A Difficult Beast

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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:

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

 

How do we diagnose it?

Diagnostic Criteria

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 the 72h before or after 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, other (e.g. TB, cryptococcus).
  • Cerebral abscess (below) and other forms of intra-cranial suppuration.

  • Infection associated encephalopathy (e.g. septic encephalopathy, acute nectrotising encephalopathy (ANE)).
  • Vascular disease: ischaemic/haemorrhagic cerebro-vascular 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 disease), 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 are important because they are often treatable.

 

Selected 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. Mean age 5–8 years old, slight male predominance. Diagnosis 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 has been shown to be 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 moluscs: 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:

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. 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 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 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:

  • Overall mortality of encephalitis is approximately 10%.
  • Up to 50% of patients experience short-term deficits with 20% experiencing severe sequelae; long-term outcome is poorly characterised, and neuro-cognitive sequelae likely underestimated.
  • Adverse prognostic features: depression of consciousness at presentation is the main adverse prognostic feature. 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 pneumoniae 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 the performance of 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 is likely to 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

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About 

A general paediatric trainee in Queensland who enjoys clinical teaching, positive teamwork, research, and medication safety. Alyssa also loves travelling, scuba diving and camping with her family. A true child at heart, she loves playing games with her patients.

Author: Alyssa Courtney

A general paediatric trainee in Queensland who enjoys clinical teaching, positive teamwork, research, and medication safety. Alyssa also loves travelling, scuba diving and camping with her family. A true child at heart, she loves playing games with her patients.

2 Responses to "A Difficult Beast"

  1. Wendy Station, Founder and President, Encephalitis Global
    Wendy Station, Founder and President, Encephalitis Global 2 months ago .Reply

    Quote: “Recovery from encephalitis reaches a plateau at approximately 6–12 months.”

    The above statement is very disheartening. Society used to believe that recovery post encephalitis happens only for the first two years post-encephalitis…. More recent research has proven that due to the plasticity of the brain, recovery continues for the remainder of the survivor’s lifetime.
    And I’m a living breathing example of this.

    • Liz Ayub
      Liz Ayub 1 month ago .Reply

      Wendy, I agree that recovery continues. Possibly not as dramatically as during the initial stages, but notable progress can be seen. We have observed this in my daughters case 6 years following approximately a year of hospitalization.

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