# ICANS, and whether thinking recovers after CAR-T

Source: https://onco.cc/technologies/rejuv-tx-icans-and-neurocognition/  
OnCo record `rejuv-tx-icans-and-neurocognition` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

CAR-T can cause a short-lived brain disturbance in the first weeks: confusion, trouble finding words, tremor, sometimes seizures. It almost always resolves. Afterwards, measured outcomes for most people are close to the general population, while a substantial minority report trouble with memory or concentration.

## Summary

The acute syndrome, immune effector cell-associated neurotoxicity syndrome, is covered by OnCo's existing term record `icans` and is graded by the ASTCT consensus criteria. What this record covers is what comes after it.

The best-conducted study of long-term outcomes used patient-reported measures in 40 patients with relapsed or refractory chronic lymphocytic leukaemia, non-Hodgkin lymphoma or acute lymphoblastic leukaemia, assessed one to five years after CD19-directed CAR-T. Its headline finding is reassuring: mean PROMIS T-scores for global mental health, global physical health, social function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. Its second finding qualifies the first. Nineteen patients, 47.5 per cent, reported at least one cognitive difficulty, clinically meaningful depression or anxiety, and 7 patients, 17.5 per cent, scored 40 or below on global mental health, at least one standard deviation worse than the general population mean. Fifteen patients, 37.5 per cent, reported cognitive difficulties after CAR-T. Younger age was associated with worse long-term global mental health (P = 0.02), anxiety (P = 0.001) and depression (P = 0.01). Anxiety before CAR-T predicted anxiety after it (P = 0.001), and depression before CAR-T was associated with a higher likelihood of self-reported cognitive difficulties afterwards (P = 0.02), with a non-significant trend for an association between acute neurotoxicity and later self-reported cognitive difficulty (P = 0.08). The authors concluded that overall neuropsychiatric outcomes were good but that nearly half the cohort reported at least one clinically meaningful negative outcome and would likely benefit from mental health services.

Forty patients is a small cohort and the measures are self-reported rather than formal neuropsychological testing, which is the main limitation of the best available evidence. A systematic review of eighteen studies of cognitive function, psychological outcomes and quality of life after CAR-T reported that up to 44 per cent of recipients experienced cognitive impairment, particularly in memory, attention and executive function, that ICANS was reported in 25 to 70 per cent of patients with severe ICANS in 10 to 20 per cent, that persistent cognitive deficits were observed beyond twelve months in a subset of patients and particularly in those with severe ICANS, and that anxiety and depression were reported in around 35 per cent. Systematic reviews of heterogeneous observational studies give ranges rather than estimates, and the ranges here are wide enough to show how unsettled the field is.

There is a separate and distinct late neurological syndrome after BCMA-directed CAR-T in myeloma, described as movement and neurocognitive treatment-emergent adverse events, with parkinsonian features including bradykinesia, rigidity, tremor and cognitive slowing. It is rare and it is not ICANS. A 2026 case report described an apparently similar syndrome after CD19-directed therapy, which, being a single case, extends the differential rather than the incidence.

Two honest statements belong here. First, no study has disentangled the contribution of CAR-T itself from the contribution of everything that came before it, which in this population is several lines of chemotherapy, sometimes a transplant, sometimes central nervous system disease and sometimes cranial radiotherapy. Second, the two consistent predictors of worse long-term neuropsychiatric outcome in the best study were pre-existing anxiety or depression and younger age, which points at a service response, access to psychological care, rather than a drug one. OnCo covers the general problem of cognitive change after cancer treatment on `cognitive-impairment-after-cancer-treatment`; this record is the cell therapy part of it.

## Fields

- Kind: Technology
- Status: established
- Last checked: 2026-10-02
- Also known as: neurotoxicity after CAR-T; immune effector cell-associated neurotoxicity syndrome; cognitive recovery after CAR-T; late neurocognitive effects of CAR-T
- Tags: rejuvenation; survivorship; transplant; cell-therapy; cognition
- Principle: Acute ICANS reflects endothelial activation and blood-brain barrier disruption during CAR-T expansion, with cytokine entry into the central nervous system and reactive astrocyte and microglial responses. Whether that produces lasting injury, and in whom, is unresolved; the plausible candidates are the severity and duration of barrier disruption, pre-existing cerebrovascular and cognitive reserve, and the cumulative neurotoxicity of earlier treatment.
- Strengths: Acute neurotoxicity resolves in the great majority of cases; Mean patient-reported mental and physical health one to five years out were close to general population norms in the best study; Risk factors for worse long-term outcomes are identifiable before treatment; Pre-existing anxiety and depression are treatable, which makes the main predictor actionable
- Limitations: The best long-term study has 40 patients and uses self-report rather than formal neuropsychological testing; A systematic review reports cognitive impairment in up to 44 per cent, with wide ranges across heterogeneous studies; No study separates the effect of CAR-T from that of prior treatment; Late parkinsonian syndromes after BCMA-directed therapy are described but not quantified

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cytokine_release_syndrome
- Ruark et al., Patient-reported neuropsychiatric outcomes of long-term survivors after chimeric antigen receptor T cell therapy (Biol Blood Marrow Transplant 2020): https://doi.org/10.1016/j.bbmt.2019.09.037
- The neurocognitive impact of CAR T cell therapy in hematological cancers: a systematic review of cognitive function, quality of life and psychological outcomes (Health Sci Rep 2025): https://doi.org/10.1002/hsr2.71571
- Non-ICANS neurotoxicities of CD19-directed CAR T-cell therapy and the emergence of movement and neurocognitive treatment-emergent adverse events: a case report (Front Immunol 2026): https://doi.org/10.3389/fimmu.2026.1749587
- Rejeski et al., Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations (Blood 2023): https://doi.org/10.1182/blood.2023020578

## Connected records

- technologies: [After a transplant or cell therapy: what to ask for](https://onco.cc/technologies/rejuv-tx-what-to-ask-for/), [Blood counts that do not come back after CAR-T: ICAHT](https://onco.cc/technologies/rejuv-tx-prolonged-cytopenias/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Measuring memory and concentration after treatment](https://onco.cc/technologies/rejuv-measure-cognitive-function/), [Quality of life after transplant and cell therapy](https://onco.cc/technologies/rejuv-tx-quality-of-life/), [Secondary T-cell malignancy after CAR-T, and what the FDA's 2024 action actually says](https://onco.cc/technologies/rejuv-tx-secondary-t-cell-malignancy/), [Thinking and memory after cancer treatment: what is measurable, and what helps](https://onco.cc/technologies/cognitive-impairment-after-cancer-treatment/)
- fronts: [Recovery & Rejuvenation](https://onco.cc/fronts/rejuvenation/), [Supportive Care & Survivorship](https://onco.cc/fronts/supportive-care/)
- terms: [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [ICANS (neurotoxicity)](https://onco.cc/terms/icans/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Quality of life](https://onco.cc/terms/quality-of-life/)
- bottlenecks: [No treatment restores the thinking that cancer treatment takes](https://onco.cc/bottlenecks/rejuv-agenda-nothing-restores-cognition/), [Survivorship and late effects are neglected](https://onco.cc/bottlenecks/b-survivorship/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)

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