Table 3

irDemyelinating

Subtypes:
(Median 8, range 7–9)
Possible symptoms:
(Median 8, range 7–9)
Supportive examination findings:
(Median 8, range 7–9)
Diagnostic criteria: All levels of diagnostic certainty for irDemyelinating disease require a supportive history, examination, and timing relative to ICI therapy plus:
(Accuracy median 8, range 6–9; usability median 8, range 6–9)
  • Optic neuritis

  • Transverse myelitis

  • ADEM (acute demyelinating encephalomyelitis)

  • Other myelitis

  • AHEM (acute hemorrhagic encephalomyelitis)

  • Clinically isolated syndrome

  • Radiologically isolated syndrome

  • Numbness

  • Paresthesias, tingling

  • Weakness

  • Ataxia, loss of balance

  • Vision loss, pain with eye movements

  • Double vision

  • Vertigo

  • Autonomic symptoms (bladder and bowel control, etc)

  • Altered mental status (in ADEM)

Focal neurologic deficits, including:
  • Deficits localizing to cerebral hemispheres (see irEncephalitis supportive examination findings for more extensive list; weakness, hyperreflexia, positive Babinski or Hoffmann sign, sensory changes)

  • Deficits localizing to posterior fossa (diplopia, internuclear ophthalmoplegia, nystagmus, ataxia, dysmetria, dysarthria, dysphagia)

  • Signs of optic neuropathy (decreased visual acuity, visual field loss, dyschromatopsia, relative afferent pupillary defect, optic disc edema)

  • Signs of transverse myelitis (sensory deficits including sensory level, weakness, hyperreflexia, positive Babinski or Hoffmann sign, positive Romberg sign)

Definite
Required:
Option A:
  1. Symptoms and signs consistent with CNS disease (including optic neuritis, transverse myelitis) AND

  2. Biopsy-proven CNS demyelination


Option B:
  1. Symptoms and signs consistent with CNS disease (including optic neuritis, transverse myelitis) AND

  2. Stabilization or improvement with immunomodulation including steroids and/or discontinuation of checkpoint inhibitor AND At least one of

  3. Demyelinating autoimmune antibodies (aquaporin 4, myelin oligodendrocyte glycoprotein) OR

  4. Abnormality on MRI imaging* consistent with acute demyelination (contrast enhancement and/or T2 hyperintensity with neuroanatomic correlation with symptoms and signs) in at least one of the following locations:

    1. Spinal cord

    2. Optic nerve

    3. Two or more brain regions (periventricular, cortical or juxtacortical, infratentorial)


Supportive:
  1. Presence of CSF-specific oligoclonal bands and/or elevated IgG index

  2. Inflammation on CSF studies (lymphocytic pleocytosis, elevated protein)

  3. Abnormal evoked potentials

  4. Abnormal ophthalmology/neuro-ophthalmology evaluation including abnormal formal visual field testing or optical coherence tomograph


*If a scan fulfills these criteria, it is considered demyelinating rather than encephalitis
Evaluation may include:
(Median 8, range 6–9)
Common:
  1. MRI with contrast of brain, orbit, cervical and thoracic spinal cord

  2. Lumbar puncture with CSF studies including those for irEncephalitis and CSF-restricted oligoclonal bands

  3. Serum demyelinating autoimmune antibody evaluation (aquaporin 4 and myelin oligodendrocyte glycoprotein); may additionally consider serum and/or CSF neural autoimmune antibody evaluation as part of irEncephalitis and irMyelitis differential diagnosis

Probable
Required:
  1. Symptoms and signs consistent with CNS disease (including optic neuritis, transverse myelitis) AND At least one of

  2. Demyelinating autoimmune antibodies (aquaporin 4, myelin oligodendrocyte glycoprotein) OR

  3. Presence of CSF-specific oligoclonal bands and/or elevated IgG index OR

  4. Abnormality on MRI imaging* consistent with acute demyelination (contrast enhancement and/or T2 hyperintensity with clear neuroanatomic correlation with symptoms and signs) in at least one of the following locations:

    1. Spinal cord

    2. Optic nerve

    3. Two or more brain regions (periventricular, cortical or juxtacortical, infratentorial)


Supportive:
  1. Inflammation on CSF studies (lymphocytic pleocytosis, elevated protein)

  2. Abnormal evoked potentials

  3. Abnormal ophthalmology/neuro-ophthalmology evaluation including abnormal formal visual field testing or optical coherence tomography


*If a scan fulfills these criteria, it is considered demyelinating rather than encephalitis
Possible:
  1. Formal ophthalmology/neuro-ophthalmology evaluation that may include formal visual field testing and optical coherence tomography

  2. CSF autoimmune antibody evaluation (aquaporin 4 and myelin oligodendrocyte glycoprotein)

  3. Evoked potentials

  4. JC virus PCR

Uncommon:
1. Brain biopsy
Possible
Required:
1. Symptoms and signs consistent with CNS disease (including optic neuritis, transverse myelitis)
Supportive:
  1. Inflammation on CSF studies (lymphocytic pleocytosis, elevated protein)

  2. Abnormal evoked potentials

  3. Abnormal ophthalmology/neuro-ophthalmology evaluation including abnormal formal visual field testing or optical coherence tomography of the optic nerve

  • CNS, central nervous system; CSF, cerebrospinal fluid; ICI, immune checkpoint inhibitor.