By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Immune checkpoint inhibitors have become an important part of the armamentarium for the medical treatment of cancers such as melanoma and lung carcinomas. A number of immune-mediated neurological complications have been identified during the use of these agents, including polyradiculoneuropathy.
SOURCE: Okada K, Seki M, Yaguchi H, et al. Polyradiculoneuropathy induced by immune checkpoint inhibitors: A case series and review of the literature. J Neurol 2021;268:680-688.
Typically, neurologic complications associated with immune checkpoint inhibitors (ICI) develop within three months of initiating therapy, and affect 1% to 14% of patients. The most common complications are headache and peripheral sensory neuropathy, but rarely include myasthenia gravis, posterior reversible encephalopathy syndrome (PRES), aseptic meningitis, transverse myelitis, pancerebellitis, autoimmune encephalitis, and cranial and peripheral neuropathies. Polyradiculoneuropathy, in the form of both Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), also has been reported. What are the clinical characteristics of polyradiculoneuropathy induced by ICIs?
To answer this question, the study investigators performed a retrospective records review of all inpatients with neurological immune-related adverse events treated between January 2017 and December 2019 at the neurology departments of Keio University Hospital, Jikei University Kashiwa Hospital, and Tokyo Saiseikai Central Hospital, Japan. This review was supplemented by a systematic PubMed database literature search of such patients, using keywords GBS, CIDP, polyradiculoneuropathy, polyneuropathy, polyradiculitis, polyradiculopathy, and demyelinating polyneuropathy.
Among a total of 36 patients identified with polyradiculopathy (four inpatients and 32 culled from the literature), the mean age was 61 years. There were 28 men and eight women, of which 27 received ICI monotherapy, and nine received combination ICIs. Melanoma was the predominant cancer (n = 26), with non-small cell lung cancer present in four, renal or gastric cancer in two each, and bladder or nasal cancer in one each. Only three had a prior infection or vaccination. Symmetric limb weakness, more so in the legs than in the arms, was evident in all but two cases, bulbar involvement was present in seven cases, and facial weakness was present in three cases. Among 17 patients, muscle weakness progressed rapidly over two weeks. Demyelinating polyradiculoneuropathy was found on electrodiagnostic studies in 22 patients, with 10 showing an axonal pattern, and cerebrospinal fluid demonstrated elevated protein in all but one, with elevated lymphocytes in 13 patients. Non-neurologic immune-related adverse events were present in 10. Patients responded favorably to corticosteroids, which were used in 25 patients, and intravenous methylprednisolone, used in 15, with intravenous immunoglobulin (IVIG) used in 21 patients in combination with steroids. The following features of polyradiculoneuropathy induced by ICIs were observed: significant motor weakness, manifesting particularly as gait impairment; elevation of both protein and lymphocytes in the spinal fluid; demyelination on nerve conduction studies; and a positive response to corticosteroid therapy. Polyradiculoneuropathy induced by ICIs may be more severe than sporadic GBS and CIDP. Early recognition and treatment are crucial to having a positive outcome.
COMMENTARY
ICIs may prove beneficial for the treatment of COVID-19, the acute and severe pneumonia caused by the severe acute respiratory syndrome-associated coronavirus2 (SARS-CoV-2). Patients with COVID-19 exhibit lymphocytopenia and, following a period of T-cell activation, shift to T-cell exhaustion, as well as demonstrate a decrease in the number of natural killer cells, which also express the exhaustion marker, NKG2A. T-cell exhaustion may be a leading cause of severe COVID-19. Of note, cancer patients are usually immunocompromised but may restore their antitumoral immune response when treated with ICIs. Additionally, when infected with virus, mice and men exhibit a T-cell exhaustion, similar to observations following SARS-CoV-2 infection. Among ICIs, some antibodies can block the programmed death-1 pathway, such that when treated with antiprogrammed death antibodies, T-cell competence is restored and efficiently counteracts the viral infection. Currently, clinical trials are underway to examine this potential avenue of COVID-19 treatment.
