Background: Chimeric Antigen Receptor T-cell (CAR-T) therapy has transformed treatment for hematologic malignancies but is associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication typically marked by cortical dysfunction such as encephalopathy, aphasia, and seizures. Current ICANS grading criteria uses the Immune Effector Cell-Associated Encephalopathy (ICE) score and relevant neurologic findings, with motor deficits falling under grade 4. However, spinal cord–predominant presentations are rare and not well represented in existing grading criteria.

Case Presentation: A 30-year-old female with refractory B-cell acute lymphoblastic leukemia and KMT2A rearrangement underwent CAR-T therapy with brexucabtagene autoleucel. After developing cytokine release syndrome (CRS), she experienced a progressive decline in mental status consistent with grade 2 ICANS. Despite aggressive immunosuppression with corticosteroids, tocilizumab, and anakinra, she developed sudden paraplegia and bowel/bladder dysfunction by day 8 post-infusion. MRI revealed diffuse T2 hyperintensities and cord expansion throughout the cervical and thoracic spinal cord, consistent with inflammatory myelitis. Intrathecal cytarabine and hydrocortisone were administered, followed by intravenous immunoglobulin (IVIG). While her cognitive status fully recovered, motor deficits persisted and only some sensory function recovered. At one-year follow-up, she remained paraplegic with persistent spinal cord atrophy and T2 intensities demonstrated on MRI.

Discussion: Spinal cord-predominant ICANS is a distinct clinical presentation that challenges current pathophysiologic models centered on cortical dysfunction. The decoupling of cognitive recovery from persistent motor deficits suggests a localized spinal cord injury, likely mediated by cytokine-induced blood–spinal cord barrier disruption. Spinal MRI was key to diagnosis, and earlier imaging may have facilitated more targeted intervention. Current ICANS grading systems, which rely heavily on ICE scores and encephalopathy, may overlook spinal presentations, delaying diagnosis and treatment. Revised grading criteria that account for spinal cord involvement, as well as research into optimal management strategies, are warranted to better identify and treat this rare but serious form of neurotoxicity.