The time to onset varies from 6 to 13 weeks. A range of neurological irAEs have been described, including irAEs involving the central nervous system (CNS; encephalitis and aseptic meningitis) and those involving the peripheral nervous system (acute immune demyelinating polyneuropathy, chronic immune demyelinating polyneuropathy, cranial nerve neuropathies, myasthenic syndromes and myositis).

Neuromuscular disorders account for 50% of neurological irAEs, which primarily include myositis, myasthenia gravis (MG), demyelinating polyradiculoneuropathy and overlapping syndromes. It is important to recognise IR-myositis and monitor for myocardial involvement, as well as bulbar involvement that may rapidly lead to cardiac or respiratory failure, persisting disability or even death.

IR-MG-like syndrome is an increasingly recognised and feared ICI-related complication. Typical symptoms include exercise-dependent fluctuating weakness of the proximal extremities or bulbar muscle groups and ocular symptomssuch as ptosis and diplopia.

Generally, IR-MG-like syndrome occurs de novo and two-thirds of patients are positive for anti-acetylcholine receptor antibodies. Early involvement of neurological expertise is mandatory. In addition to ICI discontinuation, CSs and pyridostigmine are the first-line management approach. Similar to IR-myositis, severe initial presentation, including respiratory and bulbar symptoms, often requires the immediate use of IVIG and/or plasma exchange or selective separation. Importantly, remission without long-term use of immunosuppression has been noted in only a few patients with mild symptoms limited to the ocular or facial muscles.

As both myasthenia and myositis may involve weakness of ocular, facial and bulbar muscles as well as proximal tetraparesis, it is essential to recognise clinical signs for potential myositis and myocarditis (e.g. CK elevation, troponin T or I elevation, pain). See sections on IRrheumatological and IR-CV toxicities.

IR-neuropathies are mostly demyelinating and may presentas an acute polyradiculoneuritis [IR-GuillaineBarré syndrome (GBS)] with an incidence of 0.2%-0.4%. Clinical findings resemble classical ascending GBS symptoms, including bilateral proximal weakness, ataxia, distal sensory, autonomic disturbances and cranial nerve involvement. Corresponding swelling of nerve roots impairs cerebrospinal fluid flow leading to cytoalbuminary dissociation. Antiganglioside antibodies are negative. Prompt recognition of symptoms is essential to prevent respiratory insufficiency due to affected cervical nerve roots. Unlike non-ICI associated GBS, CSs are associated with a favourableoutcome in IR-GBS and are recommended as first-linetreatment. IVIG is used as an additional or alternative treatment if CSs are not possible.

Aseptic meningitis may present with headache and neck stiffness with or without fever. In contrast to encephalitis, patients are cognitively not impaired.

Diagnostic work-up should include MRI and lumbar puncture to rule out viral or bacterial infection. Adrenal insufficiency should also be ruled out. In case of grade 1 toxicity, ICI treatment should be withheld. For higher grades, prednisolone (0.5-1 mg/kg) is the treatment of choice.

Patients with encephalitis present with confusion and altered behaviour. Seizures and a decreased level of consciousness are also typical symptoms. A neurological consultation is mandatory.

Further work-up includes brain MRI,electroencephalogram and lumbar puncture to rule out infection. In case of grade 1 toxicity, ICI treatment should be withheld. For grade 2,  prednisolone (0.5-1 mg/kg) is the treatment of choice. For higher grades, high-dose CSs at a dose of 1000 mg methylprednisolone i.v. daily for 3-5 days should be considered with or without IVIG. Rituximab or plasmapheresis may also be considered.

Purple: general categories or stratification; turquoise: combination of treatments or other systemic treatments; white: other aspects of management.ADL, activities of daily living; CS, corticosteroid; GBS, GuillaineBarré syndrome; ICI, immune checkpoint inhibitor; IR, immune-related; irAE, immune-related adverseevent; i.v., intravenous; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; PE, plasma exchange.aPatients presenting with any neurological symptoms should be referred to a neurologist and ICI should be held until the grade of symptoms is confirmed. bIn all scenarios, pyridostigmine starting from 3  30 mg orally up to 600 mg daily may be used in case of myasthenic symptoms; in i.v. application, 30 mg oralpyridostigmine corresponds to 1 mg i.v. or 0.75 mg neostigmine i.m. In case of intubation, pyridostigmine may be discontinued or withheld.cTimely consultation of a neurologist.dCSs are not usually recommended for idiopathic GBS; in mild ICI-related forms, however, a trial is reasonable (methylprednisolone 2-4 mg/kg/day) followed by slow CStaper. Pulse CS dosing (methylprednisolone 1 g/day for 5 days) may also be considered for grade 3-4 events along with IVIG or plasmapheresis.eFor life-threatening symptoms, PE might be the favourable option; consider contraindications: renal failure, hypercoagulable states, sepsis, haemodynamic instability.

Purple: general categories or stratification; turquoise: combination of treatments or other systemic treatments; white: other aspectsof management.Abs, antibodies; ACTH, adrenocorticotrophic hormone; ANA, antinuclear antibody; CNS, central nervous system; CS,corticosteroid; EEG, electroencephalogram; HIV, human immunodeficiency virus; HSV, Herpes simplex virus; IgG, immunoglobulinG; IR, immune-related; i.v., intravenous; IVIG, intravenous immunoglobulin; M/C/S, microscopy, culture and susceptibility; MRI,magnetic resonance imaging; PRES, Posterior Reversible Leukoencephalopathy Syndrome; TSH, thyroid-stimulating hormone;WBC, white blood cell.Reproduced from Haanen et al

• Referral to a neurologist should be considered for mild (or more severe) symptoms of GBS, leukoencephalopathy, MG, myopathy and peripheral neuropathy. The type and frequency of assessments vary according to the grade of symptoms [IV, B].
• Patients presenting with any neurological symptoms should be referred to a neurologist and ICI should beheld until the grade of symptoms is confirmed [IV, B]. For grade 1 symptoms, ICI treatment can be continued and the patient monitored for deterioration [IV, B].
• For grade 2 symptoms, ICI treatment should be interrupted and oral or i.v. (methyl)prednisolone initiated [IV, B].
• For grade 3 or 4 symptoms, more intensive immunemodulation may be required in addition to CSs or by exchanging CSs for IVIG (or plasma exchange or selective separation in cases of GBS, leukoencephalopathy, MG orIR-myopathy) [V, B].