dyskinesias/myorhythmia), rabies, Whipple disease (oculomasticatory myorhythmia).

uncommon

Other Factors

Frequency

Expand All

cough

common

  • Upper and lower respiratory tract symptoms and signs (e.g., cough) can occur in herpes simplex virus-1, influenza, parainfluenza, Mycoplasma pneumoniae, Q fever, Coccidioides, Histoplasma, blastomycosis, or rabies.

common

gastrointestinal infection

common

  • Enteroviruses, rotavirus, Whipple disease.

common

seizures

common

  • Generalized tonic-clonic seizures and focal seizures (with or without secondary generalization) are very frequently seen at some point in the clinical course. Most frequently seen in patients with measles causing subacute sclerosing panencephalitis, human herpesvirus-6 infection, and herpes simplex virus-1 infection. Status epilepticus that is particularly resistant to treatment is sometimes seen. Faciobrachial dystonic seizures (e.g., rapid jerks of the face and/or ipsilateral arm and shoulder) are seen in limbic encephalitis associated with leucine-rich glioma-inactivated 1 antibodies.[34]

common

biphasic illness

uncommon

  • Enterovirus, Colorado tick fever.

uncommon

autonomic and hypothalamic disturbances

uncommon

  • Loss of temperature and vasomotor control (dysautonomia), diabetes insipidus, and syndrome of inappropriate secretion of antidiuretic hormone are sometimes part of the clinical picture in encephalitis and can contribute to morbidity and mortality.

  • Seen in anti-N-methyl-D-aspartate receptor encephalitis and anti-voltage gated potassium channel encephalitis.

uncommon

myocarditis/pericarditis

uncommon

  • Enterovirus, mumps.

uncommon

jaundice

uncommon

  • May be seen in leptospirosis.

uncommon

arthritis

uncommon

  • Seen in Lyme disease, systemic lupus erythematosus.

uncommon

retinitis

uncommon

  • Cytomegalovirus, toxoplasmosis, West Nile virus, paraneoplastic syndrome.

uncommon

parkinsonism

uncommon

  • Arbovirus, toxoplasmosis.

uncommon

Tests

1st Tests to Order

Result

Expand All

CBC

often elevated WBC

  • A routine test. An elevated WBC count occurs in most infectious causes of encephalitis. Depressed WBC counts and pancytopenia can be seen in HIV and immunomodulating/immunosuppressive drug use.

  • A relative lymphocytosis may occur in viral encephalitis. Rickettsial and viral fevers are associated with leukopenia and thrombocytopenia.

  • Eosinophilia is seen in certain parasitic infections (Baylisascaris procyonis).

often elevated WBC

peripheral blood smear

detection of Plasmodium falciparum and Ehrlichia

  • It is preferable to collect blood for the smear at the time of a fever spike in cases of suspected malarial illness, to increase the likelihood of finding the trophozoites. This is essential in malarial-endemic areas. Cytoplasmic inclusions in monocytes are seen in ehrlichiosis.

detection of Plasmodium falciparum and Ehrlichia

serum electrolytes

hyponatremia

  • A routine test. Hyponatremia is seen in rickettsial infections and syndrome of inappropriate secretion of antidiuretic hormone, and anti-voltage-gated potassium channel-associated encephalitis (anti-leucine-rich glioma-inactivated 1/contactin-associated protein-like 2 encephalitis).

hyponatremia

liver function tests

elevated

  • Coxiella burnetii, Rickettsia, tick-borne disease, cytomegalovirus, Epstein-Barr virus.

elevated

blood cultures

detection and confirmation of systemic bacterial infections and most arboviral infections

  • Should be obtained as part of the routine workup of a febrile illness. Arboviral cultures are rarely performed and are available only through specialized reference laboratories.

detection and confirmation of systemic bacterial infections and most arboviral infections

throat swab

detection of viruses

  • Cultures (and some antigen detection tests) are performed on throat swabs to detect enterovirus, poliovirus, cytomegalovirus, adenovirus, mumps, measles, influenza, and parainfluenza.

detection of viruses

nasopharyngeal aspirate

detection of respiratory viruses; polymerase chain reaction confirmation for adenovirus or influenza virus

  • Obtained in children (less commonly used in adults) with respiratory symptoms.

detection of respiratory viruses; polymerase chain reaction confirmation for adenovirus or influenza virus

sputum culture

detection of Mycoplasma, tuberculosis (acid-fast stain), and fungal infections

  • Obtained in patients with a febrile illness and pulmonary symptoms or signs.

detection of Mycoplasma, tuberculosis (acid-fast stain), and fungal infections

chest radiography

may detect a noninfectious or infectious cause (e.g., tuberculosis, sarcoidosis)

  • Routinely performed as part of a febrile workup. May detect Mycoplasma, Legionella, influenza, parainfluenza, tuberculosis, Coccidioides, Histoplasma, blastomycosis, Coxiella burnetii, or sarcoidosis.

may detect a noninfectious or infectious cause (e.g., tuberculosis, sarcoidosis)

CT brain

frequently normal early in the clinical course of encephalitis, but may see more prominent changes

  • Used more as a screening tool due to its widespread availability and ease of acquisition in an uncooperative patient. It should be ordered in all patients with altered mental state. Post-contrast CT scans (if obtained) can demonstrate diffuse meningeal enhancement, which is a frequent co-occurrence in encephalitis.

  • Herpes simplex virus encephalitis: often normal or subtly abnormal. Later, hypodense lesions and mild mass effect in temporal lobes, insula, hemorrhage, and enhancement can be seen.

  • HIV-1: normal/mild atrophy with hypodense white matter lesions. Opportunistic infections and complications of HIV infection have their own characteristic findings.

  • Acute disseminated encephalomyelitis (ADEM): normal in 40%; low-density, flocculent, asymmetric multifocal punctuate or ring-enhancing lesions can be seen.

  • Amoebae: diffuse edema.Image

frequently normal early in the clinical course of encephalitis, but may see more prominent changes

MRI brain

depends on etiology; often hyperintense lesions (T2 and fluid-attenuated inversion recovery [FLAIR] sequences), increased diffusion on diffusion-weighted imaging (DWI) indicating edema, contrast enhancement on T1 post-contrast sequences indicating blood-brain barrier breakdown; MRI is normal in up to a third of patients with autoimmune encephalitis

  • Highly recommended (preferably initially) in suspected encephalitis and is invaluable in diagnosis.[49] [50] However, MRI is less widely available compared with CT, and may require sedation for optimal image quality.

  • Early lesions in the form of signal abnormalities are seen in most cases.

  • Herpes simplex virus encephalitis: gyral edema on T1, high signal on T2, FLAIR, and DWI (with increased diffusion on Apparent Diffusion Coefficient [ADC] maps) in temporal lobe and cingulate gyrus.

  • HIV: atrophy and nonspecific white matter high signal on T2 and FLAIR. Opportunistic infections and complications of HIV infection have their own characteristic findings.

  • Polio and Coxsackie: T2 hyperintensities in the midbrain and anterior horn of the spinal cord.

  • Epstein-Barr virus: T2 hyperintensities in the basal ganglia, thalami, and cerebellum.

  • Varicella zoster virus: white and gray matter hyperintensities.

  • West Nile virus: Leptomeningeal periventricular enhancement.

  • Japanese encephalitis: T2 hyperintensities in bilateral thalami, brainstem, and cerebellum.

  • Acute disseminated encephalomyelitis (ADEM): multifocal, bilateral, asymmetric, large hyperintense lesions of the white and gray matter on T2 and FLAIR. Ring-enhancing lesions may be seen on post-contrast T1 images.

  • Rasmussen encephalitis: T2 hyperintensities in cortex and white matter, cortical atrophy of the fronto-insular region, enlargement of lateral ventricle, and moderate atrophy of the caudate nucleus, all limited to one cerebral hemisphere.

  • Creutzfeldt-Jakob disease: T2/FLAIR hyperintensities and/or DWI changes in the globus pallidus, thalamus, and cortex (cortical ribboning).

  • Paraneoplastic limbic encephalitis: bilateral involvement of the medial temporal lobes and multifocal lesions on FLAIR and DWI.Images

depends on etiology; often hyperintense lesions (T2 and fluid-attenuated inversion recovery [FLAIR] sequences), increased diffusion on diffusion-weighted imaging (DWI) indicating edema, contrast enhancement on T1 post-contrast sequences indicating blood-brain barrier breakdown; MRI is normal in up to a third of patients with autoimmune encephalitis

electroencephalogram (EEG)

often shows background slowing

  • Background slowing is an early and sensitive indicator of cerebral involvement but very nonspecific, especially if the patient has required sedation.

  • Temporal lobe abnormalities are frequently seen in viral encephalitides.

  • Repetitive sharp wave complexes over the temporal lobes or periodic lateralizing epileptiform discharges can be seen in herpes simplex virus encephalitis.[51] [52]

  • In subacute sclerosing panencephalitis, a typical generalized periodic EEG pattern repeating with intervals between 4 and 15 seconds, synchronous with the myoclonus of the patient, may be seen.[52] [53]

  • Creutzfeldt-Jakob disease findings: high-amplitude periodic (1 Hz) complexes. Extreme delta brush may be seen in anti-N-methyl-D-aspartate receptor encephalitis. This is characterized by rhythmic delta activity at 1 Hz to 3 Hz, with superimposed bursts of rhythmic 20 Hz to 30 Hz beta frequency activity "riding" on each delta wave.[54]

often shows background slowing

cerebrospinal fluid (CSF) analysis

findings depend on etiology; may have elevated WBC, normal/elevated protein, normal/low glucose, normal/elevated red blood cell (RBC); up to a third of patients with autoimmune encephalitis have normal CSF

  • A lumbar puncture (LP) is always recommended as long as there is no contraindication, and 2 out of the following 4 symptoms are present: fever, headaches, altered mental status of unknown etiology, meningismus. Contraindications to LP include mass effect causing potential herniation, coagulopathy, or open skin lesion at the site of entry.

  • LP should be delayed only under abnormal circumstances.

  • Opening pressure: usually normal in viral encephalitis but can be increased especially when meningoencephalitis is present.

  • Color and clarity: variable, usually clear, can be mildly xanthochromic or blood-tinged in certain necrotizing and hemorrhagic encephalitides (herpes simplex virus [HSV], acute hemorrhagic leukoencephalitis, listerial and primary amebic meningoencephalitis).

  • Protein: normal or mildly elevated in most cases of viral encephalitis. Moderately elevated in bacterial infections, autoimmune diseases, limbic encephalitis, and acute disseminated encephalomyelitis. Markedly elevated in tuberculosis (TB) and sarcoidosis.

  • Glucose: normal to low normal in viral encephalitis except mumps, lymphocytic choriomeningitis virus, late stages of HSV-1. Low glucose levels are also seen in bacterial, fungal, parasitic, and neoplastic etiologies.

  • Cell counts: in the absence of a traumatic tap, RBC count is usually normal. In cases of HSV (40%), acute hemorrhagic leukoencephalitis, listerial and primary amebic meningoencephalitis, RBC >500/mm^3 can be seen. WBC usually elevated in most cases and suggestive of an inflammatory process of the brain parenchyma, meninges, or both (meningoencephalitis). May be normal early in disease course and in immunocompromised patients who cannot mount an inflammatory response.[55] [56] [57] [58] [59] In viral encephalitis an initial polymorphonuclear (PMN) predominance followed by a mononuclear shift in 24 to 48 hours (except in West Nile virus) is seen. Lymphocytosis (viruses, TB); atypical lymphocytes (Epstein-Barr virus, cytomegalovirus, rarely in HSV); PMN leukocytosis (bacterial infections, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, amebic infections, occasionally in some viruses such as West Nile virus). Eosinophilia (TB, fungal infection, Baylisascaris procyonis, Angiostrongylus cantonensis, Gnathostoma species).

  • CSF protein >100 mg/dL, or CSF glucose <2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset suggests TB or fungal infection.

  • CSF protein >100 mg/dL or CSF glucose <2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and recent antibiotic use suggests Streptococcus pneumoniae or Neisseria meningitidis.

findings depend on etiology; may have elevated WBC, normal/elevated protein, normal/low glucose, normal/elevated red blood cell (RBC); up to a third of patients with autoimmune encephalitis have normal CSF

CSF culture

findings depend on etiology

  • Culture: very useful in identifying bacterial and fungal etiologies. Only useful for a few viruses (mumps, enterovirus, lymphocytic choriomeningitis virus). Viral cultures are rarely positive, and if negative do not exclude infection.

  • Antigen testing: useful in rapidly identifying bacterial and fungal etiologies of encephalitis.

  • Gram stain: detection of organisms in bacterial causes.

  • Acid-fast stain: tuberculosis.

  • India ink: Cryptococcus.

findings depend on etiology

CSF serology

findings depend on etiology; detection of arboviruses, herpes simplex virus (HSV)-1 and HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus, rabies, West Nile virus, mumps, and measles

  • Serologic indexing is required for definitive diagnosis and compares CSF to serum-specific antibody levels in reference to total CSF, serum albumin, or total immunoglobulin. For viruses, a 4-fold rise in IgG from acute to convalescent specimens, or a single positive IgM, is also considered diagnostic.[60] [61]

findings depend on etiology; detection of arboviruses, herpes simplex virus (HSV)-1 and HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus, rabies, West Nile virus, mumps, and measles

CSF polymerase chain reaction (PCR)

findings depend on etiology; viruses (enterovirus, poliovirus, arboviruses, herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus, adenovirus, measles, HIV, rabies); bacteria (Mycoplasma pneumoniae, tuberculosis); fungus (cryptococcus, aspergillosis)

  • CSF analysis should include PCR for common viral causes of encephalitis as a first-line screen and subsequent targeted PCRs for additional viruses based on the risk factors, exposure, and clinical picture.

findings depend on etiology; viruses (enterovirus, poliovirus, arboviruses, herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus, adenovirus, measles, HIV, rabies); bacteria (Mycoplasma pneumoniae, tuberculosis); fungus (cryptococcus, aspergillosis)

Other Tests to consider

Result

Expand All

stool enteroviral culture

detection of enterovirus

  • Obtained more frequently in children when gastrointestinal symptoms precede the development of encephalitis. Stool culture may also be used to detect poliovirus.

detection of enterovirus

IgG and IgM antibodies (blood)

detection of IgG/IgM antibodies to enterovirus, poliovirus, arboviruses, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus, mumps, measles, HIV, rabies, and West Nile virus

  • Obtained when a viral cause for encephalitis is suspected. IgG and IgM antibodies directed against specific viral pathogens may be detected by serum studies.

detection of IgG/IgM antibodies to enterovirus, poliovirus, arboviruses, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus, mumps, measles, HIV, rabies, and West Nile virus

PCR (blood)

detection of enterovirus, poliovirus, arboviruses, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and HIV

  • Obtained when a viral cause for encephalitis is suspected

detection of enterovirus, poliovirus, arboviruses, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and HIV

HIV serology/RNA test

positive in cases of HIV infection

  • Should be tested in people with risk factors for HIV infection. HIV may result in an acute encephalopathy with seroconversion. Quantitative viral RNA in plasma is used to confirm acute retroviral syndrome (i.e., symptomatic patients before the HIV antibody test is positive). HIV-associated encephalitis may also be due to an opportunistic infection.

positive in cases of HIV infection

CSF biomarkers/prion protein assay

elevated 14-3-3 protein, elevated tau protein; detection of prion protein

  • Patients with suspected prion disease should have CSF testing. Biomarkers include brain-derived proteins (14-3-3, tau); however, these tests should be interpreted with caution as their sensitivity and specificity varies in the literature.[47] [48] Real-time quaking-induced conversion assay (RT-QuIC) uses amplification technology to detect prion protein (PrPSc) and has higher detection sensitivity than biomarkers.[48]

elevated 14-3-3 protein, elevated tau protein; detection of prion protein

paraneoplastic antibodies (blood and CSF)

paraneoplastic antibodies such as anti-N-methyl-D-aspartate receptor, anti-LGI1, anti-CASPR2, anti-Hu, anti-Yo, anti-Ri, anti-Tr, anti-CV2, anti-Ma, anti-amphiphysin may be found

  • Obtained when an underlying cancer is suspected.

paraneoplastic antibodies such as anti-N-methyl-D-aspartate receptor, anti-LGI1, anti-CASPR2, anti-Hu, anti-Yo, anti-Ri, anti-Tr, anti-CV2, anti-Ma, anti-amphiphysin may be found

abdominal/pelvic ultrasound

detection of underlying ovarian teratoma

  • Obtained when anti-N-methyl-D-aspartate receptor encephalitis is suspected. If malignancy screening is negative, repeating the assessment 3 to 6 months later should be considered in cases where the autoantibody found is strongly associated with malignancy.[1] [38]

detection of underlying ovarian teratoma

whole-body CT

detection of underlying cancers

  • Performed later in the clinical course as part of the clinical workup for suspected underlying cancers (e.g., lung, breast, or ovarian) that are associated with limbic or brainstem encephalitis. If malignancy screening is negative, repeating the assessment 3 to 6 months later should be considered in cases where the autoantibody found is strongly associated with malignancy.[1] [38]

detection of underlying cancers

whole-body PET scans

detection of underlying cancers

  • Performed later in the clinical course as part of the clinical workup for suspected underlying cancers (e.g., lung, breast, or ovarian) that are associated with limbic or brainstem encephalitis. If malignancy screening is negative, repeating the assessment 3 to 6 months later should be considered in cases where the autoantibody found is strongly associated with malignancy.[1] [38]

detection of underlying cancers

magnetic resonance spectroscopy

metabolic data aiding identification of etiology

  • Specialist centers only. Obtained in patients with a clinical diagnosis of encephalitis but in whom the etiology is unknown, or if the diagnosis of encephalitis is suspected but cannot be differentiated from brain tumors.

metabolic data aiding identification of etiology

next-generation sequencing of CSF

detection and identification of organism

  • Specialist centers only. The use of personalized genomics to diagnose etiologic infectious agents.[62] As opposed to directed PCR amplification of a selected number of targets, technology is now available to detect organisms in an unbiased manner. Genetic material is isolated from organisms, and select DNA and RNA sequences can be amplified with universal primers. The sequence is then compared with publicly available sequences to identify the organism.

detection and identification of organism

brain biopsy

damage to the brain parenchyma (usually nerve cell damage or loss, eventually demyelination), reactive gliosis, and inflammatory cellular infiltration

  • Currently the criterion standard for diagnosis. Not routinely performed as it is invasive, requires general anesthesia, and is associated with some morbidity. With the increasing availability of MRI and PCR-based diagnostic methods, the need for brain biopsy is decreasing. It is still very useful in diagnostically challenging cases. Immunocytochemistry, in situ hybridization, and PCR can be performed on biopsy/autopsy specimens, and have had a profound impact on the ability to diagnose the various etiologies of encephalitis.

  • Classic encephalitic nodules are composed of a mixture of microglia, astrocytes, and lymphocytes around affected neurons, cytologic features such as inclusion bodies (intranuclear in herpes simplex virus, varicella zoster virus, subacute sclerosing panencephalitis, and cytoplasmic Negri bodies in rabies), and cytomegalic cell changes (cytomegalovirus). In acute disseminated encephalomyelitis, multiple small demyelinated foci are arranged around small veins of the white matter, with infiltration by lymphocytes, macrophages, and microglia. In cryptococcal meningoencephalitis, the Cryptococcus can be seen. In HIV encephalitis, distinctive multinucleated giant cell can be seen. In toxoplasmosis, the organism can be identified. Creutzfeldt-Jakob disease presents with spongiform changes.Images

damage to the brain parenchyma (usually nerve cell damage or loss, eventually demyelination), reactive gliosis, and inflammatory cellular infiltration

Differential Diagnosis

Disease/Condition

  • Viral meningitis

    Differentiating Signs/Symptoms

    • Headache, neck stiffness, and fever with no altered mental status (maybe mild somnolence) or focal neurologic signs.

    • Frequently meningitis and encephalitis coexist (meningoencephalitis).

    Differentiating Tests

    • MRI evidence of meningeal enhancement, with no evidence of brain parenchymal involvement.

  • Encephalopathy (toxic/metabolic)

    Differentiating Signs/Symptoms

    • A multitude of metabolic factors and remote infections can cause brain parenchymal dysfunction without structural damage to the brain.

    • Frequently encountered in hospital/nursing home settings.

    • Altered mental status and even focal neurologic signs (hypoglycemia) can be seen with both conditions, and there are no specific clinical differentiating features.

    Differentiating Tests

    • Normal cerebrospinal fluid analysis, normal MRI, electroencephalogram - diffuse slowing, triphasic waves.

  • Status epilepticus

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features, and status epilepticus is not uncommonly seen in patients with encephalitis so can be considered a clinical feature of this disease.

    • In cases that are clearly not due to encephalitis (MRI, cerebrospinal fluid negative), the patient frequently has a known seizure disorder with subtherapeutic levels of medications.

    Differentiating Tests

    • Electroencephalogram - evidence of ongoing seizure activity.

  • Central nervous system vasculitis

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features. Headaches and focal neurologic signs can be seen.

    Differentiating Tests

    • Differentiated by MRI, angiography, and biopsy.

    • MRI - evidence of multiple small strokes, usually cortical.

    • Angiography - can be normal but frequently a typical angiographic appearance of multisegment narrowing/beading of the vessels is noted.

    • Definitive diagnosis sometimes requires brain and meningeal biopsy, which will show evidence of inflammation (i.e., presence of inflammatory cells such as lymphocytes in the vessel wall and surrounding the blood vessel, along with structural alterations of the involved vessels).

  • Confusional migraine with pleocytosis

    Differentiating Signs/Symptoms

    • Acute confusion, psychosis, and focal neurologic deficits in association with migraine headache is seen in some migraine patients,[63] and in familial hemiplegic migraine.[64] These are suggestive of but not specific to migraine.

    • Another term for this syndrome is "transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL)".

    Differentiating Tests

    • Cerebrospinal fluid - elevated WBC count with no evidence of infection.

  • Malignant hypertension

    Differentiating Signs/Symptoms

    • High blood pressure, headaches, altered mental status, and visual symptoms can be seen.

    Differentiating Tests

    • Elevated BP (usually >220/110 mmHg). But may be sudden acute elevations even at lower blood pressure.

    • Differentiated by fundoscopy, CT, and MRI.

    • Fundus examination - papilledema and hemorrhage.

    • CT usually normal, but occasionally hypodense lesions seen over occipital lobes.

    • MRI: T2 and fluid attenuated inversion recovery (FLAIR) hyperintense lesions over the occipital lobes (usually asymmetric). Increased diffusion on diffusion-weighted imaging (with apparent diffusion coefficient maps showing increased diffusion) is also seen. The term "posterior reversible leukoencephalopathy syndrome (PRES)" is also used to describe the MRI changes.

  • Posterior reversible leukoencephalopathy syndrome (PRES)

    Differentiating Signs/Symptoms

    • Headache, confusion, seizures, visual loss, focal deficits; pathogenesis includes immunosuppressive therapy, renal failure, eclampsia, hypertension, lupus.

    Differentiating Tests

    • MRI: T2/fluid attenuated inversion recovery (FLAIR) lesions throughout the brain.

  • Intracranial tumors and cysts

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features.

    • A variety of clinical presentations, such as headache worse on awakening, altered mental status, seizures, and focal neurologic deficits are seen with intracranial neoplasms.

    Differentiating Tests

    • CT and MRI imaging of the brain (preferably MRI) can help diagnose these conditions. Biopsy - required in some cases to make a definitive diagnosis.

  • Neurosarcoidosis

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features. Cranial neuropathies (especially CN II and VII), spinal cord involvement, disruption of the hypothalamic/pituitary axis, and peripheral neuropathy may be accompanying features. Additional systemic features include lung disease, erythema nodosum, lymphadenopathy, arthralgias, and uveitis.

    Differentiating Tests

    • Brain MRI with contrast may demonstrate meningeal enhancement. LP may show pleocytosis (lymphocytic predominant) and elevated total protein; glucose levels are sometimes low. Serum and cerebrospinal fluid ACE levels can be assessed, but may yield both false negative and false positive results. Chest radiography, whole-body (18F)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and gallium scanning can be considered in individuals without a known diagnosis of sarcoidosis. Biopsy should be considered for pathologic diagnosis of noncaseating granulomas, especially if a non-CNS lesion is identified.

  • Systemic lupus erythematosus (SLE)

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features. Headache, neuropsychiatric issues, and seizures can be seen.

    • Systemic features include skin changes (e.g., butterfly rash, discoid rash), arthritis, serositis, hematologic abnormalities, renal disorder, and immunologic abnormalities.

    Differentiating Tests

    • Serum immunology tests for antinuclear antibody, anti-double stranded DNA antibody, anti-Smith antibody, and antiphospholipid antibody are positive in most patients with SLE.

  • Intracranial bleed

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features. Headache, altered mental status, seizures, and focal neurologic deficits can be seen.

    Differentiating Tests

    • CT and MRI can clearly demonstrate acute intracranial bleeds. In subarachnoid hemorrhage, a lumbar puncture may show xanthochromia and no change in the number of red blood cells from tube 1 to tube 4.

  • Traumatic brain injury

    Differentiating Signs/Symptoms

    • A history of head injury is frequently obtained, but can be unavailable in someone who is found unresponsive.

    • Headache, varying degrees of altered mental status, and focal neurologic findings can be seen.

    • There are no specific clinical differentiating features.

    Differentiating Tests

    • CT and MRI will reveal various intracranial bleeds that are associated with head injury; concussions have normal imaging findings; diffuse axonal damage can be seen as signal abnormality in MRI images.

  • Ischemic stroke

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features.

    • Sudden onset of focal neurologic deficits, altered mental status, seizures, and headaches.

    • Certain strokes, such as those involving the posterior cerebral artery, basilar artery, and anterior cerebral artery, can present with an encephalopathic clinical picture.

    • It is important to note that ischemic stroke can also occur as a complication of some cases of encephalitis.

    Differentiating Tests

    • CT scan - low attenuation in the involved areas.

    • MRI - diffusion-weighted imaging evidence of decreased diffusion is characteristic of acute ischemic stroke. Fluid attenuated inversion recovery (FLAIR) and T2 hyperintense lesions are seen in subacute cases.

  • Mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS)

    Differentiating Signs/Symptoms

    • There are no specific clinical differentiating features. Hearing loss, encephalopathy, seizures, stroke-like episodes, and presence of lactic acidosis are characteristic clinical features.

    Differentiating Tests

    • Cerebrospinal fluid lactate - elevated

    • MRI - T2 hyperintense signal in territory not conforming to major vascular regions. Diffusion-weighted imaging evidence of increased diffusion.

    • Genetic test - mitochondrial DNA point mutations (A3243G mutation in 80% of cases).

    • Muscle biopsy - ragged red fibers on modified Gomori trichrome stain.

  • Inborn errors of metabolism

    Differentiating Signs/Symptoms

    • History of parental consanguinity, early neonatal death, maternal acute fatty liver of pregnancy and HELLP syndrome (elevated liver enzymes and low platelets) in pregnancy. May be lethargic and irritable with poor feeding. Physical exam may reveal jaundice, cataracts, hepatosplenomegaly, abnormal muscle tone, dysmorphism (e.g., coarse facial features), and abnormal body odor. May present with life-threatening encephalopathy.[65] [66]

    Differentiating Tests

    • Serum ammonia may be elevated (urea cycle defect, organic acidemias). Arterial blood gas can show a metabolic acidosis with elevated anion gap. Urine orotic acid is low in carbamyl phosphate synthetase deficiency and elevated in ornithine transcarbamylase deficiency.[66]

  • Bacterial meningitis

    Differentiating Signs/Symptoms

    • History of headache, neck stiffness, photophobia, and fever.

    • Physical exam may reveal fever, neck stiffness, and focal neurologic abnormalities.

    Differentiating Tests

    • Cerebrospinal fluid shows elevated WBC often with neutrophil predominance, elevated protein, and low glucose. Gram stain and polymerase chain reaction may reveal the causative organism.[67]

  • Fungal meningitis

    Differentiating Signs/Symptoms

    • History of headache, neck stiffness, photophobia, and fever.

    • History of immunosuppression may be present.

    • Physical exam may reveal fever, neck stiffness, and focal neurologic abnormalities.

    Differentiating Tests

    • Cerebrospinal fluid culture may demonstrate fungal growth.

Treatment Approach

This is a medical emergency; hence, management consists of basic resuscitation measures ensuring adequacy of the airway, breathing, and circulation, and empiric antiviral therapy in cases of suspected viral encephalitis concurrently with diagnostic steps.
All suspected cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]
Prompt isolation is required for all forms of encephalitis until the etiology is determined; encephalitides with airborne or contact transmission to immunocompetent hosts (herpes simplex virus [HSV], varicella, mumps, rubella, enteroviruses, upper respiratory viral infections) require isolation according to local regulations. Most cases of infectious encephalitis involve close collaboration between the treating clinicians and infectious disease team.
Etiology is often unknown, and therefore no specific treatment options exist for the majority of cases. However, for cases where a diagnosis is reasonably certain, treatment is directed toward the underlying offending agent if available (e.g., antivirals for viral encephalitis; appropriate anti-infective measures in bacterial, fungal, or parasitic infections).

Supportive measures

Supportive care is the cornerstone of treatment in most cases. This may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70] For certain opportunistic infections, such as cryptococcus, antiretroviral therapy should be delayed based on World Health Organization guidelines.[71] [72]
In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO₂ of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP. In children with elevated ICP, maintaining cerebral perfusion pressure ≥60 mm Hg, using normal saline bolus and vasoactive therapy-dopamine, may be superior to maintaining intracranial pressure <20 mm Hg, using osmotherapy while ensuring normal blood pressure, in reducing mortality and morbidity.[73]

Antiviral therapies

All cases of suspected community-acquired viral encephalitis are started empirically on acyclovir until the cause is determined.[74] As most cases of sporadic viral encephalitis are secondary to HSV, this is good clinical practice supported by biopsy-proven randomized controlled trials, and it reduces mortality.[75] Delays in treatment initiation beyond 48 hours after hospital admission are associated with a worse outcome in both children and adults.[76] [74] In an immunocompromised patient, cytomegalovirus (CMV) encephalitis is a consideration. If suspected, ganciclovir and foscarnet are given with acyclovir until HSV polymerase chain reaction is available. If HSV encephalitis is excluded, then acyclovir can be discontinued. In some cases, magnetic resonance imaging findings and clinical features strongly suggest a diagnosis of CMV encephalitis, so acyclovir may not be necessary.
Specific viruses and the drugs used against them are:[77]

  • HSV-1 and HSV-2: acyclovir.

  • Varicella-zoster virus (VZV): acyclovir or ganciclovir.

  • CMV: ganciclovir plus foscarnet.

  • Epstein-Barr virus (EBV): acyclovir is first line in suspected viral encephalitis, but once the diagnosis of EBV is confirmed, ganciclovir or cidofovir is a possible alternative.

  • Herpes B virus: ganciclovir or acyclovir (intravenous therapy may be preferable over oral therapy). For post-exposure prophylaxis, valacyclovir is the preferred agent.

  • Human herpes 6: ganciclovir or foscarnet should be used in immunocompromised patients. However, use of these agents in immunocompetent patients can also be considered, but there are no good data on their effectiveness.

Corticosteroids

The use of large doses of corticosteroids is controversial.[68] Expert opinion is that they seem to have a significant therapeutic role in certain cases and in the treatment of some of the complications of encephalitis.[74] The duration of corticosteroid therapy should be short (3 to 5 days) to minimize adverse effects (e.g., gastrointestinal bleeds, predisposition to secondary bacterial infections, neuropsychiatric disturbance). Corticosteroids should not be prescribed before consultation with specialists.

  • VZV encephalitis: cerebral vasculitis can occasionally complicate primary or reactivation VZV infection. Some experts recommend high-dose short-duration corticosteroid therapy with methylprednisolone.[74]

  • EBV encephalitis: combined treatment with corticosteroids and antivirals is recommended by some experts. Overall risk-benefit assessments should be determined on an individual basis. Some uncontrolled trials and anecdotal reports have shown benefits, but there is risk of worsening viral infection. Recommend conferring with specialists before initiation.[77]

Surgical intervention

Monitoring devices such as catheters or bolts may be placed to measure ICP. Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68] This can be considered no matter the etiology of encephalitis; however, most outcome data have been published for viral encephalitis. In some cases of HSV encephalitis, surgical decompression has been shown to improve outcome.[78]

Therapy for nonviral etiologies

If the clinical picture and initial tests suggest a nonviral infective encephalitis (bacterial, fungal, parasitic) appropriate antimicrobial therapy is started.
If cerebrospinal fluid studies do not show a clear infectious etiology, or the disease manifestation is classic for an autoimmune encephalitis, aggressive immunotherapy with intravenous corticosteroids, immune globulin, or plasma exchange should be considered. The decision to fight infection or suppress the immune system needs to be balanced in each case.
Blood-borne infections can rarely be transmitted by immune globulin. Immunoglobulin (Ig)A-deficient patients are at risk of allergic reactions (this is less of a problem, as technology used to prepare immune globulin ensures removal of most IgA). Plasma exchange is performed by placing a double-lumen catheter in a central vein, and mechanically filtering and replacing the patient's plasma with pooled donor plasma. This is done in consultation with a hematologist. As many as 4 to 5 exchanges are typically performed, on alternate days.
Cases with persistent altered mental status not responsive to first-line therapy should be treated with rituximab and/or cyclophosphamide.[79] [80] [36] [38] [37] In most newly diagnosed cases, it is difficult to determine clinically whether autoimmune encephalitis is antibody or cell-mediated before the antibody results are available.[81] Some clinical clues may help the clinician come to a preliminary hypothesis regarding etiology (e.g., leucine-rich glioma-inactivated 1 antibodies are associated with faciobrachial dystonic seizures, such as rapid jerks of the face and/or ipsilateral arm and shoulder, while patients with known or increased cancer risk are more likely to have cell-mediated autoimmune encephalitis).[26] Based on these clues, clinicians may decide to use rituximab or cyclophosphamide as a second-line agent if antibody results are delayed, or if there is no access to antibody testing.[26] Rituximab is now generally preferred over cyclophosphamide if monotherapy is used in highly suspected antibody-mediated autoimmunity (e.g., N-methyl-D-aspartate receptor-antibody encephalitis).[82] Rituximab is less toxic than cyclophosphamide.[26] [83] Cyclophosphamide may be considered if rituximab is contraindicated or not available in these cases.[82] Some patients may be treated with a combination of rituximab and cyclophosphamide.[81] Cyclophosphamide can be considered in known or highly suspected cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome) since rituximab may not be as effective for cell-mediated inflammation.[26] Some patients may be treated with a combination of cyclophosphamide and rituximab.[81]
Management of autoimmune encephalitis associated with malignancy (i.e., paraneoplastic encephalitis) involves diagnostic testing and treatment of the underlying tumor. However, in order to avoid the risk of permanent sequelae, treatment directed toward the paraneoplastic syndrome should not be delayed by a failure to identify the underlying tumor. Oophorectomy is indicated as an acute treatment if ovarian teratomas are present. Tumor resection is associated with faster rate of recovery and reduced relapse rate.[36] [84]
High-dose corticosteroids are advocated by experts for patients with acute disseminated encephalomyelitis.[85] [86] In cases where corticosteroids fail to show benefit, plasma exchange or immune globulin can be considered.[85] [86]

Rehabilitation

The results of one systematic review suggested that rehabilitative interventions, including cognitive therapy, behavioral therapy, and physical therapy, may help to improve functionality in children and adults after infectious encephalitis. However, most of the included studies were observational in nature.[87]
One retrospective study based on 8 patients noted that, although patients with encephalitis can make some functional gains with acute rehabilitation therapy, the rate of recovery varies and is generally less than that of stroke and traumatic brain injury.[88] The most frequently used nonpharmacological treatments to treat dementia and apathy following encephalitis are music therapy and cognitive rehabilitation.[89]
View treatment guideline references

Treatment Options

  • presumptive
    Expand All

    • immunocompetent host: suspected viral etiology

        • 1st

          acyclovir

          Primary Options

            • acyclovir

              10 mg/kg intravenously every 8 hours for 10-21 days

          Comments

          • All cases of suspected community-acquired viral encephalitis are started empirically on acyclovir until the cause is determined.[74] As most cases of sporadic viral encephalitis are secondary to herpes simplex virus, this is good clinical practice supported by biopsy-proven randomized controlled trials, and it reduces mortality.[75]

        • plus

          supportive care

          Comments

          • All suspected cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management has failed to control elevated ICP, and for impending uncal herniation.[68] This can be considered no matter the etiology of encephalitis; however, most outcome data have been published for viral encephalitis.

    • immunocompromised host: suspected viral etiology

        • 1st

          combination antiviral therapy

          Primary Options

            • ganciclovir

              5 mg/kg intravenously every 12 hours for 14-21 days

              and

            • foscarnet

              60 mg/kg intravenously every 8 hours; or 90 mg/kg intravenously every 12 hours for 14-21 days

              and

            • acyclovir

              10 mg/kg intravenously every 8 hours for 21 days

          Comments

          • If cytomegalovirus (CMV) encephalitis is suspected in an immunocompromised patient, ganciclovir and foscarnet are given with acyclovir until herpes simplex virus (HSV) polymerase chain reaction (PCR) is available.

          • Ganciclovir and foscarnet are given for 14 to 21 days unless nephrotoxicity or myelotoxicity occurs in which case one of the agents should be stopped.[90]

          • Acyclovir is given until HSV infection can be excluded (HSV PCR). In some cases, magnetic resonance imaging findings and clinical features strongly suggest a diagnosis of CMV encephalitis, so acyclovir may not be necessary. If a diagnosis of CMV infection is established, then acyclovir should be discontinued as it is not effective against this virus.

        • plus

          supportive care

          Comments

          • All suspected cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management has failed to control elevated ICP, and for impending uncal herniation.[68] This can be considered no matter the etiology of encephalitis; however, most outcome data have been published for viral encephalitis.

  • acute
    Expand All

    • confirmed herpes simplex virus (HSV) encephalitis

        • 1st

          acyclovir

          Primary Options

            • acyclovir

              10 mg/kg intravenously every 8 hours for 14-21 days

          Comments

          • Confirmed HSV encephalitis should be treated with acyclovir.[74] This is supported by biopsy-proven randomized controlled trials, showing reduced mortality.[75]

          • Immunosuppressed patients should receive a full 21 days of treatment.

          • The clinician should consider repeating the lumbar puncture at day 12 to 13 with repeat polymerase chain reaction to guide the decision of whether to stop the treatment or to continue up to 21 days.

        • plus

          supportive care

          Comments

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68] In some cases of HSV encephalitis, surgical decompression has been shown to improve outcome.[78]

    • confirmed varicella zoster virus (VZV) encephalitis

        • 1st

          acyclovir or ganciclovir

          Primary Options

            • acyclovir

              10 mg/kg intravenously every 8 hours for 14 days

            • ganciclovir

              5 mg/kg intravenously every 12 hours for 14-21 days

          Comments

          • Confirmed VZV encephalitis should be treated with acyclovir or ganciclovir.[91]

        • plus

          supportive care

          Comments

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68]

        • adjunct

          corticosteroid

          Primary Options

            • methylprednisolone sodium succinate

              1000 mg intravenously once daily for 3-5 days

          Comments

          • Cerebral vasculitis can occasionally complicate primary or reactivation VZV infection. Adjunctive short-duration corticosteroid therapy with methylprednisolone can be considered.[74]

    • confirmed cytomegalovirus (CMV) encephalitis

        • 1st

          ganciclovir plus foscarnet

          Primary Options

            • ganciclovir

              5 mg/kg intravenously every 12 hours for 14-21 days initially, followed by a maintenance dose of 5 mg/kg/day given once daily for 7 days/week or 6 mg/kg/day given once daily for 5 days/week

              and

            • foscarnet

              60 mg/kg intravenously every 8 hours; or 90 mg/kg intravenously every 12 hours for 14-21 days

          Comments

          • Confirmed CMV encephalitis should be treated with ganciclovir plus foscarnet.[91]

        • plus

          supportive care

          Comments

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68]

    • confirmed Epstein-Barr virus (EBV) encephalitis

        • 1st

          acyclovir, ganciclovir, or cidofovir

          Primary Options

            • acyclovir

              10 mg/kg intravenously every 8 hours for 14 days

            • ganciclovir

              consult specialist for guidance on dose

          Secondary Options

            • cidofovir

              consult specialist for guidance on dose

          Comments

          • Acyclovir is first line in suspected viral encephalitis, but once the diagnosis of EBV is confirmed, ganciclovir or cidofovir are possible alternatives.[77] There are limited data to guide therapy of EBV central nervous system infections. No controlled studies have been conducted. There are case reports that suggest ganciclovir improves outcomes.

        • plus

          corticosteroid

          Primary Options

            • methylprednisolone sodium succinate

              1000 mg intravenously once daily for 3-5 days

          Comments

          • Combined treatment with corticosteroids and antivirals is recommended by some experts. Overall risk-benefit assessments should be determined on an individual basis. Some uncontrolled trials and anecdotal reports have shown benefits, but there is risk of worsening viral infection. Recommend conferring with specialists before initiation.[74] [77]

        • plus

          supportive care

          Comments

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Immune globulin can be used for agammaglobulinemic patients and neonates with sepsis syndrome.[60] Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68] In some cases of herpes simplex virus encephalitis, surgical decompression has been shown to improve outcome.

    • confirmed herpes B encephalitis

        • 1st

          ganciclovir, acyclovir, or valacyclovir

          Primary Options

            • ganciclovir

              5 mg/kg intravenously every 12 hours for 14-21 days

          Secondary Options

            • acyclovir

              10 mg/kg intravenously every 8 hours for 14-21 days

            • valacyclovir

              1 g orally every 8 hours for 14 days

          Comments

          • Intravenous therapy may be preferable in acute central nervous system (CNS) disease. However, the efficacy of the intravenous approach has not been studied. Ganciclovir may be preferable as a first option in CNS disease.[77] Duration of treatment should be decided in conjunction with an infectious disease specialist.

          • There is also expert opinion that life-long suppression of latent infection with valacyclovir may be considered.[77]

        • plus

          supportive care

          Comments

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68]

    • confirmed human herpes 6 encephalitis

        • 1st

          ganciclovir or foscarnet

          Primary Options

            • ganciclovir

              5 mg/kg intravenously every 12 hours for 14-21 days

            • foscarnet

              60 mg/kg intravenously every 8 hours; or 90 mg/kg intravenously every 12 hours for 14-21 days

          Comments

          • Ganciclovir or foscarnet should be used in immunocompromised patients.[91]

          • Use of these agents in immunocompetent patients can also be considered, but there are no good data on their effectiveness.[91]

        • plus

          supportive care

          Comments

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68]

    • confirmed nonherpes virus etiology

        • 1st

          supportive care ± antiviral therapy

          Comments

          • For cases where a specific virus has been isolated and specific antiviral treatment is available, treatment is directed toward the underlying isolated virus.

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection).[70]

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[68]

    • nonviral etiology

        • 1st

          supportive care + treatment of underlying etiology

          Comments

          • Etiology is often unknown, and therefore no specific treatment options exist for the majority of cases. However, for cases where a diagnosis is reasonably certain, treatment is directed toward the underlying offending agent, with appropriate anti-infective measures in bacterial, fungal, or parasitic infections. If cerebrospinal fluid studies do not show a clear infectious etiology, immunotherapy should be considered.[79] [80] The decision to fight infection or suppress the immune system needs to be balanced in each case.

          • All cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[24] [69]

          • Supportive care is the cornerstone of treatment in most cases. This may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis.

          • In patients with elevated ICP, management with corticosteroids and mannitol should be considered. Initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and hyperventilation to a PaCO2 of around 30. Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.

          • Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management has failed to control elevated ICP, and for impending uncal herniation.[68] This can be considered no matter the etiology of encephalitis; however, most outcome data have been published for viral encephalitis.

      • autoimmune/paraneoplastic encephalitis

        • plus

          immune-modulating therapy

          Primary Options

            • methylprednisolone sodium succinate

              1000 mg intravenously once daily for 3-5 days

            • immune globulin (human)

              2 g/kg intravenously given in divided doses over 4-5 days

          Secondary Options

            • rituximab

              consult specialist for guidance on dose

              and/or

            • cyclophosphamide

              consult specialist for guidance on dose

          Comments

          • If cerebrospinal fluid studies do not show a clear infectious etiology, or the disease manifestation is classic for an autoimmune encephalitis, aggressive immunotherapy with intravenous corticosteroids, immune globulin, or plasma exchange should be considered. Cases with persistent altered mental status not responsive to first-line therapy should be treated with rituximab and/or cyclophosphamide.[79] [80] [36] [38] [37]

          • In most newly diagnosed cases, it is difficult to determine clinically whether autoimmune encephalitis is antibody or cell-mediated before the antibody results are available.[81] Some clinical clues may help the clinician come to a preliminary hypothesis regarding etiology (e.g., leucine-rich glioma-inactivated 1 antibodies are associated with faciobrachial dystonic seizures, such as rapid jerks of the face and/or ipsilateral arm and shoulder, while patients with known or increased cancer risk are more likely to have cell-mediated autoimmune encephalitis).[26] Based on these clues, clinicians may decide to use rituximab or cyclophosphamide as a second-line agent if antibody results are delayed, or if there is no access to antibody testing.[26]

          • Rituximab is now generally preferred over cyclophosphamide if monotherapy is used in highly suspected antibody-mediated autoimmunity (e.g., N-methyl-D-aspartate receptor-antibody encephalitis).[82] Rituximab is less toxic than cyclophosphamide.[26] [83] Cyclophosphamide may be considered if rituximab is contraindicated or not available in these cases.[82] Some patients may be treated with a combination of rituximab and cyclophosphamide.[81]

          • Cyclophosphamide can be considered in known, or highly suspected, cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome), since rituximab may not be as effective for cell-mediated inflammation.[26] Some patients may be treated with a combination of cyclophosphamide and rituximab.[81]

        • adjunct

          treatment of underlying malignancy

          Comments

          • Management of autoimmune encephalitis associated with malignancy (paraneoplastic encephalitis) involves diagnostic testing and treatment of the underlying tumor. However, treatment directed toward the paraneoplastic syndrome should not be delayed by failure to identify the underlying tumor, as there is a risk for development of permanent sequelae.

          • Oophorectomy is indicated as an acute treatment if ovarian teratomas are present.[7] Tumor resection is associated with a faster rate of recovery and reduced relapse rate.[36] [84]

      • acute disseminated encephalomyelitis

        • plus

          immune-modulating therapy

          Primary Options

            • methylprednisolone sodium succinate

              1000 mg intravenously once daily for 3-5 days

          Secondary Options

            • immune globulin (human)

              2 g/kg intravenously given in divided doses over 4-5 days

          Comments

          • High-dose corticosteroids are advocated by experts.

          • In cases where corticosteroids fail to show benefit, plasma exchange or immune globulin can be considered.[92] [85] Plasma exchange is performed in consultation with a hematologist. As many as 4 to 5 exchanges are typically performed, on alternate days. Immune globulin has been shown to reduce duration of the illness.

      • confirmed syphilis encephalitis

        • plus

          penicillin G

          Primary Options

            • penicillin G sodium

              18-24 million units/day intravenously given in divided doses every 4 hours for 10 days

          Comments

          • Treatment for this organism is specifically noted in this topic, as targeted therapy is available if isolated.

      • confirmed listeria encephalitis

        • plus

          ampicillin plus gentamicin

          Primary Options

            • ampicillin

              1-2 g intravenously every 4 hours for 21 days

              and

            • gentamicin

              2 mg/kg intravenously as a loading dose, followed by 1.7 mg/kg every 8 hours

          Comments

          • Treatment for this organism is specifically noted in this topic, as targeted therapy is available if isolated.

          • Listeria encephalitis is rare but carries a high mortality rate. While listeria meningitis is more common, patients with high risk factors may also end up developing meningoencephalitis.

          • In vitro studies of gentamicin show it has a synergistic and bactericidal effect when given with ampicillin.

          • Total duration of gentamicin should be determined based on clinical picture and risk and benefits of extended aminoglycoside therapy.

      • confirmed Mycoplasma pneumoniae encephalitis

        • plus

          doxycycline or erythromycin

          Primary Options

            • doxycycline

              100 mg intravenously/orally every 12 hours for 5-10 days

            • erythromycin base

              500-1000 mg intravenously/orally every 6 hours for 5-10 days

          Comments

          • Treatment for this organism is specifically noted in this topic, as targeted therapy is available if isolated.

          • Mycoplasma pneumoniae is rarely detected from cerebrospinal fluid. However, M pneumoniae is commonly attributed to upper and lower respiratory tract infections in pediatric patients and central nervous system symptoms may reflect extrapulmonary infections or postinfectious encephalitis.[93]

        • adjunct

          immune-modulating therapy

          Primary Options

            • methylprednisolone sodium succinate

              1000 mg intravenously once daily for 3-5 days

            • immune globulin (human)

              2 g/kg intravenously given in divided doses over 4-5 days

          Comments

          • Immunomodulatory treatments have been hypothesized to benefit these patients based on the proposed antibody response to the pathogen. Immunotherapy with intravenous corticosteroids, immune globulin, or plasma exchange is typically considered as a first-line option.

          • Case reports suggest possible benefit.

          • Plasma exchange is performed in consultation with a hematologist. As many as 4 to 5 exchanges are typically performed, on alternate days.

      • confirmed Rocky Mountain spotted fever encephalitis

        • plus

          doxycycline

          Primary Options

            • doxycycline

              100 mg intravenously/orally every 12 hours for 5-10 days

          Comments

          • Treatment for this organism is specifically noted in this topic, as targeted therapy is available if isolated.

  • ongoing
    Expand All

    • convalescent phase: all etiologies

        • 1st

          rehabilitation

          Comments

          • Starts once the acute, life-threatening phase has passed. It can begin with the initial evaluation during acute hospitalization by the rehabilitation medicine personnel and be continued in various in- or outpatient settings.

          • The need for rehabilitation is varied and depends on the functional deficits present in the individual patient. It can include cognitive/behavioral rehabilitation and motor/ambulatory rehabilitation.[87]

          • The most frequently used nonpharmacological treatments to treat dementia and apathy following encephalitis are music therapy and cognitive rehabilitation.[89]

Emerging Tx

Intravenous immune globulin for viral encephalitis

One Cochrane review suggested a clinical benefit of adjunctive intravenous immune globulin treatment for children with viral encephalitis for some measures (i.e., mean length of hospital stay, time to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever). However, the quality of evidence in the included studies was very low.[94] Immune globulin with high titer to West Nile virus has been proposed as a potential treatment for severe West Nile virus infections but data have so far been inconclusive.[95] [96]

Neuraminidase inhibitors

Neuraminidase inhibitors may be considered if the influenza virus is the suspected etiologic agent. According to the Centers for Disease Control and Prevention and the American Academy of Pediatrics recommendations, oral oseltamivir, inhaled zanamivir, and intravenous peramivir should be used for the treatment of acute uncomplicated influenza within 2 days of illness onset; oral oseltamivir and inhaled zanamivir can also be used for chemoprophylaxis.[97] CDC: Influenza (Flu)

Prevention

Primary Prevention

Vaccines are available for mumps, measles, rubella, and poliovirus (universal immunization); rabies; Japanese encephalitis (in the appropriate geographic and clinical setting); tuberculosis (Bacille Calmette-Guerin); and various bacteria (Pneumococcus and Meningococcus).
Tick-borne encephalitis
Four inactivated vaccines for tick-borne encephalitis (TBE) have been tested in clinical trials and shown to be safe and effective: FSME-Immun® (TicoVac®) and Encepur® are licensed in many European countries, and TBE-Moscow® and EnceVir® are licensed in Russia and some neighboring countries.[27] Where the disease is highly endemic, the World Health Organization recommends that vaccination be offered to all age groups, including children.[28]
The Food and Drug Administration approved TicoVac® in August 2021 to prevent TBE in people ages 1 year and older. The Advisory Committee on Immunization Practices (ACIP) is due to publish guidance on the use of TicoVac®.[29] Travelers anticipating high-risk activities may consider being vaccinated in Europe. However, because the vaccination series requires more than 6 months for completion, most travelers will find avoiding tick bites and unpasteurized dairy products to be more practical than vaccination.[30]
Japanese encephalitis
Four types of vaccines for Japanese encephalitis exist. Most vaccines are cell-culture based. In the US only one vaccine is available, the Vero cell-derived, inactivated, and alum-adjuvanted Japanese encephalitis vaccine based on SA-14-14-2 strain (JE-VC). This is also available in Australia and various European countries. Two different Vero cell-derived inactivated vaccines are available in Japan. Both of these are based on the Beijing-1 strain. A live attenuated vaccine also based on the SA 14-14-2 strain is commonly used in China and other East Asian and Southeast Asian countries. Lastly, a new live, attenuated, Japanese encephalitis-yellow fever chimeric vaccine is now available in Australia and Thailand. Different vaccines have different recommended schedules based on seroconversion rates and individual studies for specific vaccines. For some of the newer vaccines, booster schedules may not have been determined yet.
Vaccination is recommended for travelers to Asia or the western Pacific who plan to spend one month or longer in an endemic area during the transmission season. Vaccination should also be considered for travelers to an endemic area during the transmission season with a shorter than one-month stay if they plan to visit nonurban areas and their activities may increase the risk of disease transmission (e.g., spending substantial time outdoors, especially during the night, or staying in accommodation lacking screens, bed nets, or air-conditioning) or if they visit an area with an ongoing outbreak. Vaccination should also be considered for travelers to endemic areas who are uncertain of specific duration of travel, destinations, or activities.[31]
Vaccination of people living in endemic areas is also recommended.
Meningococcal vaccination
Many developed countries offer routine childhood vaccination for the prevention of meningococcal disease. For full details of US immunization schedules, including indications for booster doses, the ACIP guidelines should be consulted.
CDC: recommended child and adolescent immunization schedule for ages 18 years or younger
CDC: recommended adult immunization schedule for ages 19 years or older
Pneumococcal vaccination
Rates of pneumococcal meningitis have decreased among children and adults since the pneumococcal conjugate vaccine (PCV7, subsequently PCV13) vaccine was introduced. Although the overall effect of the vaccine is substantial, increases in meningitis caused by nonvaccine serotypes, including strains nonsusceptible to antibiotics, remain a concern.[32] [33]
Influenza vaccination
Annual seasonal influenza vaccination can also be recommended to reduce potential extrapulmonary complications including encephalitis.

Secondary Prevention

Certain measures are available for the prevention of a limited number of agents (viral and bacterial) that can cause encephalitis.

  • Specific drugs: isoniazid for purified protein derivative positivity in tuberculosis and for post-exposure prophylaxis.

  • Education and avoidance of risk-taking behavior (unprotected sexual acts): prevention of HIV, syphilis.

  • Environmental control (sanitation, vector control and avoidance): Nipah and Hendra virus, all the arboviruses, enteroviruses, typhoid.

  • Isolation should be considered for patients who are severely immunosuppressed and those with rabies encephalitis, exanthematous encephalitis, or contagious viral hemorrhagic fever.[68]

  • As West Nile virus encephalitis has been reported to occur after blood transfusion and solid organ transplantation, sensitive screening laboratory tests are in development, which may guide future preventive measures.[121] [122]

Follow-Up Overview

Prognosis

Due to the varied etiology, survivors of the critical phases of the illness are a heterogeneous group. Mortality and morbidity vary depending on the underlying etiology, the immune status of the host, the extent and location of anatomic lesions, the development of complications, and the time to initiate treatment. Mortality as an outcome occurs in 6% to 9% in the US, and in 12% in England in infectious encephalitis.[98] [6] [99] [3] Age >65 years old, immunocompromised (HIV or immunosuppressive medication-induced), mechanical ventilation, coma, acute thrombocytopenia, elevated cerebrospinal fluid polymorphonuclear count, cerebral edema, and status epilepticus are associated with poor outcomes.[99] [100]
The development of the late sequelae depends on age, etiology of the encephalitis, and severity of the clinical episode.[61] Severe disability occurs in more than half of survivors. In children, long-term morbidity occurs in up to two-thirds of patients. This includes fatigue, cognitive impairment, attention and deficit disorders, dysphasia, motor impairment, ataxia, epilepsy, and personality changes.[101] [102] [103] [104] Children with isolated cerebellar involvement or respiratory syncytial virus encephalitis tend to have a good prognosis.
Postencephalitic epilepsy occurs in 10% by 5 years and 20% by 20 years.[105] The presence of seizures during hospitalization and an abnormal brain magnetic resonance imaging are the strongest predictors of development of postencephalitic epilepsy. The etiology of encephalitis, presence of focal neurologic deficits, and interictal electroencephalographic abnormalities do not influence development of postencephalitic epilepsy.[106]
For herpes simplex virus encephalitis, older age, decreased level of consciousness, and delay or lack of treatment with acyclovir are associated with high mortality rates. Diffuse cerebral edema and intractable seizures are additional poor prognostic indicators. Survivors frequently have disabling neurologic sequelae such as (short-term) memory impairment, personality and behavioral changes, psychiatric issues, and anosmia.[107] Severe behavioral and personality changes including Kluver-Bucy syndrome, seen before acyclovir became widely available, are no longer common.
Mortality rates in autoimmune encephalitis are generally lower than in infectious cases; however, prolonged recovery and potential for relapse make longer-term management challenging.[1] Mortality rates for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis are up to 6%, and relapse occurs in 12% to 25% of patients.[36] [108] [109] Earlier immune treatment has been associated with better outcomes but cognitive and behavioral changes may persist.[109] [36] [110] Mortality rates may be lower for anti-leucine-rich glioma-inactivated 1 encephalitis than anti-NMDA encephalitis, but longer-term relapse rates might be higher.[1] [111] [112]

Monitoring

Survivors must undergo intensive inpatient rehabilitation therapy after hospital discharge if their mental status and functional abilities allow. The extent of their functional recovery should be monitored and documented to make suitable arrangements for their further care and living situation. More specifically, these patients should be monitored for the development of a seizure disorder and treated with appropriate antiepileptic drugs. Some patients can develop hydrocephalus, and may benefit from a permanent cerebrospinal fluid drainage procedure such as placement of a ventriculoperitoneal shunt. Encephalitis may increase risk of ADHD and cognitive problems, especially in the pediatric population.[114] Neuropsychological testing is recommended for survivors of childhood encephalitis.[101] [113]
Patients with acute disseminated encephalomyelitis (ADEM) should be followed with serial office visits (to document the appearance of new symptoms) and should undergo a repeat magnetic resonance imaging (MRI) of the brain 6 months to one year later, to document resolution of lesions. The appearance of new symptoms or MRI changes one month after the clinical episode of ADEM raises the suspicion of a chronic demyelinating disease (multiple sclerosis), and disease-modifying therapy should be considered.

Complications

High Likelihood

Timeframe

Expand All

death

short term

  • Mortality rates vary according to the underlying etiologic agent. Untreated herpes simplex virus (HSV) encephalitis has a mortality rate of around 70%, with early treatment reducing this to approximately 10%.[6] [107] Older age and depressed levels of consciousness (Glasgow Coma Scale <6) are poor prognostic indicators. Rabies and amebic encephalitis are almost universally fatal. High mortality rates are seen with Eastern equine encephalitis, Japanese encephalitis, Nipah virus, and viral hemorrhagic fevers. HIV infection forebodes higher mortality rates in encephalitis.[6]

  • Early treatment with acyclovir and adequate supportive critical care can decrease mortality associated with HSV encephalitis. For other cases, in addition to specific treatments if available, good supportive critical care medicine is advocated, and there is some indirect evidence that this is associated with decreased mortality rates.

short term

neurologic sequelae

variable

  • Neurologic sequelae occur within one month and include abulia, akinetic mutism, aphasia, amnesia, neuropsychiatric issues, and motor problems. ADHD and cognitive issues can be seen in children.[101] [113] [114] Acute rehabilitation services, speech language therapy, and neuropsychiatric services should be provided for these patients.

variable

Medium Likelihood

Timeframe

Expand All

hypothalamic and autonomic dysfunction

short term

  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), diabetes insipidus (DI), loss of temperature control, and vasomotor instability can occur in patients with encephalitis.

  • SIADH: avoidance of hypotonic fluids and fluid restriction (if possible).

  • DI: maintenance of normovolemia and use of desmopressin.

  • Hyperthermia: antipyretics or cooling devices are used to maintain normothermia, as hyperthermia is associated with worse functional outcomes.

  • Vasomotor instability: monitored in an intensive care unit setting with adequate intravenous access and cardiac and blood pressure monitoring. Treatment is tailored to stabilize these parameters, with the institution of advanced cardiac life support protocols as required.

short term

seizures

variable

  • A frequent component of encephalitis and a consequence of the extensive inflammatory reaction that is integral to encephalitis. The formation of gliotic scars marks the healing phase and can lead to the formation of epileptogenic foci.

  • Intravenous lorazepam is used initially to treat ongoing convulsive activity. Intravenous fosphenytoin loading is administered, followed by maintenance dosing. For refractory seizures/status epilepticus, intubation ventilation, intravenous sedatives at high doses (midazolam, propofol, or pentobarbital) to achieve a burst suppression pattern on the electroencephalogram (EEG), along with concomitant intravenous antiepileptic medications (phenytoin, valproic acid, and/or the newer antiepileptic drugs such as levetiracetam and lacosamide) should be instituted. Based on the EEG findings, a cautious withdrawal of sedatives can be attempted after 12 to 24 hours of suppression. This is best done in consultation with a specialist in neurocritical care or neurology. Seizures can occur in the long term and need to be treated with standard antiepileptic drugs in consultation with a neurologist.

variable

hypersomnolence and sleep disorders

variable

  • Sleep disorders in patients with autoimmune encephalitis include parasomnia, insomnia, hypersomnia, and sleep-disordered breathing.[117] [118] These can be acute and severe, and can often persist beyond the initial stage of the disease.[119] Untreated sleep disturbances may worsen autonomic instability, thereby challenging attempts to wean patients from mechanical ventilation. Over the long term, sleep disorders may compromise recovery and return to meaningful function.[120] Because sleep disorders are often overshadowed by other neurologic and psychiatric symptoms, patients and caregivers should be specifically questioned about new-onset sleep disruption or behaviors.[120]

variable

Low Likelihood

Timeframe

Expand All

ischemic stroke

short term

  • Depending on the extent and severity, worsens the outcome. Antiplatelet or anticoagulant agents can be considered.

short term

cerebral hemorrhage

variable

  • Depending on the extent and severity, worsens the outcome. Hemorrhages are usually medically managed with supportive care and monitoring of blood pressure. Larger bleeds may require surgical interventions.

variable

cerebral vein thrombosis

variable

  • Depending on the extent and severity, worsens the outcome. The treatment of cerebral vein thrombosis is difficult, as anticoagulant use can increase the risk of hemorrhage.

variable

cerebral vasculitis

variable

  • Varicella-zoster virus (VZV) encephalitis is frequently associated with a cerebral vasculitic picture. Corticosteroids are used to treat the vasculitis of VZV infection, along with acyclovir.

variable

hydrocephalus

variable

  • Can develop as a late complication with bacterial, fungal, and parasitic encephalitis. This is due to the decreased efficiency of absorption of cerebrospinal fluid from arachnoid granulations. Placement of a draining ventricular catheter/ventriculoperitoneal shunt should be considered.

variable

postviral chronic fatigue syndrome

variable

  • The syndrome of prolonged and persistent fatigue, myalgia, difficulty concentrating, and postexertional malaise is sometimes seen after viral encephalitis.[115] No specific treatments exist for this condition, but a multidisciplinary approach is advocated.

variable

encephalitis lethargica (Von Economo disease)

long term

  • Occurs after 6 months. An extrapyramidal syndrome characterized by somnolence, fatigue, and ophthalmoplegia was seen after the influenza epidemic of 1918. Occasional cases are now reported after sporadic viral encephalitis, especially Japanese encephalitis.[116]

long term

Citations

    Key Articles

    • Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium. Clin Infect Dis. 2013 Oct;57(8):1114-28.[Abstract][Full Text]

    • Miller JM, Binnicker MJ, Campbell S, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2018 update by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect Dis. 2018 Aug 31;67(6):e1-94.[Abstract][Full Text]

    • Steiner I, Budka H, Chaudhuri A, et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2010 Aug;17(8):999-e57.[Abstract][Full Text]

    • Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults--Association of British Neurologists and British Infection Association National Guidelines. J Infect. 2012 Apr;64(4):347-73.[Abstract][Full Text]

    • Kneen R, Michael BD, Menson E, et al. Management of suspected viral encephalitis in children - Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group national guidelines. J Infect. 2012 May;64(5):449-77.[Abstract][Full Text]

    • Vora NM, Holman RC, Mehal JM, et al. Burden of encephalitis-associated hospitalizations in the United States, 1998-2010. Neurology. 2014 Feb 4;82(5):443-51.[Abstract]

    Other Online Resources

    • CDC: Division of vector-borne diseases (DVBD)
    • CDC: recommended child and adolescent immunization schedule for ages 18 years or younger
    • CDC: recommended adult immunization schedule for ages 19 years or older
    • CDC: Influenza (Flu)

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Guidelines

Diagnostic

  • EAN consensus review on prevention, diagnosis and management of tick‐borne encephalitis[12]

    Summary

    Provides recommendations on the diagnosis of tick‐borne encephalitis based on evidence or consensus decisions.

    Published by

    European Academy of Neurology (European Federation of Neurological Societies)

    Published

    2017

  • Viral meningoencephalitis: a review of diagnostic methods and guidelines for management[68]

    Summary

    Diagnosis should be based on medical history and examination. Cerebrospinal fluid should be analyzed for protein and glucose levels, cellular analysis, and identification of the pathogen by polymerase chain reaction amplification and serology. Neuroimaging (preferably magnetic resonance imaging) is essential. Lumbar puncture (LP) follows neuroimaging if no mass lesions are present. LP should be delayed only under unusual circumstances.

    Published by

    European Academy of Neurology (European Federation of Neurological Societies)

    Published

    2010

  • Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium[2]

    Summary

    Diagnostic guidance for evaluation of adults and children with suspected encephalitis.

    Published by

    International Encephalitis Consortium

    Published

    2013

Treatment

  • EAN consensus review on prevention, diagnosis and management of tick‐borne encephalitis[12]

    Summary

    Includes recommendations for the management and prevention of tick‐borne encephalitis, based on evidence or consensus decisions.

    Published by

    European Academy of Neurology (European Federation of Neurological Societies)

    Published

    2017

  • Viral meningoencephalitis: a review of diagnostic methods and guidelines for management[68]

    Summary

    Guidelines recommend that patients must be hospitalized with easy access to intensive care units. Acyclovir is available for herpes encephalitis and may also be effective for varicella-zoster virus encephalitis. Ganciclovir and foscarnet can be given to treat cytomegalovirus encephalitis, and pleconaril can be given for enterovirus encephalitis. The use of corticosteroids as an adjunct treatment for acute viral encephalitis is controversial. Surgical decompression is indicated for impending uncal herniation or increased intracranial pressure refractory to medical management.

    Published by

    European Academy of Neurology (European Federation of Neurological Societies)

    Published

    2010

Credits

Authors

Topic last updated: 2022-11-18

Payal B. Patel, MD

Assistant Professor of Neurology

Department of Neurology

University of Washington

Seattle

WA

[disclosures]

Acknowledgements:

Dr Payal B. Patel would like to gratefully acknowledge Dr Leo H. Wang, Dr Louise T. Wang, Dr Catalina C. Ionita, Dr Manjunath Markandaya, Dr David Janicke, Dr Robert Schmidt, and Dr Kimiko Domoto-Reilly, previous contributors to this topic.

[disclosures]

Peer Reviewers

Russel Dale, MBChB, MRCPCH, MSc, PhD

Professor of Paediatric Neurology

The University of Sydney

Consultant Neurologist

The Children's Hospital at Westmead

Sydney

Australia

[disclosures]

Arun Venkatesan, MD, PhD

Associate Professor, Neurology

Director

Johns Hopkins Encephalitis Center

Johns Hopkins Hospital

Baltimore

MD

[disclosures]

Patient Instructions

There is no general advice for patients, but in the event of certain infections, contact tracing and limiting contamination of the environment (by placing in isolation room, avoiding travel) may be advised. Participation in rehabilitation for those with cognitive and/or motor sequelae should be advised.
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