Etiologies

• Infectious, para-infectious, autoimmune, toxic

• California Encephalitis Project

  • 1998 -2000, 334 patients (immunocompetent, ≥ 6 months of age)

  • Standardized testing for 14 specific viral, bacterial and parasitic pathogens.

  • Confirmed or probable:

  • Viral etiology - 31 cases (9%)

  • Bacterial etiology - 9 cases (3%)

  • Parasitic etiology - 2 cases (1%)

  • Noninfectious etiology - 32 cases (10%)

  • Non-encephalitis infection - 11 (3%)

  • Unexplained - 208 cases (62%)

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Differential Diagnosis

• Autoimmune/vascular disorders

  • Vasculitis​

  • Hashimoto encephalopathy

  • Cerebrovascular accident

  • Venous thrombosis

  • Lupus cerebritis

  • Intracerebral hemorrhage

  • Multiple sclerosis

  • Acute disseminated encephalomyelitis (ADEM)

• Neoplastic​

  • Lymphoma​

  • Paraneoplastic syndrome

• Infectious​

  • Myobacterium tuberculosis​

  • Creutzfeldt-Jakob disease

• Metabolic​

  • Mitochondrial disease​

  • Adrenoleukodystrophy

  • Diabetic ketoacidosis

• Toxin​

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Limbic Encephalitis

Definition: All 4 must be present

1. Subacute onset ( < 3 months) working memory deficits, seizures or psychiatric symptoms suggesting involvement of the limbic system

2. Bilateral brain abnormalities on T2- weighted fluid attenuated inversion recovery MRI highly restricted to the medial temporal lobes

3. At least one of the following

   • CSF pleocytosis (WBC > 5)​

   • EEG with epileptic or slow wave activity involving the temporal lobes

4. Reasonable exclusion of alternative causes ​

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• Associated autoantibodies: Anti- Hu, Anti- Ma, Anti- GAD, Anti-AMPA, Anti- GABA, Anti- Lgl1, Anti- CASPR2

• GAD Ab (serum) is seen in 80% of patients with type I diabetes mellitus.

• GAD Ab (serum) associated with limbic encephalitis have high titers (100-1,000 x).  Mild elevations are present in general population (~1%)

• GAD Ab (CSF) better support the diagnosis

• Poor outcomes reported, even with immune modulating therapies.

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Bickerstaff Brainstem Encephalitis

Probable (must have both)

1. Subacute onset ( < 4 weeks) of all the following

   1. Decreased consciousness​

   2. Bilateral external ophthalmoplegia

   3. Ataxia

2. Reasonable exclusion of alternative causes

Definite Bickerstaff's brainstem encephalitis

• Positive IgG anti-GQ1b antibodies

 

Common additional symptoms:

• Pupillary abnormalities

• Bilateral facial palsy

• Generalized limb weakness

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MRI often normal but when abnormal, T2 changes are noted in the brainstem

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Outcome is favorable

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Differential diagnosis: Listeria, EV 71 encephalitis, neurosarcoidosis, primary CNS lymphoma, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)

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Anti-N-methyl-D-aspartate receptor (NMDAR) Encephalitis

Pathophysiology

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• Anti-NMDAR antibodies cause a selective and reversible decrease in NMDAR surface proteins, cluster density, and synaptic localization

• NMDAR antibodies cause neuronal dysfunction not death

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Clinical symptoms:

• Prodrome

• fever, headache, viral-like illness

• Psychiatric and behavioral problems

• Insomnia

• Altered consciousness/encephalopathy

• Seizures (not typically refractory)

• Dyskinesias (chorea, dystonia)

• Autonomic instability

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Diagnostic Studies

Labs

• -+/-    CSF pleocytosis and/or elevated protein

• CSF antibodies more sensitive than serum (~14% w/ + CSF Ab but – serum Ab)

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Imaging

• Brain MRI is abnormal in ~ 31% of children

• MRI abnormalities include cortical and subcortical T2 changes and/or transient cortical-meningeal enhancement

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Neurophysiology

• EEG abnormal in 60-70% (diffuse/focal slowing, RD and extreme delta brush)

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Treatment

• Immunotherapy for NMDA Encephalitis:

  • First line immunotherapy:

    • IVIg

    • Steroids

    • Plasmapheresis

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• Second line immunotherapy:

  • Rituximab

  • Cyclophosphamide

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Outcome:

• Observational study of 577 patients with lab confirmed NMDA Ab encephalitis

• Patients enrolled 2007 and 2012. Age range 8 months to 85 years

• 211 were children

• Outcomes were measured with modified Rankin

• 30 died

• 53% (251/472) improved within 4 weeks to first line therapy/tumor removal

• 57% (125/221) with 2nd line therapy; showed improvement (mRS 0-2)

• Outcomes continued to improved beyond 18 months.

• Predictors of good outcome were:

  • Early treatment and no admission to the ICU

  • Outcomes were similar for children and adults

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Febrile infection–related epilepsy Syndrome (FIRES)

FIRES is an epileptic encephalopathy seen in children with refractory status epilepticus (RSE) after febrile illness

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Diagnostic criteria

• SE or fulminant onset of bilateral focal or generalized seizures of different types for days or weeks despite treatment

• Illness with fever or other clinical evidence suggestive of infection preceding seizures

• Absence of previous neurological disease

• Absence of evidence for infectious encephalitis and metabolic disorders

• Absence of abnormal behavioral and movement disorders

• Negative neuronal antibody test results

• Drug resistant focal epilepsy and neuropsychological impairments immediately following the phase of high seizure frequency in nearly all patients.

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Pathophysiology is not well understood but there is a suggestion of maladaptive activation of the innate immune system  (e.g. elevated CSF neopterin)

• Sustained seizures lead to neuroinflammation, higher seizure burden, further inflammation.