What does the workup for immune effector cell-associated neurotoxicity syndrome (ICANS) include?

ICANS Workup

The workup for ICANS includes serial ICE score assessments at least twice daily, neuroimaging (MRI preferred) for grade ≥2, EEG for unexplained altered mental status or grade ≥2, lumbar puncture for grade ≥3, and comprehensive laboratory monitoring including inflammatory markers, coagulation studies, and metabolic panels. 1

Cognitive and Neurologic Assessment

ICE Score Monitoring

• Perform the 10-point Immune Effector Cell-Associated Encephalopathy (ICE) score at least twice daily during the at-risk period (typically days 1-30 post-infusion) to screen for early neurotoxicity 1, 2
• The ICE assessment evaluates orientation (to year, month, city, hospital), naming (ability to name three objects), following commands, writing a complete sentence, and attention (counting backwards from 100 by 10) 1, 2
• For children younger than 12 years or patients with developmental delay, substitute the Cornell Assessment of Pediatric Delirium (CAPD) for ICE scoring 1
• Changes in CAPD from baseline may precede formal ICANS diagnosis by 24-72 hours in pediatric patients 3

Motor Function Assessment

• Assess for motor weakness, tremor, myoclonus, asterixis, ataxia, and parkinsonism at least twice daily 1
• Document any focal neurologic deficits including hemiparesis or paraparesis 1

Level of Consciousness

• Continually monitor and document level of consciousness using standardized descriptors (awake, somnolent but arousable to voice, arousable only to tactile stimulus, stupor, coma) 1

Neuroimaging

Brain MRI

• Obtain brain MRI with and without contrast for all patients with grade ≥2 ICANS 1
• MRI is preferred over CT for superior detection of focal edema, diffuse cerebral edema, and subtle parenchymal changes 1
• For grade ≥3 ICANS that persists, repeat neuroimaging (MRI or CT) every 2-3 days to monitor for progression or development of cerebral edema 1
• If MRI is not available or feasible (e.g., patient has pacemaker, too unstable for transport), obtain CT head without and with contrast 1

Timing Considerations

• Perform initial neuroimaging promptly when ICANS is suspected or confirmed at grade 2 or higher 1
• Repeat imaging is indicated for clinical deterioration or lack of improvement within 24 hours despite treatment 1

Electroencephalography (EEG)

Indications for EEG

• Obtain EEG for unexplained altered mental status to assess for subclinical seizure activity or non-convulsive status epilepticus 1
• Perform EEG for all patients with grade ≥2 ICANS 1
• EEG is mandatory for any patient with clinical seizure activity (focal, generalized, or suspected) 1

EEG Findings

• EEG patterns correlate with ICANS severity and can serve as an objective biomarker for grading neurotoxicity 4
• Abnormal EEG findings may include generalized slowing, epileptiform discharges, or electrographic seizures 4

Lumbar Puncture

Indications

• Perform lumbar puncture for all patients with grade ≥3 ICANS 1
• Consider LP for grade 2 ICANS, particularly if diagnosis is uncertain or infection cannot be excluded 1
• LP should be performed after neuroimaging to exclude contraindications such as mass effect or elevated intracranial pressure 1

CSF Studies

• Obtain opening pressure measurement when feasible 1
• Send CSF for cell count with differential, protein, glucose, Gram stain, bacterial culture, and cytology 1
• Consider viral studies (HSV, VZV, enterovirus PCR) to exclude infectious encephalitis 1
• CSF analysis helps differentiate ICANS from infectious or malignant causes of altered mental status 1

Laboratory Monitoring

Serial Laboratory Tests

• Monitor the following labs serially (at least daily during acute ICANS): 1
  • Complete blood count (CBC) with differential
  • Comprehensive metabolic panel (CMP) including sodium, as severe hyponatremia can worsen neurotoxicity
  • C-reactive protein (CRP)
  • Ferritin (elevated ferritin is associated with higher ICANS risk) 3
  • Lactate dehydrogenase (LDH)
  • Fibrinogen
  • Prothrombin time/partial thromboplastin time (PT/PTT)
  • Magnesium and phosphorus 1

Infection Workup

• Obtain blood cultures and urinalysis with culture if fever is present 1
• Chest radiograph if fever or respiratory symptoms are present 1
• Consider screening for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation 1

Supportive Care Measures

Aspiration Precautions

• Implement aspiration precautions immediately upon recognition of any grade of ICANS 1
• Elevate head of bed to 30-45 degrees 1
• Suspend oral nutrition and convert oral medications to intravenous routes for grade ≥2 ICANS 1

Seizure Prophylaxis Considerations

• Consider levetiracetam 500-750 mg PO/IV every 12 hours for 30 days for CAR T-cell products known to be associated with high ICANS rates (particularly CD19-directed products) 1, 2
• Seizure prophylaxis is also indicated for patients with seizure history, CNS disease involvement, concerning EEG findings, or neoplastic brain lesions 1

Specialist Consultation

• Initiate neurology consultation immediately for any patient with signs of neurotoxicity 1
• Consider ICU transfer for grade ≥2 ICANS, particularly if concurrent with grade ≥2 cytokine release syndrome 1

Critical Pitfalls to Avoid

• Do not rely solely on ICE score decline to diagnose ICANS; subtle personality changes, occupational confusion, or inability to answer simple dichotomous questions may precede ICE score deterioration 5
• Do not administer tocilizumab for isolated ICANS without concurrent CRS, as it does not resolve neurotoxicity and may worsen it 1, 2
• Do not delay neuroimaging in patients with grade ≥2 ICANS; early detection of cerebral edema is critical 1
• Ensure consistent evaluation by the same clinical provider familiar with the patient's baseline to detect early behavioral or cognitive changes 5
• Monitor and correct severe hyponatremia promptly, as it can exacerbate neurologic symptoms 1