What is ICANS (Immune Checkpoint Inhibitor-Associated Neurotoxicity Syndrome)?

What is ICANS?

ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome) is a potentially life-threatening neurological toxicity that occurs primarily after CAR T-cell therapy, characterized by encephalopathy, language disturbances, motor dysfunction, and in severe cases, seizures or cerebral edema. 1

Definition and Context

ICANS is specifically associated with chimeric antigen receptor (CAR) T-cell therapy, not immune checkpoint inhibitors (which cause different neurological immune-related adverse events). 1 This is a distinct toxicity syndrome that develops in a substantial proportion of patients treated with CD19-targeted CAR T cells and a smaller percentage with BCMA-targeted CAR T cells. 1

Clinical Manifestations

Core Symptoms

• Encephalopathy with confusion and behavioral changes 1
• Language disturbances including expressive aphasia, dysphasia, and hesitant speech 1
• Dysgraphia (deterioration in handwriting) - a prominent early sign 1
• Motor impairment including dysarthria, fine motor dysfunction, tremor, and myoclonus 1
• Headache (though not diagnostically useful alone as it commonly co-occurs with fever) 1

Severe Manifestations

• Obtundation or depressed level of consciousness 1
• Seizures (clinical or subclinical) requiring intubation for airway protection 1
• Malignant cerebral edema - very rare but potentially fatal 1

Timing and Duration

• Onset: Typically 4-10 days after CAR T-cell infusion 1
• Timing patterns: May occur concurrently with cytokine release syndrome (CRS), shortly after CRS resolves, or with delayed onset up to one month post-infusion 1
• Duration: Self-limited, most often lasting 5-17 days 1
• Product variation: Time of onset, duration, and severity vary by CAR product and patient disease state 1

Pathophysiology

• Mechanism: Endothelial cell activation and increased vascular permeability in the central nervous system leading to blood-brain barrier breakdown 1
• Inflammatory mediators: Elevated cerebrospinal fluid cytokines including IL-6, IFN-γ, and TNF-α 1
• Cerebral edema: Results from inflammatory cytokine-mediated vascular permeability in some cases 1

Risk Factors

• CRS severity: Strong risk factor, with severity of CRS correlating with ICANS severity 1
• CAR product type: CD28-CAR-T products and CD19-directed CAR have higher rates than BCMA-directed CAR 1
• Disease burden: Higher tumor burden increases risk 1
• Baseline factors: Pre-existing neurological conditions, low platelet count, high baseline inflammatory state 1
• CAR T-cell dose: Higher doses associated with increased risk 1
• Early predictors: High fever (≥38.9°C) and hemodynamic instability within 36 hours of infusion predict severe ICANS 1

Grading System

Use the ASTCT (American Society of Transplantation and Cellular Therapy) Consensus Grading System, which incorporates: 1

Five Domains Assessed

1. ICE Score (Immune Effector Cell-Associated Encephalopathy): 10-point assessment evaluating orientation, naming, command following, writing, and attention 1

   • Grade 1: ICE score 7-9
   • Grade 2: ICE score 3-6
   • Grade 3: ICE score 0-2
   • Grade 4: ICE impossible to assess 1

2. Level of consciousness 1

3. Seizures 1

4. Motor findings (severe motor weakness) 1

5. Elevated intracranial pressure/cerebral edema 1

• Pediatric modification: For children <12 years or those with developmental delay, use Cornell Assessment of Pediatric Delirium (CAPD) score instead of ICE 1
• Overall grade: Determined by the most severe symptom in any of the five domains 1

Management Algorithm

Grade 1 ICANS

• Supportive care with close monitoring 1
• ICE assessment: Use as daily screen during at-risk period 1
• Workup: EEG, MRI, and lumbar puncture as clinically indicated for differential diagnosis 1
• Nutrition: Consider suspending oral nutrition and switching oral drugs to IV 1
• May resolve without intervention 1

Grade 2 or Higher ICANS

• Corticosteroids: Mainstay of treatment 1
  • Dexamethasone 10 mg IV every 6 hours for 1-3 days 1
  • If no improvement within 24 hours: repeat neuroimaging followed by CSF evaluation with opening pressure measurement 1
• Alert neurology and consider ICU transfer (recommended from grade 2 in centers with limited experience) 1

Grade 3 ICANS

• Transfer to ICU 1
• High-dose methylprednisolone: 500-1000 mg IV every 12 hours for 3 days, followed by structured taper (250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, 60 mg every 12 hours for 2 days) 1
• Seizure management: Levetiracetam for prophylaxis; benzodiazepines for active seizures or status epilepticus 1
• Cerebral edema: Consider hyperosmolar therapy 1

Grade 4 ICANS

• Immediate ICU transfer 1
• Dexamethasone 20 mg IV every 6 hours for 3 days with progressive tapering over 3-7 days 1
• Refractory cases: Consider methylprednisolone 1000 mg IV twice daily or alternative therapies 1

Alternative Therapies (Under Investigation)

• Anakinra (anti-IL-1R), siltuximab (anti-IL-6), lenzilumab, defibrotide 1
• Intrathecal or systemic chemotherapy for refractory ICANS on case-by-case basis 1

Critical Management Principles

Tocilizumab Contraindication

Tocilizumab does not resolve ICANS and may worsen it. 1 Management of ICANS takes precedence over low-grade CRS when both occur simultaneously due to this risk. 1 In grade 1 CRS with concurrent grade 2 ICANS, use steroids (not tocilizumab). 1

Antifungal Prophylaxis

Strongly consider antifungal prophylaxis in patients receiving steroids for CRS and/or ICANS treatment. 1

Seizure Prophylaxis

Routine anti-convulsant prophylaxis is not recommended except in high-risk cases. 1 Any single clinical or subclinical electrographic seizure is grade 3; prolonged (>5 minutes) or repetitive seizures without return to baseline are grade 4. 1

Monitoring During Treatment

• Repeat neuroimaging if no improvement within 24 hours of corticosteroid initiation 1
• CSF evaluation with opening pressure measurement when safe to perform 1
• Differential diagnosis: Exclude infection (CMV, EBV, adenovirus), metabolic causes, and disease progression 1

Prognosis

• Self-limited: ICANS typically resolves with symptoms lasting 5-17 days 1
• Favorable outcomes: Most patients respond to corticosteroids and supportive care 1
• Duration variation: May be slightly shorter with BCMA-directed CAR T-cell therapies compared to CD19-directed 1
• Late presentations: Psychiatric manifestations have been reported as delayed complications 1
• Fatal cases: Very rare malignant cerebral edema can be fatal 1

Key Pitfalls to Avoid

• Do not confuse with immune checkpoint inhibitor neurotoxicity - these are distinct entities with different mechanisms and treatments 1, 2, 3
• Do not use tocilizumab for ICANS - it may worsen neurotoxicity 1
• Do not delay corticosteroids for grade 2 or higher ICANS 1
• Do not overlook concurrent CRS - manage ICANS first when both present 1
• Do not forget antifungal prophylaxis when using prolonged steroids 1