Immune Effector Cell–Associated Neurotoxicity Syndrome

Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS)

Definition

  • A neurologic toxicity associated with immune effector cell (IEC) therapies, especially CAR T-cells and sometimes bispecific T-cell engagers (BiTEs).
  • Thought to result from endothelial activation, cytokine-mediated inflammation, and disruption of the blood-brain barrier.
  • Frequently occurs alongside Cytokine Release Syndrome (CRS), but may appear independently.

Onset & Risk Factors

  • Onset: Typically 4–10 days post–CAR T infusion (after CRS begins).
  • Risk factors:
    • Severe CRS
    • High tumor burden
    • CD28-based CAR constructs (earlier generation)
    • High-dose CAR T expansion

Clinical Presentation

  • Early symptoms: confusion, impaired handwriting, word-finding difficulty, expressive aphasia.
  • Progression: delirium, tremor, seizures, somnolence.
  • Severe cases: cerebral edema, coma, increased ICP, death (rare).

Grading (ASTCT Consensus Criteria)

Grade Findings
1 Mild confusion, word-finding difficulty, impaired handwriting; ICE score 7–9
2 Moderate impairment, ICE score 3–6
3 Severe impairment, ICE score 0–2; seizures responsive to meds
4 Life-threatening: obtundation, coma, unarousable, ↑ICP, cerebral edema

ICE score (Immune effector Cell–associated Encephalopathy): 10-point bedside test (orientation, naming, commands, writing, attention).

Monitoring

  • Baseline neuro exam + ICE score daily during hospitalization after CAR T.
  • If ICANS suspected → neuro checks q4h, EEG, MRI, lumbar puncture (to exclude infection or leukemic meningitis).

Management

  1. Supportive care
    • Seizure prophylaxis: levetiracetam often given prophylactically.
    • Avoid CNS depressants unless needed.
  2. Steroids (mainstay for ICANS)
    • Grade ≥2: Dexamethasone 10 mg IV q6h or methylprednisolone 1–2 mg/kg/day.
    • Taper when symptoms improve.
  3. Tocilizumab (IL-6R blocker)
    • Very effective for CRS, but not effective for isolated ICANS (doesn’t cross BBB).
    • If CRS + ICANS → tocilizumab for CRS + steroids for neurotoxicity.
  4. Severe cases
    • ICU transfer, ICP management (mannitol, hyperventilation, neurology consult).

Oncology Pharmacy Pearls

  • Differentiate CRS vs ICANS: both can coexist, but ICANS needs steroids (tocilizumab won’t help).
  • Always start seizure prophylaxis in CAR T patients (levetiracetam).
  • Steroids do not reduce CAR T efficacy significantly if used appropriately for toxicity.
  • Document ICE score daily for early recognition.
  • High vigilance in first 2 weeks post-infusion (highest risk window).

Takeaway:

ICANS = neurotoxicity from CAR T/bispecific therapy → graded by ICE score → managed primarily with steroids (not tocilizumab unless CRS present too) + seizure prophylaxis/supportive care.