Autoimmune Encephalitis

Diagnosis

A review of clinical approaches to diagnosis of autoimmune encephalitis (Graus et al, 2016)

• Diagnostic criteria for definite autoimmune limbic encephalitis (all 4 criteria must be met)

1. Subacute onset (rapid progression in less than 3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system
2. Bilateral brain abnormalities on FLAIR MRI highly restricted to the medial temporal lobes (or on FDG-PET)
3. At least one of the following:
   1. CSF pleocytosis (white blood cell count more than 5 cells / mm)
   2. EEG with epileptic or slow-wave activity involving the temporal lobes
4. Reasonable exclusion of alternative causes

• Diagnostic criteria for possible autoimmune encephalitis (all 3 criteria must be met)

1. Subacute onset (rapid progression in less than 3 months) of working memory deficits (short-term memory loss), altered mental status (decreased or altered level of consciousness, lethargy, or personality change), or psychiatric symptoms
2. At least one of the following:
   1. New focal CNS findings
   2. Seizures not explained by a previously known seizure disorder
   3. CSF pleocytosis (white blood cell count of more than 5 cells / mm)
   4. MRI features suggestive of encephalitis (hyperintense signal on FLAIR highly restricted to one or both medial temporal lobes (limbic encephalitis), or in multifocal areas involving grey matter, white matter, or both compatible with demyelination or inflammation)
3. Reasonable exclusion of alternative causes

• Diagnostic criteria for autoantibody-negative but probable autoimmune encephalitis (all 4 criteria must be met)

1. Rapid progression (less than 3 months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms
2. Exclusion of well-defined syndromes of autoimmune encephalitis (e.g., typical limbic encephalitis, Bickerstaff’s brainstem encephalitis, acute disseminated encephalomyelitis)
3. Absence of well characterized autoantibodies in serum and CSF, and at least 2 of the following criteria:
   1. MRI abnormalities suggestive of autoimmune encephalitis
   2. CSF pleocytosis, CSF-specific oligoclonal bands or elevated CSF IgG index, or both
   3. Brain biopsy showing inflammatory infiltrates and excluding other disorders (e.g., tumor)
4. Reasonable exclusion of alternative causes

Antibodies in the diagnosis of autoimmune encephalitis (Graus et al, 2016)

• Antibodies against intracellular antigens
  • Hu (ANNA1)
    • Syndrome: limbic encephalitis
    • Diagnostic assay: Western blot
    • Frequency of cancer: >95% (most commonly small-cell lung carcinoma)
  • Ma2
    • Syndrome: limbic encephalitis
    • Diagnostic assay: Western blot
    • Frequency of cancer: >95% (most commonly testicular seminoma)
  • GAD
    • Syndrome: limbic encephalitis
    • Diagnostic assay: radioimmunoassay
    • Frequency of cancer: 25% (most commonly thymoma, small-cell lung carcinoma)
• Antibodies against synaptic receptors
  • NMDA receptor
    • Syndrome: Anti-NMDA receptor encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: varies with age and sex (most commonly associated cancer is ovarian teratoma)
  • AMPA receptor
    • Syndrome: limbic encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 65% (most commonly thymoma, small-cell lung carcinoma)
  • GABAb receptor
    • Syndrome: limbic encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 50% (most commonly small-cell lung carcinoma)
  • GABAa receptor
    • Syndrome: encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: <5% (most commonly thymoma)
  • mGluR5
    • Syndrome: encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 70% (most commonly Hodgkin's lymphoma)
  • Dopamine 2 receptor
    • Syndrome: basal ganglia encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 0%
• Antibodies against ion channels and other cell-surface proteins
  • LG1
    • Syndrome: limbic encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 5-10% (most commonly thymoma)
  • CASPR2
    • Syndrome: Morvan's syndrome or limbic encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 20-50% (most commonly thymoma)
  • DPPX
    • Syndrome: encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: <10% (most commonly Lymphoma)
  • MOG
    • Syndrome: acute disseminated encephalomyelitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 0%
  • Aquaporin 4
    • Syndrome: encephalitis
    • Diagnostic assay: cell-based assay
    • Frequency of cancer: 0%
  • GQ1b
    • Syndrome: Bickerstaff's brainstem encephalitis
    • Diagnostic assay: ELISA
    • Frequency of cancer: 0%

References

Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016). https://pubmed.ncbi.nlm.nih.gov/26906964/