PracticeUpdate Neurology June 2019

EDITOR’S PICKS 8

Clinical Spectrum of Neuromuscular Complications After Immune Checkpoint Inhibition Neuromuscular Disorders

Neural Basis of Induced Phantom Limb

Pain Relief Annals of Neurology

Take-home message • The authors of this study sought to evaluate the use of task-concurrent noninvasive brain stim- ulation (NIBS) in the management of phantom limb pain (PLP). They used a within-participants, double-blind, sham-controlled design to eval- uate durable relief of PLP (lasting ≥1 week) following task-concurrent NIBS stimulation over the primary sensorimotor missing hand cortex (S1/M1). A single session of task-concurrent NIBS intervention significantly relieved PLP with effect durations lasting a week or more. Pain relief was associated with reduced activity in the S1/M1 missing hand cortex following NIBS. • The study authors conclude that these findings provide the foundation for development of novel PLP treatments. Abstract OBJECTIVE Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS- induced PLP relief is needed for future implementation of such treatment and generalization to related conditions. METHODS We used a within-participants, double-blind, and sham-controlled design to alleviate PLP via task-concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal pro- cessing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation. RESULTS A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/ M1 activity correlated with preceding activity changes during stimulation in the mid- and posterior insula and secondary somatosensory cortex (S2). INTERPRETATION The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid- and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP inter- vention using task-concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. Neural Basis of Induced Phantom Limb Pain Relief. Ann Neurol 2019 Jan 01;85(1)59-73, S Kikkert, M Mezue, J O’Shea, et al. www.practiceupdate.com/c/80045

Take-home message • Immune checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, are finding increasing use in chemotherapy regimens, including first-line treatment for non-small cell lung cancer. These chemotherapeutic agents have been associated with neurological complications in up to 6% of patients, including the new onset of autoimmune neurological disorders. The authors of this review searched the literature for all reports of neuromuscular complications following immune checkpoint inhibition through February 2018. They identified 61 publications of 81 patients, with 30 patients who acquired myasthenia gravis, 29 with neuropathy, and 40 with muscle-related complications. Autoimmune myopathy was described in 10 patients. Overlap syndromes that do not usually occur were found in these patients, including myasthenia with myocarditis or polymyositis and myasthenia with hyperCK(creatine kinase)emia and neuropathy. The authors also present data regarding which treatments were effective in managing these complications; it is notable that some patients experienced recurrence of neuromuscular symptoms when they were rechallenged with these chemotherapeutic agents. • This review may be helpful for neurologists who provide consults in the hospital, especially involving cancer patients, as these therapies are likely to become more widely used. Sarah Matteson Kranick MD Abstract Cancer immunotherapy has transformed the field of oncology and enabled more effective management of previously refractory neoplasms by activation of the immune response. Upregulation of the immune response may also trigger autoimmune adverse events, including neuromuscular complications. We performed a systematic review of autoimmune neuromuscular complications following immune checkpoint block- ade. We searched PubMed database and identified 81 cases described, including 30 cases of myasthenia gravis (MG), 29 cases of neuropathy and 22 cases of myopathy. Most patients (89%) developed neuromuscular complications within 3 months from starting immune checkpoint blockade and 40% of all patients had elevated serum CK>1000 IU/L (typical normal <200). Guillain-Barre syndrome variants and overlaps of MG with myositis and/or myocarditis also occurred. One quarter of myasthenia patients presented with exacerbations of previously diagnosed myasthenia gravis, while neuropathy and myopathy typically presented with a new onset. Most patients improved with immunomodulatory treatment, but neuromuscular complications were sometimes refractory and associated with high mortality of 26% from cancer recur- rence, comorbidities, or treatment complications. Poor outcomes were more common with exacerbations of pre-existing myasthenia gravis and myocarditis overlap. Future prospective studies are needed to elucidate mechanisms and risk factors for auto- immune adverse events following immune checkpoint blockade. Clinical Spectrum of Neuromuscular Complications After Immune Checkpoint Inhibi- tion. Neuromuscul Disord 2019 Feb 01;29(2)127-133, A Puwanant, M Isfort, D Lacomis, SA Živković. www.practiceupdate.com/c/80615

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