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Immunotherapy rarely inflames the nerves, the brain or the junction between nerve and muscle. Drooping eyelids, double vision, trouble swallowing or speaking, weakness spreading up the legs, numbness, severe headache with a stiff neck, confusion or a seizure need urgent assessment. Treatment is quick high-dose steroids, often with immunoglobulin or plasma exchange, and a neurologist.
Neurological irAEs occur in about 6% on PD-(L)1 inhibitors, 4% on CTLA-4 inhibitors and 12% on combinations, mostly grade 1 to 2; grade 3 or more is under 1% but can be fatal or permanent, usually within the first 3 months (SITC 2021). Myasthenia gravis carries about 20% mortality and clusters with myositis and myocarditis.
SITC 2021: refer every neurological irAE to a specialist whatever the grade. Myasthenia: antibody testing, a search for myositis, myocarditis and thyroid dysfunction, negative inspiratory force and vital capacity; stop the checkpoint inhibitor; steroids (prednisone 1 to 1.5 mg/kg for grade 2), pyridostigmine, and IVIG or plasma exchange (LE: 1); admission and possibly intensive care for grade 3 to 4. Guillain-Barré: spine MRI, lumbar puncture, EMG and nerve conduction; permanent discontinuation with IVIG or plasma exchange plus steroids (LE: 1). Encephalitis: MRI, lumbar puncture, EEG, autoimmune and paraneoplastic panels and infection PCR, empirical antivirals; pulse methylprednisolone 1000 mg for 3 to 5 days with IVIG or plasma exchange, then rituximab if refractory (LE: 1). Aseptic meningitis: MRI, lumbar puncture, cortisol and ACTH, antibiotics until bacterial meningitis is excluded, prednisone 0.5 to 1 mg/kg (LE: 4). The 2021 neurologic consensus definitions (seven core disorders, graded by certainty) standardise the diagnosis and advise brain imaging before lumbar puncture.
Why: These conditions overlap, can worsen quickly and need specialist tests to tell apart.
“Patients diagnosed with neurological irAEs should be referred to a specialist, regardless of severity.”
Why: Myasthenia often comes with heart and muscle inflammation, and weak breathing muscles can fail.
“Workup should include diagnostic antibody testing for myasthenia gravis and evaluation for concurrent myositis, myocarditis, and thyroid dysfunction. Electrodiagnostic studies may be performed to distinguish myasthenia gravis from myositis. Pulmonary function should be assessed with negative inspiratory force (NIF) and vital capacity (VC).”
Why: Prompt immune treatment and close watch on breathing reduce the risk of respiratory failure.
“Patients diagnosed with myasthenia gravis should discontinue ICI therapy and should receive IVIG or PLEX with corticosteroid therapy and pyridostigmine. These patients should receive frequent pulmonary assessments”
Why: Severe myasthenia can stop the breathing muscles working.
“Patients with grade 3 or 4 myasthenia gravis should be admitted to the hospital and may need ICU-level monitoring. ICIs should be permanently discontinued, and frequent pulmonary function assessments and daily neurological review should be performed.”
Why: These exclude spinal cord compression and confirm nerve root inflammation.
“Workup for patients with suspected Guillain-Barré syndrome should include MRI of the spine to rule out a compressive lesion, LP, EMG, nerve conduction studies, and ganglioside antibody panel of blood and CSF.”
Why: Ascending weakness can reach the breathing muscles; immunoglobulin or plasma exchange is the standard treatment.
“Patients diagnosed with Guillain-Barré syndrome should always permanently discontinue ICI therapy, and should receive IVIG or PLEX with corticosteroid therapy”
Why: A mass in the brain can make lumbar puncture dangerous, and the puncture can itself alter the scan.
“Head imaging (CT or MRI) should be performed prior to lumbar puncture (LP) to exclude mass lesions that may cause herniation and because LP can cause pachymeningeal enhancement.”
Why: Infection, cancer in the meninges and hypophysitis can all look the same.
“Workup for patients with suspected aseptic meningitis should include MRI of the brain and pituitary with and without contrast, lumbar puncture (LP), cortisol, and ACTH.”
Why: Viral encephalitis must be treated while the cause is found.
“Workup for patients with suspected encephalitis should include MRI of the brain, LP, CBC, CMP, autoimmune encephalopathy and paraneoplastic panels of blood and cerebrospinal fluid (CSF), PCR for infectious encephalitis, thyroid panel, and electroencephalogram (EEG).”
Why: These are the most dangerous neurological side effects and are treated at full strength from the start.
“Patients with any grade of encephalitis or Guillain-Barré syndrome should receive pulse-dose methylprednisolone at 1000 mg IV daily for 3–5 days, and should additionally receive IVIG or PLEX.”
Why: Steroid-resistant encephalitis needs another immune treatment.
“If ICI-related encephalitis does not respond to pulse-dose corticosteroids, patients may receive IVIG (2 g/kg in divided doses over the course of 5 days), PLEX (one session every other day for 5–7 cycles), or rituximab (375 mg/m2 weekly infusion for 4 weeks)”
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
SITC 2021 is the guideline read in full, and it grades its key treatments LE: 1: IVIG or plasma exchange with steroids and pyridostigmine for myasthenia gravis, IVIG or plasma exchange with steroids and permanent discontinuation for Guillain-Barré syndrome, and IVIG, plasma exchange or rituximab for steroid-refractory encephalitis. These grades describe the evidence for the treatments in the non-immunotherapy forms of these diseases; there are no trials in checkpoint inhibitor patients. The 2021 neurologic consensus definitions do not give treatment but standardise the diagnosis into seven core disorders with a certainty level, and note that treatment often starts at probable or possible certainty. ASCO 2021 (abstract) makes neurological toxicity an exception to continuing treatment at grade 1. ESMO 2022 could not be read.
SITC, Journal for ImmunoTherapy of Cancer 2021 · Journal for ImmunoTherapy of Cancer 2021 · ASCO, Journal of Clinical Oncology 2021 · ESMO, Annals of Oncology 2022
Where it differs: Classifies each event as immune-related meningitis, encephalitis, demyelinating disease, vasculitis, neuropathy, neuromuscular junction disorder or myopathy, each as definite, probable or possible, with severity, antibody status and any concurrent irAE recorded.
Evidence: Modified Delphi consensus of 27 panellists from 15 academic centres; definitions, not graded recommendations.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Myasthenia gravis: stop the checkpoint inhibitor; IVIG or plasma exchange with steroids and pyridostigmine | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Guillain-Barré syndrome: permanent discontinuation; IVIG or plasma exchange with steroids | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Steroid-refractory encephalitis: IVIG, plasma exchange or rituximab | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Ocular myasthenia or non-Guillain-Barré polyneuropathy of grade 2 or less: prednisone 0.5 to 1 mg/kg/day | LE: 2 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Aseptic meningitis: prednisone 0.5 to 1 mg/kg/day | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Painful peripheral neuropathy: gabapentin, pregabalin or duloxetine until it resolves “Patients diagnosed with painful peripheral neuropathy should receive neuropathic pain medication such as gabapentin, pregabalin, or duloxetine until neuropathy resolves” | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Neurological toxicity is an exception to continuing treatment at grade 1 | expert consensus | ASCO, Journal of Clinical Oncology 2021 |
Shares Methylprednisolone, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae, acute-oncology.
Shares Methylprednisolone, Checkpoint inhibitor hypophysitis and adrenal insufficiency: emergency treatment, replacement and steroid emergency card, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer and the tags protocol, irae, acute-oncology.
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Shares Checkpoint inhibitor hypophysitis and adrenal insufficiency: emergency treatment, replacement and steroid emergency card, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae.
Shares Methylprednisolone, Checkpoint inhibitor hypophysitis and adrenal insufficiency: emergency treatment, replacement and steroid emergency card, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer and the tags protocol, irae.
Shares ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab, Tremelimumab and the tags protocol, irae.