Encephalitis – a difficult beast

A 14-year-old girl was brought in by her family with lethargy, agitation, and confusion. Her past medical history includes depression and a recent viral upper respiratory tract infection.

Bottom Line

Encephalitis is caused by inflammation of the brain and is difficult to diagnose and manage.

Up to 50% of patients experience short-term deficits, with 20% experiencing severe sequelae.

Overall, 10% mortality.

Discover the risk factors and first-line investigations!

Unique Australian aetiologies: Hendra virus, Australian bat lyssavirus, Murray Valley encephalitis virus and West Nile virus (Kunjin virus) infection.

Immune-mediated encephalitides are increasingly noted, these potentially respond to immunomodulatory treatments and have association with underlying tumours.

Definitive aetiology may not be identified for 30%–40% of patients with encephalitis.

Recovery from encephalitis reaches a plateau at approximately 6–12 months.

Rehabilitation assessment (medical and non-medical) should be considered, especially in those with neurological or neuropsychological deficits at discharge.

Epidemiology

• The annual Australian hospitalisation rate is 5.2/100 000.
• The case fatality rate is estimated to be 4.6%.
• The highest admission rates are observed in males, those aged less than 9, and those over 60.

How do we diagnose it?

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 – lasting ≥24h.

Minor Criteria (2 for possible encephalitis; ≥3 for probable or confirmed encephalitis):

• Documented fever ≥38°C (100.4°F) within 72h before or after the presentation.
• Generalised or partial seizures not fully attributable to a pre-existing seizure disorder.
• New onset of focal neurologic 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.

Important Differential Diagnoses

Consider:

• Meningitis without parenchymal involvement: bacterial, viral, or other (e.g. TB, Cryptococcus).
• Cerebral abscess or other forms of intracranial suppuration.

• Infection associated encephalopathy (e.g. septic encephalopathy, acute nectrotising encephalopathy (ANE)).
• Vascular disease: ischaemic/haemorrhagic cerebrovascular accident (CVA), cerebral vasculitides (e.g. systemic lupus erythematosus).
• Hypertensive encephalopathy, including posterior reversible encephalopathy syndrome (PRES).
• Neoplastic: primary CNS or malignancies.
• Toxin-induced encephalopathy: alcohol, illicit drugs, other drugs (especially neuroleptics, cyclosporin).
• Metabolic encephalopathy: hepatic, renal, hypoglycaemia, hyponatraemia, hypocalcaemia, thiamine deficiency, Wilson disease.
• Neurodegenerative: Creutzfeld-Jacob disease (other prion diseases), neuroacanthocytosis.
• Demyelinating disease: multiple sclerosis (MS), neuromyelitis optica (NMO or Devic disease).
• Endocrine: Hashimoto’s encephalopathy/steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), Addisonian crisis.
• Psychiatric: psychosis, catatonia.
• Seizure disorder.
• Traumatic brain injury.

Causes

Viruses are the most commonly identified agent in all settings.

Immune-mediated aetiologies are increasingly recognised in up to one-third of cases, and they are important because they are often treatable.

Paediatric immune-mediated encephalitides

ADEM

Acute disseminated encephalomyelitis is an inflammatory, multi-focal, demyelinating condition of the central nervous system. It presents with encephalopathy and multi-focal neurological deficits. The mean age is 5–8 years old, with a slight male predominance. Diagnosis is by MRI. Corticosteroids are the established first-line therapy, with other immune-modulatory therapies used in refractory cases.

Acute haemorrhagic leuco-encephalopathy (AHLE) is a rare, hyper-acute form of ADEM that overlaps with cerebral vasculitis.

Anti-NMDAR

Anti-N-methyl-D-aspartate receptor encephalitis is one of the principal causes of encephalitis. It typically presents with psychiatric symptoms, seizures, memory loss and mutism. The syndrome evolves to include movement disorders, dysautonomia and sometimes hypoventilation. MRI is most often normal. It is diagnosed by identifying CSF or serum antibodies against the NR1 subunit of the NMDA receptor.

Anti-VGKC

Anti-voltage-gated potassium channel-complex encephalitis includes a broad clinical spectrum. In children, it presents as temporal lobe focal seizures, status epilepticus and encephalopathy (behavioural disturbance, hallucinations) and cognitive decline.

Check out these vital risk factors!

• Neonate (<4 weeks): HSV-2, CMV, toxoplasmosis, T. pallidum (syphilis), L. monocytogenes, enteroviruses parechovirus.
• Infant/Child: HSV, VZV, enteroviruses, HHV6/7, M. pneumoniae, EBV, parechovirus, Bartonella sp., ADEM.
• Female: anti-NMDAR.
• Immunocompromised patient: HHV6, CMV, EBV, measles, VZV, LCMV, toxoplasma, cryptococcus, JCV, BKV, Bartonella sp.
• Tropical Australia: JEV, dengue, MVEV, KUNV, B. pseudomallei.
• Travel history
  • Asia: JEV, dengue, malaria, MTB, Nipah, Angiostrongylus cantonensis.
  • Pacific: JEV, dengue, malaria, MTB, Angiostrongylus cantonensis.
  • North America: WNV, LACV, SLEV, CTFV, EEEV, neuroborreliosis, Rickettsia rickettsia (RMSF), ehrlichiosis (HME), anaplasmosis (HGA), babesiosis, coccidiomycosis.
  • South America: WNV, VEEV, dengue, MTB, trypanosomiasis (Chagas).
  • Europe: TBEV, TOSV, neuroborreliosis, anaplasmosis (HGA).
  • Africa: malaria, trypanosomiasis, MTB.
• Animal exposure
  • Monkeys: herpes B, rabies.
  • Bats: rabies, ABLV.
  • Dogs and other canids outside Australia: rabies.
  • Cats: Bartonella hensellae.
  • Horse: Hendra, KUNV.
  • Rodents: LCMV, leptospirosis.
  • Snails/other molluscs: Angiostrongylus cantonensis.
  • Swine: Nipah.
  • Mosquito or Tick bite history.
  • Arboviruses: MVEV, KUNV, JEV, dengue in Australia by region.
  • Rickettsiae: Rickettsia typhi, R. australis, R.honei, Orientalis tsutsugamushi in Australia by region.
  • Other: neuroborreliosis, ehrlichiosis (HME), anaplasmosis (HGA).
• Recreational
  • Sexually transmitted: HIV.
  • Fresh water: leptospirosis, Naegleria fowleri.
  • Soil/mud: Balamuthia mandrillis.
• Occupational
  • Animal husbandry, farming: C. burnetii (Q fever), leptospirosis.
  • Abbatoir workers: C. burnetii (Q fever).
• Unvaccinated: measles, mumps, rubella, VZV.

Examination findings

Level of consciousness, subtle seizure activity, meningism, abnormal movements (e.g. chorea, parkinsonism), weakness, sensory loss and cranial nerve involvement (including deafness and anosmia).

Features of raised intracranial pressure or autonomic dysfunction. The mental status examination should be recorded. A rash or other skin lesions, respiratory or gastrointestinal signs may give clues to the aetiology.

First-line Investigations

CSF: Opening pressure, microscopy, gram stain and bacterial culture, cell count and type. Biochemistry: protein, glucose. PCR: HSV, enterovirus, VZV. Antibodies: oligoclonal bands, VZV IgG Antigen: cryptococcal Ag.

Serum Serology: HIV, flavivirus, M. pneumoniae, EBV

Respiratory PCR testing for enterovirus, influenza A and B, adenovirus

Faeces PCR or antigen testing for enterovirus, adenovirus, rotavirus (child); enterovirus culture/typing

Skin swabs (where lesions present) PCR testing for HSV 1/2, VZV, enterovirus

Neuroimaging MRI (sequences to include: T1,T2, FLAIR, DWI, gradient-echo, gadolinium contrast)

EEG

Directed Management

HSV: Minimum 14 days intravenous acyclovir for immunocompetent patients and 21 days for immunocompromised patients. Consider repeat lumbar puncture for CSF HSV PCR at planned completion of treatment especially in immunocompromised and children.

VZV: Consider 7–14 days of intravenous acyclovir with or without corticosteroids in consultation with an infectious diseases specialist.

Enterovirus: Intravenous immunoglobulin if hypogamma-globulinaemic. Intravenous immunoglobulin is used widely in Asia for enterovirus.

CMV/HHV6: Reduce immunosuppression and consider ganciclovir and/or foscarnet in consultation with infectious diseases specialist.

Rabies or ABLV: Consider Milwaukee protocol in consultation with an infectious diseases specialist.

ADEM: Methylprednisolone 30 mg/kg daily in children up to1000 mg (adult daily dose) for 3–5 days in consultation with a neurologist. Second-line treatments in consultation with a neurologist. Ab-mediated: Immunosuppressive therapy in consultation with a neurologist. Investigation for underlying tumour and removal (where indicated). Ongoing tumour surveillance.

Prognosis

• The overall mortality of encephalitis is approximately 10%.
• Up to 50% of patients experience short-term deficits, with 20% experiencing severe sequelae; long-term outcomes are poorly characterised, and neuro-cognitive sequelae are likely underestimated.
• Adverse prognostic features: depression of consciousness at presentation is the main adverse prognostic feature. The poor outcome has also been associated with refractory status epilepticus, intensive care unit admission, focal neurologic signs, abnormal MRI findings, extremes of age and immune compromise, a diagnosis of HSV in adults, and JEV or mycoplasma pneumonia in children, or delay in the initiation of directed therapy.

Recovery from encephalitis reaches a plateau at approximately 6–12 months. Rehabilitation assessment (medical and non-medical) should be considered, especially in those with neurological or neuropsychological deficits at discharge.

In Summary

Encephalitis presents a complex challenge. It requires a detailed clinical assessment, consultation, and judicious investigation. Unnecessary delays must be avoided, and it is essential to institute empiric therapies appropriately and provide high-quality, supportive management. Optimal application of current knowledge will likely improve diagnosis; however, even with an extensive diagnostic work-up, definitive aetiology may not be identified for 30%–40% of patients with encephalitis.

References

Britton PN, Eastwood K, Brew B, Nagree Y, and Jones CA. Consensus guidelines for the investigation and management of encephalitis. Med J Aust 2015; 202 (11): 576-577. || doi: 10.5694/mja14.01042