Autoimmune radiculoplexus neuropathy under adjuvant nivolumab treatment of a female patient with melanoma
Authors: T. Gambichler, L. Susok, M. Fels, C. Schneider‐Gold, F. Hof zum Berge, E. Stockfleth, I. Ayzenberg
Journal: British Journal of Dermatology (2019)

Dear Editor, Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, represent a major breakthrough in the treatment of metastatic melanoma. Moreover, both nivolumab and pembrolizumab have recently been approved in Europe for completely resected stage III melanoma.1 However, in about 15% of patients, grade 3 and 4 immune-related adverse events (irAEs) may occur under adjuvant anti-programmed cell death 1 (PD-1) blockers, and even treatment-related deaths (grade 5) have been reported.2, 3 We report a 57-year-old woman with stage IIIb melanoma of unknown primary in the right groin negative for BRAF who for 6 months had received adjuvant nivolumab infusions every other week (3 mg kg−1 bodyweight). Prior to nivolumab treatment she had undergone complete lymph node dissection. About 3 months after the initiation of nivolumab, she developed lower-back pain with diffuse radiating pain into both legs. Then she noted a gradually increasing paresis of the right leg accompanied by a slight numbness of her right leg. Thoracic and abdominal computed tomography and brain magnetic resonance imaging (MRI) revealed no evidence of melanoma recurrence. Nivolumab was discontinued. Neurological examination revealed a mild sensory loss and profound flaccid paresis of the right leg [British Medical Research Council (BMRC) score: 2–3/5 proximally and 3/5 distally] with bilateral loss of deep tendon reflexes. There were no signs of compression or other relevant pathology on the pelvic and lumbar MRI. Cerebrospinal fluid (CSF) analysis demonstrated unspecific inflammatory changes by the slightly elevated protein (516 mg dL−1) and primary lymphocytic cell count (14 cells mL−1). Polymerase chain reactions (viral, bacterial, fungal) and Borrelia burgdorferi antibodies (in both blood and CSF) were negative, and no tumour cells could be detected in the CSF. Paraneoplastic, vasculitis and ganglioside antibodies were not found. Nerve conduction studies showed prolongation of the F-wave latency, in particular of both tibial nerves; decreased motor conduction velocity in the right tibial nerve; and decreased sensory nerve action potential and conduction velocity in the right peroneal nerve. Electromyography showed signs of acute denervation (positive sharp waves and fibrillation potentials) in the right rectus femoris, adductor magnus, tibialis anterior and gastrocnemius muscle, while the examination of the left leg was normal. Based on the clinical and electrophysiological findings, an autoimmune–inflammatory lumbar plexopathy and radiculopathy under ongoing ICI therapy was diagnosed. Under treatment with initially intravenous and later oral methylprednisolone and intensive physical therapy an almost complete improvement with minimal signs of the paresis was achieved (BMRC 4+/5 proximally and 5/5 distally). Eight weeks later, electroneurography showed mild increase of distal compound muscle action potential amplitudes and complete normalization of F-wave latencies, as well as marked reduction of A-waves of the right tibial and peroneal nerves. Electromyography showed a few positive sharp waves and fibrillation potentials only. On voluntary effort a markedly increased number of recruited motor units with polyphasic reinnervation potentials due to collateral sprouting could be demonstrated in all muscles, with a still slightly reduced interference pattern. As the patient refrained from reuse of nivolumab, we recommended low-dose interferon α-2a at 3 million IU 3 weekly as further adjuvant melanoma treatment. Frequently occurring irAEs with ICIs include dermatitis, colitis, hepatitis, thyroid dysfunction, pneumonitis and hypophysitis. The vast majority of irAEs are reversible with corticosteroids and other immune-modulating medications.2, 3 Neurological irAEs, including encephalitis, myasthenia gravis, myositis, Guillain–Barré syndrome and polyneuropathy, are rare, occurring in < 1% patients treated in large clinical trials. In the literature, we found four patients who developed brachial plexus neuritis or mesenteric neuritis under treatment with ICI.4-6 One patient with enteric plexus neuropathy even died after one cycle of nivolumab plus ipilimumab.6 Data on the specific pathogenesis of ICI-related neurological toxicity are scarce, although inflammation around the endoneural microvessels and subperineural oedema may explain some presentations.2, 3 Ding et al.7 have shown that PD-L1, which is the ligand of PD-1, attenuates experimental autoimmune neuritis (EAN) through a phosphoinositide 3-kinase–AKT–mammalian target of rapamycin-mediated subtype shift in T helper cells. The anti-inflammatory effects of PD-L1 in EAN may also indirectly exert neuroprotective effects that lessen the degenerative symptoms. These results are in accordance with some other studies purporting that blockade or deficiency of PD-1 and PD-L1 resulted in accelerated and more severe disease, and that administering PD-L1 directly inhibited disease (e.g. in experimental autoimmune encephalomyelitis).7 In conclusion, we report a case of ICI-related inflammatory lumbar radiculoplexus neuropathy widely remitting after high-dose corticosteroids. The broad spectrum of secondary autoimmune complications under ICIs should be taken into account.3 In particular, in the adjuvant treatment setting, close collaboration between dermato-oncologists, neurologists and other specialists is critical for establishing the correct diagnosis and patient management.