Table 2

irEncephalitis

Subtypes:
(Median 8, range 5–9)
Possible symptoms:
(Median 8, range 5–9)
Supportive examination findings:
(Median 8, range 7–9)
Diagnostic criteria: All levels of diagnostic certainty for irEncephalitis require a supportive history, examination, and timing relative to ICI therapy plus:
(Accuracy median 8, range 7–9; usability median 8, range 7–9)
  • Encephalitis

  • Meningoencephalitis

  • Encephalomyelitis

  • Limbic encephalitis

  • Cerebellitis

  • Rhombencephalitis

  • Opsoclonus-myoclonus-ataxia syndrome

  • Stiff-person syndrome/progressive encephalomyelitis with rigidity and myoclonus

  • Altered arousal: lethargy, somnolence, obtundation, coma

  • Confusion, delirium, agitation

  • Headache

  • Memory deficits including working memory and short-term memory

  • Psychiatric symptoms including delusions and hallucinations

  • Speech problems

  • Weakness

  • Sensory changes

  • Imbalance

  • Bowel and bladder problems, erectile dysfunction

  • New-onset seizures

  • Encephalopathy or decreased arousal

  • Abnormal cognitive screening testing

  • Aphasia and other cortical cognitive deficits

  • Delusion/hallucinations

  • Motor/sensory/coordination deficits

  • Hyperreflexia, spasticity

  • Positive Babinski, Hoffman signs

  • Abnormal movements including tremor, hypokinesia, bradykinesia, choreiform movements

  • Rigidity/myoclonus

  • Ataxia

  • Dysarthria

  • Eye movement abnormalities including nystagmus

  • Cranial neuropathies, optic disc edema

  • May be febrile or afebrile

Definite
Required:
  1. Symptoms and signs consistent with encephalitis AND

  2. Exclusion of infectious cause (including negative HSV PCR, VZV PCR), primary or metastatic cancer (including absence of typical lesion on MRI brain) and radiation necrosis (including absence of typical lesion on MRI brain)


And at least one of
  1. Brain biopsy demonstrating CNS inflammation without evidence of malignancy or infection OR

  2. CNS inflammation as demonstrated by at least one of the following plus stabilization or improvement with immunomodulation including steroids and/or discontinuation of checkpoint inhibitor:

    1. Parenchymal abnormality on MRI brain (T2-FLAIR hyperintensity and/or contrast enhancement) and/or spine

    2. Inflammation on CSF studies (pleocytosis (>5 WBC) and/or elevated protein)

    3. Abnormal EEG (epileptiform changes and/or other changes that localize to symptoms and signs)

    4. Neural specific autoantibodies in serum and/or CSF with known syndrome consistent with symptoms and signs


Supportive:
1. Presence of CSF-specific oligoclonal bands and/or elevated IgG index
Evaluation may include:
(Median 8, range 5–8)
Probable
Required:
  1. Symptoms and signs consistent with encephalitis AND

  2. Exclusion of infectious cause (including negative HSV PCR, VZV PCR), primary or metastatic cancer (including absence of typical lesion on MRI brain) and radiation necrosis (including absence of typical lesion on MRI brain) AND

  3. CNS inflammation as demonstrated by at least one of following:

    1. Parenchymal abnormality on MRI brain (T2-FLAIR hyperintensity and/or contrast enhancement) and/or spine

    2. Inflammation on CSF studies (pleocytosis (>5 WBC) and/or elevated protein)

    3. Abnormal EEG (epileptiform changes and/or other changes that localize to symptoms and signs)

    4. Neural autoimmune antibodies in serum and/or CSF with known syndrome consistent with symptoms and signs.


Supportive:
1. Presence of CSF-specific oligoclonal bands and/or elevated IgG index
Common:
  1. MRI brain with contrast and/or MRI cervical and thoracic spine

  2. Lumbar puncture with CSF studies including opening pressure; cell count and differential; total protein and glucose measurement*; oligoclonal bands* and IgG index*; cytology and/or flow cytometry**; Gram stain and culture; HSV PCR, VZV PCR, other viral and other infectious studies as appropriate***

  3. Metabolic evaluation including CBC, BMP, LFTs, TSH, ammonia, arterial or venous blood gas, urinalysis

  4. ESR, CRP

  5. Serum and CSF neural and demyelinating autoimmune antibody evaluation

  6. EEG


*These studies typically require corresponding serum levels for interpretation
**As appropriate for primary cancer
***Consider specific studies based on local epidemiology, seasonal incidence, travel history and other patient risk factors; a film array may incorporate testing of many infectious agents and obviate the need for separate testing
Possible
Required:
1. Symptoms and signs consistent with encephalitis
Supportive:
1. Diagnostic findings of CNS inflammation per Probable diagnostic criteria but other causes cannot be excluded
Possible:
  1. CT head (should consider performing with contrast if unable to perform MRI brain)

  2. Additional infectious serologies based on local epidemiology, seasonal incidence, travel history and other patient risk factors

  3. ANA and extractable nuclear antigens

  4. ANCA

  5. Additional antibody studies associated with encephalitis, myelitis or ataxia: TPO and thyroglobulin antibodies, Gq1b antibodies, celiac antibody panel

  6. Brain biopsy

  7. PET brain

Uncommon:
  1. CSF cytokine levels (eg, IL-6, IL-10)

  2. Metagenomic next-generation sequencing for infectious causes

  • Note: If patients fulfill demyelinating criteria, they should not be included in this category.

  • ANA, anti-nuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; BMP, Basic Metabolic Panel; CBC, complete blood count; CNS, central nervous system; CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; FLAIR, fluid attenuated inversion recovery; HSV, herpes simplex virus; IL, interleukin; LFT, Liver Function Test; TPO, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; VZV, varicella-zoster virus.