ICANS — Immune Effector Cell-Associated Neurotoxicity Syndrome

Understanding, grading, and managing neurotoxicity after CAR-T cell therapy and bispecific antibodies

Key Points

• ICANS is a neurological toxicity syndrome that occurs after CAR-T cell and bispecific antibody therapy — distinct from CRS and requires independent assessment.
• Symptoms range from mild word-finding difficulty and confusion to seizures, cerebral edema, and coma.
• ICANS is graded 1–4 using the ASTCT ICANS consensus criteria, incorporating the ICE (Immune Effector Cell-Associated Encephalopathy) score.
• Corticosteroids (dexamethasone) are the cornerstone of ICANS treatment — tocilizumab is NOT effective for ICANS.
• ICANS typically follows CRS by 1–5 days, though it can occur independently; most cases resolve with prompt treatment.
• Patients must be closely monitored for seizures; prophylactic levetiracetam is used at many centers for moderate-severe ICANS.

What Is ICANS?

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is a disorder characterized by pathologic involvement of the central nervous system (CNS) following any immune therapy that results in T-cell activation and engagement. The syndrome was previously called CAR-T cell-related encephalopathy syndrome (CRES) or neurotoxicity; the ICANS term was adopted in 2019 to encompass all immune effector cell therapies. ICANS occurs in approximately 20–60% of CAR-T cell recipients, depending on the product, target, and patient population. It is also increasingly recognized with bispecific T-cell…

Symptoms and Clinical Presentation

ICANS has a broad spectrum of presentations. Symptoms typically begin 4–10 days after CAR-T infusion (median 5 days), often overlapping with or following the peak of CRS. With bispecific antibodies, neurologic symptoms usually coincide with or closely follow CRS episodes. **Early / mild ICANS:** - Word-finding difficulty (expressive aphasia) — often the first and most characteristic symptom; patients may have difficulty naming objects or completing sentences despite normal comprehension - Impaired handwriting — a specific and sensitive marker; many centers assess handwriting at regular…

Grading — ICE Score and ASTCT Criteria

ICANS grading uses the ASTCT 2019 consensus criteria, which incorporate the ICE (Immune Effector Cell-Associated Encephalopathy) assessment tool: **ICE Assessment Tool (10 points total):** - Orientation (year, month, city, hospital): 4 points - Naming: name 3 objects: 3 points - Following commands (simple commands like "show me 2 fingers"): 1 point - Writing: write a standard sentence: 1 point - Attention: count backward from 100 by 10s: 1 point **ICANS Grade by ASTCT Criteria:** **Grade 1:** ICE score 7–9; OR depressed level of consciousness (awakens spontaneously); no seizures; no…

Management by Grade

The cornerstone of ICANS management is corticosteroid therapy. Unlike CRS, tocilizumab does NOT adequately treat ICANS — it does not cross the blood-brain barrier in sufficient concentrations and may worsen ICANS in some cases by increasing CNS IL-6 levels. All centers administering CAR-T therapy should have institutional ICANS management protocols. **Grade 1:** - Neurologic monitoring every 8–12 hours (ICE score, handwriting sample) - EEG monitoring recommended if confusion is prominent - No mandatory corticosteroid treatment, but consider if worsening rapidly - Levetiracetam prophylaxis…

Recovery and Long-Term Outlook

The prognosis for ICANS varies by grade. Grade 1–2 ICANS resolves in the vast majority of patients, typically within 3–7 days with appropriate steroid treatment. Grade 3 ICANS resolves in most patients, though recovery may take 2–4 weeks. Grade 4 ICANS carries significant morbidity and some mortality risk, particularly when associated with cerebral edema. Long-term neurological sequelae are uncommon but recognized. Cognitive effects — including mild difficulties with memory, processing speed, and word-finding — can persist for weeks to months in some patients. Formal neuropsychological…