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Cefepime is a fourth-generation cephalosporin that is widely used to treat sepsis but is associated with a potentially dangerous neurotoxicity syndrome, cefepime-induced neurotoxicity (CIN). As a result, patients treated with cefepime may be at higher risk for morbidity, including seizures, and mortality. Though the recent ACORN trial concluded that cefepime does not increase the risk of mortality, most of these patients were not critically ill or elderly, two of the most at risk populations for CIN. Further, diagnosis may be difficult in the critical care setting as patients may have multiple reasons for encephalopathy. Therefore, this population in particular should be studied and monitored closely for CIN. Importantly, there are not well defined diagnostic criteria for CIN to guide evaluation and management. Defining the risk factors for CIN and using laboratory and EEG to help support the clinical diagnosis could be helpful in early recognition of CIN to help institute treatment and to rule out seizures. In this mini review, we highlight risk factors for CIN, discuss the possible value of EEG, and propose a diagnostic and management approach in the evaluation and management of CIN., Competing Interests: Declarations. Conflict of interest: Drs. Freund and Husari have no conflicts to report. Dr. Kaplan receives honoraria from Demos and Wiley textbooks, has served as expert witness on quantitative EEG and issues of coma and EEG, and is on the DSMB for EpiWatch. Ethical approval: Not applicable. Informed consent: Not applicable., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Patients who develop chimeric antigen receptor (CAR) T-cell-related immune effector cell-associated neurotoxicity syndrome (ICANS) frequently undergo evaluation with electroencephalography (EEG). We hypothesize that EEG features and Synek scale score, a measure of degree of EEG abnormality, are associated with ICANS severity. Here, we performed a retrospective review of 125 adult patients at Memorial Sloan Kettering Cancer Center (MSKCC) who received CAR-T cell therapy from 2010 to 2019, including 53 patients with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 72 patients with large B-cell lymphoma (LBCL) treated with the commercial CAR T products axicabtagene ciloleucel or tisagenlecleucel. We collected video EEG monitoring (27 with B-ALL and 20 with LBCL) and recorded daily EEG features, Synek scores, and ICANS grade for 47 eligible patients. Synek scale and ICANS grade were positively correlated (correlation coefficient 0.47, 95% CI: 0.31-0.60). This was further corroborated in the univariable model associating high Synek scale (3 or 4) with high ICANS grade (OR = 15.2; 95%CI:7.8-29.7, p < 0.0001). EEG features such as discontinuity, absence of posterior dominant rhythm, and presence of generalized sharp waves were statistically significantly associated with higher ICANS grade in univariable models. In the multivariable model, discontinuity (OR = 4.2 (95%CI:1.3-13.8, p = 0.02) and absence of posterior dominant rhythm (OR = 10.5 (95%CI:4.6-23.9, p < 0.0001) were statistically associated with higher ICANS grade. Overall, EEG discontinuity and absence of posterior dominant rhythm were independently associated with higher severity of neurotoxicity. Further, our data suggest that Synek Scale, may be a severity marker for neurotoxicity., Competing Interests: Declarations. Competing interests: Dr. Perales reports honoraria from Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics, Medigene, and Sellas Life Sciences, and the scientific advisory board of NexImmune. He has ownership interests in NexImmune, Omeros and OrcaBio. He has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis., (© 2024. The Author(s).)

Clinical Relevance: Pupil size evaluation using clinical examination may be important for detecting and monitoring individuals at risk of neurotoxic effects from chemical exposure, as it may enable early intervention and the implementation of preventive measures., Background: This work aimed to investigate the association between pesticide exposure and pupil size. Pupil size is regulated by muscarinic and nicotinic receptors, and it is well-established that common pesticide chemicals disrupt this regulation., Methods: Twenty agricultural workers exposed to pesticides, and twenty participants not exposed, underwent visual screening, and pupil size evaluation under mesopic and photopic conditions. Additionally, signs of neurotoxicity and pesticide exposure in both groups were evaluated using the modified version of the neurotoxic symptoms questionnaire (Q16) and measuring cholinesterase (AChE) levels in blood, respectively., Results: Agricultural workers exposed to pesticides had a score indicating medium-high level of neurotoxicity (49.85 (SD ± 8.94)) which was significantly higher (t (36) = 7.659, p  ≤ 0.0001) than non-exposed participants who had low levels of neurotoxicity (27.25 SD ± 8.86). There was a significant difference in pupil size (mm) under mesopic (t (19) 4.42 p  = 0.003) and scotopic (t (19) 4.63, p  = 0.0002) conditions between the two groups. Additionally, there was a significant difference in AChE blood levels (t (19) 2.94 p  = 0.008) between exposed and non-exposed participants, indicating that exposed workers had low levels of this enzyme (average exposed group 3381 U/L (SD ± 1306)) compared to the non-exposed group (average non-exposed group 4765 U/L (SD ± 1300)). A significant negative correlation between AChE levels, years of exposure, and pupil size was found. The latter finding importantly showed that smaller pupils are associated with the accumulation of acetylcholine or a decrease in the activity of the enzyme AChE., Conclusion: Pupil size of agricultural workers exposed to pesticides can be abnormal and is associated with neurotoxicity as indicated by symptomatology and cholinesterase levels. Evaluation of pupil size may be useful for clinically detecting neurotoxicity.

Background: Nelarabine is a purine analog with demonstrated efficacy in the treatment of T-cell Lymphoblastic Leukemia and Lymphoma (T-ALL/LBL). Despite its efficacy and excellent blood-brain barrier penetration, it has a significant side effect profile which is namely concerning for neurotoxicity. Reported neurotoxicity has varied from mild peripheral neuropathy to debilitating grade 4 neurologic complications including Guillain-Barre like syndrome and myelopathy., Patients and Methods: We conducted a single centered, retrospective case series to study patients who developed severe neurotoxicity after receiving nelarabine as part of T-ALL treatment. One hundred thirty-five patients were identified. Thirteen patients were reviewed for severe neurotoxicity (defined as ≥grade 3), and of those five patients were deemed to have neurotoxicity secondary to nelarabine exposure., Results: Five patients (4%) developed severe neurotoxicity as manifested by Guillain-Barre like syndrome or myelopathy within a timeframe of eight to fifty-eight days from last nelarabine dose. Upon diagnosis, patients received formal neurologic evaluation by our neuro-oncology specialists including imaging, cerebrospinal fluid testing, and electromyography. Patients were treated with IVIG, and steroids upon diagnosis, but the majority of neuro-deficits were irreversible., Conclusion: Our study shows that nelarabine is generally well-tolerated, and the incidence of severe neurotoxicity is rare. Given the potential risk of severe neurotoxicity, we propose capped dose of nelarabine 1000 mg/day, neurological assessment before subsequent dosing, and avoidance of simultaneous IT therapy during nelarabine administration., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, the consequential over activation of the immune system is often complicated by adverse events that can affect several organs and systems, including the nervous system. The precise pathophysiology underlying neurological irAEs (n-irAEs) is not completely known. Around 3.8% of patients receiving anti-CTLA-4 agents, 6.1% of patients receiving anti-PD-1/PD-L1, and 12% of patients receiving combination therapies have n-irAEs. Most n-irAEs are low-grade, while severe toxicities have rarely been reported. in this article, we performed an updated literature search on immuno-related neurotoxicity on main medical research database, from February 2017 to December 2023., Areas Covered: We have also compared the latest national and international guidelines on n-irAEs management with each other in order to better define patient management., Expert Opinion: A multidisciplinary approach appears necessary in the management of oncological patients during immunotherapy. Therefore, in order to better manage these toxicities, we believe that it is essential to collaborate with neurologists specialized in the diagnosis and treatment of n-irAEs, and that a global neurological assessment, both central and peripheral, is necessary before starting immunotherapy, with regular reassessment during treatment.

Introduction: The use of performance validity tests (PVTs) in a neuropsychological assessment to determine indications of invalid performance has been a common practice for over a decade. Most PVTs are memory-based; therefore, the Groningen Effort Test (GET), a non-memory-based PVT, has been developed., Objectives: This study aimed to validate the GET in patients with suspected chronic solvent-induced encephalopathy (CSE) using the criterion standard of 2PVTs. A second goal was to determine diagnostic accuracy for GET., Method: Sixty patients with suspected CSE referred for NPA were included. The GET was compared to the criterion standard of 2PVTs based on the Test of Memory Malingering and the Amsterdam Short Term Memory Test., Results: The frequency of invalid performance using the GET was significantly higher compared to the criterion of 2PVTs (51.7% vs. 20.0% respectively; p < 0.001). For the GET index, the sensitivity was 75% and the specificity was 54%, with a Youden's Index of 27., Conclusion: The GET showed significantly more invalid performance compared to the 2PVTs criterion suggesting a high number of false positives. The general accepted minimum norm of specificity for PVTs of >90% was not met. Therefore, the GET is of limited use in clinical practice with suspected CSE patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background/importance: Arachnoiditis is a rare but devastating disorder caused by various insults, one of which is purported to be local anesthetic neurotoxicity following neuraxial blockade. However, the relationship between local anesthetics administered into the neuraxis and the development of arachnoiditis has not been clearly elucidated., Objective: We aimed to summarize the existing complex body of literature and characterize both the essential features and strength of any association between neuraxial local anesthetic neurotoxicity and arachnoiditis with a view toward mitigating risk, enhancing prevention, and refining informed consent discussions., Evidence Review: We reviewed all published reports of arachnoiditis attributed to local anesthetic neurotoxicity following perioperative neuraxial anesthesia. This narrative review was based on a systematic search methodology, which included articles published up until December 2022., Findings: Thirty-eight articles were included, comprising 130 patients, over one-half of which were published prior to this century and inconsistent with modern practice. Neuraxial techniques included 78 epidurals, 48 spinals, and 5 combined spinal-epidurals, mostly for obstetrics. Reporting of essential procedural data was generally incomplete. Overall, at least 57% of patients experienced complicated needle/catheter insertion, including paresthesia, pain, or multiple attempts, irrespective of technique. The onset of neurological symptoms ranged from immediate to 8 years after neuraxial blockade, while the pathophysiology of arachnoiditis, if described, was heterogeneous., Conclusions: The existing literature attributing arachnoiditis to local anesthetic neurotoxicity is largely outdated, incomplete, and/or confounded by other potential causes, and thus insufficient to characterize the features and strength of any association., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Tranexamic acid is a commonly used hemostatic agent with broad clinical uses across multiple specialties. Systemic toxicity is due to gamma-aminobutyric acid type A and glycine receptor competitive antagonism and has been reported by multiple routes, but toxicity after pulmonary administration via nebulization and BAL has not yet been described. A 44-year-old man with a history of congenital pulmonary arteriovenous malformations underwent routine bronchoscopy for hemoptysis. He received preprocedure nebulized tranexamic acid 500 mg three times daily for 48 h. An additional 1,000 mg was given via BAL for intraprocedural hemostasis. One hour after the procedure, he developed altered mental status, myoclonus, and hyperthermia, which was ultimately controlled with propofol and vecuronium. As the use of pulmonary tranexamic acid increases, toxicity from this agent should be considered. Dose reductions and alternate treatment modalities should be considered in patients with advanced age, arteriovenous malformations, and renal insufficiency., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Published by Elsevier Inc.)

Oxapliplatin-induced peripheral neuropathy (OIPN) is a significant adverse effect encountered in patients with colorectal cancer undergoing oxaliplatin therapy. However, the pathogenesis of OIPN remains unclear. This study aimed to identify potential diagnostic biomarkers for OIPN and discover the metabolic pathways associated with the disease. Serum samples were collected from 218 subjects, including patients with OIPN and control (CONT). The metabolite profiles were analyzed using nontargeted liquid chromatography-mass spectrometry (LC-MS) serum metabolomics method. Subsequently, differentially altered metabolites were identified and evaluated through multivariate statistical analyses. In this study, patients with OIPN and CONT were distinguished by ten significant metabolites. The levels of racemethionine, O-acetylcarnitine, stearolic acid, aminoadipic acid, iminoarginine, galactaric acid, and all-trans-retinoic acid were increased, whereas the levels of 3-methyl-L-tyrosine, 5-aminopentanoic acid, and erythritol compared were found to be diminished in patients with OIPN when compared to the CONT. Through receiver operating characteristic (ROC) curve analysis, racemethionine, stearolic acid, 5-aminopentanoic acid, erythritol, aminoadipic acid, and all-trans-retinoic acid were pinpointed as promising biomarkers for OIPN. Significantly altered pathways included amino acids (arginine biosynthesis, beta-alanine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, lysine degradation, and phenylalanine, tyrosine and tryptophan biosynthesis), lipid (linoleic acid metabolism and the biosynthesis of unsaturated fatty acids), and energy metabolism. This study, by identifying serum biomarkers and dissecting metabolic pathways, offers a groundbreaking perspective on the susceptibility mechanisms underlying OIPN. It stands as an invaluable resource for the adjunctive diagnosis of OIPN, with the potential to diminish the incidence of adverse reactions and to enhance the objectivity and reliability of clinical diagnoses of OIPN., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: New anti-tumor treatments, such as immune checkpoint inhibitors and CAR T-cell therapy, are associated with an increasing number of neurological issues linked to tumors not arising from nervous system such as neurological and neuropsychological side effects that can significantly impair quality of life in the short or long term. The science of pathomechanisms, therapeutic approaches, and preventive measures is still in its early stages, and the progress is hampered by the lack of studied connection between neurological and oncological disciplines., Objectives: This work aimed to provide an overview of the questions raised in the field of clinical neuroscience that concern the outcomes of oncological diseases and their treatment. Furthermore, we give an outline of how a collaborative approach between neurology and oncology, with the implementation of neuroscience techniques including up-to-date diagnostics and therapy, can help to improve the quality of oncological patients' lives., Evidence Review: The covered areas of investigation in the evaluated articles primarily encompassed the review of known neurological complications of oncological diseases caused by neurotoxic mechanisms of performed therapies or those linked to concurrent pathological conditions. Similarly, the methods of their diagnostics were assessed., Findings: Our literature review of 65 articles, including clinical trials, cohort studies, reviews, and theoretically based in vitro studies published between 1998 and 2023, outlines the broad spectrum of neurological complications primarily associated with malignant diseases and the anti-tumor therapies employed. Notably, immune-mediated complications, whose incidence is increasing due to the expanding use of new immunotherapies, require early detection and targeted treatment to prevent severe progression. In this context, neurological complications mediated by immune checkpoint inhibitors are often associated with significant impairments and high mortality, necessitating specialist consultation for early detection and differentiation from other phenotypically similar syndromes. Current data on the pathophysiology of these neurological complications are not reliable due to the limited number of studies. Moreover, there is a lack of evidence regarding the appropriate oncological approach in the event of therapy-related complications. Initial study results suggest that the establishment of interdisciplinary treatment interfaces for the management of oncology patients could improve the safety of these therapies and enhance the patients' quality of life., Conclusions and Relevance: The accumulated knowledge on neurotoxicity caused by oncological diseases shows that the challenges in diagnosing and managing this condition are expanding in tandem with the growing array of therapies being employed. Therefore, it requires interdisciplinary approach with the introduction of new facilities enabling more personalized patient care., (© 2024. The Author(s).)

Immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant cause of morbidity associated with CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. Early prediction of patients who will develop ICANS would be crucial to better guide individualized management of high-risk patients, but specific predictive markers are still missing. Serum neurofilament light chain (NfL) levels are a sensitive indicator of neuroaxonal injury in neurological diseases. Elevated NfL levels at the time of CAR T-cell infusion have been associated with the severity of ICANS, but their utility for earlier identification of patients with subclinical neurological damage has not been evaluated.We studied all consecutive adult patients who received commercial CAR T cells for relapsed/refractory B-cell lymphomas at Saint-Louis Hospital between January 2019 and February 2023. Patients with pre-existing or current neurological disease were excluded. NfL levels were quantified in frozen serum collected at the time of the decision to treat (ie, the day of leukapheresis) and at the time of treatment (ie, the day of infusion).Of the 150 study patients, 28% developed ICANS of any grade, including 15.3% of grade 2-4. Receiving a CAR construct with a CD28 domain (58% of patients) was the strongest predictor of grade 2-4 ICANS. Serum NfL levels were significantly higher in patients with grade 2-4 ICANS than in those with grade 0-1 ICANS, both at the time of leukapheresis and infusion. In multivariate models, NfL above the cut-off value was independently associated with grade 2-4 ICANS at leukapheresis (NfL>75 pg/mL, OR 4.2, 95% CI 1.2 to 14.2, p=0.022) and infusion (NfL>58 pg/mL, OR 4.3, 95% CI 1.3 to 13.7, p=0.015).In conclusion, high NfL levels at the time of the decision to proceed with CAR T-cell manufacturing may represent an early surrogate of underlying loss of neuroaxonal integrity that increases the risk of subsequent neurotoxicity. Incorporating NfL levels into the decision-making process based on each patient's risk profile could help determine the appropriate CAR product when possible, and guide the prophylactic or therapeutic management of ICANS., Competing Interests: Competing interests: RU, Honorarium from Kite/Gilead; AFC, Honoraria from Kite/Gilead and Novartis; EA, Research funding from MSD avenir, GE, Alexion, Study drug from Pfizer, Fees for lectures from Pfizer, Alexion, Mindray and Sanofi; CT, Scientific Advisory Board of AstraZeneca, BeiGene, AbbVie, Takeda, Roche, Novartis, Kite/Gilead, Bristol Myers Squibb; RDB, Scientific Advisory Board of Novartis, Gilead, Janssen and BMS, Fees for lectures from Novartis, Kite/Gilead, Pfizer, AbbVie, and Incyte., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neurological disease caused by toxins is widespread but under-recognised. Despite increasing public interest and a growing number of novel potential neurotoxins, diagnosis of neurotoxic disease is often delayed or missed, resulting in poorer patient outcomes. This article discusses neurotoxic syndromes using a systems-based approach, focusing on environmental and occupational agents. We do not discuss recreational drugs, pharmaceutical agents or developmental neurotoxins in detail. We aim to provide neurologists with a working understanding of the scenarios in which a clinical presentation may be due to a neurotoxin and how to approach confirmation of the diagnosis., Competing Interests: Competing interests: FWV is supported by a Guarantors of Brain postdoctoral clinical fellowship., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy is a successful treatment for B-cell malignancies associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cardiovascular toxicities have also been reported in this setting. However, there is scarce data regarding development of autonomic disorders after CAR-T cell therapy., Patient Concerns: We report a case with a patient with non-Hodgkin B-cell lymphoma, refractory to 2 prior lines of immunochemotherapy, treated with CAR-T therapy., Diagnoses: Orthostatic hypotension secondary to autonomic dysfunction was diagnosed as manifestation of ICANS., Interventions: The patient received metilprednisolone 1000 mg IV daily for 3 days and anakinra 100 mg IV every 6h., Outcomes: The vast majority of autonomic symptoms ceased and 4 months after CAR-T therapy, autonomic dysfunction was resolved., Lessons: New-onset autonomic dysfunction can occur as manifestation of ICANS in patients who experience persistent neurologic and cardiovascular symptoms after resolution of acute neurotoxicity and should be early recognized. Differences in differential diagnosis, mechanisms and treatment approaches are discussed., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

With expansion of chimeric antigen receptor (CAR) T cell therapy and broader utilization of anti-cytokine directed therapeutics for toxicity mitigation, the routine assessment of cytokines may enhance understanding of toxicity profiles, guide therapeutic interventions, and facilitate cross-trial comparisons. As specific cytokine elevations can correlate with and provide insights into CAR T cell toxicity, mitigation strategies, and response, we explored the reporting of cytokine detection methods and assessed for the correlation of cytokines to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) across clinical trials. In this analysis, we reviewed 21 clinical trials across 60 manuscripts that featured a US Food and Drug Administration-approved CAR T cell construct or one of its predecessors. We highlight substantial variability and limited reporting of cytokine measurement platforms and panels used across CAR T cell clinical trials. Specifically, across 60 publications, 28 (46.7%) did not report any cytokine data, representing 6 of 21 (28.6%) clinical trials. In the 15 trials reporting cytokine data, at least 4 different platforms were used. Furthermore, correlation of cytokines with ICANS, CRS, and CRS severity was limited. Considering the fundamental role of cytokines in CAR T cell toxicity, our manuscript supports the need to establish standardization of cytokine measurements as a key biomarker essential to improving outcomes of CAR T cell therapy., Competing Interests: Declaration of interests N.N.S. receives research funding from Lentigen, VOR Bio, and CARGO Therapeutics. N.N.S. has attended advisory board meetings for VOR, ImmunoACT, and Sobi (all no honoraria)., (Published by Elsevier Inc.)

Introduction: Metronidazole-induced encephalopathy is an uncommon but potentially severe complication of metronidazole treatment. Although the exact pathophysiology remains elusive, proposed hypotheses include RNA binding, neurotoxicity from free radicals, and modulation of neurotransmitter receptors. Most cases demonstrate improvement upon discontinuation of metronidazole, highlighting the importance of early recognition. Magnetic resonance imaging plays a critical role in diagnosing metronidazole-induced encephalopathy, with characteristic imaging findings frequently observed in the dentate nuclei and corpus callosum., Case Summary: A 63-year-old man treated with metronidazole for lumbar spondylodiscitis developed neurological symptoms consistent with metronidazole-induced encephalopathy., Images: Magnetic resonance imaging revealed characteristic bilateral hyperintense lesions in the cerebellar dentate nuclei, corpus callosum, and brainstem. Prompt recognition and discontinuation of metronidazole led to symptom resolution., Conclusion: This case underscores the importance of clinicians and radiologists being aware of this condition and emphasizes the pivotal role of magnetic resonance imagining in establishing the diagnosis.

Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is common after chimeric antigen receptor T-cell (CAR-T) therapy., Objective: This study aimed to assess the impact of preinfusion electroencephalography (EEG) abnormalities and EEG findings at ICANS onset for predicting ICANS risk and severity in 56 adult patients with refractory lymphoma undergoing CAR-T therapy., Study Design: EEGs were conducted at the time of lymphodepleting chemotherapy and shortly after onset of ICANS., Results: Twenty-eight (50%) patients developed ICANS at a median time of 6 days after CAR-T infusion. Abnormal preinfusion EEG was identified as a risk factor for severe ICANS (50% vs. 17%, P = 0.036). Following ICANS onset, EEG abnormalities were detected in 89% of patients [encephalopathy (n = 19, 70%) and/or interictal epileptiform discharges (IEDs) (n = 14, 52%)]. Importantly, IEDs seemed to be associated with rapid progression to higher grades of ICANS within 24 h., Conclusions: If confirmed in a large cohort of patients, these findings could establish the basis for modifying current management guidelines, enabling the identification of patients at risk of neurotoxicity, and providing support for preemptive corticosteroid use in patients with both initial grade 1 ICANS and IEDs at neurotoxicity onset, who are at risk of neurological impairment., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Areas Covered: This paper outlines the selection of NAMs, including in vitro assays using primary rat cortical neurons, zebrafish embryos, and Caenorhabditis elegans . These assays aim to assess neurotoxic endpoints such as neuronal activity and behavioral responses. Microelectrode array recordings of rat cortical neurons provide insights into the impact of botanical extracts on neuronal function, while the zebrafish embryos and C. elegans assays evaluate neurobehavioral responses. The paper also provides an account of the selection of botanical case studies based on expert judgment and existing neuroactivity/toxicity information. The proposed battery of assays will be tested with these case studies to evaluate their utility for neurotoxicity screening., Expert Opinion: The complexity of botanicals necessitates the use of multiple NAMs for effective neurotoxicity screening. This paper discusses the evaluation of methodologies to develop a robust framework for evaluating botanical safety, including complex neuronal models and key neurodevelopmental process assays. It aims to establish a comprehensive screening framework.

Oxaliplatin (L-OHP), a third-generation platinum-based anti-tumor drug, finds widespread application in the first-line treatment of metastatic colorectal cancer. Despite its efficacy, the drug's usage is curtailed by a litany of side effects, with L-OHP-induced peripheral neuropathy (OIPN) being the most debilitating. This condition can be classified into varying degrees of severity. Employing serum metabolomics, a high-sensitivity, high-throughput technique, holds promise as a method to identify biomarkers for clinical assessment and monitoring of OIPN patients across different severity levels. In our study, we analyzed serum metabolites in patients with different OIPN levels using ultra-performance liquid chromatography-high resolution mass spectrometry. By employing statistical analyses and pathway enrichment studies, we aimed to identify potential biomarkers and metabolic pathways. Our findings characterized the serum metabolic profiles of patients with varying OIPN levels. Notably, pathway analysis revealed a significant correlation with lipid metabolism, amino acid metabolism, and energy metabolism. Multivariate statistical analysis and receiver operator characteristic curve evaluation pointed to anhalamine and glycochenodeoxycholic acid as potential biomarkers for OIPN C and A, which suggest that serum metabolomics may serve as a potent tool for exploring the metabolic status of patients suffering from diverse diseases and for discovering novel biomarkers., (© 2024 Wiley‐VCH GmbH.)

Lithium may cause toxicity as it has a narrow therapeutic range. Lithium intoxication may manifest in the form of acute, acute on chronic and chronic intoxication. Neurotoxicity is a common component of chronic lithium intoxication and the symptoms include tremor, ataxia, dysarthria, extrapyramidal symptoms, hyperreflexia, seizures and status epilepticus. Although rare, catatonia could as a manifestation of lithium neurotoxicity. In this report, we present a patient with bipolar disorder presenting with catatonic symptoms secondary to lithium intoxication. We will discuss the risk factors, differential diagnosis and the treatment of catatonic symptoms. Lithium neurotoxicity may present with various clinical symptoms including catatonia, and differential diagnosis should be made well in such cases. If lithium neurotoxicity is suspected, rapid and appropriate intervention is required to prevent permanent neurological damage. Keywords: Lithium, Neurotoxicity, Catatonia.

We describe a 64-year-old woman with relapsing encephalopathy. She initially presented with 5 days of psychomotor agitation, progressing to mania, psychosis and seizures that mimicked autoimmune limbic encephalitis. During her first hospital admission, extensive investigation failed to establish the underlying cause, and she improved with antiseizure medication alone. After a month at home, she relapsed with identical symptoms, and only then did we recognise that both episodes had been provoked by clarithromycin, prescribed for Helicobacter pylori eradication. Clarithromycin-induced neurotoxicity is rarely reported but likely to be under-recognised. It usually manifests within days of starting treatment, with delirium, mania, psychosis or visual hallucinations, sometimes termed 'antibiomania'. Seizures and status epilepticus appear to be less frequent. A full recovery is expected on stopping the medication., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: International guidelines regarding the management of immune effector cell-associated neurotoxicity syndrome (ICANS) recommend several diagnostic investigations, including magnetic resonance imaging (MRI), lumbar puncture (LP), and electroencephalogram (EEG) based on ICANS grade. However, the impact of these investigations has not yet been evaluated. Here, we aimed to describe the role of MRI, LP, and EEG in the management of ICANS in a cohort of real-life patients treated with chimeric antigen receptor (CAR) T cells at the University Hospital of Rennes, France. Between August 2018 and January 2023, a total of 190 consecutive patients were treated with CAR T cells. Among those, 91 (48%) developed ICANS. MRI was performed in 71 patients (78%) with ICANS, with a therapeutic impact in 4% of patients, despite frequent abnormal findings. LP was performed in 43 patients (47%), which led to preemptive antimicrobial agents in 7% of patients, although no infection was eventually detected. Systematic EEG was performed in 51 patients (56%), which led to therapeutic modifications in 16% of patients. Our study shows that EEG is the diagnostic investigation with the greatest therapeutic impact, whereas MRI and LP appear to have a limited therapeutic impact. Our results emphasize the role of EEG in the current guidelines but question the need for systematic MRI and LP, which might be left to the discretion of the treating physician., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Neurotoxicity associated with cephalosporins is an increasingly recognized complication, although among cephalosporins, ceftazidime is rarely reported for such an adverse reaction. Moreover, subacute, rather than acute, presentation of neurotoxicity associated with cephalosporins is rare. A 77-year-old female patient with stage 4 chronic renal disease was admitted due to cellulitis in her right lower limb, multiorgan dysfunction complicated by oliguric acute kidney injury, and a need for hemodialysis via a central venous catheter. On the 13th day after admission, she became febrile, and bacteremia associated with a central venous catheter was identified, which prompted the initiation of empirical antibiotic therapy with vancomycin and ceftazidime. After 13 days of antibiotic therapy with vancomycin and ceftazidime, the patient became confused, with temporal-spatial disorientation and myoclonus, especially in the upper limbs, with worsening renal function. Ceftazidime was discontinued, and the patient's condition improved with complete remission of symptoms on the 8th day after symptom onset. Neurotoxicity associated with ceftazidime is a rare but probably underdiagnosed adverse reaction. It is more frequent in elderly patients with previous neurological dysfunction and end-stage kidney disease and/or acute kidney injury, and it usually manifests soon after starting treatment. Early identification and monitoring of risk factors and symptoms should lead the physician to a rapid withdrawal of the offending drug.

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

Purpose: Neurotoxicity concerns have been raised over general anesthesia and sedation medication use in children. Such concerns are largely based on animal studies, historical anesthetic agents, and assessment tools, thus warranting further investigations. Blood biomarkers in detecting neuronal inflammation and apoptosis are novel methods for detecting neuronal damage. Therefore, the aim of this feasibility study was to assess the usefulness of the levels of four plasma biomarkers in dental general anesthesia (DGA) as surrogate markers of neurotoxicity in children. The secondary aim was to compare changes in motor manipulative skills pre- and post-anesthetic exposure., Methods: This single-center prospective observational study included 22 healthy children aged between 3 and 6 years old who underwent DGA. Subclinical neurotoxicity was measured with a panel of four plasma biomarkers: Caspase-3, neuron-specific enolase (NSE), neurofilament light chain, and S100B at three time points (1; at start, 2; end and 3; on recovery from DGA). The Skillings-Mack test was used to identify the difference in the biomarker levels at three time points. Motor manipulative score assessment, prior and two weeks after DGA was also performed., Results: A total of 22 study participants (mean age = 5 ± 1 years) were included with a median DGA duration of 106 ± 28 min. A reduction in Caspase-3 levels was recorded, with pairwise comparison over three time points, reporting a statistical significance between time point 2 vs. 1 and time point 3 vs. 1. Although fluctuations in NSE levels were recorded, no significant changes were found following pairwise comparison analysis. Among other biomarkers, no significant changes over the three periods were recorded. Furthermore, no significant changes in manipulative motor scores were reported., Conclusion: Caspase-3 reduced significantly in the short time frames during day-care DGA; this might be due to the relatively short anesthesia duration associated with dental treatment as compared with more extensive medical-related treatments. Therefore, further studies on Caspase-3 as a potential biomarker in pediatric DGA neurotoxicity are required to further ascertain results of this study., (© 2024. The Author(s).)

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are useful markers to assess the effects of exposure to anticholinesterase insecticides (Anti-AChE). In addition, lymphocyte neuropathy target esterase (LNTE) has been used as biomarker of neuropathic organophosphate compounds (OPs). Thus, this study evaluates the main types of circulating biomarkers related to the cholinergic system and to the neuropathy induced by OPs in standardized human samples. To achieve this objective, total protein of human plasma, erythrocytes and lymphocytes were first standardized, and then AChE, BChE and LNTE activities in human blood were evaluated in the presence of inhibitors. The acceptance criteria of the regulatory agency were respected with coefficients of regression of curves of 0.9972 for cholinesterase and 0.9956 for LNTE analyses. The wavelength established to perform cholinesterase assay was 450 nm and the time of incubation of the enzymes with inhibitors was 30 min. Differences were observed among the IC 50 values regarding the in vitro inhibition of AChE, BChE and LNTE in the presence of OPs. In conclusion, the procedures demonstrated by the present work were simple, fast, inexpensive, sensitive, easy to be replicated and suitable to make conclusions about the neurotoxicity induced by Anti-AChE and neuropathic OPs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Guilherme Luz Emerick reports a relationship with Federal University of Mato Grosso that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage., Methods: We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density., Results: NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement., Interpretation: NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage., (© 2023 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background: Studies in adult patients suggest cefepime can cause neurotoxicity, including disorientation, seizures, and coma, particularly when present at high concentrations. Patients with underlying kidney dysfunction or central nervous system anomalies are at particularly high risk. There is a relative paucity of pediatric literature on the neurotoxic effects of cefepime. Case Report: Herein is reported the case of a 2-year-old patient with chronic kidney disease receiving cefepime for Serratia marcescens bacteremia who experienced agitation, tremor, and inconsolability in the setting of an elevated cefepime trough that improved with cefepime discontinuation alone. Conclusions: Pediatric patients with acute and chronic kidney disease are at risk of cefepime-related neurologic changes. Therapeutic drug monitoring for cefepime in patients with kidney dysfunction or baseline neurologic abnormalities may help inform appropriate antimicrobial dosing and avoidance of toxicity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Acute carbon monoxide (CO) poisoning survivors may experience persistent delayed neurological sequelae (DNS). No studies have investigated the serum neurofilament light chain (NFL) as a prognostic biomarker in acute CO poisoning. This study aimed to determine the serum NFL levels to predict the DNS after acute CO poisoning., Methods: Patients with acute CO poisoning who were consecutively admitted from October 2020 to September 2022 were included. The predictive performance of NFLs for the DNS was assessed through the analyses of the correlation, the logistic regression, and the receiver operating characteristic (ROC) curve., Results: Overall, 9.7% (15/155) of the patients had DNS. The serum NFLs in patients with DNS was 113.7 pg/mL, which is significantly higher than that in the non-DNS group (25.8 pg/mL; P < 0.001). Correlation analysis shows that the serum NFLs are positively correlated with DNS (r = 0.567, P < 0.001). After multiple adjustments, the serum NFLs are independently correlated with DNS [adjusted odds ratio 1.032; 95% confidence interval (CI) 1.001, 1.064; p = 0.043]. The ROC curve indicates an area under the curve (AUC) of 0.923 (95% CI 0.869, 0.960), with a sensitivity of 100% and a specificity of 84.3% at the best cutoff value of 73.4 pg/mL. Pairwise comparison shows that the AUC of the NFL is significantly higher than that of the neuron specific enolase (AUC = 0.779) using the Hanley and McNeil test (Z = 2.283, p = 0.022)., Conclusion: Serum NFL could be a biomarker of the DNS after acute CO poisoning., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Cefepime is a fourth-generation cephalosporin with extended antimicrobial coverage. Concerns have been raised about the side effects of cefepime including myoclonus, encephalopathy, and seizures, especially when renal impairment is present. There have been reports of cases of adverse neurological consequences despite appropriate renal adjustment. Here, we present a case of a 69-year-old patient initially diagnosed with pneumonia and treated with cefepime. The patient later developed altered mental status, leading to differential diagnoses including stroke, drug overdose, or non-convulsive seizures. Following a comprehensive workup, it was determined that she had cefepime-induced encephalopathy, despite having normal kidney function, which resolved completely after discontinuing the medication. In addition, we include similar cases retrieved from PubMed up to the present date, to the best of our knowledge., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Methotrexate-induced neurotoxicity is a well-defined side-effect of high-dose and intrathecal methotrexate with characteristic clinico-radiological findings and transient nature. Our experience in managing this entity in children with acute lymphoblastic leukemia(ALL) is reported here. All children with de novo ALLregistered from January 2016 through December 2021 who developed methotrexate-induced neurotoxicity were included. Of children with ALL treated during the study period, thirty-three experienced methotrexate induced neurotoxicity with an incidence of 1.25%. Stroke-like symptoms(36.36%; 12/33) were the most common clinical manifestation followed by seizures(30.3%, 10/33). Twenty-three patients had radiological features consistent with methotrexate-induced leukoencephalopathy. With emerging evidence, thirty-one patients were re-challenged with methotrexate (IV/IT), of whom 4 patients had recurrence of symptoms. No long-term neurological sequalae were noted in our cohort, despite rechallenging. Therefore in our study, methotrexate induced neurotoxicity is a self-limiting toxicity and methotrexate can be re-challenged safely without compromising theintensity of CNS-directed therapy.

There is a need to assess compounds reliably and quickly for neurotoxicity (NT) and developmental neurotoxicity (DNT). Adverse outcome pathways (AOPs) enable the mapping of molecular events to an apical endpoint in a chemical agnostic manner and have begun to be applied in NT and DNT testing frameworks. We assessed the status of NT/DNT AOPs in the AOP-Wiki (ca. 2/1/23; https://aopwiki.org/), to characterize the state of AOP development, identify strengths and knowledge gaps, elucidate areas for improvement, and describe areas for future focus. AOPs in the Wiki database were assessed for inclusion of NT/DNT molecular events and endpoints, AOP development and endorsement, as well as the linkages of key neurodevelopmental processes with in vitro new approach methods (NAMs). This review found that 41 AOPs have been proposed detailing NT/DNT, of which eight were endorsed by working parties in OECD. Further, this review determined that learning and memory is included as an adverse outcome in eight NT/DNT AOPS, often without distinction regarding the varying forms of learning and memory, regional specification, temporal dynamics, or acquisition mechanisms involved. There is also an overlap with key events (KEs) and in vitro NAMs, which synaptogenesis appeared as a common process. Overall, progress on NT/DNT AOPs could be expanded, adding in modes of action that are missing, improvement in defining apical endpoints, as well as utilizing NAMs further to develop AOPs and identify gaps in current knowledge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Objective: To investigate the efficacy of cryocompression therapy to prevent chemotherapy-induced peripheral neuropathy., Methods: This single-institution, randomized, self-controlled trial of cryocompression enrolled gynecologic cancer patients planned for five to six cycles neurotoxic chemotherapy. Exclusion criteria were prior neurotoxic chemotherapy or baseline peripheral neuropathy. Participants were randomized to cryocompression on dominant versus non-dominant hand and foot (treatment), with no intervention on the opposite side (control). Compression socks and gloves and ice bags were applied 15 minutes before, during, and 15 minutes after infusion. Primary outcome measures included the PNQ (Patient Neurotoxicity Questionnaire) and the Semmes-Weinstein monofilament test; secondary outcomes included the FACT/GOG-NTX (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity) and patient acceptability and tolerability. Sixty patients completing the study were necessary to detect a 70% reduction in the odds of PNQ grade C or higher peripheral sensory neuropathy with 80% power., Results: Ninety-one patients were enrolled from January 2021 to October 2022; 69 were eligible for final analysis. Of the 91 patients, 64.8% were White, 30.8% were Black, and 1.1% were Hispanic or Latina. With successive cycles, more patients had sensory PNQ grade C or higher neuropathy on the control side compared with the cryocompression side. Cryocompression decreased the odds of sensory neuropathy (PNQ grade C or higher) by 46% at final visit (odds ratio 0.54, 95% CI 0.31-0.94; P =.03). There was no difference in tactile sensitivity based on the monofilament test between sides at the final visit. At the final visit, average FACT/GOG-NTX-11 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 11 Item Version) scores were significantly lower on the cryocompression than the control side (estimate -0.97, 95% CI -1.89 to -0.06; P =.04), as were FACT/GOG-NTX-4 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 4 Item Version) scores (estimate -0.35, 95% CI -0.64 to -0.05; P =.02). More than 85% of patients assessed the intervention as acceptable and tolerable., Conclusions: Cryocompression therapy reduces subjective chemotherapy-induced peripheral sensory neuropathy in patients who are receiving paclitaxel or cisplatin for gynecologic cancer., Clinical Trial Registration: ClinicalTrials.gov , NCT04563130., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: To examine electroencephalogram (EEG) as a diagnostic tool for late-onset efavirenz (EFV) neurotoxicity syndrome (LENS), an uncommon but severe and potentially fatal complication of EFV therapy., Methods: We conducted a Retrospective case-control study. EEGs from confirmed cases of LENS (clinical syndrome and plasma EFV >4ug/mL) recorded from June 2016 to May 2021 were compared with control EEGs from the same time-period. Controls were adults (18-70 years) with a similar indication for EEG (eg. encephalopathy or confusion), dysrhythmia generalised grade II, and LENS excluded. EEGs were reviewed by two blinded interpreters given a description of the characteristic EEG changes, ie. persistent, diffuse, high voltage, bisynchronous, monomorphic 4-7 Hz theta frequency waveforms with transient attenuation on eye opening. Interpreters were asked to determine whether EEGs showed definite, probable or no changes., Results: Thirteen LENS cases were compared with 50 control EEGs. Interpreter 1 labelled 11/13 LENS cases as having define or probable changes, and interpreter 2 labelled 10/13. Interpreter 1 labelled probable changes in 1/50 controls and interpreter 2 in 3/50. Neither interpreter labelled any controls as having definite changes. Interrater reliability was good with 95% agreement and a Cohen's kappa of 0.83. Sensitivity of EEG under these conditions for the diagnosis of LENS was 85% and 77% for interpreters 1 and 2 respectively, and specificity was 98% and 94%., Conclusions: EEG is a useful tool in the diagnosis of LENS which can be used to aid clinical decisions while awaiting EFV levels, or in low-resource settings where EFV levels are not available., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nightingale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an under-recognized complication of several chemotherapy agents used as part of curative-intent therapy for Hodgkin Lymphoma (HL). In the absence of validated self- or proxy-report measures for children and adolescents, CIPN reporting has relied on clinician rating, with grading scales often restricted to severe manifestations. In a proof-of-concept study, we assessed the feasibility and psychometric performance of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), a unidimensional CIPN symptom scale widely used adults with CIPN, in pediatric HL at risk for CIPN., Methods: Youth (11+ years) and parents of all children (5-17.9 years) with newly diagnosed high-risk HL enrolled on Children's Oncology Group AHOD1331 (NCT02166463) were invited to complete the FACT-GOG-Ntx and a health-related quality of life (HRQL) measure at pre-treatment (Time 1), and during cycles 2 (Time 2) and 5 (Time 3) of chemotherapy during the first half of study accrual. Clinical grading of CIPN by providers was also assessed using the Balis Pediatric Neuropathy Scale. We evaluated Cronbach's alpha, construct validity, and agreement between raters. Change in FACT-GOG-Ntx scores over time was assessed using a repeated measures model., Results: 306 patients had at least one completed FACT-GOG-Ntx with time-specific completion rates of > 90% for both raters. Cronbach's alpha was > 0.7 for youth and parent-proxy report at all time points. Correlations between FACT-GOG-Ntx and HRQL scores were moderate (0.41-0.48) for youth and parent-proxy raters across all times. Youth and parent-proxy raters both reported worse FACT-GOG-Ntx scores at Time 3 for those who had clinically-reported CIPN compared to those who did not. Agreement between raters was moderate to high. Compared to baseline scores, those at Time 3 were significantly lower for youth (β = - 2.83, p < 0.001) and parent-proxy raters (β = - 1.99, p < 0.001)., Conclusions: High completion rates at all time points indicated feasibility of eliciting youth and parent report. Psychometric performance of the FACT-GOG-Ntx revealed acceptable reliability, evidence of validity, and strong inter-rater agreement, supporting the use of this self- or proxy-reported measure of CIPN in youth with high-risk HL exposed to tubulin inhibitors, as part of a Phase 3 clinical trial., Clinical Trial Information: Clinical Trials Registry, NCT02166463. Registered 18 June 2014, https://clinicaltrials.gov/ct2/show/study/NCT02166463., (© 2023. The Author(s).)

Introduction: Organophosphorus compounds (OPC) are one of the most commonly used pesticides worldwide and are often misused for suicidal poisoning due to their easy availability. Acute manifestations and management of organophosphorus (OP) poisoning have been reported several times. Organophosphorus-induced delayed neurotoxicity (OPIDN) is a rare delayed presentation of OP poisoning that involves central-peripheral distal axonopathy., Case Presentation: In this study, we report two cases of OPIDN developed after a few weeks of OP poisoning. Clinical features, electrodiagnostic study findings, and rehabilitative measures adopted for the patients and their follow-up have been described in the report., Discussion: Organophosphorus (OP) poisoning may rarely produce features of delayed neurotoxicity, which may gradually appear after acute cholinergic symptoms. This report shows the importance of considering the delayed presentation of possible OPC toxicity in patients with neurological symptoms and a history of OPC exposure., (© 2023. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Tacrolimus is the most common immunosuppressant used after transplant, yet it can result in moderate-to-severe neurotoxicity in up to 32% of patients. Signs of neurotoxicity can vary from mild (tremor or headache) to severe (posterior reversible encephalopathy syndrome or psychosis. Prompt recognition and management is needed to lead to symptom resolution., Objective: The objective of this study is to describe the clinical presentation of tacrolimus-induced psychosis, a type of tacrolimus-inducted neurotoxicity, and distinguish it from other central nervous system disturbances, including delirium., Methods and Results: We present a case of delayed onset tacrolimus-induced psychosis with focus on unique clinical features and management strategies. We conducted a systematic review of cases of tacrolimus-induced psychosis using the PubMed database and included 15 manuscripts in our review., Conclusions: Tacrolimus-induced psychosis is a unique presentation of tacrolimus-related neurotoxicity and can present without the cardinal symptoms of delirium. The data on isolated psychotic symptoms are limited with current literature focusing on more common presentations of tacrolimus-induced neurotoxicity, such as delirium and tremor. Development of psychosis can occur later in the treatment course and at normal tacrolimus serum levels. It can improve with antipsychotic therapies, but primary management should include cross-titration to an alternate immunosuppressant regimen., (Copyright © 2023 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial screening, but it is not presently a complete or surrogate approach to determine whether a chemical is a DNT in humans. By itself, the DNT IVB does not have the ability to capture nuances and complexity of the developing nervous system and associated outcomes including behavioral ontogeny, motor activity, sensory function, and learning/memory. Presently, such developmental landmarks cannot be adequately assessed in the DNT IVB or by other NAMs. The expert panel (all who serve as co-authors of this review) recommended that additional data generation and validation is required before the DNT IVB can be considered for application within global regulatory frameworks for decision-making., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The neurotoxicity associated to the anticancer treatments has received a growing body of interest in the recent years. The development of innovating therapies over the last 20years has led to the emergence of new toxicities. Their diagnosis and management can be challenging in the clinical practice and further research is warranted to improve the understanding of their pathogenic mechanisms. Conventional treatments as radiation therapy and chemotherapy are associated to well-known and under exploration emerging central nervous system (CNS) and peripheral nervous system (PNS) toxicities. The identification of the risk factors and a better understanding of their pathogeny through a "bench to bedside and back again" approach, are the first steps towards the development of toxicity mitigation strategies. New imaging techniques and biological explorations are invaluable for their diagnosis. Immunotherapies have changed the cancer treatment paradigm from tumor cell centered to immune modulation towards an efficient anticancer immune response. The use of the immune checkpoints inhibitors (ICI) and CAR-T cells (chimeric antigen receptor) lead to an increase in the incidence of immune-mediated toxicities and new challenges in the neurological patient's management. The neurological ICI related adverse events (n-irAE) are rare but potentially severe and may present with both CNS and PNS involvement. The most frequent and well characterized, from a clinical and biological standpoint, are the PNS phenotypes: myositis and polyradiculoneuropathy, but the knowledge on CNS phenotypes and their treatments is expanding. The n-irAE management requires a good balance between dampening the autoimmune toxicity without impairing the anticancer immunity. The adoptive cell therapies as CAR-T cells, a promising anticancer strategy, trigger cellular activation and massive production of proinflammatory cytokines inducing frequent and sometime severe toxicity known as cytokine release syndrome and immune effector cell-associated neurologic syndrome. Their management requires a close partnership between oncologist-hematologists, neurologists, and intensivists. The oncological patient's management requires a multidisciplinary clinical team (oncologist, neurologist and paramedical) as well as a research team leading towards a better understanding and a better management of the neurological toxicities., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a highly prevalent, dose-limiting, costly, and tough-to-treat adverse effect of several chemotherapy agents, presenting as sensory and motor dysfunction in the distal extremities. Due to limited effective treatments, CIPN can permanently reduce patient function, independence, and quality of life. One of the most promising interventions for CIPN is physical therapy which includes exercise, stretching, balance, and manual therapy interventions. Currently, there are no physical therapy guidelines for CIPN, thus limiting its uptake and potential effectiveness., Methods: Utilizing the authors' collective expertise spanning physical therapy, symptom management research, oncology, neurology, and treating patients with CIPN, we propose a comprehensive clinical workflow for physical therapists to assess and treat CIPN. This workflow is based on (1) physical therapy guidelines for treating neurologic symptoms like those of CIPN, (2) results of clinical research on physical therapy and exercise, and (3) physical therapy clinical judgement., Results: We present detailed tables of pertinent physical therapy assessment and treatment methods that can be used in clinical settings. CIPN assessment should include detailed sensory assessment, objective strength assessments of involved extremities, and validated physical performance measures incorporating static and dynamic balance, gait, and functional mobility components. CIPN treatment should involve sensorimotor, strength, balance, and endurance-focused interventions, alongside a home-based exercise prescription that includes aerobic training. We conclude with action items for oncology teams, physical therapists, patients, and researchers to best apply this framework to address CIPN., Conclusions: Physical therapists are in a unique position to help assess, prevent, and treat CIPN given their training and prevalence, yet there are no physical therapy clinical practice guidelines for CIPN. Our preliminary suggestions for CIPN assessments and treatments can catalyze the development of guidelines to assess and treat CIPN. We urge oncology teams, physical therapists, patients, and researchers to develop, adapt, and disseminate this framework to help alleviate the burden of chemotherapy on patients with cancer., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is a need for biomarkers to predict and measure the severity of immune effector cell-associated neurotoxicity syndrome (ICANS). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are well-validated biomarkers of astroglial and neuronal injury, respectively. We hypothesized that pretreatment GFAP and NfL levels can predict the risk of subsequent ICANS and that increases in GFAP and NfL levels during treatment reflect ICANS severity. We measured cerebrospinal fluid GFAP (cGFAP) and NfL (cNfL) along with serum NfL (sNfL) levels at pretreatment and day 7 to 10 after chimeric antigen receptor (CAR) T-cell infusion in 3 pediatric cohorts treated with CD19- or CD19/CD22-directed CAR T cells. cGFAP and cNfL levels increased during grade ≥1 ICANS in patients treated with CD19-directed CAR T cells but not in those who received CD19/CD22-directed CAR T cells. The sNfL levels did not increase during ICANS. Prelymphodepletion cGFAP, cNfL, and sNfL levels were not predictive of subsequent ICANS. Elevated baseline cGFAP levels were associated with a history of transplantation. Patients with prior central nervous system (CNS) radiation had higher cNfL levels, and elevated baseline sNfL levels were associated with a history of peripheral neuropathy. Thus, cGFAP and cNfL may be useful biomarkers for measuring the severity of CNS injury during ICANS in children. Elevated baseline levels of cGFAP, cNfL, and sNfL likely reflect the cumulative injury to the central and peripheral nervous systems from prior treatment. However, levels of any of the 3 biomarkers before CAR T-cell infusion did not predict the risk of ICANS., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A 55-year-old man presented a slowly progressive sensory disorder, predominantly in both lower limbs, and gait disturbance. Neurological examinations revealed abnormal sensation and spasticity in both lower limbs, and a wide-based gait. Although examination revealed mild hyperchloremia and decreased motor conduction velocity in the peroneal nerve, head and whole spine MRI, and spinal fluid examination were normal. His job history revealed he had been engaged in metal cleaning work using 1-bromopropane (1-BP) for three years. His serum bromide concentration was increased to 175.6 mg/l (standard value: 5 or less), so we diagnosed him as having 1-BP neurotoxicity. The serum bromide concentration decreased after avoidance of exposure to 1-BP, but the gait disturbance remained. It was considered that we should obtain a detailed job history and measure the serum bromide concentration in patients with a sensory disorder in the extremities and gait disturbance of unknown origin.

Background: Cefepime is a fourth-generation cephalosporin with a broad spectrum coverage and anti-pseudomonal activity. The safety profile of cefepime was relatively favourable until neurotoxicity was first reported in 1999. Despite cefepime-induced neurotoxicity (CIN), it continues to be a principal part of parenteral treatment for various infections., Objective: The study aimed to determine the incidence and risk factors for CIN compared to other antibiotics., Methods: A retrospective cohort study was conducted involving 738 patients over eight months in Kasturba Medical College and Hospital, Manipal, India. Patients with cefepime were selected as study cohort (SC; n= 496), and other antibiotics were included in the reference cohort (RC; n=242)., Results: The results showed that 53 (10.7%) patients developed neurotoxicity in the SC, whereas 12 (5%) patients in the RC. A significant association was found between neurotoxicity and cefepime use (X 2 =6.641; p=0.01). SC has a 2.29 times increased risk of neurotoxicity than RC (OR: 2.29; 95% CI: 1.2-4.38). Risk estimation showed that renal failure patients had a 5.5 times higher risk for CIN than non-renal failure patients (OR: 5.5; 95% CI: 2.98 - 10.17). CIN symptoms were disorientation (38.5%), loss of consciousness (23.1%), drowsiness (18.5%), etc. The calculated number needed to harm (NNH) for cefepime was 17.2., Conclusion: The study found a higher incidence of CIN compared to other antibiotics-induced neurotoxicity and a harmful association between cefepime use and CIN development. Besides, renal failure is a risk factor for CIN. Therefore, the study warrants the use of cefepime, where no other alternatives are available., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: With the increase in the number of people exposed to anesthetic gases, there is a critical need to examine the prevalence of neurotoxic symptoms in these individuals using reliable tools. The aim of this study was to evaluate the psychometric characteristics of EUROQUEST questionnaire and to measure the rate of neurotoxic symptoms in the anesthesiology personnel., Methods: This research was a cross-sectional study. This study was a cross-sectional one. Participants included 404 personnel of the operating room in western Iran. EUROQUEST questionnaire was translated into Persian and used to measure the rate of neurotoxic symptoms. Reliability of the questionnaire was examined by Cronbach's alpha, while face and construct validities were evaluated using SPSS 16 (SPSS Inc., Chicago, IL, USA) and AMOS 18 (IBM, Chicago, IL, USA) software., Results: The results indicated that EUROQUEST questionnaire had acceptable reliability and validity. The most prevalent symptoms were observed in memory and concentration, fatigue, and sleepiness. The prevalence of fatigue was higher than other dimensions, with 28% of participants in the third and fourth quartiles. Also, there was no relationship between symptoms and work experience., Conclusions: EUROQUEST questionnaire can be applied in studies of the neurotoxic symptoms. The study of the prevalence of symptoms also indicated that most participants complained about memory and concentration, fatigue, and sleepiness, and these symptoms were observed in all individuals regardless of their work experience.

Chemotherapy-induced peripheral neurotoxicity (CIPN) diagnosis is largely based on patient reported outcomes. Wearables, sensors, and smart devices may potentially provide early detection and monitoring of CIPN. We systematically reviewed data on wearables, sensors, and smart devices to detect and/or monitor signs and symptoms of CIPN. Moreover, we provide directions and recommendations for future studies. A literature search using PubMed/MEDLINE, Web of Science, IEEE Xplore, and CINHAL databases was conducted from database inception until March 2021. The search was further updated in July 2022 to ensure currency of results. A total of 1885 records were title-abstract screened, 33 full texts were assessed, and 16 were included. The retrieved papers were heterogeneous in terms of study design, sample size, CIPN severity, chemotherapy agents, type of wearable/sensor/device applied, parameters of interest, and purpose. Data are promising and provide preliminary evidence on wearables, sensors, and smart devices for CIPN detection and monitoring. There are several issues and knowledge gaps that should be addressed. We propose a framework for future studies., (© 2022 Peripheral Nerve Society.)