Question 21

A 59-year-old female is transferred to your ICU febrile with a reduced level of consciousness. Her family have noted major behavioural change over the past three weeks.

MRI scan with contrast (two days ago) showed increased T2 and FLAIR signal in both frontal lobes, not conforming to a vascular pattern.

CSF Examination has shown the following:


Patient Value

Adult Normal Range

Opening pressure

40 cm*

15 – 25


4.8 mmol/L

3.3 – 6.1


2.24 g/L*

0.10 – 0.50

Red Cell count

50 cells/high power field*

0 – 5

White Cell Count

270 cells/high power field*

0 – 5



Gram stain

Nil bacteria seen

She has been receiving Ceftriaxone and Acyclovir at appropriate doses since admission. Please outline:

  1. The differential diagnosis for her presentation. (40% marks)
  2. The specific investigations you would order and the specific treatment for the differentials. (60% marks)

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College answer

The differential diagnosis for her presentation

The clinical presentation is suggestive of Encephalitis with numerous possible aetiologies


HSV still possible, but less likely with relatively normal MRI (no temporal involvement) VZV

Enterovirus HIV


Cryptococcal disease (unlikely without leptomeningeal involvement) Lyssavirus, Hendravirus if bat exposure

Arthropod borne viruses

Murray Valley


Japanese encephalitis

many others up to and including rabies

Post infectious encephalitis (acute disseminated encephalomyelitis)

Auto-immune and para-neoplastic

anti-NMDA receptor encephalitis is the best studied, many other targets now described: association with ovarian cancer, endometrial cancer, small cell lung cancer; esp. anti-NMDA systemic auto-immune disease, e.g. SLE (limbic encephalitis)


unlikely with minimal MRI findings lymphoma given lymphocyte predominance

Specific Investigations

CSF (existing sample or repeat) for viral PCR (HSV, VZV, enteroviruses) and serology for suspected pathogens, oligoclonal bands Anti-NMDA antibodies, other CNS antibodies, oligo-clonal bands, Cytology & flow cytometry

Auto-antibodies: ANA, anti-dsDNA etc. HIV testing


Imaging to look for systemic malignancy (ovarian, endometrial, breast, lung) Investigations to consider down the track

Brain biopsy

Repeat MRI to assess for evolution

Specific treatment

Specific treatment depends on underlying aetiology, which may be challenging to establish

Some comment on current antimicrobial therapy: would be reasonable to broaden current therapy given progression and ongoing fevers:

Viral encephalitis

No specific therapies for most viruses other than HSV

Could consider broadening anti-virals to ganciclovir (as guided by ID) Auto-immune encephalitis:

These disorders are highly responsive to immunomodulatory therapies and early initiation of treatment improves outcomes.

Once infectious cause ruled out, and there are no contraindications, commence immunotherapy in discussion with neurology/ID

no RCT, strong recommendations for pulse steroid, plasma exchange, IVIG other therapies for resistance incl. rituximab, pulse cyclophosphamide

Look for and treat underlying malignancy.


First of all, this presentation clearly meets the (vague) internationally agreed-upon criteria for encephalitis. We have evidence of an altered level of consciousness, abnormal imaging and CSF pleocytosis with a very elevated protein. There is a million different potential causes for somtheing like this, but generally they tend to fall into "infectious" and "autoimmune" categories:

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

Specific investigations: To borrow from the 2014 paper by Venkatesan, the following routine and "conditional" investigations are recommended for various specific pathologies:

Routine studies

  • CSF:  opening pressure, cell count with differential, protein, glucose
  • Gram stain and bacterial culture
  • 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
  • Oligoclonal bands and IgG index
  • VDRL for syphilis


  • Routine blood cultures
  • HIV serology (consider RNA)
  • Treponemal testing (rapid plasma reagin, specific treponemal test)


  • Neuroimaging (MRI preferred to CT, if available)
  • Chest imaging (chest x-ray or CT)


  • 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

Specific management is defined by the specific aetiology, which is difficult if the list of differentials is so broad. However, a few different specific management strategies should be mentioned:

  • 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
      • Methylprednisolone
      • Dexamethasone
      • Rituximab
      • Cyclophosphamide
      • Plasmapheresis



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