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:
Adult Normal Range
15 – 25
3.3 – 6.1
0.10 – 0.50
Red Cell count
50 cells/high power field*
0 – 5
White Cell Count
270 cells/high power field*
0 – 5
Nil bacteria seen
She has been receiving Ceftriaxone and Acyclovir at appropriate doses since admission. Please outline:
- The differential diagnosis for her presentation. (40% marks)
- The specific investigations you would order and the specific treatment for the differentials. (60% marks)
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
Cryptococcal disease (unlikely without leptomeningeal involvement) Lyssavirus, Hendravirus if bat exposure
Arthropod borne viruses
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
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
Repeat MRI to assess for evolution
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:
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:
Aetiologies of encephalitis
|Mimics of encephalitis|
Inflammatory and idiopathic
Inflammatory and idiopathic
Specific investigations: To borrow from the 2014 paper by Venkatesan, the following routine and "conditional" investigations are recommended for various specific pathologies:
- 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)
- When clinical features of extra-CNS involvement are present, this may be appropriate (e.g., biopsy of skin lesions; bronchoalveolar lavage or endobronchial biopsy)
- 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
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