Table 5

irNeuropathy

Subtypes:
(Median 8, range 4–9)
Possible symptoms:
(Median 8, range 4–9)
Diagnostic criteria: All levels of diagnostic certainty for irNeuropathy require a supportive history, examination, and timing relative to ICI therapy plus:
(Accuracy median 8, range 6–9; usability Median 8, range 5–9)
  • Polyneuropathy

  • Polyradiculopathy

  • Axonal polyradiculoneuropathy, radiculoplexus neuropathy

  • CIDP, AIDP (GBS), Lewis-Sumner syndrome, MADSAM, MMN, GBS variants (AMAN, AMSAN, MFS, cervical-brachial-pharyngeal variant)

  • Sensory neuronopathy

  • Mononeuritis multiplex, vasculitic neuropathy

  • Brachial neuritis, lumbosacral radiculoplexus neuropathy

  • Acute mononeuropathy

  • Cranial neuropathy

  • Small fiber neuropathy

  • Autonomic neuropathy

  • Paresthesia, burning, itching, allodynia, neuropathic pain

  • Numbness, weakness

  • Diplopia, dysphagia or respiratory failure

  • Muscle cramps and/or fasciculations

  • Autonomic symptoms (eg, dry mouth, dry eyes, anhidrosis, orthostasis, diarrhea/constipation, impotence, early satiety)

  • Imbalance, incoordination, ataxia, falls

Definite
Required (large fiber):
  1. Electrodiagnostic studies abnormal and demonstrate a neuropathy subtype associated with ICI AND

  2. Evaluation reveals laboratory or imaging evidence supportive of an immune mediated etiology for the neuropathy phenotype (eg, ANCA and mononeuritis multiplex, cytoalbuminologic dissociation in CSF and GBS) AND

  3. No other lab abnormality, clinical characteristic or imaging finding provides a reasonable alternate explanation for the presentation


Supportive when present but not required:
  1. Nerve biopsy performed and shows inflammatory infiltrate or vasculitis without other cause

  2. Autonomic function testing abnormal

Supportive examination findings:
(Median 8, range 6–9)
  • Loss of sensation (temperature, pinprick, vibration, proprioception)

  • Weakness usually distal or proximal/distal (AIDP/CIDP/GBS)±atrophy

  • Hyporeflexia or areflexia

  • Gait dysfunction (steppage, ataxic, other)

Evaluation may include:
(Median 8, range 6–9)
Probable
Required (large fiber):
  1. Electrodiagnostic studies abnormal and demonstrate a neuropathy subtype associated with ICI AND

  2. Evaluation reveals another plausible etiology may exist (eg, patient received prior neurotoxic chemotherapy) but not thought to account for the irNeuropathy presentation OR

  3. Nerve biopsy performed and inconclusive


OR
Required (small fiber)*:
  1. History and examination consistent with small fiber neuropathy with or without autonomic dysfunction AND

  2. Skin biopsy or autonomic function testing abnormal and supportive of small fiber/autonomic neuropathy AND

  3. No other lab abnormality in common diagnostic labs (HbA1c, B12, TSH, SPEP/IFE) or relevant labs or imaging provide an alternate explanation for symptoms


*An isolated small fiber neuropathy after ICI therapy is extremely rare. Workup may be limited or inconclusive so it is excluded from the definite category
Common:
  1. Serum testing: HbA1c, TSH, vitamin B12, SPEP/IFE, CK

  2. Electrodiagnostic studies (including EMG/NCS)

  3. MRI with gadolinium contrast of brain, spine, plexus or nerve

Possible:
  1. Lumbar puncture with CSF studies (cell counts including cytology, glucose, protein, infectious studies if nerve root enhancement or clinical suspicion)

  2. Additional laboratory testing guided by neuropathy phenotype: ANCA, ANA, ESR, anti-SM, Ro, La, RNP, anti-DS DNA, ganglioside ab, anti-MAG, anti-Hu, additional specialized antibody testing, thiamine, folate, vitamin B6, hepatitis B/C, HIV, Lyme

  3. Bedside pulmonary function tests and/or swallow evaluation

Uncommon:
  1. Autonomic function testing (AFT) and/or thermoregulatory sweat test

  2. Genetic testing (ie, Charcot-Marie-Tooth neuropathies, hereditary amyloidosis)

  3. Nerve biopsy

  4. Skin biopsy

Possible
Required:
  1. Clinical criteria only for large fiber or small fiber neuropathy AND

  2. No EDX, laboratory studies or additional workup performed

  • AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy; ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; CIDP, chronic inflammatory demyelinating polyneuropathy; CK, creatine kinase; CSF, cerebrospinal fluid; EDX, electrodiagnostic studies; EMG, electromyography; ESR, erythrocyte sedimentation rate; GBS, Guillain-Barré syndrome; ICI, immune checkpoint inhibitor; MADSAM, multifocal acquired demyelinating sensory and motor neuropathy; MFS, Miller-Fisher Syndrome; SPEP/IFE, serum protein electrophoresis/immunofixation; TSH, thyroid stimulating hormone.