Neurological Immune-related Adverse Events Research Articles

Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events.

Neurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n. In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies. IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis. Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.

Neurological Immune-Related Adverse Events After COVID-19 Vaccination: A Systematic Review

Objective The goal of this study is to compile published data reporting neurological immune-related adverse events following COVID-19 vaccination, not including those relating to hematologic abnormalities such as thrombosis or hemorrhage. Background COVID-19 vaccination has been repeatedly shown to reduce the incidence and severity of COVID-19 infection. The expedited timeline of these vaccines has given rise to many discussions pertaining to their safety. Many neurological and non-neurological adverse events have been linked to COVID-19 vaccination including acute MI, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, transverse myelitis, and many others. Design/Methods The following databases were searched in April 2021 using different keywords: PubMed, Medline, Embase, Scopus, Web of Science, Science, Direct, MedRxiv, and Lens.org. Studies were included if they reported any adverse immune-related neurological events secondary to COVID-19 vaccination. Studies were excluded if they were not in English, included self-reported events only, or did not report primary data. Screening and extraction were conducted by 2 different reviewers using Covidence. Results The search strategy yielded 18 studies which reported a total of 61 patients who had received a COVID-19 vaccination and experienced = 1 neurological adverse events. Most reported adverse events were facial nerve palsy (52.5%), reactivation of herpes zoster (11.5%), Guillian-Barré syndrome (6.6%), demyelinating disease (6.6%), and neuropathy (11.5%). Other reported adverse effects were delirium, periauricular vesicular rash, bilateral sensorineural hearing loss, visual disturbance, gait disturbance, serotonin syndrome, and vestibular ataxia (16.4%). Conclusions The symptoms were time-limited and self-resolving in nature. In addition, the incidence of the reported events following COVID-19 vaccination compared to the general population is similar. Hence, there is little to no evidence suggesting a causal relationship between COVID-19 vaccination and neurological adverse events.

A Case of Pembrolizumab (Anti-PD-1) Induced Encephalitis

Objective N/A. Background PD-1 Immune checkpoint inhibitors (ICI) have been associated with neurologic immune-related adverse events including meningoencephalitis and limbic encephalitis that can manifest as paraneoplastic syndromes. We present a case of suspected pembrolizumab (anti PD-1) induced limbic encephalitis presenting as episodic aphasia. Design/Methods N/A. Results A 62-year-old man with poorly differentiated papillary thyroid carcinoma with extensive brain, lung, lymphatic metastases post thyroidectomy, radioiodine therapy, chemotherapy with dabrafenib and trametinib, and stereotactic radiation surgery presented with recurrence of brain metastases one year after the diagnosis of a 2.1 cm metastatic lesion in the left parieto-occipital region causing right homonymous hemianopsia. The metastases initially improved in size and number with radiation and serial brain MRIs were stable. Biopsy of the mets revealed a poorly differentiated carcinoma. He was subsequently treated with pembrolizumab for six months. Two months after treatment initiation, he reported episodic behavioral arrest, confusion, and expressive aphasia concerning for seizures. Continuous EEG monitoring revealed a left-sided focus without seizures, and the episodes persisted despite levetiracetam and clobazam. Four lumbar punctures revealed lymphocytic pleocytosis (10-14 cells), elevated protein (48–68 mg/dl), negative cytology, flow cytometry and viral studies including JC virus. Paraneoplastic panels in serum and cerebrospinal fluid were negative. Repeat MRIs findings were most consistent with radionecrosis and noted improvement of the metastatic lesions. Suspicion was raised for pembrolizumab-induced encephalitis and he received high-dose steroids with minimal response however, clinical improvement noted with reduced episode frequency after intravenous immunoglobulin induction therapy and rituximab maintenance therapy. Conclusions PD-1 ICI-related encephalitis is a diagnosis of exclusion that should be considered in patients with encephalopathy or other neurological deficits following 3 months of treatment initiation and response to immunosuppressive therapy. Higher incidences are reported in males. Early recognition is crucial to prevent long-term neurologic damage. Outcomes are depend on patient characteristics and clinical presentation.

Predictors for the Development of Neurological Immune-Related Adverse Events of Immune Checkpoint Inhibitors and Impact on Mortality

Objective To report the incidence, predictors for development, impact on mortality, and impact on pre-existing neurological conditions of neurological immune-related adverse events (irAEs) in a large clinical cohort. Background Immune checkpoint inhibitors (ICI) are associated with irAEs. Although neurological complications have been described, little is known about risk factors for their development and their impact on mortality. The impact of ICIs on pre-existing neurological conditions is also not well understood. Design/Methods Patients who received ICI between January 2013 and December 2018 were identified using a tertiary cancer center registry. Patient demographics, cancer characteristics, treatment type, and concurrent oncologic therapy were summarized using descriptive statistics. Patients with neuro-irAE were compared to those without neuro-irAE during the study timeframe. Odds ratios from univariable and penalized multivariable logistic regression models were calculated to identify potential predictors for developing a neuro-irAE. The impact of a neuro-irAE on overall survival was estimated by Kaplan-Meier and multivariable Cox proportional-hazard models. Results Overall frequency of neurological irAEs was 2.3% (28/1228). Peripheral nervous system complications such as myasthenia gravis, myositis, and neuropathies were the most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA-4 ICI exposure, and combination ICI exposure had significantly higher odds for developing a neuro-irAE (p &lt;0.05), but these findings were not statistically significant in the multivariable models. Those with a neuro-irAE had greater survival at 3 years compared to those without a neuro-irAE (69% vs 55%, p = 0.004), but after adjusting for patient and cancer characteristics, this effect was no longer statistically significant. Relapse rate of pre-existing neurological condition after exposure to ICI was 15.4% (2/13). Conclusions Neuro-irAEs are rare and are not associated with an increase in mortality. Potential predictors for the development of neuro irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA-4, or combination ICI exposure. Relapse of a pre-existing neurological condition was uncommon.

Neuro-ophthalmic complications of immune checkpoint inhibitor therapy: Current status and future directions.

Since 2011, use of immune checkpoint inhibitors (ICI) in cancer immunotherapy dramatically expanded, both alone and in combination with either a different cancer treatment or with two different ICIs. With this increase in use have come a myriad of adverse effects from enhanced immune activation, including ophthalmic and neurologic immune related adverse events (irAE). Neuro-ophthalmic immune related adverse events (NOirAE) associated with use of ICIs are increasingly recognized and their severity may actually limit use of potentially life-saving immunotherapy. NOirAEs comprise a wide variety of presentations involving both the central and peripheral nervous system. They cause afferent or efferent visual dysfunction, including among them optic neuropathy and edema, orbital inflammatory disease, and ocular myasthenia. While treatment for irAEs typically involves immunosuppression with corticosteroids, there is no expert consensus regarding best practices for treatment of NOirAEs and whether to stop ICI immunotherapy for the cancer or not. This state-of-the-art review explores the pathophysiologic basis for NOirAEs, provides a framework for categorizing them within neuro-ophthalmology, and discusses what is needed to close the current knowledge gaps in diagnosis and management of an increasing population of cancer patients requiring neuro-ophthalmic care.

NCOG-38. PEMBROLIZUMAB (ANTI-PD-1) INDUCED LIMBIC ENCEPHALITIS PRESENTING AS EPISODIC APHASIA

Abstract PD-1 immune checkpoint inhibitors (ICI) have been associated with neurological immune-related adverse events including meningioencephalitis and limbic encephalitis that can manifest as paraneoplastic syndromes. We present a case of pembrolizumab (Anti-PD-1) induced limbic encephalitis presenting as episodic aphasia. A 62-year-old man with poorly differentiated papillary thyroid carcinoma with extensive brain, lung, lymphatic metastases, post total-thyroidectomy, radioiodine therapy, chemotherapy with dabrafenib and trametinib, and stereotactic radiation presented with recurrence of brain metastasis 1 year after diagnosis of a 2.1 cm metastatic lesion in the left parieto-occipital region. The metastases had initially improved in size and number with radiation, followed on serial MRI Brain - that were stable. Biopsy of recurrence revealed a poorly differentiated cancer. He was subsequently treated with pembrolizumab for 6 months for refractory carcinoma. Two months after treatment initiation, he reported episodic behavioral arrest, confusion, and expressive aphasia, initially concerning for seizures. Continuous EEG monitoring revealed non-epileptogenic left-sided foci and no seizures were captured. Patient empirically started on levetiracetam and clobazam - however, episodes persisted. Lumbar puncture revealed lymphocytic pleocytosis (10-14 cells), elevated protein (48-68 mg/dL), negative cytology, flow cytometry, and viral studies including JC virus. Paraneoplastic panel in serum and cerebrospinal fluid were negative. Repeat MRI findings were most consistent with radionecrosis and on contrary improvement of the previous metastatic lesions. This rose suspicion for pembrolizumab-induced encephalitis and he received high dose steroids with minimal response but great clinical improvement with IVIG and induction/maintenance therapy with rituximab. Marked reduction in aphasic episodes were noticed thereafter. PD-1 ICI-related encephalitis is diagnosis of exclusion that should be considered in patients with encephalopathy or neurological deficit following 3 months of treatment initiation and response to immunosuppressive therapy. Higher incidences reported in males. Early recognition is crucial to prevent long-term neurological damage. Outcomes depend on patient characteristics and timeline of presentation.

NCMP-17. PLASMA EXCHANGE FOR IMMUNE CHECKPOINT INHIBITOR INDUCED ACUTE DEMYELINATING POLYNEUROPATHY REFRACTORY TO IVIG

Abstract The use of immune checkpoint inhibitors in the treatment of cancer has gained prominence due to their effectiveness. Unfortunately, neurological immune-related adverse events represent a growing problem in neuro-oncology practice. Many of these cases are rare and their diagnoses and management can be challenging. We present a case of a 69-year-old male with urothelial carcinoma status post left nephrectomy who developed bilateral lower extremity weakness that began following his first dose of Atezolizumab. After three doses, his lower extremity weakness worsened to the point where he could not walk. A NCV study was performed and was consistent with acute demyelinating polyneuropathy. A cervical MRI (Magnetic Resonance Imaging) showed an enhancing lesion at C6-C8. He was treated with three days of intravenous methylprednisolone every six hours for three days followed by three days of 0.4gm/kg IVIG. He regained his ability to walk after IVIG treatment. The enhancing lesion noted on MRI remained. Three weeks after the first IVIG treatment, he declined significantly, redeveloping symptoms where he could not ambulate and required assistance to use the toilet. He had no lower extremity reflexes and had loss of proprioception of his hands. He was scheduled for another IVIG infusion at .4gm/kg followed by a dose of IVIG .6gm/kg the next day, and then four more days of IVIG .25gm/kg. His lower extremity weakness and difficulty walking remained so he was arranged for plasmapheresis x five cycles. His weakness improved, reflexes returned, and he no longer had proprioceptive loss of his hands. A cervical MRI obtained one month after plasma exchange showed resolution of the C6-C8 enhancing lesion. He is now ambulating with a cane. This case highlights the effectiveness of plasma exchange in a case that was refractory to IVIG

Chinese expert consensus on diagnosis and treatment of neurologic immune-related adverse events associated with immune checkpoint inhibitors (2022 edition)

Neurologic immune-related adverse events (NAEs) are rare complications of immune checkpoint inhibitors (ICI). NAEs can affect the central nervous system, peripheral nervous system and neuroendocrine system, they can lead to death and serious dysfunction. NAEs requires standardized diagnosis, treatment and clinicians' high attention. The diagnosis of NAEs is very challenging due to its complexity, diversity and some non-specific clinical manifestations. It needs to be carefully distinguished from neurological dysfunction caused by other diseases such as tumor, infection, metabolism and iatrogenic (non-immune mediated) complications. Therefore, Committee of Neoplastic Supportive-Care of China Anti-Cancer Association and Cancer Clinical Chemotherapy Committee of China Anti-Cancer Association organized experts to conduct literature analysis and evidence level discussion on the clinical key issues related to NAEs, including the epidemiology, pathogenesis, risk factors, general principles of diagnosis and treatment, clinical manifestations and diagnosis and treatment strategies of specific types of NAEs, and the principles of ICI rechallenge after NAEs. Based on the latest clinical evidence and combined with China's clinical practice, the expert committee finally formulated a Chinese expert consensus on diagnosis and treatment of nAEs (2022 edition) for the prevention, diagnosis, comprehensive treatment and follow-up of NAEs.

Immune Checkpoint Inhibitor-Associated Myositis: A Distinct Form of Inflammatory Myopathy.

Research on the relationship between inflammatory myopathy and malignancy has grown considerably within the last century. Now, the burgeoning field of inflammatory myopathy has yet another player in the mix: immune checkpoint inhibitor-associated myositis (ICI myositis). Immune checkpoint inhibitor-associated myositis is indicated by clinical diagnosis of inflammatory myopathy after initiation of immune checkpoint inhibitor for cancer management. Current literature reflects low prevalence but high mortality associated with ICI myositis, especially when involving myasthenia gravis and myocarditis. Immune checkpoint inhibitor-associated myositis tends to have muscle pain along with weakness, infrequent presentation with dermatitis, or interstitial lung disease and is typically seronegative with scattered, endomysial inflammatory infiltrates on biopsy. The differential diagnosis of ICI myositis includes myasthenia gravis and other neurological immune-related adverse events. Therapeutic approach involves high doses of corticosteroids with a choice of steroid-sparing immunomodulating agent(s) that is primarily driven by expert opinion due to lack of robust research to support one agent over another. There is wide variation in the inclusion criteria for ICI myositis used in previous studies. We review previously used inclusion criteria and suggest an expertise-based classification criterion to provide a standardized definition and allow comparability between studies. There is a critical need for prospective translational and clinical studies that elucidate the pathophysiology of ICI myositis in order to improve evaluation and management of these patients.

Immune Checkpoint Inhibitor Rechallenge Following Neurologic Immune-Related Adverse Events in Cancer Patients: A Systematic Review (P8-1.002)

Immune Checkpoint Inhibitor Rechallenge Following Neurologic Immune-Related Adverse Events in Cancer Patients: A Systematic Review (P8-1.002)

Neurologic Immune-related Adverse Events of Immune Checkpoint Inhibitors (P1-1.Virtual)

Neurologic Immune-related Adverse Events of Immune Checkpoint Inhibitors (P1-1.Virtual)

Consider Myocarditis When Patients Treated with Immune Checkpoint Inhibitors Present with Ocular Symptoms.

Immune checkpoint inhibitors (ICIs) have been associated with neurological immune related adverse events (irAE-N) and patients with ICI toxicity may present with neurological or ocular symptoms. Furthermore, patients on ICI may initially present to oncology or neurology. We report a case series of 3 patients treated with ICIs presenting with diplopia or ptosis, found to have concurrent myocarditis in addition to immune-related myopathy (irMyopathy) or myasthenia gravis (irMG). None of the patients described cardiac symptoms, underscoring the importance of screening for myocarditis in patients presenting with diplopia and/or other neuromuscular symptoms which may suggest either irMyopathy or irMG.

Anti-GAD65 Antibody-Associated Autoimmune Encephalitis With Predominant Cerebellar Involvement Following Toripalimab Treatment: A Case Report of a Novel irAE of Toripalimab

Toripalimab (Junshi Bioscience Co., Ltd) is a new immune checkpoint inhibitor (ICI) that targets programmed cell death protein 1 (PD-1) in various cancers, including metastatic melanoma. No neurological immune-related adverse events (n-irAEs) of toripalimab have been reported, except for neuromuscular involvement. We report a case of a 63-year-old woman who presented with severe vertigo, vomiting, nystagmus, cerebellar ataxia, and cognitive impairment after toripalimab treatment for metastatic melanoma. Compared with the concomitant cognitive dysfunction and a pathological reflex involving the cerebral cortex, the signs and symptoms of cerebellar involvement were much more prominent. Anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody was positive in both serum and cerebrospinal fluid (CSF). After intravenous immunoglobulin (IVIG) and methylprednisolone (IVMP) administration, the symptoms of vertigo and vomiting resolved, with cognitive impairment and cerebellar ataxia remaining. This is the first report of autoimmune encephalitis (AIE) as an n-irAE of toripalimab.

Neurotoxicity of Tumor Immunotherapy: The Emergence of Clinical Attention.

Tumor immunotherapy brings substantial and long-term clinical benefits that can even cure tumors. However, the accumulation of evidence suggests that immunotherapy also induces severe and complex neurologic immune-related adverse events (ir-AEs) and even leads to immunotherapy-related death, which arouses the concern of clinicians. The timely and accurate identification of neurotoxicity helps clinicians detect and treat these complications early, thereby enhancing treatment efficiency and improving the prognosis of patients. At present, the mechanism of neurotoxicity caused by immunotherapy has not been completely elucidated. This paper mainly reviews the clinical features, pathogenesis, and therapeutic strategies of neurologic ir-AEs.

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization.

BackgroundThe inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.MethodsWe screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.ResultsWe identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.ConclusionCerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.

Neurologic Complications of Immune Checkpoint Inhibitors

The clinical use of cancer immunotherapy with immune checkpoint inhibitors has transformed the management of cancer and added another effective treatment option for different types of malignancies. The blockade of immune checkpoint pathways triggers an enhanced immune response leading to cancer regression but may also lead to autoimmune toxicities or immune-related adverse events, which may involve skin, endocrine, respiratory, gastrointestinal or neurologic manifestations. Clinically relevant neurologic complications involving the central and/or peripheral nervous system affect up to 1% of patients treated with immune checkpoint inhibitors and may be associated with significant morbidity and mortality. Common neurologic complications include aseptic meningitis and encephalitis, hypophysitis, myasthenia, myositis and neuropathies. Neurologic immune-related adverse events after immune checkpoint inhibition should be distinguished from cancer progression or other complications of cancer therapy (e.g. infections). The treatment of neurologic complications may include holding or withdrawing cancer immunotherapy, anti-inflammatory and immunosuppressive therapies with corticosteroids and steroid-sparing agents, immunomodulation with intravenous immune globulin or plasmapheresis and symptomatic treatment (e.g. antiepileptic medications, pain medications).

Correction: Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

Correction: Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

A review of neurotoxicities associated with immunotherapy and a framework for evaluation.

Immuno-oncology agents, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapies, are increasing in use for a growing list of oncologic indications. While harnessing the immune system against cancer cells has a potent anti-tumor effect, it can also cause widespread autoimmune toxicities that limit therapeutic potential. Neurologic toxicities have unique presentations and can progress rapidly, necessitating prompt recognition. In this article, we review the spectrum of central and peripheral neurologic immune-related adverse events (irAEs) associated with ICI therapies, emphasizing a diagnostic framework that includes consideration of the therapy regimen, timing of symptom onset, presence of non-neurologic irAEs, pre-existing neurologic disease, and syndrome specific features. In addition, we review the immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CAR-T cell therapy and address diagnostic challenges specific to patients with brain metastases. As immunotherapy use grows, so too will the number of patients affected by neurotoxicity. There is an urgent need to understand pathogenic mechanisms, predictors, and optimal treatments of these toxicities, so that we can manage them without sacrificing anti-tumor efficacy.

How to diagnose and manage neurological toxicities of immune checkpoint inhibitors: an update.

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-Barré 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.

A brief report on incidence, radiographic feature and prognostic significance of brain MRI changes after anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer.

Neurologic immune-related adverse events (nirAEs) are uncommon but potentially lethal complications of immune checkpoint inhibitor (ICI) treatment. However, the incidence, radiographic features and prognostic significance of brain magnetic resonance imaging (MRI) changes after ICI treatment remain largely unknown. Consecutive patients with advanced non-small cell lung cancer (NSCLC) at three participating institutions receiving anti-PD-1/PD-L1 therapy from June 2017 to September 2020 were screened, and those who received brain MRI within 6weeks before ICI initiation and at least one follow-up brain MRI after ICI treatment were included. Serial brain MRI images were independently reviewed by two experienced radiologists. With a median follow-up of 13.2months, 27 (20.0%) of the 135 enrolled patients developed certain kind of brain MRI aberration. The 1-, 2- and 3-year cumulative incidence of brain MRI aberration was 17.1%, 36.3% and 52.2%, respectively. Brain MRI aberration indicative of stroke, mimicking typical white matter lesions and presenting as T2-hyperintensity suggestive of CNS vasculitis or encephalitis, was documented in 11, 9 and 4 patients, respectively. Patients with brain MRI aberration had higher clinical benefit rate (p = 0.030), longer progression-free survival (p = 0.015) and a tendency of improved overall survival (p = 0.054). Brain MRI aberrations developed after ICI treatment are not uncommon, and their manifestations vary a lot. Patients developing brain MRI aberrations tended to have better prognosis, which needed to be further investigated.