Polyradiculoneuropathy induced by immune checkpoint inhibitors: a case series and review of the literature.
TL;DR: Polyradiculoneuropathy induced by ICIs has a distinct subset of neurological irAEs and requires early recognition, which was observed symmetrically and predominantly in the legs rather than the arms.
Abstract: The purpose of the present study is to report the clinical characteristics of polyradiculoneuropathy induced by immune checkpoint inhibitors (ICIs). We retrospectively reviewed lists of all inpatients with neurological immune-related adverse events (irAEs) treated at the neurology departments of three hospitals in January 2017 and December 2019. We also performed a review of the previous case reports with polyradiculoneuropathy induced by ICI therapy. We had 4 patients with polyradiculoneuropathy following ICI therapy. We comprehensively reviewed our 4 patients and 32 previous case reports. There were 28 men and 8 women with a mean onset age of 61 years. ICI monotherapy was performed in 27 patients, whereas the combination of ICIs was administered in 9 patients. All patients except 2 showed limb weakness, which was observed symmetrically and predominantly in the legs rather than the arms. Bulbar involvement was observed in 7 patients. The laboratory findings were demyelination in electrophysiological studies and elevated protein with lymphocytes in the cerebrospinal fluid. Disease severity was ranked on the Hughes functional scale; 17 patients were grade 4 or greater. The treatment responses to corticosteroid and intravenous methylprednisolone were favorable. Intravenous immunoglobulin was also used in combination with steroids. Seven patients died, including 4 who on mechanical ventilation. Polyradiculoneuropathy induced by ICIs has a distinct subset of neurological irAEs and requires early recognition.
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TL;DR: Among diverse neurological immune-related adverse events (irAEs), autoimmune encephalitis, aseptic meningitis, Guillain-Barre syndrome (GBS), myasthenia gravis (MG), and myositis are particularly important as mentioned in this paper.
Abstract: Among diverse neurological immune-related adverse events (irAEs), autoimmune encephalitis, aseptic meningitis, Guillain-Barre syndrome (GBS), myasthenia gravis (MG), and myositis are particularly important. The clinical presentation may be different from that of patients with conditions unrelated to immune checkpoint inhibitors (ICIs). Many of the autoantibodies detected in patients' sera are committed to the pathogenesis, while the clinical significance of such autoantibodies in cases of neurological irAEs is different from the significance in cases of typical neuronal disorders. A broad range of clinical symptoms complicates the diagnosis of autoimmune encephalitis. The clinical features of aseptic meningitis induced by classical drugs are different from those of aseptic meningitis induced by ICIs. Although autoantibodies against synaptic receptors or neuronal cell surface proteins are not detected, anti-Ma2 antibodies, which are onconeural antibodies against intracellular proteins, are detected in patients with autoimmune encephalitis associated with ICIs. GBS induced by ICIs sometimes shows gradual progression and a relapse of symptoms, suggesting chronic inflammatory demyelinating polyneuropathy. Bulbar symptoms and myasthenic crisis are frequently observed in ICI-induced MG. Anti-acetylcholine receptor antibodies are found in only half of patients with MG occurring as an irAE. ICI-induced myositis is accompanied by ocular muscle symptoms, such as ptosis and diplopia, which can suggest MG. Patients receiving ICI treatment present clinical features and laboratory findings that represent a mixture of MG and myositis. Anti-striational antibodies may act as biomarkers in cases in which MG and myositis overlap. A correct understanding of neurological adverse events is required to achieve the best management of patients.
17 citations
TL;DR: In this paper, the authors provide an update of the recent advances in the diagnosis and treatment of neurological toxicities related to ICI use, focusing on the exclusion of alternative diagnoses, diagnostic specificities, and treatment.
Abstract: As the use of cancer immunotherapy with immune checkpoint inhibitors (ICIs) is expanding rapidly for the treatment of many tumor types, it is crucial that both neurologists and oncologists become familiar with the diagnosis and treatment of neurological immune-related adverse events (n-irAEs). These are rare complications, developing in their severe forms in only 1-3% of the patients, but are highly relevant due to their mortality and morbidity burden. The diagnosis of n-irAEs is-however-challenging, as many alternative diagnoses need to be considered in the complex scenario of a patient with advanced cancer developing neurological problems. A tailored diagnostic approach is advisable according to the presentation, clinical history, and known specificities of n-irAEs. Several patterns characterized by distinct clinical, immunological, and prognostic characteristics are beginning to emerge. For example, myasthenia gravis is more likely to develop after anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) treatment, while meningitis appears more frequently after anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) therapy. Also, peripheral neuropathy and Guillain-Barre syndrome seem to be more common in patients with an underlying melanoma. Central nervous system disorders (CNS) are less frequent and are more often associated with lung cancer, and some of them (especially those with limbic encephalitis and positive onconeural antibodies) have a poor prognosis. Herein, we provide an update of the recent advances in the diagnosis and treatment of neurological toxicities related to ICI use, focusing on the exclusion of alternative diagnoses, diagnostic specificities, and treatment of n-irAEs.
11 citations
TL;DR: This case report may provide a new alternative and complementary therapy for immune checkpoint inhibitor-induced Guillain–Barré syndrome, but more definitive and robust evidence is needed to support its efficacy.
Abstract: Guillain–Barré syndrome(GBS) is an autoimmune-mediated peripheral neuropathy. Immune checkpoint inhibitors (ICIs) are the standard treatment for cancer and may lead to immune-related adverse events (irAEs) such as GBS. Corticosteroids, plasma exchange (PE), and intravenous immunoglobulin (IVIG) are currently accepted treatments for ICI-induced GBS. However, there are still adverse reactions, and the effect of relieving symptoms is not as good as expected. Safe and effective complementary replacement therapy to alleviate GBS symptoms and ameliorate the quality of life is urgently required. In this case, a 63-year-old man received ICI therapy and antitumor chemotherapy for lung malignancy. After two courses of treatment, the patient gradually developed limb weakness, numbness, and pain at the ends of the limbs, with cerebrospinal fluid (CSF) albuminocytological dissociation, and electromyography (EMG) suggested demyelinating changes and was diagnosed as GBS. Although the patient received high doses of intravenous gamma globulin and limb weakness symptoms were alleviated, there was still significant numbness and pain in the extremities. After four times of acupuncture treatments, the patient complained that the symptoms of limb numbness and fatigue were significantly alleviated without any discomfort. This case report may provide a new alternative and complementary therapy for immune checkpoint inhibitor-induced GBS, but more definitive and robust evidence is needed to support its efficacy.
8 citations
TL;DR: The treatment of ICI-associated AE should be more individualized with prudent decision-making and should balance the tumor progression and AE treatment, thus broadening the understanding of the neurological complications caused by ICI.
Abstract: Immune checkpoint inhibitors (ICIs) are being used in patients with various advanced malignancies, and patient outcomes have improved considerably. Although ICIs can effectively treat tumors, 30–60% of patients experience immune-related adverse events (irAEs). Autoimmune encephalitis (AE) is a rare irAE that has become a novel topic in neuroimmunology and has received increasing attention in recent years. Herein, we report a rare case of GAD65-antibody–associated AE after metastatic small cell lung cancer treatment with pembrolizumab. The patient received IVIg therapy for AE and continuous pembrolizumab therapy without suspension of tumor treatment. At 1 year follow-up, both the patient’s AE symptoms and tumors were stable. We consider that the treatment of ICI-associated AE should be more individualized with prudent decision-making and should balance the tumor progression and AE treatment. In addition, we have also comprehensively reviewed the literature of ICI-associated AE, and summarized the clinical features, treatment, and prognosis of AE caused by ICI, thus broadening our understanding of the neurological complications caused by ICI.
7 citations
TL;DR: The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors.
Abstract: Immune checkpoint inhibitors have entailed a change of paradigm in the management of multiple malignant diseases and are acquiring a key role in an increasing number of clinical sceneries. However, since their mechanism of action is not limited to the tumor microenvironment, their systemic activity may lead to a wide spectrum of immune-related side effects. Although neurological adverse events are much less frequent than gastrointestinal, hepatic, or lung toxicity, with an incidence of <5%, their potential severity and consequent interruptions to cancer treatment make them of particular importance. Despite them mainly implying peripheral neuropathies, immunotherapy has also been associated with an increased risk of encephalitis and paraneoplastic disorders affecting the central nervous system, often appearing in a clinical context where the appropriate diagnosis and early management of neuropsychiatric symptoms can be challenging. Although the pathogenesis of these complications is not fully understood yet, the blockade of tumoral inhibitory signals, and therefore the elicitation of cytotoxic T-cell-mediated response, seems to play a decisive role. The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors.
6 citations
References
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Journal Article•
620 citations
University of Duisburg-Essen1, University of Zurich2, University of Erlangen-Nuremberg3, University of Tübingen4, Hannover Medical School5, Heidelberg University6, Otto-von-Guericke University Magdeburg7, University Hospital Heidelberg8, University of Münster9, RWTH Aachen University10, University of Würzburg11, Technische Universität München12
TL;DR: Anti-PD-1 antibodies can induce a plethora of irAEs and the knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
451 citations
TL;DR: In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-Barré syndrome, and the median time of nAEs onset was 6 weeks.
348 citations
TL;DR: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important and postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died.
Abstract: Objective: To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan. Methods: We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used. Results: There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti–acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients9 daily living activity. Conclusions: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.
274 citations
"Polyradiculoneuropathy induced by i..." refers background in this paper
...In cases of myasthenia gravis and/or myositis, disease onset was usually within the first 4 cycles of ICI treatment [22]....
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TL;DR: The findings support the standard treatment of withholding or discontinuing ipilimumab and plasmapheresis or high-dose intravenous steroids may be considered as the initial choice of treatment for severe ipILimumab-related neurological adverse events.
Abstract: Melanoma is an immunogenic cancer, and numerous immunotherapies have been used to control its progression, including α-interferon, interleukin (IL)-2, and monoclonal antibodies. Ipilimumab is a novel FDA-approved immunotherapy agent that has been used to treat patients with unresectable and/or metastatic melanoma since May 2011. Ipilimumab is a recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, which is an inhibitor of T-cell activation; thereby, ipilimumab potentiates an immune response. Immune-related adverse events (irAEs) may occur in patients treated with ipilimumab, however. Reported neurological irAEs include inflammatory myopathy,1 aseptic meningitis, posterior reversible encephalopathy syndrome,2 Guillain-Barre syndrome, myasthenia gravis–type syndrome, sensorimotor neuropathy,2,3–5 and inflammatory enteric neuropathy.6
We report 3 cases of metastatic melanoma treated with ipilimumab in which the patient developed rare ipilimumab-related adverse events: chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), and concurrent myositis and myasthenia gravis–type syndrome, respectively. We believe these events were due to immunological pathogenesis involving various human leukocyte antigen subgroups and immunotherapy regimens. We report 3 cases of ipilimumab-related irAEs presented with rare neurological symptoms to raise awareness of the wide spectrum of neurological side effects of this medication and provide our experience on their treatment.
259 citations