ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome)
ICANS is a central nervous system inflammatory disorder occurring after CAR T-cell therapy, typically presenting 4-10 days post-infusion with language disturbances, encephalopathy, and motor dysfunction, lasting 14-17 days, and requiring corticosteroids as the cornerstone of management for grade ≥2 toxicity. 1
Definition and Pathophysiology
ICANS is defined by the American Society for Transplantation and Cellular Therapy (ASTCT) as a pathologic process in the central nervous system leading to elevated inflammation. 1 The underlying mechanism involves endothelial cell activation and leak in the CNS, though the complete pathophysiology remains incompletely understood. 1 Multiple cytokines are implicated, including IL-6, IFN-γ, and TNF-α. 1
Onset and Duration
- Typical onset: 4-10 days after CAR T-cell infusion 1
- Duration: 14-17 days (may be slightly shorter with BCMA-directed CAR T-cell therapies) 1
- Delayed onset: Can occur up to one month after infusion 1
- Temporal relationship: May occur concurrently with CRS, shortly after CRS resolves, or independently 1
Clinical Features
Characteristic Triad
The distinct common features that differentiate ICANS from other encephalopathies are: 1
- Language disturbances (expressive aphasia, dysarthria, dysgraphia)
- Encephalopathy (confusion, behavioral changes, delirium)
- Motor dysfunction (fine motor impairment, weakness, tremor, myoclonus, ataxia)
Full Spectrum of Manifestations
Heterogeneous neurologic symptoms include: 1
- Lethargy and altered level of consciousness
- Headache (very common but not diagnostically useful alone as it frequently co-occurs with fever) 1
- Sleep disorders (insomnia)
- Anxiety and agitation
- Signs of psychosis
- Dizziness
Severe Manifestations
Life-threatening complications include: 1
- Seizures (any clinical or subclinical electrographic seizure)
- Depressed level of consciousness or obtundation
- Cerebral edema (very rare but potentially fatal) 1
- Requirement for intubation and airway protection 1
Risk Factors
CRS is the strongest risk factor for ICANS, with CRS severity correlating directly with ICANS severity. 1 Additional risk factors include: 1
- Higher disease burden
- High baseline inflammatory state
- Pre-existing neurologic comorbidities
- Higher CAR T-cell dose
- CD19-directed CAR (higher-grade ICANS more common than with BCMA-directed CAR) 1
Grading System
ASTCT ICANS Consensus Grading Scale
The NCCN panel recommends following the ASTCT ICANS Consensus grading scale, which evaluates five domains with the overall grade determined by the most severe symptom in any domain. 1
Five Grading Domains:
ICE Score (Immune Effector Cell-Associated Encephalopathy): 10-point screening tool evaluating orientation, naming, command following, writing, and attention 1
- For children <12 years or those with developmental delay: Cornell Assessment of Pediatric Delirium (CAPD) score replaces ICE 1
Level of Consciousness 1
Seizures:
Motor Findings 1
Elevated Intracranial Pressure/Cerebral Edema (rare but included in grading) 1
ICE Assessment Tool
The ICE score is a modified version of the CARTOX-10 screening tool that can be used daily or every shift as a screen during the at-risk period. 1 This objective 10-point tool improves grading ease compared to earlier CTCAE methods that graded multiple overlapping terms. 1
Management
Cornerstone Therapy
Corticosteroids form the cornerstone of ICANS management, along with careful monitoring and supportive care. 1 For grade ≥2 ICANS, corticosteroids are generally used. 1
Grade-Specific Approach
Grade 1 ICANS:
- Supportive care and close monitoring 1
Grade 2 ICANS (ICE score 3-6, mild somnolence, or confusion):
Grade 3-4 ICANS (severe altered consciousness, seizures, or focal neurologic deficits):
Critical Management Principles
Tocilizumab does not resolve ICANS and may worsen it. 1 Because tocilizumab may worsen neurotoxicity, management of ICANS takes precedence over management of low-grade CRS when both occur simultaneously. 1
Refractory Cases
For patients not showing improvement within 24 hours: 1
- Repeat neuroimaging
- CSF evaluation including opening pressure measurement (if possible)
- Consider investigational approaches: anakinra, lenzilumab, defibrotide 1
Seizure Management
- Levetiracetam 500-750 mg orally every 12 hours for 30 days starting on infusion day for high-risk products 2
- Continue prophylaxis if EEG shows no seizure activity 2
- Escalate treatment if non-convulsive status epilepticus detected 2
Supportive Care Measures
- Aspiration precautions and head of bed elevation 2
- Avoid medications causing CNS depression 2
- Strongly consider antifungal prophylaxis in all patients receiving corticosteroids 1, 3
- Neurologic evaluation with ICE score assessment at least twice daily during high-risk period 2
Common Pitfalls to Avoid
- Do not dismiss headache alone as ICANS, as it is very common and frequently co-occurs with fever; it is not diagnostically useful by itself 1
- Do not use tocilizumab for isolated ICANS symptoms, as it has not been shown to mitigate neurologic toxicity and may worsen ICANS 2
- Do not routinely administer corticosteroids as pre-medication before CAR T-cell infusion, as this may mask early toxicity symptoms 2
- Always perform formal ICE score assessment rather than dismissing neurologic symptoms in the context of headache 2
Clinical Outcomes
ICANS is typically self-limited with most symptoms resolving between 5-17 days. 1 Development of ICANS of any grade does not affect complete remission rates, progression-free survival, or overall survival. 4 Duration and total steroid dose for ICANS treatment do not influence treatment outcomes. 4