What are the neurologic adverse effects of chimeric antigen receptor (CAR) T-cell therapy?

Updated: Dec 17, 2020
  • Author: Sameh Gaballa, MD, MS; Chief Editor: Emmanuel C Besa, MD  more...
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Neurologic toxicity is common after CAR T cell therapy and can occur with or without CRS. Symptoms can be mild to moderate (eg, headache, confusion, dysmetria, ataxia, dysphasia, tremors), but can also be severe and life-threatening (eg, seizures, coma requiring intubation and mechanical ventilation for airway protection).

ICANS typically occurs within 4-5 days after CAR T infusion, lasts 5-10 days, and is typically reversible. The incidence of neurologic toxicity in published reports varies from 0% to 50% and differs among the different CAR T constructs. [5, 36, 37]  

The mechanism of neurologic toxicity after CAR T cell therapy is poorly understood, but might be related to increased trafficking of cytokines into the central nervous system, or related to the CAR T cells that cross the blood-brain barrier. [38]  Several groups have found anti-CD19 CAR T cells with elevated IL-6 levels in the cerebrospinal fluid in patients who developed neurotoxicity. [5, 37, 39] However, neurotoxicity is not exclusive to CAR T cell therapy and has also been reported with other immunotherapies, such as bispecific antibodies. [40]  

ICANS grading includes the Immune Effector Cell–Associated Encephalopathy (ICE) score. The assessments and points are as follows:

  • Orientation (to year, month, city, hospital): 4 points
  • Naming (ability to name 3 objects [eg, point to clock, pen, button]): 3 points
  • Following commands (ability to follow simple commands [eg, “Show me 2 fingers” or “Close your eyes and stick out your tongue”]): 1 point
  • Writing (ability to write a standard sentence [eg, “Our national bird is the bald eagle”]: 1 point
  • Attention (ability to count backwards from 100 by 10): 1 point

ICE scoring is as follows:

  • 10 points: no impairment
  • 7-9 points: grade 1 ICANS
  • 3-6 points: grade 2 ICANS
  • 0-2 points: grade 3 ICANS
  • 0 points (patient unable to be assessed because unarousable): grade 4 ICANS

Incorporation of ICE scoring into ASTCT ICANS grading is shown in Table 2, below.

Table 2. American Society for Transplantation and Cellular Therapy Immune Effector Cell–mediated Neurotoxicity Syndrome (ICANS) Consensus Grading for Adults (Open Table in a new window)

Neurotoxicity Domain

Grade 1

Grade 2

Grade 3

Grade 4

ICE score




0 (patient is unarousable and unable to perform ICE)

Depressed level of consciousness

Awakens spontaneously

Awakens to voice

Awakens only to tactile stimulus

Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma




Any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG

that resolve with intervention

Life-threatening prolonged seizure (>5 min), or repetitive clinical or electrical seizures without return to baseline in between

Motor findings




Deep focal motor weakness such as hemiparesis or paraparesis

Elevated ICP/ cerebral edema



Focal/local edema on neuroimaging

Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing's triad

EEG=encephalography; ICE=immune effector cell–mediated encephalopathy; ICP=intracranial pressure


  • A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, or as grade 4 ICANS if unarousable.
  • Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication).
  • Tremors and myoclonus associated with immune effector cell therapies may be graded according to Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0), but they do not influence ICANS grading.
  • Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to CTCAE v5.0.

Treatment of ICANS is mainly with glucocorticosteroids and supportive care. Treatment is mostly effective at reversing the signs and symptoms.

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