Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature

We found high-quality evidence that many treatments offer better efficacy than chemotherapy, especially recently implemented treatments, such as small-molecule targeted drugs, which are used to treat melanoma with specific gene mutations. Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival. However, there was no difference between polychemotherapy and monochemotherapy in terms of achieving progression-free survival and overall survival. Biochemotherapy did not significantly improve overall survival and has higher toxicity rates compared with chemotherapy.There was some evidence that combined treatments worked better than single treatments: anti-PD1 monoclonal antibodies, alone or with anti-CTLA4, improved progression-free survival compared with anti-CTLA4 monoclonal antibodies alone. Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival, and a combination of BRAF plus MEK inhibitors was associated with better overall survival for BRAF-mutated melanoma, compared to BRAF inhibitors alone.The combination of BRAF plus MEK inhibitors (which can only be administered to people with BRAF-mutated melanoma) appeared to be the most effective treatment (based on results for progression-free survival), whereas anti-PD1 monoclonal antibodies appeared to be the least toxic, and most acceptable, treatment.Evidence quality was reduced due to imprecision, between-study heterogeneity, and substandard reporting of trials. Future research should ensure that those diminishing influences are addressed. Clinical areas of future investigation should include the longer-term effect of new therapeutic agents (i.e. immune checkpoint inhibitors and targeted therapies) on overall survival, as well as the combination of drugs used in melanoma treatment; research should also investigate the potential influence of biomarkers.

To define the clinical characteristics, management, and outcome of neurologic immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs). Systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on CNS disorders (109/428, 25%). The most common n-irAEs reports were myositis (136/428, 32%), Guillain-Barré syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared with the whole sample, myasthenic syndromes were significantly more Ab positive (33/56, 59%; p < 0.001). Anti-programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; p = 0.005) and less common in meningitis (2/13, 15%; p < 0.001) and cranial neuropathies (13/31, 42%; p = 0.005). Anti-cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; p < 0.001) and less common in encephalitis (2/56, 4%; p = 0.009) and myositis (12/136, 9%; p = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p = 0.003) and less common in encephalitis (19/56, 34%; p = 0.001). The highest mortality rate was reached in myasthenic syndromes (28%). Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.

To investigate the characteristics and risk factors for neurologic adverse events (AEs) induced by immune checkpoint inhibitors (ICIs). An observational, retrospective, and pharmacovigilance study based on the FAERS database collected between January 2014 and December 2019 was conducted. ICI-related AEs were defined as adverse reactions in patients using anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab). Neurologic AEs previously reported to be associated with ICI were evaluated in the disproportionality analysis using the reporting odds ratio (ROR). Among 50,406 ICI-related reports, 3619 (7.2%) neurological case was found: 1985 with anti-PD-1, 372 with anti-PD-L1, 366 with anti-CTLA-4, and 896 with the combination of ICIs. In comparison to non-ICI drug use, ICI use demonstrated higher risk for neurologic complication, including hypophysitis/hypopituitarism, myasthenia gravis, encephalitis/myelitis, meningitis, Guillain-Barre syndrome, vasculitis, and neuropathy. The risk of neurologic AEs associatedwith ICI combination therapy was as high as or even higher than ICI monotherapy, most significantly in hypophysitis/hypopituitarism. The proportion of serious neurological events and death related to combination therapy has been decreasing in recent years. Older age, male and female sex, and metastasis were not significant risk factors for the incidence of neurologic ICI-related AEs. Patients at older age, with melanoma or non-small cell lung cancer, or on dual ICI therapy may be at higher risk of fatal neurologic AEs. ICI use is associated with a higher risk of neurological complications, with dual ICI therapy posing a higher risk, while older age, sex, or metastasis were not. Patients at older age, with certain cancer types, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.

Immune checkpoint inhibitors (ICIs) initiate antitumor immunity by blocking the action of immune inhibitor-signaled cytotoxic proteins, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, and programmed cell death ligand 1. However, in rare cases (∼1%-12% of patients), ICI treatment causes neurologic immune-related adverse events (irAEs). These include, but are not limited to, headache, encephalitis, neuropathies, myasthenia gravis, and myositis. The symptoms associated with irAEs can range from mild (grade 1-2) to severe (grade 3-4); however, they are often challenging to diagnose because they may present as generalized symptoms, such as fatigue and weakness, that can also be caused by the cancer itself. Here, we present an illustrative case of a 67-year-old woman who presented with signs of a neurologic irAE, including progressive dysphagia and weakness leading to falls, which started during treatment with pembrolizumab and worsened following initiation of ipilimumab. Following neurological and pathological evaluation, she was diagnosed with myositis. She was treated with steroids and improved rapidly. In this article, we review previous literature to provide guidance to frequently asked questions concerning the diagnosis and management of neurologic irAEs in patients with advanced cancer. With prompt and effective treatment, most patients will achieve a complete recovery. KEY POINTS: Neurologic immune-related adverse events (irAEs) affect approximately 1% of patients treated with immune checkpoint inhibitor (ICI) monotherapy and 2%-3% treated with combination therapy. These irAEs can affect any portion of the nervous system, although peripheral nerve system manifestations are most common. Overlap syndromes with multiple neurologic irAEs or other affected organ systems frequently exist.Diagnosis of neurologic irAEs can be challenging. Routine testing may be unremarkable and symptoms frequently mimic those from cancer or side effects of other therapies. Optimal management is currently unknown. A systematic, highly coordinated, and multidisciplinary approach is critical.Outcomes from neurologic irAEs are typically favorable with the current practice of holding the ICI and starting corticosteroids. Some patients are even successfully retreated with an ICI. A subset of patients, however, have a fulminant and potentially fatal course.Improved risk assessments and targeted therapies are needed.

Lambert Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular junction disorder involving loss of functional pre-synaptic P/Q-type voltage-gated calcium channels. Many cases occur as a paraneoplastic disorder, often in small cell lung cancer (SCLC). Recently, immune checkpoint inhibitors (ICI) have emerged as treatment of choice for various malignancies. While generally well tolerated, certain ICI-treated patients experience neurologic immune-related adverse events (irAEs). Here, we explore therapeutic and diagnostic conundrums from the unclear etiology (paraneoplastic vs. irAE) of a case of LEMS in a patient with SCLC treated with ICI therapy. A 62-year-old female patient with SCLC was referred to EMG laboratory with 7 weeks of progressive weakness, shortness of breath and dysphagia. Due to tumor progression, immunotherapy with pembrolizumab was initiated five months prior to presentation. On examination, she had mild non-fatigable right-sided ptosis and diplopia, normal bulbar strength, and proximal greater than distal weakness of lower greater than upper extremities. Her reflexes were 2-/4 throughout, with left biceps reflex facilitating after 30 seconds of exercise. On nerve conduction studies (NCS), there was an amplitude increase in multiple nerves including the left median nerve (160%) and left ulnar nerve (370%) after 10 seconds of exercise. Paraneoplastic panel came back with elevated LEMS-related anti-P/Q-type voltage gated calcium channel antibodies at 0.19nmol/L (normal: ≤0.02nmol/L). This case illustrates the diagnostic and therapeutic challenges that surround LEMS in SCLC patients on immunotherapy. Diagnosis hinges on clinical presentation, motor NCS, and antibody testing while determination of the etiology (paraneoplastic vs ICI related LEMS) is more complex and may affect selection of the correct treatment. Therapy for ICI-related neuromuscular irAEs depends on symptom severity, but typically should include holding immunotherapy and administration of high dose corticosteroids as first line treatment with possible addition of IVIg and plasmapheresis. This differs from the common first line treatment for paraneoplastic LEMS, highlighting the importance of understanding of the etiology. Further research is needed to better understand optimal management.

Immune checkpoint inhibitors (ICPI), a breakthrough immunotherapy for cancer, can cause serious neurological adverse events (AEs). We aimed to investigate the characteristics of the neurological and related AEs associated with ICPI treatment, using a large pharmacovigilance database from Japan. We conducted disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing 566,698 patient cases recorded between April 2004 and March 2019, to detect neurological and related AE signals associated with ICPI treatment by calculating reporting odds ratio (ROR). Among 7604 cases with ICPI usage, we identified 583 cases (7.67%) with a significantly high reporting of neurological and related AEs (lower 95% of the ROR > 1), including myasthenia gravis (MG), inflammatory myositis, non-infectious encephalitis/myelitis, non-infectious meningitis, hypophysitis/hypopituitarism, and peripheral neuropathy including Guillain-Barre syndrome (GBS). Among the ICPI subtypes, when compared to nivolumab as a reference, number of hypophysitis, hypopituitarism, and meningitis reports from the use of ipilimumab and number of encephalitis/myelitis and meningitis reports from the use of anti-programmed cell death-ligand-1 (PD-L1) agents were significantly higher. Additionally, time to AE onset of symptoms post administration was short in meningitis (median 21days), MG (median 28days), myositis (median 28days), and encephalitis/myelitis (median 32.5days), while it was longer in peripheral neuropathy (median 42days), hypophysitis (median 94days), and hypopituitarism (median 112days). Our results showed characteristic features of neurological and related AEs associated with each ICPI subtype, reported in a large number of Japanese patients. This would help in prompt identification and treatment of neurological AEs associated with ICPI treatment.

37 Background: Immune checkpoint inhibitors (ICI) have provided landmark breakthrough achieving success in prolonging survival in multiple cancer types. As a new class of therapy immune related serious adverse drug reactions (sADRs) have had limited reporting. This includes neurologic based, with reports limited to clinical trials and case-based. Ours is the largest database analysis to date reporting neurological adverse events after ICI therapy. Methods: We analyzed the FDA Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, and ipilimumab two years prior their FDA approval to September 2017, to include all cases reported with Guillain-Barré syndrome (GBS), Myasthenia gravis, ocular myasthenia, and myasthenic syndrome after the usage of ICI. Results: A total 35,726 cases were reported in FAERS. We identified a total of 263 cases of which 121 (46%) were GBS, 112 (42.6%) myasthenia gravis, 22 myasthenic syndrome (8.4%), and 8 (3%) ocular myasthenia. The mean age in our study was 66 years, with 63% being male. The majority of the cases were reported in the United States (49%), followed by Japan (10%), France (6%), and Australia (5.7%). Over 30% of patients presented more than one significant symptom. Around 20% of these patients were taking more than one immune checkpoint inhibitor, combining ipilimumab with either nivolumab or pembrolizumab. A significantly higher proportion of patients with GBS taking more than one ICI (28.1%, p = 0.013). Nivolumab was the most common ICI in patients with myasthenia gravis, myasthenic syndrome, and ocular myasthenia, while ipilimumab was the most common in patients with GBS. Sixty four percent of these patients required hospitalization, 17% were reported as life threatening events, 7% resulted in disability, and 22% died. Conclusions: Neurological adverse events associated with ICI are relatively uncommon, but can have serious clinical consequences. Recognizing and detailing neurological immune syndromes in relation to ICI therapy are essential in the oncological and neurological practice due to the growing usage of these agents in cancer treatment.

Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune-related NAEs in cancer patients. Medical records of ICI-treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno-related NAEs. A total of 1185 ICIs-treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty-four from the overall ICIs-treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1-10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain-Barre-like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS-related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune-modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune-related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.

Lay abstract Real-world safety experience with immune checkpoint inhibitors in Saudi Arabia: Immune Checkpoint Inhibitors (ICIs) are rapidly growing and changing cancer care. With introduction of ICIs the landscape for cancer treatment has changed significantly. ICIs are known to induce immune-related adverse effects. This research is intended to shed light on ICIs and describe our safety experience with these agents. This study is a retrospective cohort study aimed to determine the safety of ICIs and its related adverse events at a tertiary hospital in Saudi Arabia. The study was conducted in the oncology center at King Abdulaziz Medical City, Riyadh. We identified study participants by using electronic health care system (BestCare)® to involve patients who received ICIs treatment during the study period from January 2016 up to December 2018, to include a total of 53 patients. Most of our patients were on nivolumab (37 patients) followed by atezolizumab (10 patients), and pembrolizumab (6 patients). The average number of emergency room visits after receiving treatment was three visits per patient. Renal adverse events occurred following ICIs use in nine patients, and none of the reported cases experienced a grade ≥3 event. Moreover, 13 patients experienced a hepatic adverse event, of whom only 1 patient experienced a grade ≥3 event leading to treatment discontinuation. As for diarrhea, among all patients who received ICIs, 14 patients experienced diarrhea, and 5 of them had grade ≥3 events. Also, thyroxine abnormalities occurred in seven patients. While, Pneumonitis occurred in four patients following ICIs use. In addition, we noticed other adverse events with ICIs including (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia, and neurological adverse events). Furthermore, 17 patients required steroids to manage ICIs adverse events. And, no patients in our study required additional management with other immunosuppressive agents.Immunotherapies are rapidly growing and changing cancer care. Immune Checkpoint Inhibitors (ICIs) have the ability to block inhibitory checkpoints and restore the functions of the immune system. ICIs are used for the treatment of several types of cancer, and nowadays, many studies are ongoing in order to get approvals for newer indications. ICIs are known to induce immune-related adverse effects. The safety of ICIs and the most common immune-related adverse events are not yet well recognized for our population since this class of medications is lately introduced in our region, where only limited studies in our population are available in the literature. This research is intended to shed light on ICIs and describe our safety experience with these agents. This study is a retrospective cohort study aimed to determine the safety of ICIs and its related adverse events at a tertiary hospital in Saudi Arabia. The study was conducted in the oncology center at King Abdulaziz Medical City, Riyadh. Study participants were identified by using the electronic health care system (BestCare)® to include patients who were treated with ICIs during the study period from January 2016 up to December 2018. A total of 53 patients were included. Most of our patients were on nivolumab (37 patients) followed by atezolizumab (10 patients), and pembrolizumab (6 patients). The average number of emergency room visits after receiving ICIs was three visits per patient. Renal adverse events occurred following ICIs use in nine patients, and none of the reported cases experienced a grade ≥3 event. Moreover, 13 patients experienced a hepatic adverse event, of whom only 1 patient experienced a grade ≥3 event leading to treatment discontinuation. As for diarrhea, among all patients who received ICIs, 14 patients experienced diarrhea, and 5 of them had grade ≥3 events. Also, thyroxine abnormalities occurred in seven patients. While, pneumonitis occurred in four patients following ICIs use. In addition, we noticed other adverse events with ICIs, including (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia, and neurological adverse events). Furthermore, 17 patients required steroids to manage ICIs adverse events. And, no patients in our study required additional management with other immunosuppressive agents. Patients treated with immune checkpoint inhibitors could have a variety of adverse drug events that might lead to treatment discontinuation and increase overall emergency room visits. This study highlights the most common adverse drug events associated with ICIs use at a tertiary care center in Saudi Arabia.

Immune checkpoint inhibitors (ICIs), an antitumor therapeutic strategy, have shown great potential for cancer treatment. With the widespread use of ICIs, immune-related adverse events (irAEs) have increased gradually. Neurotoxicity, as an irAE, has a low incidence rate, but high disability and mortality rates, warranting clinical attention. This study aimed to quantify the association between neurological adverse events and ICI treatment and describe the characteristics of ICI-related neurological complications in real-world practice. Data were sourced from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2025. Data mining was performed using the reporting odds ratio (ROR) method. Classification and statistics were conducted using the system organ class (SOC), high-level group term (HLGT), and preferred term (PT) from the Medical Dictionary for Regulatory Activities (MedDRA) terminology set (version 28.0). The entire FAERS database included 56,321,150 adverse event records, of which 26,629 records were identified as being related to neurological immune-related adverse events (n-irAEs) following ICI therapy. The main adverse events include encephalitis, encephalopathy, myasthenia gravis, paraneoplastic syndromes, and peripheral neuropathy. Among these reports, males (53.51%) outnumbered females (37.82%), and the median patient age was 67 years. The number of reports in 2024 was slightly higher than that in other years, but the difference was not significant. Physicians were the primary reporters (43.23%) and the United States had the highest number of reports (35.78%). The median time to the onset of adverse events was 30 days. Serious reports accounted for a high proportion of the patients (91.23%). Pharmacovigilance analysis indicated that neurological immune-related adverse events associated with ICIs mainly involved central nervous system inflammation and neuromuscular junction dysfunction. Different ICI immunotherapies are associated with distinct neurological disease characteristics, and combination therapies may influence the reporting patterns of neurotoxicity. In clinical practice, the early recognition and management of ICI-related n-irAEs are critical.

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 61years. 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.

Neurologic adverse events (NAEs) due to immune checkpoint inhibitors (ICIs) can be fatal but are underexplored. To compare NAEs reported in randomized clinical trials (RCTs) of US Food and Drug Administration-approved ICIs with other forms of chemotherapy and placebo. Bibliographic databases (Embase, Ovid, MEDLINE, and Scopus data) and trial registries (ClinicalTrials.gov) were searched from inception through March 1, 2020. Phase II/III RCTs evaluating the use of ICIs were eligible for inclusion. Unpublished trials were excluded from the analysis. Two investigators independently performed screening of trials using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. NAEs were recorded for each arm. Data were pooled using a random-effects model. The risk of NAEs with ICI use compared with any drug regimen, cytotoxic chemotherapy, and placebo. A total 39 trials including 23 705 patients were analyzed (16 135 [68.0%] men, 7866 [33.1%] White). The overall risk of a NAE was lower in the ICI group (risk ratio [RR], 0.59; 95% CI, 0.45-0.77) and in the subgroup of RCTs comparing ICI use with chemotherapy (RR, 0.22; 95% CI, 0.13-0.39). In the subgroup of RCTs comparing ICI with placebo, the overall risk of NAE was significantly higher in the ICI group (RR, 1.57; 95% CI, 1.30-1.89). Peripheral neuropathy (RR, 0.30; 95% CI, 0.17-0.51) and dysgeusia (RR, 0.41; 95% CI, 0.27-0.63) were significantly lower in the ICI group. Headache was more common with the use of ICIs (RR, 1.32; 95% CI, 1.10-1.59). In the subgroup analysis of RCTs comparing ICI use with chemotherapy, peripheral neuropathy (RR, 0.09; 95% CI, 0.05-0.17), dysgeusia (RR, 0.42; 95% CI, 0.21-0.85), and paresthesia (RR, 0.29; 95% CI, 0.13-0.67) were significantly lower in the ICI group. RCTs comparing ICIs with placebo showed a higher risk of headache with ICI use (RR, 1.63; 95%, CI, 1.32-2.02). Results of this meta-analysis suggest that the overall risk of NAEs, peripheral neuropathy, and dysgeusia is lower with the use of ICI. When compared with chemotherapy, the overall risk of NAE, peripheral neuropathy, paresthesia, and dysgeusia was lower with ICI use; however, when compared with placebo, the risk of NAEs is higher with the use of ICI.

Lambert Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular junction disorder involving loss of functional pre-synaptic P/Q-type voltage-gated calcium channels. Many cases occur as a paraneoplastic disorder, often in small cell lung cancer (SCLC). Recently, immune checkpoint inhibitors (ICI) have emerged as treatment of choice for various malignancies. While generally well tolerated, certain ICI-treated patients experience neurologic immune-related adverse events (irAEs). Here, we explore therapeutic and diagnostic conundrums from the unclear etiology (paraneoplastic vs. irAE) of a case of LEMS in a patient with SCLC treated with ICI therapy. A 62-year-old female patient with SCLC was referred to EMG laboratory with 7 weeks of progressive weakness, shortness of breath and dysphagia. Due to tumor progression, immunotherapy with pembrolizumab was initiated five months prior to presentation. On examination, she had mild non-fatigable right-sided ptosis and diplopia, normal bulbar strength, and proximal greater than distal weakness of lower greater than upper extremities. Her reflexes were 2-/4 throughout, with left biceps reflex facilitating after 30 seconds of exercise. On nerve conduction studies (NCS), there was an amplitude increase in multiple nerves including the left median nerve (160%) and left ulnar nerve (370%) after 10 seconds of exercise. Paraneoplastic panel came back with elevated LEMS-related anti-P/Q-type voltage gated calcium channel antibodies at 0.19nmol/L (normal: &amp;le;0.02nmol/L). This case illustrates the diagnostic and therapeutic challenges that surround LEMS in SCLC patients on immunotherapy. Diagnosis hinges on clinical presentation, motor NCS, and antibody testing while determination of the etiology (paraneoplastic vs ICI related LEMS) is more complex and may affect selection of the correct treatment. Therapy for ICI-related neuromuscular irAEs depends on symptom severity, but typically should include holding immunotherapy and administration of high dose corticosteroids as first line treatment with possible addition of IVIg and plasmapheresis. This differs from the common first line treatment for paraneoplastic LEMS, highlighting the importance of understanding of the etiology. Further research is needed to better understand optimal management.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous tumor with high metastatic potential. In rare cases, it can be associated with paraneoplastic syndromes (PNS), which result from an antitumor immunity against antigens produced by the tumor itself. Lambert-Eaton Myasthenic Syndrome (LEMS) is a neurological autoimmune PNS characterized by an impairment of the neuromuscular junction, leading to proximal muscle weakness and fatigability. Although the development of immune checkpoint inhibitors (ICI) is a breakthrough in the management of many cancers, onset or worsen of immune diseases has been described. Thereby, in patients with previous neurological PNS like LEMS, the ICI therapy for cancer may aggravate neurological symptoms and lead to irreversible impairment. We report here 2 cases of patients with metastatic MCC associated with a LEMS at the diagnosis. Both successfully received ICI therapies (anti-PDL1 avelumab and anti-PD1 pembrolizumab) without worsening of LEMS and any major immune-related adverse effects. Their neurological condition improved and disappeared concomitantly with the efficacy of immunotherapy, and we did not observe relapse of both MCC and LEMS after treatment discontinuation. Finally, we performed a complete review of the literature, which confirmed that ICI treatment could be discussed for patients with paraneoplastic LEMS, and emphasized the need for multidisciplinary management.

Immunotherapy with checkpoint inhibitors (CPIs) has revolutionized the management of advanced cancer including advanced small cell lung cancer (SCLC). Unfortunately, those agents are not without adverse effects. Immune imbalance through enhanced cellular immune response may result in impaired endogenous immunological tolerance mechanisms that can result in a wide spectrum of immunological side effects also known as immune-related adverse events (irAEs). Scarce data are currently available about neurological immune-related adverse events (neuro irAEs), mainly obtained from clinical trials, case reports, or small case series. Most reported cases presented with nonspecific symptoms. It is important to recognize and promptly treat neuro irAEs, as it may be serious and even potentially fatal.We present a rare case of nivolumab induced brain stem encephalitis in a patient with advanced SCLC presented 10 months after starting treatment with symptoms of nystagmus, gait disturbance, and blurry vision. Nivolumab was held and the patient was started on oral steroids with tapering dose. The patient’s symptoms gradually improved over a few weeks. Re-challenging with nivolumab six weeks later resulted in recurrence of symptoms and again the patient was prescribed oral steroids with tapering dose. She maintained response off treatment for six months. This case report is aimed to highlight the importance of clinically suspecting and promptly treating neurological irAE, when managing a patient with CPIs.