Table 7.

Management of Nervous System irAEs in Patients Treated With ICPis

7.0 Nervous System Toxicities
7.1 Myasthenia gravis
Definition: Fatigable or fluctuating muscle weakness, generally more proximal than distal. Frequently has ocular and/or bulbar involvement (ptosis, extraocular movement abnormalities resulting in double vision, dysphagia, dysarthria, facial muscle weakness). May have neckand/or respiratory muscle weakness. (Note: May occurwith myositis and/or myocarditis. Respiratory symptoms may require evaluation to ruleout pneumonitis, myocarditis. Miller Fishervariantof Guillain- Barré syndrome (ophthalmoparesis) and the oculobulbar myositis (ptosis, ophthalmoparesis, dysphagia, neck and respiratory weakness) with ICPi may have overlapping symptoms.
Diagnostic work-up  AChR and antistriated muscle antibodies in blood; if AChR antibodies are negative, consider muscle specific kinase and lipoprotein-related 4 antibodies in blood  Pulmonary function assessment with NIF and VC  CPK, aldolase, ESR, CRP for possible concurrent myositis  Consider MRI of brain and/or spine, depending on symptoms to rule out CNS involvement by disease or alternate diagnosis  If respiratory insufficiency or elevated CPK, troponin T, perform cardiac examination with ECG and TTE for possible concomitant myocarditis  Neurologic consultation  Electrodiagnositic studies, including neuromuscularjunction testing with repetitive stimulation and/orjitter studies, NCS to exclude neuropathy, and needle EMG to evaluate for myositis
Grading	Management
All grades	All grades warrant work-up and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise
No G1
G2: Some symptoms interfering with ADL MGFA severity class 1 (ocular symptoms and findings only) and MGFA severity class 2 (mild generalized weakness)	Hold ICPi and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve87 Should consult neurology  Pyridostigmine starting at 30 mg orally three times a day and gradually increase to maximum of 120 mg orally four times a day as tolerated and based on symptoms  Administer corticosteroids (prednisone, 1–1.5 mg/kg orally daily) if symptoms G2; wean based on symptom improvement
G3–4: Limiting self-care and aids warranted, weakness limiting walking, ANY dysphagia, facial weakness, respiratory muscle weakness, or rapidly progressive symptoms, or MGFA severityclass 3–4 moderate to severe generalized weakness to myasthenic crisis	Permanently discontinue ICPi  Admit patient, may need ICU-level monitoring  Neurology consult  Continue corticosteroids and initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/d) or plasmapheresis for 5 days  Frequent pulmonary function assessment  Daily neurologic review
Additional considerations  Avoid medications that can worsen myasthenia: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolides  Initially a 5-day course of plasmapheresis or a 2 g/kg course of IVIG over 5 days  1–2 mg/kg methylprednisolone daily, wean based on symptom improvement  Pyridostigmine, wean based on improvement  ICPi-associated myasthenia gravis may be monophasic, and additional corticosteroid-sparing agents may not be required
7.2 Guillain-Barré syndrome
Definition: Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon reflexes. Often starts with sensory symptoms/neuropathic pain localized to lower back and thighs. May involve extremities (typically ascending weakness but not always), facial, respiratory, and bulbar and oculomotor nerves. May have dysregulation of autonomic nerves.
Diagnostic work-up  Neurologic consultation  MRI of spine with or without contrast (rule out compressive lesion and evaluate for nerve root enhancement/thickening)  Lumbar puncture: CSF typically has elevated protein and often elevated WBCs; even though this is not typically seen in classic Guillain-Barré syndrome, cytology should be sent with any CSF sample from a patient with cancer.  Serum antiganglioside antibody tests for Guillain-Barré syndromeand its subtypes (eg, anti-GQlb for Miller Fishervariantassociated with ataxia and ophthalmoplegia)  Electrodiagnostic studies to evaluate polyneuropathy Pulmonary function testing (NIF/NC)  Frequent neurochecks
Grading	Management
All grades	Warrant work-up and intervention given potential for progressive Guillain-Barré syndrome to lead to respiratory compromise Note: There is no G1 toxicity
G1: Mild, none	NA
G2: Moderate, some interference with ADL, symptoms concerning to patient G3–4: Severe, limiting self-care and aids warranted, weakness limiting walking, ANY dysphagia, facial weakness, respiratory muscle weakness, or rapidly progressive symptoms	Discontinue ICPi  Admission to inpatient unit with capability of rapid transfer to ICU-level monitoring  Start IVIG (0.4 g/kg/d for 5 days for a total dose of 2 g/kg) or plasmapheresis.  Corticosteroids are usually not recommended for idiopathic Guillain-Barré syndrome; however, in ICPi-related forms, a trial is reasonable (methylprednisolone 2–4 mg/kg/d), followed by slow corticosteroid taper  Pulse corticosteroid dosing (methylprednisolone 1 g/d for 5 days) may also be considered for G3–4 along with IVIG or plasmapheresis  Frequent neurochecks and pulmonary function monitoring  Monitor for concurrent autonomic dysfunction  Nonopioid management of neuropathic pain  Treatment of constipation/ileus
Additional considerations  Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis  May require repeat IVIG courses  Caution with rechallenging for severe cases
7.3 Peripheral neuropathy
Definition: Can present as asymmetric or symmetric sensory, motor, or sensory motor deficit. Focal mononeuropathies, including cranial neuropathies (eg, facial neuropathies/Bell palsy) may be present. Numbness and paresthesias may be painful or painless. Hypo- or areflexia or sensory ataxia may be present.
Diagnostic work-up
G1  Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein electrophoresis, and other vasculitic and autoimmune screen  Neurologic consultation  Consider MRI of spine with or without contrast
G2: in addition to above  MRI spine advised/MRI of brain if cranial nerve  Consider EMG/NCS  Consider neurology consultation
G3–4: go to Guillain-Barré syndrome algorithm
Grading	Management
G1: Mild, no interference with function and symptoms not concerning to patient. Note: Any cranial nerve problem should be managed as moderate	Low threshold to hold ICPi and monitor symptoms for a week  If to continue, monitor very closely for any symptom progression
G2: Moderate, some interference with ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation)	Hold ICPi and resume once return to G1  Initial observation OR initiate prednisone 0.5–1 mg/kg (if progressing from mild)  Neurontin, pregabalin, or duloxetine for pain
G3–4: Severe, limiting self-care and aids warranted, weakness limiting walking or respiratory problems (ie, leg weakness, foot drop, rapidly ascending sensory changes) Severe may be Guillain-Barré syndrome and should be managed as such	Permanently discontinue ICPi  Admit patient  Neurologic consultation  Initiate IV methylprednisolone 2–4 mg/kg and proceed as per Guillain-Barré syndrome management
7.4 Autonomic neuropathy
Definition: Nerves that control involuntary bodily functions are damaged. This may affect blood pressure, temperature control, digestion, bladder function, and sexual function. A case of severe enteric neuropathy with ICPi has been reported. Can present with GI difficulties such as new severe constipation, nausea, urinary problems, sexual difficulties, sweating abnormalities, sluggish pupil reaction, and orthostatic hypertension.
Diagnostic work-up  An evaluation by neurologist or relevant specialist, depending on organ system, with testing that may include   Screen for other causes of autonomic dysfunction: diabetic screen, adrenal insufficiency, HIV, parproteinemia, amyloidosis, botulism, consider chronic diseases such as Parkinson's and other autoimmune screen   •Orthostatic vital signs   •Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy   •Consider paraneoplastic autoimmune dysautonomia antibody testing (eg, anti-ganglionic acetylcholine receptor, antineuronal nuclearantibodytype 1 [ANNA-1], and N-type voltage gated calcium channel antibodies)
Grading	Management
G1: Mild, no interference with function and symptoms not concerning to patient	Low threshold to hold ICPi and monitor symptoms for a week; if to continue, monitor very closely for any symptom progression
G2: Moderate, some interference with ADL, symptoms concerning to patient	Hold ICPi and resume once return to G1  Initial observation OR initiate prednisone 0.5–1 mg/kg (if progressing from mild)  Neurologic consultation
G3–4: Severe, limiting self-care and aids warranted	Permanently discontinue ICPi  Admit patient  Initiate methylprednisolone 1 g daily for 3 days followed by oral corticosteroid taper  Neurologic consultation
7.5 Aseptic meningitis
Definition: may present with headache, photophobia, and neck stiffness; often afebrile but may be febrile. There may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis).
Diagnostic work-up  MRI of brain with or without contrast + pituitary protocol  AM cortisol, ACTH to rule out adrenal insufficiency  Consider lumbar puncture: measure opening pressure; check cell count and protein glucose; and perform Gram stain, culture, PCR for HSV, and other viral PCRs depending on suspicion, cytology  May see elevated WBC count with normal glucose, normal culture, and Gram stain; may see reactive lymphocytes or histiocytes on cytology
Grading	Management
G1: Mild, no interference with function and symptoms not Hold ICPi and discuss resumption with patient only after taking into account the risks concerning to patient. Note: Any cranial nerve problem should be managed as moderate. G2: Moderate, some interference with ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation) G3–4: Severe, limiting self-care and aids warranted	Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits  Consider empirical antiviral (IV acyclovir) and antibacterial therapy until CSF results  Once bacterial and viral infection are negative, may closely monitor off corticosteroids or consider oral prednisone 0.5–1 mg/kg or IV methylprednisolone 1 mg/kg if moderate/severe symptoms
7.6 Encephalitis
Definition: As for aseptic meningitis, need to exclude infectious causes, especially viral (ie, HSV).  Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness, focal weakness, speech abnormality
Diagnostic work-up  Neurologic consultation  MRI of brain with orwithout contrast may reveal T2/fluid-attenuated inversion recovery changes typical of what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal  Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for HSV and other viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic panels.  May see elevated WBC count with lymphocytic predominance and/or elevated protein  EEG to evaluate for subclinical seizures  Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and thyroglobulin  Rule out concurrent anemia/thrombocytopenia, which can present with severe headaches and confusion
Grading	Management
G1: Mild, no interference with function and symptoms not concerning to patient. Note: Any cranial nerve problem should be managed as moderate. G2: Moderate, some interference with ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation) G3–4: Severe, limiting self-care and aids warranted	Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits  As above for aseptic meningitis, suggest concurrent IV acyclovir until PCR results obtained and negative  Trial of methylprednisolone 1–2 mg/kg  If severe or progressing symptoms or oligoclonal bands present, consider pulse corticosteroids methylprednisolone 1 g IV daily for 3–5 days plus IVIG 2 g/kg over 5 days  If positive for autoimmune encephalopathy antibody and limited or no improvement, consider rituximab or plasmapheresis in consultation with neurology
7.7 Transverse myelitis
Definition: Acute or subacute weakness or sensory changes bilateral, often with increased deep tendon reflexes
Diagnostic work-up  Neurologic consultation  MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain  Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, onconeural antibodies  Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG  Evaluation for urinary retention, constipation
Grading	Management
G1: Mild, no interference with function and symptoms not concerning to patient. Note: Any cranal nerve problem should be managed as moderate. G2:Moderate, someinterferencewith ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation) G3–4: Severe, limiting self-care and aids warranted	Permanently discontinue ICPi  Methylprednisolone 2 mg/kg  Strongly consider higher doses of 1 g/d for 3–5 days  Strongly consider IVIG
All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate.

Abbreviations: AChR, acetylcholine receptor; ACTH, adrenocorticotropic hormone; ADL, activities of daily living; ANCA, antineutrophil cytoplasmic antibodies; CPK, creatine phosphokinase; CRP, C-reactive protein; EMG, electromyography; ESR, erythrocyte sedimentation rate; HSV, herpes simplex virus; ICPi, immune checkpoint inhibitor; ICU, intensive care unit; IgG, immunoglobulin G; IV, intravenous; IVIG, intravenous immunoglobulin; irAE, immune-related adverse event; MGFA, Myasthenia Gravis Foundation of America; MRI, magnetic resonance imaging; NA, not applicable; NCS, nerve conduction study; NIF, negative inspiratory force; PCR, polymerase chain reaction; RPR, rapid plasma reagin, TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiogram; VC, vital capacity.