Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies

Abstract

ObjectiveTo describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs).MethodsPatients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents.ResultsWe identified 19 patients with irNeuropathies. ICIs included anti-programmed death–1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.ConclusionNeuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.

Epidemiology of paraneoplastic neurologic syndromes and autoimmune encephalitides in France

“…In fact, classical PNS—a group whose antibodies were described in the 1980s and 1990s—now represents only about a third of all definite PNS and AE cases. Part of the increased incidence seen in this subgroup may be attributable to more widespread use of immune checkpoint inhibitors in oncological practice, as already observed for specific central 23 and peripheral nervous system disorders, 24 including anti-Hu 25 and anti–Ma2-associated syndromes. 26 …”

“…In fact, classical PNS-a group whose antibodies were described in the 1980s and 1990s-now represents only about a third of all definite PNS and AE cases. Part of the increased incidence seen in this subgroup may be attributable to more widespread use of immune checkpoint inhibitors in oncological practice, as already observed for specific central 23 and peripheral nervous system disorders, 24 including anti-Hu 25 and anti-Ma2-associated syndromes. 26 To address the aforementioned limitations of exhaustiveness and referral patterns, future incidence studies should strengthen interhospital collaborations and ensure increased reporting of these conditions to the National Reference Center in Lyon.…”

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

“…Twelve patients had acute or subacute presentations of immune‐mediated cranial and/or peripheral neuropathies (see Supplementary Table) . Again, the median number of ICI cycles to development of irAE‐N was 3 (range = 1–26).…”

“…On electrophysiological evaluation, the patient was diagnosed with non–length‐dependent sensory and motor polyneuropathy with axonal features and concurrent irritable myopathy. He had progressive decline and died due to septic shock and multisystem failure …”

Neurological immune‐related adverse events associated with immune checkpoint inhibitors: A review of the literature

“…According to the meta‐analysis of randomized clinical trials, the incidence of immune‐related peripheral neuropathy (irNeuropathy) is 5%, with 0.4% serious irNeuropathy (grade ≥3), significantly lower than that of chemotherapy‐induced peripheral neuropathy 24 . Compared with chemotherapy‐induced peripheral neuropathy, a significantly higher proportion of irNeuropathy had acute or subacute and nonlength‐dependent presentations 101 . Concurrent irAEs involving other organ systems are common (58%) in irNeuropathy 101 .…”