Nothing stimulates electrical activity in the diagnostic lobe of an intensivist like the Mysteriously Unconscious Seizure Patient. It is also a presentation that can ruin the day for a junior ICU trainee, as typically the patient requires numerous tests and imaging investigations (CT, MRI, DSA, LP, EEG, etc), the need and timing of which  must be debated vigorously with services that don't want to provide them. 

A sufficiently common presentation to ICU, this is a topic of many SAQs from the CICM Second Part Exam, including:

  • Question 12 from the first paper of 2022 (autoimmune encephalitis)
  • Question 6 from the first paper of 2020 (HSV vs PRES)
  • Question 21 from the second paper of 2019 (diagnostic workup)

In terms of published material, Arun Venkatesan's dossier on encephalitis appears both recent (2017) and comprehensive. Unfortunately the free copy available online does not have information regarding  what it was written for or whether it underwent peer review A slightly less recent paper by the same author (2014) seems somehow more authoritative because it has the official stamp of the AAN all over it. Both articles are excellent and each compliments the other. These papers were blended together with random factoids and pointless trivia to produce the summary offered below.

Clinical features of encephalitis

What peculiarities must one manifest in order for one's coma to be declared an "encephalitis"? What, even, is the definition of this term? Lot's of people have tried to come up with something workable, partly for the purpose of classifying papers or organising epidemiological data. In general, all are in agreement that certain fundamental features must be present:

  • Major criteria:
    • Encephalopathy and altered level of consciousness, personality or some other CNS function: i.e., with an encephalitis, clinically one should not have a perfectly functioning brain. 
    • A protracted time course, i.e. greater then 24 hrs (to discriminate this from your bog-standard delirium)
  • Minor ciriteria: some features to distnguish encephalitis from encephalopathy, to demonstrate an inflammatory change in the CNS:
    • Seizures in a non-epileptic
    • New focal neurological signs
    • Pleocytosis of the CSF
    • Fever
    • MRI (or CT) changes suggestive of inflammation
    • EEG abnormalities suggestive of encephalitis

This group of criteria comes from the Venkatesan's 2014 paper, and Venkatesan quotes himself (Venkatesan, 2012) as the source. The latter article has an enhanced credibility because it was a consensus statement of a massive international panel of experts (the  International Encephalitis Consortium).  This group themselves admitted freely that the manifestations of encephalitis are protean, and that no workable definition could possibly encompass the entire case spectrum (for example, isolated brainstem encephalitis might not satisfy the major criteria because of preserved consciousness)

Differential diagnosis for encephalitis

This, judging by what eminent authors have written, should be divided into "aetiologies of different kinds of encephalitis" and "things which are not encephalitis but are similar enough to fool the person applying a set of standard criteria". Beyond that, clearly there is a need to expand on the infectious and autoimmune aetiological categories, as they are larger than the rest and also because they account for such a large proportion of the presentations.  As such:

Different Aetiologies of Encephalitis

Aetiologies of encephalitis

Mimics of encephalitis


  • Viral (eg. HSV)
  • Bacterial (eg. tuberculosis, syphilis)
  • Protozoal (eg. malaria)
  • Fungal (eg, cryptococcus)

Neoplastic /paraneoplastic

  • Paraneopladtic encephalitis (immune-mediated)

Inflammatory and idiopathic

  • Prion disease


  • Vertically transmitted infections, eg. neurosyphilis and CMV (Arbalaez, 2014)


  • Autoimmune disseminated encephalomyelitis (ADEM)
  • Anti-NMDA receptor encephalitis
  • Paraneoplastic limbic encephalitis
  • many others (see below)


  • Stroke
  • SAH, intracranial haemorrhage
  • Cerbral venous sinus thrombosis
  • PRES
  • Reversible vasoconstriction syndrome (Ducros, 2012)


  • Septic encephalopathy

Neoplastic /paraneoplastic

  • CNS lymphoma


  • Toxins, alcohol, etc

Inflammatory and idiopathic

  • Status epiilepticus


  • Post-TBI encephalopathy


  • Hepatic encephalopathy
  • Uraemic encephalopathy
  • Hypoglycaemia
  • Electrolyte disturbances (calcium, sodium)
  • Wernicke's encephalopathy
Infectious Aetiologies of Encephalitis


  • Coxsackie 
  • Echovirus
  • Human herpersvirus 6
  • HIV
  • Adenoviruses
  • Epstein-Barr virus
  • Cytomegalovirus
  • Mumps
  • Lymphocytic choreomeningitis virus
  • Arboviruses
  • Herpes simplex
  • Rabies virus

Intracellular bacteria

  • Rickettsia
  • Rocky Mountain spotted fever
  • Typhus
  • Q fever


  • Cryptococcosis
  • Coccidioidomycosis
  • Histoplasmosis
  • North American blastomycosis
  • Candidiasis

    Typical bacteria

    • Syphilis (secondary or meningovascular)
    • Leptospirosis
    • Borrelia burgdorferi infection (Lyme disease)
    • Mycoplasma pneumoniae infection
    • Cat-scratch fever
    • Listeriosis
    • Brucellosis (particularly due to Brucella melitensis)
    • Tuberculosis
    • Typhoid fever
    • Whipple's disease

      Protozoa and parasites

      • Toxoplasmosis
      • Cysticercosis
      • Echinococcosis
      • Trichinosis
      • Trypanosomiasis
      • Plasmodium falciparum infection
      • Amebiasis (due to Naegleria and Acanthamoeba)

      The list of viral and bacterial agents comes from an excellent (but somewhat dated) paper by Johnson (1996). Specifically, the viral agents are organised in increasing order of severity (i.e. coxsackie viruses are the least severe and rabies the most severe). The same article also contains an excellent table of different historical details, joined to the aetiology they suggest. It is so good that one could not help but reproduce it in full here:

      causes of encephalitis with historical details

      Additionally, the LIFTL entry on encephalitis lists this group of locally important infectious aetiologies:

      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

      Though these lists seem comprehensive, if one is indeed in need of a significantly larger level of detail, the article by Granerod et al (2010)  has a massive table (Table 1) which goes into extensive detail regarding the specific clinical features associated with every possible pathogen. 

      Autoimmune encephalitis

      Autoimmune encephalitis is a group of diverse aetiologies which are usually associated with either cancer somewhere (i.e. they are paraneoplastic) or with some co-existing autoimmune disease (eg. lupus or sarcoidosis). A list of these is easily arranged according to what cancer and what antibody they tend to test positive for.  The table below was concocted mainly using data from Dalmau et al (2014), and is far from complete.

      Autoimmune Aetiologies for Encephalitis
      Syndrome Antibody Associated cancer  or  autoimmune disease
      PEM Anti-Hu SCLC
      PCD Anti-Yo Gynaecological and breast cancer
      Anti-CV2/CRMP5 SCLC, thymoma
      Anti-Tr  Hodgkins lymphoma
      Opsoclonus-myoclonus  Anti-Ri Gynaecological and breast cancer
      Limbic encephalitis NMDA receptor  Ovarian teratoma
      AMPA receptor  Gynaecological and breast cancer, thymoma
      GABAB receptor  Neuroendocrine tumour, esp.  lung
      LGI1 Thymoma
      mGluR5  Hodgkin lymphoma 
      PERM Glycine receptor Stiff-person syndrome
      Basal ganglial encephalitis Dopamine receptor Sydenham's chorea
      Hashimoto's Anti-TPO Eponymous thyroiditis
      MOGAD Anti-MOG Unknown
      ADEM Anti-MOG Viral diseases and vaccinations

      Other encephalitis-producing autoimmune disease:

      • Systemic lupus
      • Sarcoidosis
      • Behcet's disease

      Diagnostic tests

      Question 12 from the first paper of 2022 asked the candidates to "list the investigations needed, and explain why they are required", specifically with regards to "suspected" autoimmune encephalitis. The best way to interpret this is to make the word "suspected" do a lot of heavy lifting. As such, the answer would consist of all the normal investigations one might do in the course of an encephalitis workup, because they are all required to exclude non-autoimmune etiologies. Borrowing again from the 2014 paper by Venkatesan, the following routine and "conditional" investigations are recommended:

      CT brain 

      • To exclude structural brain lesions (stroke, haemorrhage, abscess)
      • To exclude the possibility of raised intracranial pressure for the LP that follows

      LP and CSF analysis

      • Opening pressure, cell count with differential, protein, glucose (this helps exclude infections causes, and can reveal characteristic patterns)
      • Gram stain and bacterial culture (to exclude meningitis)
      • Specific infectious PCR on CSF
        • HSV-1/2 PCR (if test available, consider HSV CSF IgG and IgM in addition)
        • VZV PCR 
        • Enterovirus PCR
        • Cryptococcal antigen or India ink staining
        • VDRL for syphilis
        • Mycobacteria PCR
      • Specific autoimmune biomarkers in the CSF
        • Oligoclonal bands and IgG index
        • Numerous antibodies (see above) which are diagnostic for autoimmune encephalitis

      Peripheral blood tests

      • Blood cultures (to exclude systemic sepsis and septic encephalopathy)
      • HIV serology (consider RNA)
      • Treponemal testing (rapid plasma reagin, specific treponemal test)
      • Autoimmune vasculitis screen (to exclude cerebral vasculitis)


      • MRI - because autoimmune encephalitis may have a characteristic pattern
      • CT imaging of the whole body, looking for:
        • Occult malignancy (associated with many types of autoimmune encephalitis)
        • Lymphadenopathy, granulomatous disease, etc (suspicion of TB) 


      • EEG

      Other tissues/fluids

      • When clinical features of extra-CNS involvement are present, this may be appropriate (e.g., biopsy of skin lesions; bronchoalveolar lavage or endobronchial biopsy)

      Conditional studies

      • Immunocompromised host:
        • CMV PCR, HHV6/7 PCR, Toxoplasma gondii; MTB, fungal infections, West Nile Virus PCR
      • Geographic factors
        • Africa—malaria, trypanosomiasias, dengue
        • Asia—Japanese encephalitis virus, dengue, malaria, Nipah virus
        • Australia—Murray Valley encephalitis, Kunjin virus, Australian bat lyssavirus
        • Europe—tick-borne encephalitis virus; if Southern Europe, consider WNV testing, Toscana virus testing
        • Central and South America—dengue, malaria, WNV, Venezuelan equine encephalitis
        • North America—geographically appropriate arboviruses (e.g., WNV, Powassan, LaCrosse, Eastern equine encephalitis virus, St. Louis encephalitis, dengue, Lyme)
      • Season and exposure
        • Summer/autumn: WNV and other arboviruses, tick-borne disease
        • Cat (particularly if with seizures, paucicellular CSF)—Bartonella
        • Tick exposure—tick-borne disease
        • Animal bite/bat exposure—rabies
        • Swimming or diving in warm freshwater or nasal/sinus irrigation—Naegleria fowleri


      It goes without saying that:

      • Different aetiologies of encephalitis require different management strategies
      • Many are so rare that expert opinion and case reports are all the guidance we have
      • Each individual case is going to be potentially very different
      • No intensivist would ever undertake to treat such a scenario in a professional vacuum, and consultation with multiple specialities is going to be the most important step they can take

      But, for the answer to Question 21 form the second paper of 2019, the trainees needed to produce a list of specific management strategies without having been given a specific aetiology. Given that the pass rate was around 23%, one might assume they found it difficult. This very basic list of steps is offered here as a launchpad for their own thinking: 

      • Supportive management
        • A, B, C: Intubate the patientto facilitate investigations (LP and MRI are challenging if they are having seizures or in the grip of a violent psychosis)
        • Manage cerebral oedema with head positioning, hypetonic saline or mannitol
        • Protect them from seizures with sedation and benzodiazepines or antiepileptics
      • Specific management
        • HSV: aciclovir 10mg/kg IV q8h
        • CMV: ganciclovir, cidofovir, foscarnet
        • HHV6: ganciclovir 5mg/kg IV q12h
        • HIV: antiretroviral drugs
        • Rabies: rabies immune globulin
        • Bacterial aetiologies:
          • TB: isoniazid, rifampicin, pyrazinamide and streptomycin
          • Typical bacteria: ceftriaxone and vancomycin
        • Autoimmune causes require a slightly more expanded approach.

      Question 12 from the first paper of 2022 asked the candidates for a lot more detail about the specific management of autoimmune encephalitis, including the common complications of each strategy. Thus:

      Management options for autoimmune encephalitis, and their complications:

      • High dose ("pulse") methylprednisolone or dexamethasone
        • Hyperglycaemia
        • Insomina, agitation, psychosis
        • Fluid retention
        • Muscle wasting, delayed weaning from ventilation
        • Impaired wound healing
        • Increased propensity to infection (eg. PJP)
      • Rituximab
        • Long term loss of humoral immunity
        • Infusion reaction
        • Lymphopenia
      • Cyclophosphamide
        • Bone marrow suppression
        • Renal tubular necrosis
        • Pulmonary fibrosis
        • Haemorrhagic cystitis
      • IV immunoglobulin
        • Risk of anaphylaxis
        • Large hyperoncotic fluid load (circulatory overload)
      • Plasmapheresis
        • Bleeding complications of anticoagulation and vascular access
        • Haemolysis and thrombocytopenia
        • Hypothermia and complement activation
        • Febrile reaction to replaced blood products
        • Unavoidable removal of useful blood components (eg. useful drugs)
        • Hypotension due to volume loss


      Venkatesan, Arun. "CLINICAL APPROACH TO ACUTE ENCEPHALITIS." (2017).

      Singh, Tarun D., Jennifer E. Fugate, and Alejandro A. Rabinstein. "The spectrum of acute encephalitis: causes, management, and predictors of outcome." Neurology 84.4 (2015): 359-366.

      Granerod, J., et al. "Challenge of the unknown: a systematic review of acute encephalitis in non-outbreak situations.Neurology 75.10 (2010): 924-932.

      Granerod, J., et al. "Causality in acute encephalitis: defining aetiologies." Epidemiology & Infection 138.6 (2010): 783-800.

      Venkatesan, Arun, and Romergryko G. Geocadin. "Diagnosis and management of acute encephalitis: A practical approach." Neurology: Clinical Practice 4.3 (2014): 206-215.

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      Venkatesan, Arun, et al. "Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.Clinical Infectious Diseases 57.8 (2013): 1114-1128.

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      Arbelaez, Andres, et al. "Congenital Brain Infections." Topics in Magnetic Resonance Imaging 23.3 (2014): 165-172.

      Ducros, Anne. "Reversible cerebral vasoconstriction syndrome." The Lancet Neurology 11.10 (2012): 906-917.

      Dalmau, Josep, and Myrna R. Rosenfeld. "Autoimmune encephalitis update." Neuro-oncology 16.6 (2014): 771-778.

      Shu, Hang, et al. "Myelin Oligodendrocyte Glycoprotein Antibody Associated Cerebral Cortical Encephalitis: Case Reports and Review of Literature." Frontiers in Human Neuroscience 15 (2022): 782490.

      Wender, Mieczysław. "Acute disseminated encephalomyelitis (ADEM)." Journal of neuroimmunology 231.1-2 (2011): 92-99.