Mononeuritis multiplex as a rare and severe neurological complication of immune checkpoint inhibitors: a case report

Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors are common immunotherapies that have been linked to adverse immune-related neurological conditions [1, 2, 4]. PD-1 and CTLA-4 play important roles in the fine tuning of T cell function to protect from potential threats while maintaining self-tolerance. Tumor cells take advantage of checkpoint negative regulation to evade immune surveillance. Anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) agents have been found to unleash the antitumor immune response of the immune system. While rare, neurological toxicity during or following immunotherapy manifests in a wide variety of complications, including Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), myelitis, myasthenia gravis, and myositis. While immune-related adverse events (irAEs) typically respond to corticosteroids or other immunosuppressive agents, rare neurologic complications from checkpoint inhibitor therapy can rarely be refractory to multiple lines of immunosuppressive therapy [2‐4].

The combination of nivolumab and ipilimumab is a standard first-line treatment for unresectable or metastatic melanoma [5, 6]. Despite the wide variety of neurological complications reported for cancer immunotherapies, mononeuritis multiplex (MM) in response to PD-1 inhibitor use for melanoma is a very rare complication, with only two reported cases in the literature [1, 7]. Here we report a case of steroid-refractory MM in which the response to intravenous immunoglobulin (IVIg) and rituximab was short lived.

A 77-year-old non-Hispanic white female with history of a right carpal tunnel release and no family history of cancer was diagnosed with melanoma of the left ankle and treated with wide local excision. The melanoma recurred and she was started on ipilimumab and nivolumab. After three cycles she developed multiple irAEs including rash, transaminitis, and hypophysitis, all of which were responsive to steroids, as well as retinopathy requiring IVIg. Further anticancer therapy was held as she had a complete response to ipilimumab and nivolumab. She subsequently began to develop nonspecific symptoms of lower back pain. Several months later, she developed left lower extremity weakness and started to use a cane. Soon after, she also developed left foot drop. Magnetic resonance imaging (MRI) of the lumbar spine showed significant spinal stenosis at L4–L5, and she underwent L4–L5 posterior fusion without improvement in her symptoms. Her weakness continued to progress to include her left hand.

Upon a comprehensive literature review, we found two previously reported cases of MM in immune checkpoint inhibitor use [1, 4]. A detailed case report from Sakai et al. discusses a patient with metastatic melanoma who developed MM following immunotherapy treatment [1]. An 81-year-old man began experiencing limb weakness and sensory disturbance 8 days after beginning nivolumab monotherapy for mediastinal metastatic melanoma. He had proximal muscle weakness in all four limbs and left ulnar and bilateral peroneal palsies. Diagnosis was confirmed based on EMG findings [1]. He also had associated rhabdomyolysis. He was treated with solumedrol followed by oral prednisone, which halted the progression of motor weakness, and there was a recovery of grip strength. Dubey et al. made a brief mention of a case of ANCA-associated MM after immunotherapy, where a patient developed a sequential foot drop over several days followed by bilateral hand numbness and weakness and sensory ataxia. Electrodiagnostic studies showed evidence of mononeuritis multiplex [4].

PD-1 and CTLA-4 inhibitors have been associated with a variety of irAEs that most commonly affect the skin, gastrointestinal (GI) tract, liver, and endocrine system. Rates of grade 3 or 4 immune-related adverse events secondary to PD-1 inhibitor use are about 3–14% [8]. Neurological irAEs are less common but are being reported at an increasing rate (1.0–2.8%) [8]. These neurological events can occur at any point after the initiation of immunotherapy and involve a wide variety of neuropathies, neuromuscular disorders, and demyelinating polyradiculoneuropathies. To date, cranial neuropathies, non-length-dependent polyradiculoneuropathies, small-fiber/autonomic neuropathy, sensory neuronopathy, length-dependent sensorimotor axonal polyneuropathy, neuralgic amyotrophy, and mononeuritis multiplex have all been reported as adverse events in response to immune checkpoint inhibitors [4, 7].

MM is an asymmetric, asynchronous, sensory and motor mononeuropathy that involves damage in at least two separate peripheral nerve areas. It typically presents as the acute or subacute onset of multifocal sensory loss, weakness, and pain. It is usually associated with vasculitis, infections, diabetes, or paraneoplastic syndromes [9]. Diagnosing MM involves a combination of autoimmune serological assays and neurological testing. It is distinguished from demyelinating polyneuropathies through clinical presentation and EMG, indicating axonal asymmetric reduced sensory and motor action potentials [10].

The case demonstrated by Sakai et al. is similar to the one presented here in a few ways. Both patients had an EMG that showed reduced sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) in a multifocal pattern. Moreover, recovery was not complete for either patient. The patient presented by Sakai et al. showed some response to treatment with corticosteroids but relapsed when dosage was decreased. Our patient was started on methylprednisolone and IVIg and showed worsening weakness in the setting of a prednisone taper and missed IVIg doses.

Checkpoint inhibitors are becoming increasingly common in treating cancers such as melanoma and, as a result, how they impact the nervous system requires continued investigation, with the goal of maximizing our scientific and clinical understanding of these treatments. Though there is no standard in treating neurological irAEs in immunotherapy, IVIg and plasmapheresis have been found to be effective in managing neurological sequelae of PD-1 inhibitors and CTLA-4 inhibitors [1, 2, 4]. In our case, the patient improved with IVIg and showed clinical and electrophysiological worsening in the setting of missed IVIg dosages. Immunosuppression was increased to rituximab with continued clinical progression and eventually an election to pursue hospice care.

Prompt suspicion, diagnosis, and therapeutic intervention provide the best opportunity for favorable outcomes for neurologic irAEs, however, the natural history of immune-mediated MM is variable. Considerations of re-challenging with immunotherapy are evaluated on a case-by-case basis, taking into account both the initial severity of irAEs and the clinical course.