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.
神经免疫相关不良事件(NAEs)是免疫检查点抑制剂(ICI)的罕见并发症，可影响中枢神经系统、周围神经系统和神经内分泌系统等，重者可导致死亡和严重的功能障碍，需要临床医师的高度重视和合理规范诊治。因NAEs复杂性、多样性和部分非特异性的临床表现，NAEs诊断需与肿瘤、感染、代谢和医源性(非免疫介导)并发症等其他疾病导致的神经功能障碍仔细鉴别。中国抗癌协会肿瘤支持治疗专业委员会和中国抗癌协会肿瘤临床化疗专业委员会就NAEs的相关临床重点问题如NAEs的流行病学、发病机制、风险因素、诊断和治疗的一般原则、特定类型NAEs的临床表现、诊治策略及NAEs后ICI再挑战治疗的原则等，组织专家进行文献检索和分析讨论，基于目前临床证据并结合中国临床实际，对NAEs的预防、诊断、综合治疗及随访等相关问题制定形成免疫检查点抑制剂的神经不良反应诊治中国专家共识(2022版)，以期指导临床实践。.

Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures.
We systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures.
This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the gap in the identification of effective rehabilitation and treatment options for CIPN.

Chimeric antigen receptor T-cells (CAR-T cells) are a new modality of oncological treatment which has demonstrated impressive response in refractory or relapsed diseases, such as acute lymphoblastic leukemia (ALL), lymphomas, and myeloma but is also associated with unique and potentially life-threatening toxicities. The most common adverse events (AEs) include cytokine release syndrome (CRS), neurological toxicities, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections, and hypogammaglobulinemia. These may be severe and require admission of the patient to an intensive care unit. However, these AEs are manageable when recognized early and treated by a duly trained team. The objective of this article is to report a consensus compiled by specialists in the fields of oncohematology, bone marrow transplantation, and cellular therapy describing recommendations on the Clinical Centers preparation, training of teams that will use CAR-T cells, and leading clinical questions as to their use and the management of potential complications.

BACKGROUND: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets.
METHODS: Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (Cmin), maximum serum concentration and area under the concentration-time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold.
RESULTS: In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758-0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%).
CONCLUSIONS: The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with Cmin of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target.

BACKGROUND: Recent research has uncovered the potential for excess manganese (Mn) intakes causing significant neurotoxic effects for early brain development.
METHODS: We identified the Mn tolerable intakes (TI) published by the U.S. Institute of Medicine (IOM), World Health Organization (WHO), Agence nationale de sécurité sanitaire (ANSES), and U.S. Environmental Protection Agency (US EPA) and examined the primary studies on which regulatory TIs are based. We converted the TIs to μg of Mn/kg/day using standard assumptions specific to each agency. We estimated μg of Mn/kg/day intakes due to formulas. Using our estimates for formula intakes, weights, and kcal content, we converted regulatory maxima and minima from μg of Mn/100 kcals to estimates of μg of Mn/kg/day.
RESULTS: Except for the proposed ANSES TI for drinking water, none of the primary studies on which Mn intake guidelines and regulations are based measured health outcomes. Some infant formulas may exceed the regulatory TIs, especially if prepared with water containing considerable concentrations of Mn (e.g. 250 μg/L), even while meeting national and international regulatory standards or guidelines.
CONCLUSIONS: Infant formula regulations must be revised to reduce the potential for excess manganese intakes and the practice of manganese supplementation of infant formulas should be ceased.

Patients with brain tumors presenting to the emergency room with acute neurologic complications may warrant urgent investigations and emergent management. As the neuro-hospitalist will likely encounter this complex patient population, an understanding of the acute neurologic issues will have value.
We discuss updated information and management regarding various acute neurologic complications among neuro-oncology patients and neurologic complications of immunotherapy. Understanding of the acute neurologic complications associated with central nervous system tumors and with common contemporary cancer treatments will facilitate the neuro-hospitalist management of these patient populations. While there are aspects analogous to the diagnosis and management in the non-oncologic population, a number of unique features discussed in this review should be considered.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is an adoptive cellular immunotherapy that is being utilized more frequently due to its initial success in advanced-stage cancers. Unfortunately, CAR T-cell therapy is often associated with acute systemic toxicities, including cytokine release syndrome (CRS) and CAR T-cell-associated neurotoxicity (neurotoxicity).
OBJECTIVE: We created a review that addresses the potential common emergency department (ED) presentations associated with CAR T-cell therapy. We reviewed the relevant research and clinical guidelines to develop a guide tailored toward addressing the needs of the emergency medicine community to manage these complications. In addition, a case is presented and the evaluation and management of CRS and neurotoxicity are reviewed in detail.
CONCLUSIONS: Despite CAR T-cell designs showing promising results, the risk of acquiring an acute toxicity is high, with CRS and neurotoxicity reported most often. The systemic toxicities associated with these adverse events can lead to end-organ damage and compromise the patient acutely or jeopardize the continuation in treatment of their underlying malignancy. Depending on the severity of the toxicity, treatment typically starts with vigilant supportive care, but may include administration of tocilizumab and possibly high-dose corticosteroids if the toxicity is deemed of high severity.
CONCLUSIONS: With the increasing administration of CAR T-cell therapy, emergency physicians will likely encounter more patients with associated adverse events, including CRS and neurotoxicity. It is increasingly important that emergency physicians are aware of these potential toxicities in order to rapidly diagnose and treat patients undergoing CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

OBJECTIVE: We reviewed the scientific background for the current health-based World Health Organization (WHO) guideline value for manganese in drinking water.
METHODS: The initial starting point was the background document for the development of the WHO\'s guideline value for manganese in drinking water as well as other regulations and recommendations on manganese intake levels. Data referred to in these documents were traced back to the original research papers. In addition, we searched for scientific reports on manganese exposure and health effects.
RESULTS: The current health-based guideline value for manganese in drinking water is based partly on debatable assumptions, where information from previous reports has been used without revisiting original scientific articles. Presently, preparation of common infant formulas with water containing manganese concentrations equivalent to the WHO guideline value will result in exceeding the maximum manganese concentration for infant formula. However, there are uncertainties about how this maximum value was derived. Concurrently, there is increasing evidence of negative neurologic effects in children from excessive manganese exposure.
CONCLUSIONS: The increasing number of studies reporting associations between neurologic symptoms and manganese exposure in infants and children, in combination with the questionable scientific background data used in setting the manganese guideline value for drinking water, certainly warrant a re-evaluation of the guideline value. Further research is needed to understand the causal relationship between manganese exposure and children\'s health, and to enable an improved risk assessment.