IMPORTANCE Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established.OBJECTIVE To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTSThis single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded.MAIN OUTCOMES AND MEASURES Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score.RESULTS Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.CONCLUSIONS AND RELEVANCE Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended....

Objective:To describe neural autoantibody profiles and outcomes in patients with neurological autoimmunity associated with immune checkpoint inhibitor (ICI) cancer immunotherapy.Methods:In this retrospective descriptive study, sixty-three patients with ICI-related neurological autoimmunity were included: 39 seen at the Mayo Clinic Neurology Department (clinical cohort), and 24 whose serum/CSF was referred to the Mayo Clinic Neuroimmunology Laboratory for autoantibody testing. Serum/CSF samples were tested for neural-specific autoantibodies. Predictors of unfavorable outcome (residual adverse event severity-grade ≥3) were explored (logistic regression).Results:Median age at neurological symptom-onset was 65 years (range, 31-86); 40% were female. Neurological manifestations were: CNS-restricted (n=26), neuromuscular (n=30); combined (n=5), or isolated retinopathy (n=2). Neural-specific autoantibodies were common in patients with CNS involvement (7/13 [54%] in the unbiased clinical cohort) and included known specificities or unidentified neural-restricted. Only 11/31 patients with CNS manifestations had neuroendocrine malignancies typically associated with paraneoplastic autoimmunity. Small-cell lung cancer (SCLC)-predictive antibodies were seen in three patients with non-neuroendocrine tumors (NIF-IgG and ANNA1 with melanoma; amphyphisin-IgG with non-SCLC). A median of 10 months from onset (range, 0.5-46), 14/39 in the clinical cohort (36%) had unfavorable outcomes; their characteristics were: age ≥70 years, female gender, CNS involvement, lung cancer, higher initial severity-grade, and lack of systemic autoimmunity. By multivariate analysis, only age remained independently associated with poor outcome (p=0.01). Four of five patients with pre-existent neurological autoimmunity experienced irreversible worsening after ICI.Conclusions:Neural-specific autoantibodies are not uncommon in patients with ICI-related neurological autoimmunity. Outcomes mostly depend on the pre-ICI-treatment characteristics and clinical phenotype.

This is a comprehensive analysis of a large cohort of patients with immune checkpoint inhibitor-associated myopathy. Shelly et al. highlight its unique features of ocular involvement and normal creatine kinase levels in some patients, mimicking myasthenia gravis. Multifocal clusters of necrotic fibers are characteristics and occur in even patients without hyperCKemia. Immune checkpoint inhibitors have revolutionized the landscape of cancer treatment. Alongside their many advantages, they elicit immune-related adverse events, including myopathy, which potentially result in substantial morbidity if not recognized and treated promptly. Current knowledge of immune checkpoint inhibitor-associated myopathy is limited. We conducted 5-year retrospective study of patients with immune checkpoint inhibitor-associated myopathy. Clinical features, survival and ancillary test findings were analyzed and compared with those of immune-mediated necrotizing myopathy patients without immune checkpoint inhibitor exposure seen during the same time period. We identified 24 patients with immune checkpoint inhibitor-associated myopathy (median age 69 years; range: 28-86) and 38 patients with immune-mediated necrotizing myopathy. Ocular involvement occurred in 9/24 patients with immune checkpoint inhibitor exposure, without electrodiagnostic evidence of neuromuscular transmission defect, and in none of immune-mediated necrotizing myopathy patients (P < 0.001). Myocarditis occurred in eight immune checkpoint inhibitor-associated myopathy patients and in none of immune-mediated necrotizing myopathy patients (P < 0.001). Median creatine kinase was 686 IU/L in immune checkpoint inhibitor cohort (seven with normal creatine kinase) compared to 6456 IU/L in immune-mediated necrotizing myopathy cohort (P < 0.001). Lymphopenia was observed in 18 and seven patients with and without immune checkpoint inhibitor exposure, respectively (P < 0.001). Myopathological findings were similar between patients with and without immune checkpoint inhibitor exposure, consisting of necrotic fibers with no or subtle inflammation. Necrotic fibers however arranged in clusters in 10/11 immune checkpoint inhibitor-associated myopathy patients but in none of immune checkpoint inhibitor-naïve patients (P < 0.001). Despite the lower creatine kinase levels in immune checkpoint inhibitor-exposed patients, the number of necrotic fibers was similar in both groups. Immune checkpoint inhibitor-associated myopathy patients had higher frequency of mitochondrial abnormalities and less number of regenerating fibers than immune-mediated necrotizing myopathy patients (P < 0.001). Anti-HMGCR (Hydroxy-3-Methylglutaryl-CoA Reductase) or signal recognition particle antibodies were absent in patients with immune checkpoint inhibitor exposure but positive in two-thirds of immune checkpoint inhibitor-naïve patients. Most patients with immune checkpoint inhibitor-associated myopathy responded favorably to immunomodulatory treatments, but four died from myopathy-related complications and one from myocarditis. Intubated patients had significantly shorter survival compared to non-intubated patients (median survival of 22 days; P = 0.004). In summary, immune checkpoint inhibitor-associated myopathy is a distinct, treatable immune-mediated myopathy with common ocular involvement, frequent lymphopenia, and necrotizing histopathology, which contrary to immune-mediated necrotizing myopathy, is featured by clusters of necrotic fibers and not accompanied by anti-HMGCR or signal recognition particle antibodies. Normal or mildly elevated creatine kinase level does not exclude the diagnosis.

Neuromuscular disorders are the most common neurological complication reported in PD-1 inhibitor-treated patients. Myasthenia gravis, immune-mediated myopathies, and Guillain-Barre syndrome are among commonly reported immune-related neuromuscular complications. HyperCKemia occurs frequently in patients with PD-1 inhibitor-associated myasthenia gravis, indicating coexisting myopathies or myocarditis. Oculobulbar weakness is a unique and common presentation of PD-1 inhibitor-associated immune-mediated myopathies with or without concomitant myasthenia gravis. High-dose steroid monotherapy may be associated with clinical deterioration in some patients with PD-1 inhibitor-associated myasthenia gravis, immune-mediated myopathies, or Guillain-Barre syndrome. PD-1 inhibitor-associated neuromuscular complications have some characteristic features compared to their idiopathic counterparts. Although steroid monotherapy is commonly used in non-neuromuscular autoimmune disorders triggered by anti-PD-1 therapy, this may lead to unfavorable outcomes in some patients with PD-1 inhibitor-associated neuromuscular complications.