TY - JOUR
AU - Guidon, Amanda C.
AB - Abstract Immune checkpoint inhibitors (ICIs) initiate antitumor immunity by blocking the action of immune inhibitor‐signaled cytotoxic proteins, such as cytotoxic T‐lymphocyte‐associated protein 4, programmed cell death protein 1, and programmed cell death ligand 1. However, in rare cases (∼1%–12% of patients), ICI treatment causes neurologic immune‐related adverse events (irAEs). These include, but are not limited to, headache, encephalitis, neuropathies, myasthenia gravis, and myositis. The symptoms associated with irAEs can range from mild (grade 1–2) to severe (grade 3–4); however, they are often challenging to diagnose because they may present as generalized symptoms, such as fatigue and weakness, that can also be caused by the cancer itself. Here, we present an illustrative case of a 67‐year‐old woman who presented with signs of a neurologic irAE, including progressive dysphagia and weakness leading to falls, which started during treatment with pembrolizumab and worsened following initiation of ipilimumab. Following neurological and pathological evaluation, she was diagnosed with myositis. She was treated with steroids and improved rapidly. In this article, we review previous literature to provide guidance to frequently asked questions concerning the diagnosis and management of neurologic irAEs in patients with advanced cancer. With prompt and effective treatment, most patients will achieve a complete recovery. Key Points Neurologic immune‐related adverse events (irAEs) affect approximately 1% of patients treated with immune checkpoint inhibitor (ICI) monotherapy and 2%‐3% treated with combination therapy. These irAEs can affect any portion of the nervous system, although peripheral nerve system manifestations are most common. Overlap syndromes with multiple neurologic irAEs or other affected organ systems frequently exist. Diagnosis of neurologic irAEs can be challenging. Routine testing may be unremarkable and symptoms frequently mimic those from cancer or side effects of other therapies. Optimal management is currently unknown. A systematic, highly coordinated, and multidisciplinary approach is critical. Outcomes from neurologic irAEs are typically favorable with the current practice of holding the ICI and starting corticosteroids. Some patients are even successfully retreated with an ICI. A subset of patients, however, have a fulminant and potentially fatal course. Improved risk assessments and targeted therapies are needed. Introduction The six immune checkpoint inhibitors (ICIs) approved by the U.S. Food and Drug Administration have improved the overall survival rate of patients with several advanced malignancies [1–7]. These breakthrough drugs act by blocking immune inhibitor‐signaled cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), programmed cell death protein 1 (PD‐1), and programmed cell death ligand 1 and thereby initiating antitumor immunity. Published clinical trials and institutional experiences report that the incidence of neurologic immune‐related adverse events (irAEs) is low but more common in patients receiving combination therapies (e.g., ipilimumab and nivolumab) [8–11]. In a recent review of 59 clinical trials with a total of 9,208 patients, the overall incidence of neurologic irAEs was 3.8% for patients receiving anti‐CTLA‐4, 6.1% for patients receiving anti‐PD‐1, and 12% for patients receiving combination CTLA‐4 + PD‐1. Most of these events were grade 1 or 2 and characterized by nonspecific symptoms such as headache. Severe toxicity, defined as grade 3–5, occurred in 0.7% of patients receiving anti‐CTLA‐4, 0.4% of patients receiving anti‐PD‐1, and 0.7% in patients receiving combination CTLA‐4 + PD‐112. Others also report grade 3–4 neurologic irAEs occuring in <1% of patients [2,3]. Although neurologic irAEs are reported to occur less frequently than irAEs affecting other organ systems, we suspect that available data underestimate their true incidence because of missed diagnoses and underreporting. Although serious neurologic toxicities (e.g., neuropathies impairing ambulation, myopathies, or myasthenia gravis causing inability to swallow and respiratory dysfunction) may be infrequent, they are complications that are critical to recognize, as they can progress rapidly and contribute to significant morbidity and mortality. If they are recognized and treated early, however, disability can often be minimized, and options for additional cancer treatment are also expanded. Neurologic irAEs can be challenging to diagnose for several reasons. First, many patients have fatigue, generalized weakness, or other cancer‐related symptoms that can mimic neurologic irAEs. Second, patients may not report mild deficits, or workup of mild symptoms may not be prioritized in the setting of serious illness. Third, oncologists may lack familiarily and comfort with the spectrum of these irAEs. Finally, neurologists may face challenges in diagnosis and management, as irAEs can present and respond atypically. For these reasons, clinicians treating ICI‐exposed patients are frequently faced with challenging questions during the process of identifying neurologic irAEs. Such questions may include: when is “fatigue” actually weakness? When is dysphagia a result of direct compression by a tumor versus general neuromuscular weakness? When is shortness of breath due to anemia versus weakness of muscles of respiration? When is altered mental status due to a neurological irAE rather than central nervous system (CNS) metastatic disease or common toxic/metabolic causes? When is neuropathy an immune‐mediated adverse event and when is it from prior chemotherapy? Patient history, physical examination, and ancillary studies typically differentiate between neurologic irAEs and mimicking conditions frequently encountered in patients with advanced cancer. In this review, we raise and answer frequently asked questions to assist in the recognition and management of these conditions. Case Vignette A 67‐year‐old woman presented 3 years prior with melanoma of the right eyelid, which was resected completely but resulted in mild right ptosis. One year later, she had melanoma recurrence in ipsilateral parotid lymph nodes. She underwent radiation therapy and was stable for 2 years, until pulmonary metastatic disease was noted. Pembrolizumab was started, but she had disease progression after four cycles. She transitioned to ipilimumab (3 mg/kg for 3 cycles), which led to stable disease, (with one lesion decreased in size by 30%) on computed tomography scans for 13 months. A fourth cycle was not given because of her neurologic irAE. During ICI therapy, she developed dysphagia and weakness. Symptoms started in retrospect while she was on pembrolizumab and worsened on ipilimumab. At the time of admission, dysphagia had become increasing severe and she was unable to eat a normal diet. She was dysarthric. Previously able to ambulate without difficulty, she could no longer climb stairs and she required a walker. She had frequent falls. Altered mental status was present and had been attributed to hepatic encephalopathy. She denied numbness/paresthesias, bowel or bladder symptoms, new ptosis, diplopia, or dyspnea. She had not experienced recent seizures. Past medical history was significant for alcoholic cirrhosis complicated by varices, epilepsy, diabetes mellitus, hyperlipidemia, and a compression fracture (status post decompression with T11‐L3 function and kyphoplasty). Her medications included atorvastatin (80 mg daily), carbamazepine (200 mg twice daily), levetiracetam (1500 mg twice daily) for seizures, and metformin and Lantus (insulin glargine; Sanofi, Bridgewater, NH) for diabetes. Upon hospital admission, neurologic examination revealed a drowsy, inattentive, and dysarthric woman with a nasogastric tube. Breathing was unlabored and vitals were stable. Cranial nerve exam was significant for chronic nonfatigable right‐sided ptosis related to melanoma excision. Extraocular eye movements were intact without diplopia. She had moderate weakness of eye closure, tongue protrusion, and cheek inflation. Motor examination revealed no evidence of limb muscle atrophy or fasciculations; however, she had moderate weakness involving neck flexion (Medical Research Council [MRC] score 3/5) and proximal greater than distal, upper and lower extremity muscle weakness (MRC range 4/5). Sensory exam was notable for absent pinprick sensation distal to the knees and absent vibration at the toes. Deep tendon reflexes were present throughout except at either Achilles. She was unable to ambulate or to participate reliably in testing of coordination. Differential diagnosis included myopathy, myasthenia gravis (MG), neuropathy associated with facial weakness and dysphagia, or a multifocal disorder involving the brain and nerve/muscle. Sensory deficits were thought to be related to mild chronic distal symmetric polyneuropathy likely related to either diabetes or prior alcohol exposure. Laboratory testing was notable for a positive antinuclear antibody, normal creatine kinase (CK) and troponin T, and negative myasthenia gravis specific autoantibodies (Table 1). Magnetic resonance imaging (MRI) of the brain revealed no leptomeningeal enhancement, tumor spread, or intracranial ischemia or hemorrhage. Neck computed tomography showed no compressive masses to account for dysphagia. Echocardiogram and electrocardiogram were unremarkable. Nerve conduction study (NCS)/electromyogram (EMG) showed mild sensory and motor polyneuropathy (axonal), which was consistent with a diabetic or alcohol‐related polyneuropathy. No findings of myopathy were observed on needle EMG, and no evidence for MG was present on repetitive nerve stimulation studies. Single‐fiber EMG, which is more sensitive for the diagnosis of MG, could not be performed in the inpatient setting because of electrical interference. Muscle biopsy of the biceps brachii revealed myopathic changes with a chronic inflammatory infiltrate, supportive of an ICI‐related inflammatory myositis. Table 1. Laboratory values Lab test . Patient's result . Normal value . CK 44 60–400 U/L TSH 2.08 0.4–5.00 ulU/mL HbA1C 5.6 4.3–6.4% B12 580 250 pg/mL PTH 48 10–65 ng/L SPEP Nl pattern Nl pattern ANA Positive, I:160, speckled Negative Smooth Mus Ab Positive, 1:320 Negative Cytoplasmic Ab Positive, 1:160 Negative Myasthenia Ab (AChR binding and modulating) Negative Negative Anti‐MuSK Ab Negative Negative Anti‐LRP4 Ab Negative Negative N‐type VGCC Ab Result 1, positive 0.05; result 2, negative Negative P/Q type VGCC Ab Negative Negative Serum paraneoplastic panel Negative Negative HBV, HCV Negative Negative Troponin T Negative <0.01 ng/mL Lab test . Patient's result . Normal value . CK 44 60–400 U/L TSH 2.08 0.4–5.00 ulU/mL HbA1C 5.6 4.3–6.4% B12 580 250 pg/mL PTH 48 10–65 ng/L SPEP Nl pattern Nl pattern ANA Positive, I:160, speckled Negative Smooth Mus Ab Positive, 1:320 Negative Cytoplasmic Ab Positive, 1:160 Negative Myasthenia Ab (AChR binding and modulating) Negative Negative Anti‐MuSK Ab Negative Negative Anti‐LRP4 Ab Negative Negative N‐type VGCC Ab Result 1, positive 0.05; result 2, negative Negative P/Q type VGCC Ab Negative Negative Serum paraneoplastic panel Negative Negative HBV, HCV Negative Negative Troponin T Negative <0.01 ng/mL Abbreviations: AChR, acetylcholine receptor; ANA, antinuclear antibody; Anti‐LRP4, lipoprotein receptor‐related protein‐4; Anti‐MuSK, muscle‐specific kinase; CK, creatine kinase; HbA1C, hemoglobin A1c; HBV, hepatitis B virus; HCV, hepatitis C virus; PTH, parathyroid hormone; Smooth Mus Ab, smooth muscle antibody; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; VGCC, voltage‐gated calcium channel. Open in new tab Table 1. Laboratory values Lab test . Patient's result . Normal value . CK 44 60–400 U/L TSH 2.08 0.4–5.00 ulU/mL HbA1C 5.6 4.3–6.4% B12 580 250 pg/mL PTH 48 10–65 ng/L SPEP Nl pattern Nl pattern ANA Positive, I:160, speckled Negative Smooth Mus Ab Positive, 1:320 Negative Cytoplasmic Ab Positive, 1:160 Negative Myasthenia Ab (AChR binding and modulating) Negative Negative Anti‐MuSK Ab Negative Negative Anti‐LRP4 Ab Negative Negative N‐type VGCC Ab Result 1, positive 0.05; result 2, negative Negative P/Q type VGCC Ab Negative Negative Serum paraneoplastic panel Negative Negative HBV, HCV Negative Negative Troponin T Negative <0.01 ng/mL Lab test . Patient's result . Normal value . CK 44 60–400 U/L TSH 2.08 0.4–5.00 ulU/mL HbA1C 5.6 4.3–6.4% B12 580 250 pg/mL PTH 48 10–65 ng/L SPEP Nl pattern Nl pattern ANA Positive, I:160, speckled Negative Smooth Mus Ab Positive, 1:320 Negative Cytoplasmic Ab Positive, 1:160 Negative Myasthenia Ab (AChR binding and modulating) Negative Negative Anti‐MuSK Ab Negative Negative Anti‐LRP4 Ab Negative Negative N‐type VGCC Ab Result 1, positive 0.05; result 2, negative Negative P/Q type VGCC Ab Negative Negative Serum paraneoplastic panel Negative Negative HBV, HCV Negative Negative Troponin T Negative <0.01 ng/mL Abbreviations: AChR, acetylcholine receptor; ANA, antinuclear antibody; Anti‐LRP4, lipoprotein receptor‐related protein‐4; Anti‐MuSK, muscle‐specific kinase; CK, creatine kinase; HbA1C, hemoglobin A1c; HBV, hepatitis B virus; HCV, hepatitis C virus; PTH, parathyroid hormone; Smooth Mus Ab, smooth muscle antibody; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; VGCC, voltage‐gated calcium channel. Open in new tab Corticosteroids were initiated for inflammatory myositis. She received Solu‐Medrol (methylprednisolone; Pfizer, New York, NY; 1,000 mg intravenous [IV] daily for 3 days) followed by prednisone (starting at 60 mg daily and tapering to 20 mg daily over 5 weeks and then off). IV immunoglobulin (IVIG) was considered but not given. A neuromuscular junction etiology was unlikely, and she improved rapidly on steroids. Within several days, her nasogastric tube was removed, and she tolerated a normal diet. She was discharged home ambulating independently. Five weeks after steroids were initiated, she reported complete resolution of dysphagia. Follow‐up neurological examination showed normal facial/tongue strength and essentially no ongoing weakness. Interestingly, her mental status also returned to baseline several days after steroid initiation. Diagnosis and Management of Neurologic irAEs What Is Important to Know Before the Start of Treatment? Prior to initiating immunotherapy, routine neurologic history, review of systems, and exam are critical. Neurologic exam highlights any tumor or treatment‐related deficits at baseline. A history of immune‐mediated neurologic disorders is most relevant to the decision to initiate therapy. However, awareness of other diseases (e.g., migraine or inherited muscle disease) is also important as they could cause baseline neurologic dysfunction or complicate the assessment of new symptoms from a possible neurologic irAE. Recommendations for pre‐ICI neurologic and laboratory evaluation are evolving. The Society for Immunotherapy of Cancer recommendations include consideration of a variety of pretreatment laboratory analyses. However, from a neurologic perspective, baseline CK, thyroid stimulating hormone, and free thyroxine are most relevant [12] in addition to routine blood counts and chemistries. If a patient has a suspected or confirmed neurologic condition, initiating or continuing ICI therapy currently proceeds on a case‐by‐case basis. The goal of collaborative, multidisciplinary care is to maximize oncological treatment options for patients while minimizing potential morbidity and mortality related to neurologic disease or irAEs. Which Neurological irAEs Have Been Reported? The spectrum of neurologic irAEs is broad and can involve disorders affecting the CNS and peripheral nervous system (PNS). Common disorders often present atypically. More than one neurologic irAE or overlap syndrome may be present in the same patient. The most commonly reported neurologic irAEs are listed by anatomic location in Figure 1; this anatomic classification provides a framework for evaluation and management. Additionally, mimics of neuromuscular disease can include fasciitis, which can be focal or generalized, and isolated anhidrosis due to direct inflammation of sweat glands. Figure 1. Open in new tabDownload slide Neurologic immune‐related adverse events. Figure 1. Open in new tabDownload slide Neurologic immune‐related adverse events. How Soon After Initiation of ICIs Do Neurologic irAEs Develop? A neurologic irAE should be suspected in any patient who develops new sensory and/or motor or other neurologic deficits after ICI exposure. Signs and symptoms typically present within 3 months of starting therapy, with median symptom onset of 6 weeks; however, there is a notable range. Neurologic irAEs are reported after a single dose of an ICI and as long as 68 weeks after the start of treatment [9–14]. What Are the Critical Components of History and Examination with Regard to Neurologic irAEs? We recommend screening for neurologic symptoms systematically (Fig. 2) in conjunction with the physcial exam for localization (Table 2). Because patients with neurologic irAEs often have multifocal involvement that is atypical, we find that a systematic approach, which may seem excessively deliberate for experienced clinicians, is helpful. This allows for prompt identification of multisystem abnormality which would not typically coexist in the same patient in idiopathic disease. Ocular weakness manifests as ptosis, diplopia, or eye closure weakness. It results from involvement of cranial nerves III, IV, and VI or weakness of extraocular and perioribital muscles themselves. Bulbar weakness manifests as difficulty chewing, swallowing, or dysarthria. Bulbar weakness can be caused by abnormality of cranial nerves V, VII, IX, X, XII and/or weakness of muscles of the face, mastication, palate, and tongue, as was the case in our patient. Although pain is atypical in idiopathic inflammatory myositis, we routinely ask patients about myalgias, which are more commonly observed in checkpoint induced myositis. We also include a thorough autonomic review of systems, as autonomic neuropathies exist in isolation and in combination with other immune‐related neuropathies. We have observed sweating dysfunction, orthostasis, and symptomsof gastroparesis as most relevant in this population. Finally, we recommend specifically asking about headaches and gait or cognitive dysfunction, as these symptoms may be underreported unless severe. Once the location of neurologic abnormality is narrowed down, additional diagnostic investigations are tailored to the patient. Figure 2. Open in new tabDownload slide Recommended ICI‐specific neurologic screening considerations at baseline and for detection of neurologic immune‐related adverse events. Abbreviation: ICI, immune checkpoint inhibitor. Figure 2. Open in new tabDownload slide Recommended ICI‐specific neurologic screening considerations at baseline and for detection of neurologic immune‐related adverse events. Abbreviation: ICI, immune checkpoint inhibitor. Table 2. Physical findings associated with anatomic location of irAE Physical findings . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Pain Usually absent Variable, back pain None/variable, ± muscle cramps None Usually none, ± myalgias Bowel/bladder function Usually normal Dysfunction often present Usually normal Normal Normal Cranial nerve function Variable, may be involved Normal Usually normal, may be involved in neuropathy. Ptosis, abnormal extraocular muscles, bulbar weakness Usually normal Weakness Variable, usually unilateral Variable, usually symmetric Segmental in radiculopathy, Usually distal > proximal in neuropathy Variable (ocular, bulbar, neck, and proximal > distal limb) Variable (ocular, bulbar, neck, and proximal > distal limb) Sensory function Variable, may be involved Variable, may have sensory level Variable in radiculopathy, usually abnormal in neuropathy Normal Normal Tone Increased Increased Normal or decreased Normal Usually normal Toes/Babinski Up/present Up/present Down/absent Down/absent Down/absent Reflexes Increased Increased Usually decreased Normal or decreased Normal or decreased Physical findings . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Pain Usually absent Variable, back pain None/variable, ± muscle cramps None Usually none, ± myalgias Bowel/bladder function Usually normal Dysfunction often present Usually normal Normal Normal Cranial nerve function Variable, may be involved Normal Usually normal, may be involved in neuropathy. Ptosis, abnormal extraocular muscles, bulbar weakness Usually normal Weakness Variable, usually unilateral Variable, usually symmetric Segmental in radiculopathy, Usually distal > proximal in neuropathy Variable (ocular, bulbar, neck, and proximal > distal limb) Variable (ocular, bulbar, neck, and proximal > distal limb) Sensory function Variable, may be involved Variable, may have sensory level Variable in radiculopathy, usually abnormal in neuropathy Normal Normal Tone Increased Increased Normal or decreased Normal Usually normal Toes/Babinski Up/present Up/present Down/absent Down/absent Down/absent Reflexes Increased Increased Usually decreased Normal or decreased Normal or decreased Abbreviations: irAE, immune‐related adverse event; NM, neuromuscular. Open in new tab Table 2. Physical findings associated with anatomic location of irAE Physical findings . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Pain Usually absent Variable, back pain None/variable, ± muscle cramps None Usually none, ± myalgias Bowel/bladder function Usually normal Dysfunction often present Usually normal Normal Normal Cranial nerve function Variable, may be involved Normal Usually normal, may be involved in neuropathy. Ptosis, abnormal extraocular muscles, bulbar weakness Usually normal Weakness Variable, usually unilateral Variable, usually symmetric Segmental in radiculopathy, Usually distal > proximal in neuropathy Variable (ocular, bulbar, neck, and proximal > distal limb) Variable (ocular, bulbar, neck, and proximal > distal limb) Sensory function Variable, may be involved Variable, may have sensory level Variable in radiculopathy, usually abnormal in neuropathy Normal Normal Tone Increased Increased Normal or decreased Normal Usually normal Toes/Babinski Up/present Up/present Down/absent Down/absent Down/absent Reflexes Increased Increased Usually decreased Normal or decreased Normal or decreased Physical findings . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Pain Usually absent Variable, back pain None/variable, ± muscle cramps None Usually none, ± myalgias Bowel/bladder function Usually normal Dysfunction often present Usually normal Normal Normal Cranial nerve function Variable, may be involved Normal Usually normal, may be involved in neuropathy. Ptosis, abnormal extraocular muscles, bulbar weakness Usually normal Weakness Variable, usually unilateral Variable, usually symmetric Segmental in radiculopathy, Usually distal > proximal in neuropathy Variable (ocular, bulbar, neck, and proximal > distal limb) Variable (ocular, bulbar, neck, and proximal > distal limb) Sensory function Variable, may be involved Variable, may have sensory level Variable in radiculopathy, usually abnormal in neuropathy Normal Normal Tone Increased Increased Normal or decreased Normal Usually normal Toes/Babinski Up/present Up/present Down/absent Down/absent Down/absent Reflexes Increased Increased Usually decreased Normal or decreased Normal or decreased Abbreviations: irAE, immune‐related adverse event; NM, neuromuscular. Open in new tab How Is the Diagnosis and Severity of Neurological irAEs Determined? There are currently no standardized case definitions to aid diagnosis of neurologic irAEs. The Common Terminology Criteria for Adverse Events (CTCAE) provides grading criteria for neurologic irAEs. In general, mild adverse events (AEs) are grade 1–2, severe are grade 3–4, and death is grade 5. The CTCAE was created prior to immunotherapy and may not adequately represent the threat that the toxicities pose to the patient because of their dynamic, potentially rapidly progressive nature. Also, the criteria may not capture the severity of very focal but severe weakness (i.e., myositis affecting muscles of swallowing and breathing disproportionately) or multifocality. As in other systemic toxicities, we think there is an unmet need for case definitions of these disorders and for tailoring the CTCAE to be ICI specific [15]. What Is the Recommended Workup of irAEs? Thorough workup of suspected neurologic irAEs must exclude other potential causes of symptoms such as infection, disease progression (e.g., leptomeningeal or parenchymal brain metastasis), paraneoplastic syndromes, or metabolic derangements. Table 3 summarizes recommended labs, imaging, and other testing. Notably, we have found added value for MRI in peripheral nervous system disorders. For example, in the Guillain‐Barré syndrome (GBS)‐like illness, nerve root enhancement or enlargement can be seen. Additionally, selected cases of myopathy/myositis have been associated with abnormal muscle MRI. Tabel 3. Recommended neurologic workup . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Labs LP: send CSF for cell counts, gram stain, HSV, viral culture, cytology, other serologies. Autoimmune encephalitis panel, including NMDA receptor antibodies. LP: send CSF for cell counts, gram stain, protein, crytptococcal antigen, PCR for HSV, VZV, CMV viral culture, cytology; other serologies include B12, HIV, syphilis, ANA, anti‐Ro, anti‐La, TSH, anti‐aquaporin‐4 IgG. B12, folate, HbA1C, T4, TSH, ANA, ESR, SPEP/IFE. Consider antiganglioside Ab panel/consider paraneoplastic antibodies. Consider ANCA [13]. AChR binding and modulating antibodies (antistriated muscle antibody can be sent but + results are not diagnostic for MG). If AChR antibodies are negative, consider MuSK antibodies and anti‐LRP4 antibodies. Consider PQ type voltage gated calcium channel antibodies if concern about Lambert Eaton myasthenic syndrome. CK, ESR, CRP, aldolase, ANA. Consider myositis antibodies and serum rheumatologic evaluation. Imaging MRI brain ± spine with and without contrast. MRI spine ± brain with and without contrast. MRI spine should be performed with thin axial cuts through the region of suspected abnormality. Consider MRI with and without contrast to evaluate for cranial neuropathies or nerve root abnormality. Consider MRI of brain and spinal cord if diagnosis uncertain. Consider MRI of affected muscles (i.e., upper arm or thigh). Electrophysiology testing EEG if seizures suspected. Consider SSEPs if imaging and LP are nondiagnostic. NCS/EMG Check for ocular, proximal muscle fatigability. NCS/EMG: RNS and/or jitter studies. NCS/EMG Other CK for concurrent muscle disease. Nerve biopsy typically unecessary for diagnosis. If respiratory symptoms, get negative inspiratory force and vital capacity to monitor. Tensilon test, ice pack test. Evaluate for concurrent thyroiditis and myocarditis (CK, CKMB, troponin, EKG ± ECHO). Consider muscle biopsy. Consider pulmonary mechanics. Evaluate for concurrent myocarditis (CK, CKMB, troponin, EKG ± ECHO). Evaluate for concurrent thyroiditis. Results Aseptic meningitis typically has WBC <500, nl glucose. Encephalitis typically WBC <250, elevated protein, nl glucose. LP may be normal or have lymphocytosis with elevated protein. GBS: acute polyneuropathy findings on NCS, elelvated protein typically with normal WBC <20 on LP. AChR are frequently absent and RNS is frequently normal. Specialized jitter studies often required to show evidence for abnormal neuromuscular transmission. CK may be normal or elevated. NCS may show low amplitude compound muscle action potentials or be normal. EMG may show irritable myopathy or be normal. Additional information Headaches, neck stiffness, photophobia can distinguish encephalitis from aseptic meningitis. Exclude infection prior to high dose steroids. Often bilateral. Motor/sensory/bowel and bladder signs/symptoms. May have localizing spinal sensory level. Involve neurology early, If progressive symmetrical weakness without reflexes, consider GBS—anti‐ganglioside antibody testing for GBS varients. These patients can have rapid progression to respiratory failure so close monitoring is essential. If there is fatigability, ptosis, repiratory, ocular, or bulbar muscles involved, consider MG. MG has been reported to overlap with myositis and myocarditis so complete workup is reasonable [14]. Consider whether the patient has received any medications which could worsen MG (list at http://www.myasthenia.org/LivingwithMG/DrugstoAvoid.aspx). As in the case presented in this manuscript, CK, NCS/EMG testing can be normal. Paraspinal muscles may appear abnormal. . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Labs LP: send CSF for cell counts, gram stain, HSV, viral culture, cytology, other serologies. Autoimmune encephalitis panel, including NMDA receptor antibodies. LP: send CSF for cell counts, gram stain, protein, crytptococcal antigen, PCR for HSV, VZV, CMV viral culture, cytology; other serologies include B12, HIV, syphilis, ANA, anti‐Ro, anti‐La, TSH, anti‐aquaporin‐4 IgG. B12, folate, HbA1C, T4, TSH, ANA, ESR, SPEP/IFE. Consider antiganglioside Ab panel/consider paraneoplastic antibodies. Consider ANCA [13]. AChR binding and modulating antibodies (antistriated muscle antibody can be sent but + results are not diagnostic for MG). If AChR antibodies are negative, consider MuSK antibodies and anti‐LRP4 antibodies. Consider PQ type voltage gated calcium channel antibodies if concern about Lambert Eaton myasthenic syndrome. CK, ESR, CRP, aldolase, ANA. Consider myositis antibodies and serum rheumatologic evaluation. Imaging MRI brain ± spine with and without contrast. MRI spine ± brain with and without contrast. MRI spine should be performed with thin axial cuts through the region of suspected abnormality. Consider MRI with and without contrast to evaluate for cranial neuropathies or nerve root abnormality. Consider MRI of brain and spinal cord if diagnosis uncertain. Consider MRI of affected muscles (i.e., upper arm or thigh). Electrophysiology testing EEG if seizures suspected. Consider SSEPs if imaging and LP are nondiagnostic. NCS/EMG Check for ocular, proximal muscle fatigability. NCS/EMG: RNS and/or jitter studies. NCS/EMG Other CK for concurrent muscle disease. Nerve biopsy typically unecessary for diagnosis. If respiratory symptoms, get negative inspiratory force and vital capacity to monitor. Tensilon test, ice pack test. Evaluate for concurrent thyroiditis and myocarditis (CK, CKMB, troponin, EKG ± ECHO). Consider muscle biopsy. Consider pulmonary mechanics. Evaluate for concurrent myocarditis (CK, CKMB, troponin, EKG ± ECHO). Evaluate for concurrent thyroiditis. Results Aseptic meningitis typically has WBC <500, nl glucose. Encephalitis typically WBC <250, elevated protein, nl glucose. LP may be normal or have lymphocytosis with elevated protein. GBS: acute polyneuropathy findings on NCS, elelvated protein typically with normal WBC <20 on LP. AChR are frequently absent and RNS is frequently normal. Specialized jitter studies often required to show evidence for abnormal neuromuscular transmission. CK may be normal or elevated. NCS may show low amplitude compound muscle action potentials or be normal. EMG may show irritable myopathy or be normal. Additional information Headaches, neck stiffness, photophobia can distinguish encephalitis from aseptic meningitis. Exclude infection prior to high dose steroids. Often bilateral. Motor/sensory/bowel and bladder signs/symptoms. May have localizing spinal sensory level. Involve neurology early, If progressive symmetrical weakness without reflexes, consider GBS—anti‐ganglioside antibody testing for GBS varients. These patients can have rapid progression to respiratory failure so close monitoring is essential. If there is fatigability, ptosis, repiratory, ocular, or bulbar muscles involved, consider MG. MG has been reported to overlap with myositis and myocarditis so complete workup is reasonable [14]. Consider whether the patient has received any medications which could worsen MG (list at http://www.myasthenia.org/LivingwithMG/DrugstoAvoid.aspx). As in the case presented in this manuscript, CK, NCS/EMG testing can be normal. Paraspinal muscles may appear abnormal. Abbreviations: AChR, acetylcholine receptor; ANA, antinuclear antibody; CK, creatine kinase; CKMB, creatine kinase‐MB; CMV, cytomegalovirus; CRP, C‐reactive protein; CSF, cerebrospinal fluid; EEG, electroencephalogram; EKG, electrocardiogram; ESR, erythrocyte sedimentation rate; GBS, Guillain‐Barré syndrome; HSV, herpes simplex virus; LP, lumbar puncture; MG, myasthenia gravis; MRI, magnetic resonance imaging; NCS, nerve conduction study; NMDA, N‐methyl‐D‐Aspartate receptor; PCR, polymerase chain reaction; RNS, repetitive nerve stimulation; SPEP/IFE, serum protein electrophoresis and immunofixation; SSEP, somatosensory evoked potential; T4, thyroxine; TSH, thyroid stimulating hormone; VZV, varicella zoster virus; WBC, white blood cell. Open in new tab Tabel 3. Recommended neurologic workup . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Labs LP: send CSF for cell counts, gram stain, HSV, viral culture, cytology, other serologies. Autoimmune encephalitis panel, including NMDA receptor antibodies. LP: send CSF for cell counts, gram stain, protein, crytptococcal antigen, PCR for HSV, VZV, CMV viral culture, cytology; other serologies include B12, HIV, syphilis, ANA, anti‐Ro, anti‐La, TSH, anti‐aquaporin‐4 IgG. B12, folate, HbA1C, T4, TSH, ANA, ESR, SPEP/IFE. Consider antiganglioside Ab panel/consider paraneoplastic antibodies. Consider ANCA [13]. AChR binding and modulating antibodies (antistriated muscle antibody can be sent but + results are not diagnostic for MG). If AChR antibodies are negative, consider MuSK antibodies and anti‐LRP4 antibodies. Consider PQ type voltage gated calcium channel antibodies if concern about Lambert Eaton myasthenic syndrome. CK, ESR, CRP, aldolase, ANA. Consider myositis antibodies and serum rheumatologic evaluation. Imaging MRI brain ± spine with and without contrast. MRI spine ± brain with and without contrast. MRI spine should be performed with thin axial cuts through the region of suspected abnormality. Consider MRI with and without contrast to evaluate for cranial neuropathies or nerve root abnormality. Consider MRI of brain and spinal cord if diagnosis uncertain. Consider MRI of affected muscles (i.e., upper arm or thigh). Electrophysiology testing EEG if seizures suspected. Consider SSEPs if imaging and LP are nondiagnostic. NCS/EMG Check for ocular, proximal muscle fatigability. NCS/EMG: RNS and/or jitter studies. NCS/EMG Other CK for concurrent muscle disease. Nerve biopsy typically unecessary for diagnosis. If respiratory symptoms, get negative inspiratory force and vital capacity to monitor. Tensilon test, ice pack test. Evaluate for concurrent thyroiditis and myocarditis (CK, CKMB, troponin, EKG ± ECHO). Consider muscle biopsy. Consider pulmonary mechanics. Evaluate for concurrent myocarditis (CK, CKMB, troponin, EKG ± ECHO). Evaluate for concurrent thyroiditis. Results Aseptic meningitis typically has WBC <500, nl glucose. Encephalitis typically WBC <250, elevated protein, nl glucose. LP may be normal or have lymphocytosis with elevated protein. GBS: acute polyneuropathy findings on NCS, elelvated protein typically with normal WBC <20 on LP. AChR are frequently absent and RNS is frequently normal. Specialized jitter studies often required to show evidence for abnormal neuromuscular transmission. CK may be normal or elevated. NCS may show low amplitude compound muscle action potentials or be normal. EMG may show irritable myopathy or be normal. Additional information Headaches, neck stiffness, photophobia can distinguish encephalitis from aseptic meningitis. Exclude infection prior to high dose steroids. Often bilateral. Motor/sensory/bowel and bladder signs/symptoms. May have localizing spinal sensory level. Involve neurology early, If progressive symmetrical weakness without reflexes, consider GBS—anti‐ganglioside antibody testing for GBS varients. These patients can have rapid progression to respiratory failure so close monitoring is essential. If there is fatigability, ptosis, repiratory, ocular, or bulbar muscles involved, consider MG. MG has been reported to overlap with myositis and myocarditis so complete workup is reasonable [14]. Consider whether the patient has received any medications which could worsen MG (list at http://www.myasthenia.org/LivingwithMG/DrugstoAvoid.aspx). As in the case presented in this manuscript, CK, NCS/EMG testing can be normal. Paraspinal muscles may appear abnormal. . Brain . Myelopathy . Nerve root/peripheral nerve . NM junction . Myopathy . Labs LP: send CSF for cell counts, gram stain, HSV, viral culture, cytology, other serologies. Autoimmune encephalitis panel, including NMDA receptor antibodies. LP: send CSF for cell counts, gram stain, protein, crytptococcal antigen, PCR for HSV, VZV, CMV viral culture, cytology; other serologies include B12, HIV, syphilis, ANA, anti‐Ro, anti‐La, TSH, anti‐aquaporin‐4 IgG. B12, folate, HbA1C, T4, TSH, ANA, ESR, SPEP/IFE. Consider antiganglioside Ab panel/consider paraneoplastic antibodies. Consider ANCA [13]. AChR binding and modulating antibodies (antistriated muscle antibody can be sent but + results are not diagnostic for MG). If AChR antibodies are negative, consider MuSK antibodies and anti‐LRP4 antibodies. Consider PQ type voltage gated calcium channel antibodies if concern about Lambert Eaton myasthenic syndrome. CK, ESR, CRP, aldolase, ANA. Consider myositis antibodies and serum rheumatologic evaluation. Imaging MRI brain ± spine with and without contrast. MRI spine ± brain with and without contrast. MRI spine should be performed with thin axial cuts through the region of suspected abnormality. Consider MRI with and without contrast to evaluate for cranial neuropathies or nerve root abnormality. Consider MRI of brain and spinal cord if diagnosis uncertain. Consider MRI of affected muscles (i.e., upper arm or thigh). Electrophysiology testing EEG if seizures suspected. Consider SSEPs if imaging and LP are nondiagnostic. NCS/EMG Check for ocular, proximal muscle fatigability. NCS/EMG: RNS and/or jitter studies. NCS/EMG Other CK for concurrent muscle disease. Nerve biopsy typically unecessary for diagnosis. If respiratory symptoms, get negative inspiratory force and vital capacity to monitor. Tensilon test, ice pack test. Evaluate for concurrent thyroiditis and myocarditis (CK, CKMB, troponin, EKG ± ECHO). Consider muscle biopsy. Consider pulmonary mechanics. Evaluate for concurrent myocarditis (CK, CKMB, troponin, EKG ± ECHO). Evaluate for concurrent thyroiditis. Results Aseptic meningitis typically has WBC <500, nl glucose. Encephalitis typically WBC <250, elevated protein, nl glucose. LP may be normal or have lymphocytosis with elevated protein. GBS: acute polyneuropathy findings on NCS, elelvated protein typically with normal WBC <20 on LP. AChR are frequently absent and RNS is frequently normal. Specialized jitter studies often required to show evidence for abnormal neuromuscular transmission. CK may be normal or elevated. NCS may show low amplitude compound muscle action potentials or be normal. EMG may show irritable myopathy or be normal. Additional information Headaches, neck stiffness, photophobia can distinguish encephalitis from aseptic meningitis. Exclude infection prior to high dose steroids. Often bilateral. Motor/sensory/bowel and bladder signs/symptoms. May have localizing spinal sensory level. Involve neurology early, If progressive symmetrical weakness without reflexes, consider GBS—anti‐ganglioside antibody testing for GBS varients. These patients can have rapid progression to respiratory failure so close monitoring is essential. If there is fatigability, ptosis, repiratory, ocular, or bulbar muscles involved, consider MG. MG has been reported to overlap with myositis and myocarditis so complete workup is reasonable [14]. Consider whether the patient has received any medications which could worsen MG (list at http://www.myasthenia.org/LivingwithMG/DrugstoAvoid.aspx). As in the case presented in this manuscript, CK, NCS/EMG testing can be normal. Paraspinal muscles may appear abnormal. Abbreviations: AChR, acetylcholine receptor; ANA, antinuclear antibody; CK, creatine kinase; CKMB, creatine kinase‐MB; CMV, cytomegalovirus; CRP, C‐reactive protein; CSF, cerebrospinal fluid; EEG, electroencephalogram; EKG, electrocardiogram; ESR, erythrocyte sedimentation rate; GBS, Guillain‐Barré syndrome; HSV, herpes simplex virus; LP, lumbar puncture; MG, myasthenia gravis; MRI, magnetic resonance imaging; NCS, nerve conduction study; NMDA, N‐methyl‐D‐Aspartate receptor; PCR, polymerase chain reaction; RNS, repetitive nerve stimulation; SPEP/IFE, serum protein electrophoresis and immunofixation; SSEP, somatosensory evoked potential; T4, thyroxine; TSH, thyroid stimulating hormone; VZV, varicella zoster virus; WBC, white blood cell. Open in new tab NCS/EMG is typically performed to evaluate disorders of the PNS. When myopathy/myositis is suspected, muscle biopsy of an involved but mild to moderately weak muscle should be considered, particularly if the remainder of the evaluation is inconclusive, as in our case vignette. Muscle MRI can be used along with electrodiagnostic studies to guide muscle selection for biopsy to increase the yield. Nerve biopsy is rarely needed for diagnosis of a neuropathy from irAE. However, if nerve inflammation cannot be distinguished from direct tumor infiltration by other methods or if vasculitic neuropathy is suspected, nerve biopsy may be indicated. Lumbar punctures are commonly performed for evaluation of both central and peripheral disorders in these patients. In addition to more routine studies, we typically perform cytology and/or flow cytometry on cerebrospinal fluid in all cases. As outlined in Table 3, the anatomic localization of the suspected neurologic irAE determines the additional lab testing that should be performed. However, it is important to be aware of the possibility of multiple concurrent toxicities. For example, a recent series reports that 30% of patients with MG had concomitant myositis and 25% had concomitant myocarditis [14]. In our practice, we screen patients with myositis for MG and cardiac involvement/myocarditis. We are testing all patients with a confirmed neurologic irAE for thyroid dysfunction/thyroiditis with thyroid function testing and antithyroperoxidase antibodies. What Treatments Are Available for Neurological irAEs? Successful neurological treatment relies on recognizing the condition followed by close monitoring and withholding the ICI in moderate‐to‐severe cases. To date, there are no reported large studies indicating the therapuetic efficacy of holding the ICI alone. Unless symptoms are very mild (i.e., grade 1), we typically initiate corticosteroids as soon as we feel confident of the diagnosis of a neurologic irAE. In general, we use oral corticosteroids for mild to moderate disease and IV solumedrol for more severe symptoms. Table 4 summarizes the published guidelines for management of neurological irAEs [9,13,16,17]. Our experience shows that most patients treated early improve significantly with steroids alone. Through collaboration between oncology and neurology consultants, we use IVIG or plasma exchange (PLEX) for patients with severe disease at onset or who are refractory to steroids alone. Additionally, some disorders (such as GBS and moderate‐to‐severe MG) are typically treated with IVIG or PLEX in addition to steroids. Some patients will need a steroid‐sparing agent if they are unable to wean off of steroids without symptom recurrence. Because there are no data to guide selection of this treatment, we typically consider this on a case‐by‐case basis. We have selected rituximab in several patients because of its secondary mechanism of action depleting and/or inactivating T cells, relatively rapid onset of action, and potentially less concern about worsening oncologic prognosis [18]. However, there is some concern about prolonged immunosupression with rituximab. Some of our patients with neurologic irAEs have also been on infliximab for concomitant refractory colitis; however, this is not typically used to treat the neurologic syndrome. Additional studies providing evidence for management of patients refractory to initial steroid treatment are needed. Tabel 4. Recommended initial treatment . Brain . Myelopathy . Nerve Root/peripheral Nerve . Neuromuscular junction . Myopathy . Grade 1 Close monitoring, consider holding ICI (per SITC hold). Close monitoring, consider holding ICI (per SITC hold). (Per ASCO) Close monitoring, consider holding ICI (per SITC hold). There is no grade 1 GBS. (Per ASCO) No grade 1. All grades warrant workup and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise. Close monitoring with serial CKs, consider holding ICI (per SITC hold). Per ASCO, continue ICI. If CK is elevated and patient has muscle weakness, may offer oral corticosteroids and treat as G2. Offer analgesia with acetaminophen or NSAIDs if there are no contraindications. Grade 2 Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily + antiviral therapy until negative results. Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily. Hold ICI, consider pregabalin or duloxetine for pain, initiate prednisone 0.5–1 mg/kg daily. Resume ICI when symptoms return to grade 1. For facial weakness (Bell's palsy), 14 day taper starting at 60 mg prednisone daily for 7 days, eye care, and patching to prevent corneal abrasion. (Per ASCO) Hold ICI and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve. 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. In all grades, avoid medications that can worsen MG. (Per ASCO) Hold ICI temporarily and may resume upon symptom control, if CK is normal and prednisone dose <10 mg; if worsens, treat as per G3. NSAIDs as needed. Referral to neurologist or rheumatologist. If CK is elevated three times or more), initiate prednisone or equivalent at 0.5–1 mg/kg. May require permanent discontinuation of ICIs in most patients with G2 symptoms and objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI, or biopsy). Grade 3 or 4 (Per ASCO) Hold ICP and discuss resumption with patient only after taking into account the risks and benefits 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. (Per ASCO) Permanently discontinue ICIMethylprednisolone 2 mg/kg. Strongly consider higher doses of 1 g/d for 3–5 days. Strongly consider IVIG. (GBS per ASCO) 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 GBS; however, in ICI‐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 neuro checks and pulmonary function monitoring. Monitor for concurrent autonomic dysfunction. Nonopioid management of neuropathic pain. Treatment of constipation/ileus. Discuss with neurology consult. (Per ASCO) Permanently discontinue ICI. 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. (Per ASCO) Hold ICI until G1 or less while off immune suppression, and permanently discontinue if any evidence of myocardial involvement. Consider hospitalization for severe weakness. Referral to neurologist or rheumatologist. Initiate prednisone 1 mg/kg or equivalent. Consider 1–2 mg/kg of methylprednisolone IV or higher‐dose bolus if severe compromise (weakness severely limiting mobility, cardiac, respiratory, dysphagia). Consider plasmapheresis. Consider IVIG therapy. Consider other immunosuppressant therapy, such as methotrexate, azathioprine, or mycophenolate mofetil, if symptoms and CK levels do not improve or worsen after 4–6 weeks; rituximab is used in primary myositis but caution is advised given its long biologic duration. . Brain . Myelopathy . Nerve Root/peripheral Nerve . Neuromuscular junction . Myopathy . Grade 1 Close monitoring, consider holding ICI (per SITC hold). Close monitoring, consider holding ICI (per SITC hold). (Per ASCO) Close monitoring, consider holding ICI (per SITC hold). There is no grade 1 GBS. (Per ASCO) No grade 1. All grades warrant workup and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise. Close monitoring with serial CKs, consider holding ICI (per SITC hold). Per ASCO, continue ICI. If CK is elevated and patient has muscle weakness, may offer oral corticosteroids and treat as G2. Offer analgesia with acetaminophen or NSAIDs if there are no contraindications. Grade 2 Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily + antiviral therapy until negative results. Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily. Hold ICI, consider pregabalin or duloxetine for pain, initiate prednisone 0.5–1 mg/kg daily. Resume ICI when symptoms return to grade 1. For facial weakness (Bell's palsy), 14 day taper starting at 60 mg prednisone daily for 7 days, eye care, and patching to prevent corneal abrasion. (Per ASCO) Hold ICI and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve. 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. In all grades, avoid medications that can worsen MG. (Per ASCO) Hold ICI temporarily and may resume upon symptom control, if CK is normal and prednisone dose <10 mg; if worsens, treat as per G3. NSAIDs as needed. Referral to neurologist or rheumatologist. If CK is elevated three times or more), initiate prednisone or equivalent at 0.5–1 mg/kg. May require permanent discontinuation of ICIs in most patients with G2 symptoms and objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI, or biopsy). Grade 3 or 4 (Per ASCO) Hold ICP and discuss resumption with patient only after taking into account the risks and benefits 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. (Per ASCO) Permanently discontinue ICIMethylprednisolone 2 mg/kg. Strongly consider higher doses of 1 g/d for 3–5 days. Strongly consider IVIG. (GBS per ASCO) 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 GBS; however, in ICI‐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 neuro checks and pulmonary function monitoring. Monitor for concurrent autonomic dysfunction. Nonopioid management of neuropathic pain. Treatment of constipation/ileus. Discuss with neurology consult. (Per ASCO) Permanently discontinue ICI. 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. (Per ASCO) Hold ICI until G1 or less while off immune suppression, and permanently discontinue if any evidence of myocardial involvement. Consider hospitalization for severe weakness. Referral to neurologist or rheumatologist. Initiate prednisone 1 mg/kg or equivalent. Consider 1–2 mg/kg of methylprednisolone IV or higher‐dose bolus if severe compromise (weakness severely limiting mobility, cardiac, respiratory, dysphagia). Consider plasmapheresis. Consider IVIG therapy. Consider other immunosuppressant therapy, such as methotrexate, azathioprine, or mycophenolate mofetil, if symptoms and CK levels do not improve or worsen after 4–6 weeks; rituximab is used in primary myositis but caution is advised given its long biologic duration. Adapted from published guidelines 13, 16, 17, and Common Terminology Criteria for Adverse Events. Abbreviations: ASCO, American Society of Clinical Oncology; CK, creatine kinase; EMG, electromyogram; GBS, Guillain‐Barré syndrome; ICI, immune checkpoint inhibitor; IV, intravenous; IVIG, intravenous immunoglobulin; MGFA, Myasthenia Gravis Foundation of America; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti‐inflammatory drug; SITC, Society for Immunotherapy of Cancer. Open in new tab Tabel 4. Recommended initial treatment . Brain . Myelopathy . Nerve Root/peripheral Nerve . Neuromuscular junction . Myopathy . Grade 1 Close monitoring, consider holding ICI (per SITC hold). Close monitoring, consider holding ICI (per SITC hold). (Per ASCO) Close monitoring, consider holding ICI (per SITC hold). There is no grade 1 GBS. (Per ASCO) No grade 1. All grades warrant workup and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise. Close monitoring with serial CKs, consider holding ICI (per SITC hold). Per ASCO, continue ICI. If CK is elevated and patient has muscle weakness, may offer oral corticosteroids and treat as G2. Offer analgesia with acetaminophen or NSAIDs if there are no contraindications. Grade 2 Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily + antiviral therapy until negative results. Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily. Hold ICI, consider pregabalin or duloxetine for pain, initiate prednisone 0.5–1 mg/kg daily. Resume ICI when symptoms return to grade 1. For facial weakness (Bell's palsy), 14 day taper starting at 60 mg prednisone daily for 7 days, eye care, and patching to prevent corneal abrasion. (Per ASCO) Hold ICI and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve. 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. In all grades, avoid medications that can worsen MG. (Per ASCO) Hold ICI temporarily and may resume upon symptom control, if CK is normal and prednisone dose <10 mg; if worsens, treat as per G3. NSAIDs as needed. Referral to neurologist or rheumatologist. If CK is elevated three times or more), initiate prednisone or equivalent at 0.5–1 mg/kg. May require permanent discontinuation of ICIs in most patients with G2 symptoms and objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI, or biopsy). Grade 3 or 4 (Per ASCO) Hold ICP and discuss resumption with patient only after taking into account the risks and benefits 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. (Per ASCO) Permanently discontinue ICIMethylprednisolone 2 mg/kg. Strongly consider higher doses of 1 g/d for 3–5 days. Strongly consider IVIG. (GBS per ASCO) 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 GBS; however, in ICI‐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 neuro checks and pulmonary function monitoring. Monitor for concurrent autonomic dysfunction. Nonopioid management of neuropathic pain. Treatment of constipation/ileus. Discuss with neurology consult. (Per ASCO) Permanently discontinue ICI. 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. (Per ASCO) Hold ICI until G1 or less while off immune suppression, and permanently discontinue if any evidence of myocardial involvement. Consider hospitalization for severe weakness. Referral to neurologist or rheumatologist. Initiate prednisone 1 mg/kg or equivalent. Consider 1–2 mg/kg of methylprednisolone IV or higher‐dose bolus if severe compromise (weakness severely limiting mobility, cardiac, respiratory, dysphagia). Consider plasmapheresis. Consider IVIG therapy. Consider other immunosuppressant therapy, such as methotrexate, azathioprine, or mycophenolate mofetil, if symptoms and CK levels do not improve or worsen after 4–6 weeks; rituximab is used in primary myositis but caution is advised given its long biologic duration. . Brain . Myelopathy . Nerve Root/peripheral Nerve . Neuromuscular junction . Myopathy . Grade 1 Close monitoring, consider holding ICI (per SITC hold). Close monitoring, consider holding ICI (per SITC hold). (Per ASCO) Close monitoring, consider holding ICI (per SITC hold). There is no grade 1 GBS. (Per ASCO) No grade 1. All grades warrant workup and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise. Close monitoring with serial CKs, consider holding ICI (per SITC hold). Per ASCO, continue ICI. If CK is elevated and patient has muscle weakness, may offer oral corticosteroids and treat as G2. Offer analgesia with acetaminophen or NSAIDs if there are no contraindications. Grade 2 Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily + antiviral therapy until negative results. Hold ICI (per SITC), oral prednisone 0.5–1 mg/kg daily. Hold ICI, consider pregabalin or duloxetine for pain, initiate prednisone 0.5–1 mg/kg daily. Resume ICI when symptoms return to grade 1. For facial weakness (Bell's palsy), 14 day taper starting at 60 mg prednisone daily for 7 days, eye care, and patching to prevent corneal abrasion. (Per ASCO) Hold ICI and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve. 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. In all grades, avoid medications that can worsen MG. (Per ASCO) Hold ICI temporarily and may resume upon symptom control, if CK is normal and prednisone dose <10 mg; if worsens, treat as per G3. NSAIDs as needed. Referral to neurologist or rheumatologist. If CK is elevated three times or more), initiate prednisone or equivalent at 0.5–1 mg/kg. May require permanent discontinuation of ICIs in most patients with G2 symptoms and objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI, or biopsy). Grade 3 or 4 (Per ASCO) Hold ICP and discuss resumption with patient only after taking into account the risks and benefits 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. (Per ASCO) Permanently discontinue ICIMethylprednisolone 2 mg/kg. Strongly consider higher doses of 1 g/d for 3–5 days. Strongly consider IVIG. (GBS per ASCO) 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 GBS; however, in ICI‐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 neuro checks and pulmonary function monitoring. Monitor for concurrent autonomic dysfunction. Nonopioid management of neuropathic pain. Treatment of constipation/ileus. Discuss with neurology consult. (Per ASCO) Permanently discontinue ICI. 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. (Per ASCO) Hold ICI until G1 or less while off immune suppression, and permanently discontinue if any evidence of myocardial involvement. Consider hospitalization for severe weakness. Referral to neurologist or rheumatologist. Initiate prednisone 1 mg/kg or equivalent. Consider 1–2 mg/kg of methylprednisolone IV or higher‐dose bolus if severe compromise (weakness severely limiting mobility, cardiac, respiratory, dysphagia). Consider plasmapheresis. Consider IVIG therapy. Consider other immunosuppressant therapy, such as methotrexate, azathioprine, or mycophenolate mofetil, if symptoms and CK levels do not improve or worsen after 4–6 weeks; rituximab is used in primary myositis but caution is advised given its long biologic duration. Adapted from published guidelines 13, 16, 17, and Common Terminology Criteria for Adverse Events. Abbreviations: ASCO, American Society of Clinical Oncology; CK, creatine kinase; EMG, electromyogram; GBS, Guillain‐Barré syndrome; ICI, immune checkpoint inhibitor; IV, intravenous; IVIG, intravenous immunoglobulin; MGFA, Myasthenia Gravis Foundation of America; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti‐inflammatory drug; SITC, Society for Immunotherapy of Cancer. Open in new tab In addition to the treatments listed, a multidisciplinary approach involving physical, occupational, and speech therapy or bracing/gait aids is necessary to avoid morbidity and long‐term disability. In general, we actively manage neurologic irAEs with neurologic care until patients are asymptomatic and off immunosupression. Subsequent monitoring for relapse can be considered in select patients (i.e., those with an identified antibody‐mediated disease or severe illness), or patients can return to the neurology clinic as needed. What Should Be Considered When Using Steroids? The side effects of prednisone are well known and include mood changes, weight gain, hyperglycemia, hypertension, gastritis, osteoporosis, opportunistic infections, and skin fragility. Therefore, when discharging a patient on high doses of steroids, coadministration of vitamin D/calcium, a proton‐pump inhibitor, or trimethoprim/sulfamethoxazole therapy should be considered. In this patient population, MG and GBS have two specific considerations. First, steroids can worsen weakness in MG and even precipitate myasthenic crisis. As such, in irMG, IVIG or plasma exchange is typically given before steroids when weakness is moderate to severe and involves bulbar and/or respiratory muscles. Second, steroids are often used with IVIG or PLEX in immune‐related Guillain‐Barré syndrome (irGBS) given the responsiveness of these irAEs to steroids. This approach differs from idiopathic GBS, in which no benefit is associated with systemic steroids [19]. These examples illustrate that further studies are needed to determine the underlying pathophysiology of these conditions to identify the best targeted therapies. Although there is theoretical concern that steroids may adversely affect the outcomes of cancer treatment, overall survival rates and time‐to‐treatment failure do not appear to be affected by the presence of a neurological irAE or the need for systemic steroids [20]. However, there is emerging data to suggest hypophysitis patients have decreased survival when treated with high‐dose glucocorticoids versus low dose [21]. Given the potential negative effect of high‐dose glucocorticoids, our practice is to use the lowest dose of steroids possible. Coordinating management of steroids with disease‐specific subspecialists or other disease‐specific consults is necessary if multiple organs are affected by irAEs. How Long Should Steroids Be Continued and How Are They Tapered? We typically continue high‐dose steroids for approximately 2 weeks and then taper over 4 weeks. If patients have a history of neurologic autoimmunity or antibody‐positive disease, we may taper more slowly. If patients have symptom relapse, the taper is halted, and therapy is re‐escalated. If patients do not respond initially to corticosteroids, we typically add another agent sooner than 4 weeks. What Is the Prognosis for Patients with Neurological irAEs? Although death has been reported in patients with neurological irAEs, most patients show significant recovery [22]. Of 27 cases reported in one series, 73% of patients had partial or complete neurological recovery, with a median time to improvement of 4 weeks [12]. Therefore, aggressive workup and management are indicated in this patient population given the potential for long‐term benefit from ICI therapy. Patients who experience any irAE, and particularly multiple irAEs, may have a longer progression free survival compared to patients without irAEs [23]. This influences decisions to retreat in several ways. The most notable is that patients may not need retreatment and may have a response to even their abbreviated course of ICI therapy. Which Patients Can Be Rechallenged with ICI Therapy After Developing a Neurological irAE? It is possible to retreat patients who have experienced a neurologic irAE. Typically, we rechallenge with a different class of ICI [24]. For patients with neurologic toxicity, it is particularly reasonable to rechallenge those with grade 1, grade 2, or grade 3 complications with rapid resolution. This treatment should be done in collaboration with neurology consultants who are familiar with the management of neurologic irAEs. Additional studies of the neurologic outcomes of retreated patients are needed. If the decision is made to rechallenge, we establish a new neurologic baseline with careful history, examination, and relevant ancillary testing if indicated (e.g., we would obtain a new baseline CK in a patient with previous immune‐related myositis). We then typically see the patient in the neurology clinic every 4–8 weeks for the first several months after starting retreatment. We recommend ongoing careful assessment to detect any relapse of the same or development of a new neurologic irAE. We have not pre‐emptively treated patients with prednisone or another therapy to prevent a neurologic irAE when rechallenging with ICI; however, this is an area where future research is needed. Conclusion Neurological irAEs will be increasingly common in oncology practices as more patients are treated with ICIs and particularly with combination therapy. Clinical presentations can be atypical and multifocal and lead to long‐term disability or death. Effective management requires a coordinated multidisciplinary effort focused on early diagnosis and treatment. Treatment typically consists of holding the ICI and administering corticosteroids with or without IVIG or plasma exchange. With this approach, most patients will have resolution of neurologic symptoms within weeks to months. Some patients have severe neurologic disease despite agressive treatment. Retreatment with an ICI can be attempted in select patients with neurologic irAEs. Author Contributions Conception/design: Kerry L. Reynolds, Amanda C. Guidon Provision of study material or patients: Kerry L. Reynolds, Amanda C. Guidon Data analysis and interpretation: Kerry L. Reynolds, Amanda C. Guidon Manuscript writing: Kerry L. Reynolds, Amanda C. Guidon Final approval of manuscript: Kerry L. Reynolds, Amanda C. Guidon Disclosures The authors indicated no financial relationships. References 1 Daud A , Robert C, Hodi FS et al. 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TI - Diagnosis and Management of Immune Checkpoint Inhibitor‐Associated Neurologic Toxicity: Illustrative Case and Review of the Literature
JF - The Oncologist
DO - 10.1634/theoncologist.2018-0359
DA - 2019-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/diagnosis-and-management-of-immune-checkpoint-inhibitor-associated-0B9H2wrnDo
SP - 435
EP - 443
VL - 24
IS - 4
DP - DeepDyve
ER -