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:
|
Parameter |
Patient Value |
Adult Normal Range |
|
Opening pressure |
40 cm* |
15 – 25 |
|
Glucose |
4.8 mmol/L |
3.3 – 6.1 |
|
Protein |
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 |
|
Lymphocytes |
99% |
|
|
Gram stain |
Nil bacteria seen |
She has been receiving Ceftriaxone and Acyclovir at appropriate doses since admission. Please outline:
The differential diagnosis for her presentation
The clinical presentation is suggestive of Encephalitis with numerous possible aetiologies
Infective:
HSV still possible, but less likely with relatively normal MRI (no temporal involvement) VZV
Enterovirus HIV
Influenza
Cryptococcal disease (unlikely without leptomeningeal involvement) Lyssavirus, Hendravirus if bat exposure
Arthropod borne viruses
Murray Valley
Equine
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)
Malignant
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
EEG
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:
|
Aetiologies of encephalitis |
Mimics of encephalitis |
|
Infectious
Neoplastic /paraneoplastic
Inflammatory and idiopathic
Congenital
Autimmune
|
Vascular
Infectious
Neoplastic /paraneoplastic
Drug-induced
Inflammatory and idiopathic
Traumatic
Metabolic
|
Specific investigations: To borrow from the 2014 paper by Venkatesan, the following routine and "conditional" investigations are recommended for various specific pathologies:
Routine studies
Serum
Imaging
Neurophysiology
Other tissues/fluids
Conditional studies
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:
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.
Virchow, Rud. "über interstitielle Encephalitis." Virchows Archiv 44.4 (1868): 472-476.
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.
Johnson, Richard T. "Acute encephalitis." Clinical Infectious Diseases (1996): 219-224.
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.