Most irAE-Ns occur early in treatment, usually within 6 months of starting or switching ICIs, although irAE-Ns may occur anytime while on treatment or after completion.24 To be considered an irAE-N, symptoms must begin within 12 months of the last ICI infusion. In general, new neurologic autoimmunity presenting more than 12 months after the last ICI infusion is unlikely to be an irAE. IrAE-Ns occurring between 6 and 12 months after completing an ICI are possible but less common. Diagnosis and evidence of relatedness in these later onset irAEs may require a higher ‘burden of proof’ in the individual patient. This area warrants additional research (median 8, range 2–9).

A careful history, baseline neurologic examination, and ancillary data help confirm or exclude pre-ICI neurologic disease. Most patients with history of mild symptoms or stable, well-established neurologic disorders do not require an additional evaluation by a neurologist when starting an ICI. However, patients with known immune-mediated neurologic disorders or patients with systemic autoimmune conditions with neurologic involvement may benefit from evaluation prior to initiating ICI therapy or soon afterward. Such evaluation is especially important for neuro-immunologic conditions of a relapsing or fluctuating nature, such as myasthenia gravis (MG) or multiple sclerosis, where ascertainment of clinical and/or radiologic disease activity provides a baseline. Additional considerations in this patient group may include risk/benefit discussions, modification of baseline immunomodulation prior to starting an ICI, and assistance with interpretation of changes in neurologic status after starting ICI treatment (median 9, range 5–9).

Patients frequently have irAEs affecting multiple organ systems or multifocal involvement of the nervous system. A concurrent, non-neurologic irAE may increase the likelihood that neurologic symptoms represent an irAE-N. A neurologic irAE also prompts consideration of other irAEs when known patterns of overlapping disease exist (ie, a diagnosis of myopathy or MG prompts evaluation for myocarditis, or diagnosis of meningitis prompts consideration of encephalitis). Sometimes it may be artificial to separate overlapping syndromes, particularly when they cause similar clinical manifestations and/or have similar management. When multiple syndromes occur, neurologic irAEs are listed separately with as much specificity regarding diagnosis, level of certainty, and severity as possible for each irAE-N, understanding that it may be difficult to ascertain which irAE-N accounts for maximum severity (median 9, range 7–9).

While improvement on holding ICI therapy and/or initiating corticosteroids or other immunomodulatory therapy is non-specific, it is expected in most patients with irAE-Ns and further supports the diagnosis of an irAE-N. Some irAE-Ns, however, may be treatment refractory/resistant or result in chronic disease or irreversible neurologic deficits. Lack of improvement with treatment typically prompts broadening of the workup for alternate etiologies but does not exclude the possibility of an irAE-N that is treatment-resistant or irreversible (median 9, range 6–9).

Symptoms such as headache, confusion, fatigue and, in some cases, tremor are too non-specific to assign an irAE-N syndrome and may be related to other irAEs (eg, headache as a manifestation of an immune-related endocrinopathy) or due to other etiologies in patients with cancer, including cancer progression. Caution is advised when attributing these symptoms to an ICI. These symptoms, however, may trigger additional workup for irAEs along with other etiologies including toxic/metabolic disorders. Symptoms that are persistent and/or severe, even if unexplained, may lead to treatment delays or discontinuation of ICI therapy, but in isolation should not be classified as a neurologic irAE. If evaluation of symptoms leads to diagnosis of a neurologic irAE (eg, presentation with headache leads to a diagnosis of irMeningitis), an appropriate core syndrome and syndrome subtype is then assigned. If there are presentations that do not fit into a category outlined, or causal association with ICI is unknown (eg, posterior reversible encephalopathy syndrome), a general description of the syndrome is recommended (median 8, range 5–9).

Some irAEs are associated with well-characterized neural-specific antibodies. These antibodies may be known prior to ICI administration or detected during evaluation of an irAE-N. When naming an irAE-N in a patient with a known antibody, we recommend including the antibody as part of the diagnosis (eg, ‘definite immune-related myasthenia gravis with acetylcholine receptor antibodies’ or ‘probable immune-related myelitis with CRMP5 antibody’). Patients may additionally have low titer abnormal antibodies after ICI therapy. As many of these antibodies may be unrelated and are non-specific (eg, N-type VGCC antibody, GAD antibody), a patient’s syndrome should be referenced back to known antibody-associated syndromes before establishing a diagnosis. Recommendations for antibody evaluation and their assessment of association in irAE-N is an evolving area with extensive published literature.25 26 References to antibodies in the diagnostic evaluation and criteria have intentionally been kept general and to the discretion of the clinician evaluating the patient, except for key selected antibody recommendations which are syndrome specific (eg, acetylcholine receptor (AChR) antibodies, Hu or aquaporin-4 antibodies) (median 8, range 2–9).

Patients may have paraneoplastic syndromes exacerbated or triggered by ICI therapy.27 28 The distinction between a process driven by an underlying cancer and an irAE can have significant treatment implications, although many aspects of diagnosis and management overlap. Similar to the approach to autoantibodies, disease definitions have been constructed to include criteria that ensure a relationship. A patient may therefore initially have a ‘possible’ or ‘probable’ diagnosis before it becomes ‘definite’ and these patients typically benefit from multidisciplinary collaboration (median 9, range 5–9).

In addition to the diagnostic tests described above, LP with CSF studies evaluates for inflammation (expect pleocytosis, elevated protein) and excludes other causes of meningeal disease (expect negative cytology and flow cytometry, negative Gram stain and culture, negative infectious studies). Specific CSF studies are recommended for universally common infectious agents such as herpes simplex virus (HSV) and cryptococcal disease. Further CSF and/or serum infectious studies may be determined by local epidemiology, seasonal incidence, travel history and patient-specific risk factors. Blood cultures evaluate for septic meningitis.

As previously discussed, MRI is generally preferred to head CT except in very urgent circumstances.

Meningeal biopsy is needed only in exceptional circumstances (eg, chronic pachymeningitis or continued concern of leptomeningeal carcinomatosis despite unrevealing CSF studies). Sometimes, CSF cytokine profiles are not widely available but can sometimes differentiate between infectious and aseptic meningitis, and etiologies such as CNS lymphoma.

In addition to brain MRI, spinal cord MRI with dedicated short tau inversion recovery (STIR) and pre-contrast and post-contrast T1 sequences may be obtained to evaluate for inflammatory, demyelinating, ischemic, or metastatic lesions. LP with CSF studies evaluates for evidence of inflammation (expect lymphocytic pleocytosis, elevated protein, CSF-restricted oligoclonal bands) and excludes other causes of encephalitis (expect negative cytology and flow cytometry, negative Gram stain and culture, negative viral and other infectious studies). Of note, HSV and varicella-zoster virus (VZV) encephalitis should either be ruled out prior to initiation of steroids or other immune suppression or be concurrently treated with antivirals while test results are pending. They can typically be excluded with commonly available tests (HSV and VZV PCR), although under certain circumstances advanced testing such as determination of a VZV CSF to serum antibody index may be appropriate.

Electroencephalogram (EEG) may reveal (subclinical) seizures or status epilepticus as a complication of encephalitis or as a cause of persistently depressed sensorium, although they are not specific to irEncephalitis. Screening metabolic tests are appropriate to assess for alternative etiologies or exacerbating factors. Serum and/or CSF autoimmune antibody evaluations assess for specific malignancy-associated neurologic syndromes.

For specific encephalomyelitic syndromes, additional antibody evaluation is considered, for example, autoimmune encephalitis panel, GQ1b antibodies (rhombencephalitis, Bickerstaff encephalitis), celiac antibody panel (ataxia). TPO and thyroglobulin antibodies are of limited utility, especially given their seroprevalence in healthy individuals, although they may be thought to reveal an autoimmune tendency. Brain biopsy may be obtained in very rare circumstances following multispecialty collaboration to rule out infectious and/or neoplastic causes when not possible by other methods. Brain PET (positron emission tomography) may be helpful in differentiating the cause of parenchymal lesions.

If concern about undiagnosed infectious disease persists, additional tests such as metagenomic next-generation sequencing can be considered.

Diagnostic evaluation for irDemyelinating syndromes commonly involves MRI with contrast of the brain, orbit, and cervical and thoracic spinal cord to the level of the conus medullaris to evaluate for evidence of parenchymal involvement. LP with CSF studies excludes other diagnoses and evaluates for evidence of CSF-restricted antibody production with oligoclonal bands. Serologic testing includes antibodies to aquaporin 4 and myelin oligodendrocyte glycoprotein, which are thought to be pathogenic in CNS demyelinating disease.

Ophthalmic or neuro-ophthalmic evaluation may be indicated. In addition, optical coherence tomography can provide evidence of prior optic neuropathy, but typically abnormalities follow clinical changes by several weeks. CSF autoimmune antibody evaluation (ie, for aquaporin 4 antibody) is unlikely to increase the sensitivity beyond serum testing alone. Evoked potential testing may provide supportive evidence of demyelination of visual, auditory or somatosensory nerve fiber pathways. A negative CSF PCR test for JC virus may exclude progressive multifocal leukoencephalopathy.

Biopsy may provide definitive evidence of CNS demyelination but is typically not necessary, as per the irEncephalitis discussion.

Diagnostic evaluation for irVasculitis commonly includes MRI brain to evaluate for infarcts and other parenchymal changes; where available, post-contrast vessel wall studies can also evaluate for concentric vessel wall enhancement that suggests a vasculitic process.46 Intracranial MR (MRA) or CT angiogram (CTA) evaluates for vascular abnormalities including narrowing and beaded vessels. MRA neck or CTA neck evaluates for vascular abnormalities more proximally including vasculitic changes and carotid atherosclerosis. Lumbar puncture with CSF studies, including VZV testing and syphilis testing (if serum testing positive), evaluates for evidence of CNS inflammation as well as other causes of vasculitis. These can typically be excluded with commonly available tests (VZV PCR in CSF, serum testing for syphilis), although under certain circumstances advanced testing such as determination of a VZV CSF to serum antibody index may be appropriate. A workup for embolic stroke including carotid Doppler, electrocardiogram (EKG), heart rhythm monitoring and echocardiogram may be performed if an infarct is found. Serum markers including C reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-neutrophil cytoplasmic antibody (ANCA) and anti-nuclear antibody (ANA) and other markers associated with systemic vasculitis provide further support of vasculitis.

Formal rheumatology and/or dermatology evaluation may provide additional consideration to systemic manifestations of vasculitis. Brain biopsy can provide definitive proof of CNS vasculitis and should include sampling of both brain and meninges. Extracranial biopsy, including temporal artery biopsy or skin biopsy, may provide evidence of a systematic vasculitis and obviate the need for brain biopsy. Retinal fluorescein angiography can provide evidence of a small vessel vasculitis. Conventional (digital subtraction) angiogram may demonstrate vessel abnormalities if MRA or CTA do not provide sufficient clarity. Angiography of other vascular beds such as the renal or splanchnic circulation can assist with establishing the presence of a systemic vasculitis. Antiphospholipid antibody panel and hypercoagulability evaluation can evaluate for alternative causes of stroke.

Body PET imaging may provide evidence of systemic vasculitis.

Serum testing evaluates for alternative causes of neuropathy and signs of autoimmunity/inflammation. Serum testing may be abnormal but not explain the clinical phenotype (ie, B₁₂ deficiency would not explain a demyelinating neuropathy; a mildly elevated hemoglobin A1c (HbA1c) would not explain an immune-mediated polyradiculopathy). Definite irNeuropathy can be achieved in such cases as long as concordance between clinical phenotype and testing is considered when applying the diagnostic criteria. EDX confirm or exclude large fiber neuropathy and characterize the type, severity, and chronicity of neuropathy if present (ie, sensory and/or motor, axonal and/or demyelinating, length-dependent or non-length-dependent). Demyelinating features or a non-length-dependent and/or asymmetric pattern of neuropathy can help distinguish irNeuropathies from chemotherapy-related neuropathies, which are more typically symmetric and axonal. EDX also evaluates for other etiologies (ie, focal entrapment neuropathy, radiculopathy, myopathy). Coexisting myopathy and NMJ disorders must be excluded in patients with prominent motor involvement with EDX and CK. Spinal imaging is often obtained to exclude metastatic disease, focal structural radiculopathy, and spinal stenosis; it may demonstrate spinal nerve root enhancement/enlargement in inflammatory radiculopathies. MRI brain with contrast is obtained when cranial nerve involvement is suspected, which may show smooth enhancement of cranial nerves.

If the diagnosis or the etiology is uncertain, LP with CSF analysis may provide further support of an immune-mediated process in certain neuropathy phenotypes (such as Guillain-Barré syndrome) and exclude infection or malignancy. CSF shows cytoalbuminologic dissociation in immune-mediated neuropathies; however, lymphocytic pleocytosis (white blood cell count <50) is common in this patient group and cytoalbuminologic dissociation may be absent in the first week after symptom onset. Selected additional laboratory tests may be performed based on patient factors and the neuropathy phenotype (ie, mononeuritis multiplex would warrant a vasculitis workup) but are not required for all patients. Bedside pulmonary function tests and/or swallowing evaluation is obtained in patients with a Guillain-Barré phenotype to screen for or monitor respiratory dysfunction or dysphagia but are not included in the diagnostic criteria.

Evaluation for irNMJ disorders includes diagnostic antibody testing for MG and evaluation for concurrent myopathy, myocarditis, and thyroid dysfunction. A positive acetylcholine receptor (AChR) binding or MuSK antibody is consistent with a diagnosis of MG. AChR modulating antibodies in isolation are not sensitive or specific. AChR binding with modulating antibodies has the highest specificity.55 Rate of ACHR ab positivity in irMG has not been definitively established. Anti-straited muscle antibodies are frequently present in irMyopathy and/or irMG but are not diagnostic for irMG.53 Chest imaging is performed to exclude thymoma once an irNMJ disorder is confirmed. Patients are screened for myopathy with CK and EDX and for myocarditis with a troponin and EKG.

The role of EDX in patients with AChR antibodies and suspected irMG has not been well studied and was debated by the panel. In idiopathic MG, AChR binding or MuSK antibody positivity in the appropriate clinical scenario is diagnostic and EDX is unnecessary. However, patients may have AChR antibodies after ICI therapy without evidence for a disorder of neuromuscular transmission. Demonstrating abnormal neuromuscular transmission on EDX either through abnormal repetitive nerve stimulation or single fiber EMG is needed for definite irMG diagnosis.

Testing for the paraneoplastic Lambert-Eaton syndrome with P/Q VGCC antibodies is performed if LEMS is suspected clinically or EDX show a characteristic pattern of facilitation and decrement. MuSK antibody testing is performed in this context if electrodiagnostic studies show evidence for a disorder of neuromuscular transmission and AChR antibodies are absent. MuSK antibody testing assesses primarily for pre-existing disease since it has not been reported de novo after ICI therapy. Single fiber EMG can provide evidence of a disorder of neuromuscular transmission but may rarely show mild abnormalities in myopathy; it is typically performed at specialized centers if MG is suspected but routine EDX and antibody testing are normal/negative. The ice pack test, performed by applying ice to a ptotic lid for 2 min, can show improvement in ptosis at the bedside and further support a diagnosis of MG.56 An EKG, serum biomarkers, transthoracic echocardiogram and cardiac MRI may be performed for further evaluation of concurrent myocarditis given syndrome overlap.56 57

Edrophonium testing may not be available and is usually not needed in this patient group.

Diagnostic evaluation for irMyopathy includes CK to assess for muscle breakdown. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are typically elevated along with CK. Gammaglutamyl transferase (GGT) evaluates for liver-specific injury and is normal when AST/ALT elevations are due to muscle disease. EDX evaluate for muscle membrane irritability (indicated by fibrillation potentials and positive sharp waves), which can be seen in inflammatory or necrotizing myopathy, and for myopathic motor unit potentials (characterized by short duration, with or without low amplitude and/or early recruitment). EMG should include needle examination of clinically weak muscles and thoracic paraspinals. Of note, abnormalities in motor unit potentials may be patchy or subtle, and recruitment is often normal, particularly in the acute setting. EDX are often performed with repetitive nerve stimulation of proximal nerve-muscle combinations to test for an overlapping neuromuscular junction disorder. Troponin-I, EKG, and echocardiogram may be used for initial screening for concurrent myocarditis.57 While troponin-T may be53 58 elevated with myositis, troponin-I is more specific for cardiac injury.57

Muscle biopsy of affected muscle, ideally 4/5 MRC grade strength, allows direct assessment of muscle inflammation, but may not be needed in many cases. T-cell infiltrate identified by biopsy is supportive of irMyopathy, although other histopathological patterns have been described.53 58 MRI showing muscle edema on STIR images and/or contrast enhancement can suggest inflammation and may help select site for muscle biopsy; however, these changes are not specific for myositis and can also be seen in denervated muscle, so imaging findings are not sufficient for diagnosis. Myositis-specific antibodies (including Jo-1, PL-7, PL-12, EJ, OJ, Mi-2, SRP, TIF-1 gamma) and anti-HMGCR antibodies may be measured to further characterize myositis subtypes. ESR, CRP, and ANA are non-specific markers of inflammation, which support a diagnosis of inflammatory myositis and may be tracked longitudinally. Aldolase is another marker of muscle breakdown, although may not provide additional information to the CK level. AChR antibodies can evaluate for a superimposed NMJ disorder, particularly in patients with ocular or bulbar symptoms. Beside pulmonary function tests may be appropriate if there is concern for respiratory muscle weakness, dysphagia or head drop. Swallowing evaluation can be considered for patients with dysphagia to ensure safe oral intake. Finally, an elevated troponin and abnormal cardiac MRI can suggest a concurrent myocarditis and consultation with a cardiology service would be advised.59

Genetic testing may be performed when there is clinical suspicion for a hereditary myopathy. Although more commonly used to evaluate malignancy, fluorodeoxyglucose (FDG)-PET can also detect skeletal muscle inflammation.