Encephalitis

Reviewed and revised 9 September 2016

OVERVIEW

• Encephalitis an acute encephalopathy due to an inflammatory cause
• Underlying causes are numerous and may be infectious or non-infectious, many of which lack effective therapies
• Herpes simplex encephalitis is the commonest cause in Australasia and acyclovir should be started as soon as the diagnosis is suspected
• Always consider epidemiological factors that may indicate an unusual cause of encephalitis (e.g. arboviruses and zoonoses), especially in Australia
• Encephalitis is commonly fatal or results in significant morbidity

PATHOPHYSIOLOGY

• inflammation of the brain parenchyma
•  results in diffuse and/or focal neuropsychological dysfunction
• there may be coexistent involvement of the meninges (meningoencephalitis)
•  most cases are viral, but inflammation may result from other infectious (e.g. bacterial, fungal, or protozoan) or autoimmune disorders

CAUSES

Infections

• Viral
  • HSV type 1 or 2, rarely zoster
  • enteroviruses
  • influenza
  • childhood viruses: measles and SSPE, mumps, rubella, EBV, CMV
  • HIV (primary encephalitis, or predispose to secondary in AIDS)
  • arboviruses (e.g. Murray Valley encephalitis, Japanese encephalitis, West Nile virus, flaviviruses, tick-borne encephalitis virus)
  • zoonoses (e.g. rabies, bat lyssavirus, Hendra, Nipah virus)
  • JC virus
• Bacteria
  • Tb, neurosyphilis, Mycoplasma, Listeria, Coxiella
• Fungal
  • Cryptococcus
• Protozoans
  • Toxoplasmosis, cerebral malaria, African trypanosomiasis
• Prions
  • e.g. CJD, kuru

Autoimmune

• Acute disseminated encephalomyelitis (ADEM) – rapid and widespread demyelination; may occur in association with vaccination or post bacterial or viral infections
• anti-NMDA receptor encephalitis (various other antibodies)
• Anti-voltage-gated potassium channel-complex (Anti-VGKC) encephalitis
• paraneoplastic limbic encephalitis
• non-paraneoplastic limbic encephalitis
  • e.g. anti-Ri, anti-Yo, anti-glutamic acid decarboxylase (GAD), anti-gamma-amino-butyric acid B receptor (GABA-B-R), anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), anti-glycine receptor (GlyR), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti- metabotropic glutamate receptor 5 (mGlu-R5)
• post-viral (e.g. zoster cerebellitis in children)

Unique infectious etiologies to consider in Australia, include:

• Hendra virus
• Australian bat lyssavirus
• Murray Valley encephalitis virus

Causes of encephalitis that are importnat regionally have potential for introduction into Australia include:

• Japanese encephalitis virus
• Enterovirus 71
• Dengue virus
• Nipah virus

DIFFERENTIAL DIAGNOSIS

Conditions that mimic encephalitis include:

• cerebral abscess
• meningitis (e.g. partially treated bacterial cause)
• seizure disorders and post-ictal states
• intoxications and drug-related hyperthermia syndromes (e.g. NMS)
• thyroid storm
• heat stroke

CLINICAL FEATURES

General

• history of exposure to mosquitoes, ticks or sick animals that transmit malaria, arboviruses or lyssaviruses
• history of travel to tropical Australia
  • Dengue, JEV, Endemic flaviviruses, melioidosis, leptospirosis
• history of immunocompromise
  • Toxoplasmosis, cryptococcus, CMV, EBV
• not vaccinated?
  • Measles, Mumps, Rubella, VZV
• may be preceded by a viral prodrome with fever, headache, nausea and vomiting, lethargy, myalgias (highly variable)

Abnormal brain function (diffuse or focal):

• altered mental status (confused, agitated, obtunded, somnolence)
• motor and sensory deficits
• altered behaviour
• personality changes
• speech disorders
• movement disorders
• seizures
• hemiparesis
• cranial nerve palsies
• exaggerated deep tendon reflexes

Associated features:

• may be co-existent meningism (meningoencephalitis)
• vesicles may be present or absent in herpes encephalitis

DIAGNOSTIC CRITERIA

Encephalitis case definition from the international encephalitis consortium:

• Major Criterion (required):
  • Patients presenting to medical attention with altered mental status defined as:
    • Decreased or altered level of consciousness, Or
    • Lethargy, Or
    • Personality change
  • And:
    • Lasting ≥ 24 hours
• Minor Criteria:
  • 2 for possible encephalitis; ≥ 3 for probable or confirmed encephalitis:
    • Documented fever ≥ 38° C within the 72 hours before or after presentation
    • Generalised or partial seizures not fully attributable to a pre-existing seizure disorder
    • New onset of focal neurological findings
    • CSF 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
  • And:
    • Exclusion of encephalopathy caused by trauma, metabolic disturbance, tumour, alcohol abuse, sepsis and other non-infectious causes.

INVESTIGATIONS

Choice depends on index of suspicion based on history and examination

Laboratory tests

• FBC, CRP, UEC, glucose
• CSF (lumbar puncture)
  • lymphocytic pleocytosis is common
  • viral meningoencehpalitis pattern:
    • WCC elevated, lymphocytes less than 250, elevated protein, normal or moderately low glucose
  • viral culture
  • PCR
    • HSV:  > 96 % sensitivity between days 3-7 of illness; false positives can occur before 3 days and sensitivity falls in the second week
    • Enterovirus
    • Parechovirus in young children
    • VZV
    • CMV
    • Other viruses if suspected: Measles, HIV, influenza, adenovirus, Hendra virus, Nipah virus,     Australian bat lyssavirus, echovirus, parechovirus.
  • Ziehl–Neelsen stain and TB culture
  • cytology
  • cryptococcal antigen or India Ink
  • CSF IgG
    • HSV IgG in CSF can be used for late diagnosis
    • HZV IgG, may in fact be more sensitive than PCR when interpreted in combination with serum IgG levels
    • Flavivirus IgM (i.e dengue)
• Serology
  • viruses (e.g. arboviruses; flavirus IgM is most useful after 5 days), HIV
  • syphilis
  • toxoplasmosis
• malaria screen (ICT, thick and thin films)
• PCR
  • CSF
  • throat/ nasopharyngeal swabs: enterovirus, influenza A and B, adenovirus
  • fecal: Enterovirus, adenovirus, rotavirus (child), parechovirus (small child/ infant)
• suspected autoimmune cause:
  • anti-NMDAR, LG1, CASPR2, AMPA, GABA-B, Anti-Hu/ Ma2, VGKC, GAD, DPPX, mGluR5 antibodies
  • vasculitis screen
  • paraneoplastic screen and imaging for underlying tumour

Imaging

• CT brain
  • second line imaging if MRI is not available
  • before LP in older patients, signs of raised ICP or focal neurology
  • only 1/3 HSV encephalitis patients have abnormal CT heads
  • can exclude differentials such as intracranial haemorrhage
  • cannot definitively rule out raised intracranial pressure
• MRI brain
  • first line imaging, more sensitive than CT brain
  • lesions are usually bilateral, in the medial temporal and inferior frontal areas, in HSV encephalitis
  • enhancing multifocal white matter changes (demyelination)
  • West Nile: basal ganglia, thalmi, mesial temporal involvement
  • normal MRI does not exclude encephalitis
  • cannot definitively rule out raised intracranial pressure
• CXR
  • e.g. TB, melioidosis, cryptococcus

Special tests

• EEG
  • highly sensitive, poorly specific
  • useful if chronic symptoms or psychiatric presentation
  • paroxysmal lateralizing epileptiform discharges may occur before imaging changes in HSV encephalitis (sensitive, not specific)
  • may diagnosis subtle or non-convulsive seizures
• Brain biopsy
  • last resort; generally not required due to the availability of PCR
  • considered in patients without a diagnosis who remain unwell or are deteriorating, especially if there are focal lesions on imaging or where CNS vasculitis is suspected
  • may identify treatable diagnoses e.g. Tb, neurosarcoidosis

MANAGEMENT

Resuscitation

• attend to ABCs
• treat seizures

Specific treatment

• acyclovir 10mg/kg Q8h IV for 14 days, start prior to definitive imaging
• empiric antibiotics to cover for bacterial meningitis is often required
• other specific agents where indicated
  • e.g. anti-malarials
  •  e.g. immunosuppressants for autoimmune causes
  • e.g. anti-HIV therapy
  • e.g. anti-toxoplasmosis agents

Supportive care and monitoring

Disposition

• may require HSU/ICU
• consult as required: infectious diseases, microbiology, neuroradiology, neurology

PROGNOSIS

Worse prognosis if:

• extremes of age (<1y, >55y)
• comorbidities
• immunodeficiency
• virulent organism

References and links

LITFL

• Anti-NMDA Receptor Encephalitis (CCC)
• HSV encephalitis (CCC)

Journal articles

• Armangue T, Leypoldt F, Dalmau J. Autoimmune encephalitis as differential diagnosis of infectious encephalitis. Curr Opin Neurol. 2014 Jun;27(3):361-8. PMID: 24792345.
• Britton PN, Eastwood K, Paterson B. Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand. Internal medicine journal. 45(5):563-76. 2015. [pubmed]
• Huppatz C, Gawarikar Y, Levi C, Kelly PM, Williams D, Dalton C, Massey P, Givney R, Durrheim DN. Should there be a standardised approach to the diagnostic workup of suspected adult encephalitis? A case series from Australia. BMC Infect Dis. 2010 Dec 15;10:353. PMC3018438.
• Irani SR, Vincent A. Autoimmune encephalitis — new awareness, challenging questions. Discov Med. 2011 May;11(60):449-58. PMID: 21616043.
• Kramer AH. Viral encephalitis in the ICU. Crit Care Clin. 2013 Jul;29(3):621-49. PMID: 23830656.
• Simon DW, Da Silva YS, Zuccoli G, Clark RS. Acute encephalitis. Crit Care Clin. 2013 Apr;29(2):259-77. PMID: 23537675.
• Venkatesan A, Tunkel AR, Bloch KC. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clinical infectious diseases. 57(8):1114-28. 2013. [pubmed]