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Its broader deployment is, however, constrained by immune-mediated toxicities, chiefly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS spans a heterogeneous spectrum from mild aphasia and tremor to seizures, cerebral edema, coma, and death, and remains difficult to predict prospectively. As CAR-T platforms expand beyond CD19 malignancies, neurotoxicity phenotypes are also broadening beyond classical ICANS. In plasma cell dyscrasias, BCMA-directed CAR-T has been associated with delayed non-ICANS neurotoxicities, including movement and neurocognitive\/behavioral symptoms, cranial nerve palsies, and peripheral neuropathic presentations. In parallel, early experiences with CAR-T and related immune effector therapies in autoimmune and neuroimmunologic diseases suggest distinct inflammatory contexts and potentially different neurotoxicity patterns, underscoring the need for indication-specific monitoring and attribution frameworks. Converging data implicate a multilayered pathophysiology involving systemic cytokine surges, disruption of the blood\u2013brain barrier, endothelial dysfunction, and context-dependent trafficking of activated CAR-T cells and other immune effectors into the CNS with baseline neurological vulnerability and the peri-infusion inflammatory milieu likely modulating individual risk. Given the frequency of these complications, an active research effort is underway to identify clinical, functional, and biological signals that could predict and improve their management. However, most biomarkers remain investigational, lacking prospective validation and straightforward clinical utility. This review synthesizes current evidence on the epidemiology, mechanisms, and monitoring of ICANS and emerging non-ICANS syndromes, and offers a fresh perspective on integrated, multimodal risk models to enable more precise stratification and timely intervention across indications.<\/jats:p>","DOI":"10.1177\/17562864261440261","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T00:35:31Z","timestamp":1778891731000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["The neurotoxic legacy of CAR-T cells: where do we stand?"],"prefix":"10.1177","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4688-2478","authenticated-orcid":false,"given":"Simona","family":"Pagliuca","sequence":"first","affiliation":[{"name":"Service d\u2019H\u00e9matologie Clinique, CHRU de Nancy, Rue du Morvan, Vand\u0153uvre-l\u00e8s-Nancy 54500, France"},{"name":"UMR 7365 IMoPA, Universit\u00e9 de Lorraine, CImIND Team, 9 Avenue de la For\u00eat de Haye, Vandoeuvre-l\u00e8s-Nancy 54500, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Jacquet","sequence":"additional","affiliation":[{"name":"S\u00e9rvice d\u2019H\u00e9matologie, CHRU de Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Th\u00e9r\u00e8se","family":"Rubio","sequence":"additional","affiliation":[{"name":"S\u00e9rvice d\u2019H\u00e9matologie, CHRU de Nancy, Nancy, France"},{"name":"UMR 7365 IMoPA, Universit\u00e9 de Lorraine, CImIND Team, Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9556-9800","authenticated-orcid":false,"given":"Pierpaolo","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Institut de Neurosciences des Syst\u00e8mes UMR1106, 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