Objective: To better characterize the underlying movement disorders and cognitive deficits that manifest as dysgraphia in immune effector cell-associated neurotoxicity syndrome (ICANS), and to identify predictors of neurotoxicity in patients receiving chimeric antigen receptor (CAR) T-cell therapy.

Background: CAR T-cell therapy has revolutionized the treatment of hematologic malignancies and is currently under investigation for autoimmune disorders. However, toxicity frequently complicates treatment. Pyroptosis of targeted cells triggers cytokine release syndrome (CRS). ICANS may follow CRS due to increased vascular permeability, microthrombi, and inflammatory infiltrate in the CNS. Symptoms can range from mild encephalopathy and dysphasia to life-threatening cerebral edema.¹ Dysgraphia is among the earliest known neurocognitive changes in ICANS, although the precise phenomenology of these changes has been scarcely studied.²

Method: Adults receiving an FDA-approved CAR T-cell product were included in the study. The Montreal Cognitive Assessment (MoCA) was performed at baseline. Handwriting and drawing samples were obtained at baseline, days 2-3, and 6-7, along with measures of coordination, tone, praxis, and attention. Detailed videotaping of neurological examination was also performed.

Results: Eleven subjects were enrolled (54.5% female, age range 52-78 years, median age 71 years). All received anti-CD19 CAR T-cell products for lymphoma (81.8% diffuse large B-cell lymphoma, 18.2% relapsed follicular lymphoma). CRS occurred in 72.7% (n=8), and 27.3% (3/11) developed ICANS.³ Relative micrographia was observed in 54.5% (n=6), including 2/3 ICANS patients. Paligraphia (repetition of words/letters/phrases) was observed in three subjects, including 2/3 with ICANS. One subject developed agraphia in the setting of severe ICANS. New or worsening tremor or myoclonus was observed in 72.7% (n=8), including all subjects with ICANS, but did not always affect handwriting.

Conclusion: Micrographia, paligraphia, and tremor/myoclonus are frequent findings in those treated with CAR T-cell therapy. Larger studies are warranted to determine if the presence or severity of these findings is predictive of clinically significant neurotoxicity. Paligraphia has been previously reported in ICANS and again demonstrated in our cohort; this unusual finding may have some specificity for ICANS.⁴

References: 1. Xiao X, Huang S, Chen S, et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. J Exp Clin Cancer Res. 2021 Nov 18;40(1):367. doi: 10.1186/s13046-021-02148-6. PMID: 34794490; PMCID: PMC8600921.
2. Vonberg FW, Malik I, O’Reilly M, Hyare H, Carr AS, Roddie C. Neurotoxic complications of chimeric antigen receptor (CAR) T-cell therapy. J Neurol Neurosurg Psychiatry. 2025 Jun 12;96(7):665-678. doi: 10.1136/jnnp-2024-333924. PMID: 40185628.
3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. PMID: 30592986; PMCID: PMC12180426.
4. Pensato U, Amore G, D’Angelo R, et al. Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity. J Neurol. 2022 Feb;269(2):609-615. doi: 10.1007/s00415-021-10766-5. Epub 2021 Aug 23. PMID: 34424399; PMCID: PMC8381707.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/micrographia-is-an-early-abnormality-in-car-t-cell-therapy-associated-icans/