Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)

Introduction
Chimeric antigen receptor T-cell therapy has revolutionized treatment for malignancies, but they are associated with a high incidence of toxicities. As many as 30-40% of patients require ICU admission, and 70-80% develop neurological symptoms. The conglomeration of symptoms is now collectively known as Immune Effector Cell-associated Neurotoxicity Syndrome (previously called CAR-associated neurotoxicity).

Recently, anti-CD19 CAR-natural killer cells have been used in 11 patients with CD19 positive chronic lymphocytic leukemia or non-Hodgkin's lymphoma. 7 patients had complete remission and 1 had improvement. There were no major neurotoxic side effects noted with this formulation.

Pathophysiology
Although it remains unknown, high levels of IL-6 and IL-15 are associated with severe neurotoxicity and these may passively enter into the CNS. Secondly, T-cells seem to enter the CNS. Other organ dysfunction such as hepatic failure or renal failure may also contribute.

Signs and Symptoms
Disorder typically lasts for 2-4 days but can last only for hours or be prolonged for weeks. Time course may be biphasic:
 * Phase 1
 * Within 5 days of treatment (usually)
 * Concurrent with high fever and signs/symptoms of cytokine release syndrome (fever, hypotension, hypoxia, arrhythmias, nausea/vomiting, diarrhea, acute kidney injury, transaminitis)
 * Usually less severe (grades 1-2, see below)
 * Phase 2
 * After 5 days of treatment, even several weeks
 * Usually more severe (grades 3-4, see below)
 * Common symptoms
 * Mental status changes (diminished attention, language disturbance, impaired handwriting progressing to confusion, disorientation, agitation, somnolence and eventually coma)
 * Tremor
 * Seizures and status epilepticus, including nonconvulsive status epilepticus in as many as 10% of patients
 * Motor weakness
 * Elevated ICP and cerebral edema (in severe cases). This tends to occur quickly, within 24 hours of onset of neurotoxicity.

Diagnosis and Grading - Children
For children under the age of 12, the Cornell Assesment of Pediatric Delirum scale is used instead

Diagnostic tests
Diagnosis is made clinically based on the grading scales and symptomatology as described above. However, some findings have been noted on diagnostic studies.

EEG
Although note well studied, there are reports of diffuse generalized slowing with or without 1-2 Hz triphasic waves, consistent with encephalopathy.

Imaging
Usually normal. MRI may show hyperintensity involving thalami, dorsal pons, or medulla. In severe cases, cerebral edema can occur.

Prevention
For any agents associated with seizures, seizure prophylaxis is recommended for 30 days from the start of the infusion, usually levetiracetam 750 mg BID due to less risk of cardiotoxicity, ability to administer safely in hepatic dysfunction, and fewer drug interactions than other agents.

General Management
This varies depending on Grade. Recommendations as per Neelapu et al. are as follows:

Grade 1

 * Aspiration precautions, neuro checks
 * Assess swallowing
 * Avoid any CNS depressants
 * For agitation, use low dose lorazepam (0.25-0.5 mg IV q8h) or haloperidol (0.5 mg IV q5h) as needed
 * Fundoscopic exam to assess for papilledema
 * MRI brain with and without contrast (CT if not feasible)
 * Lumbar puncture with opening pressure
 * EEG (daily 30 minute, or continuous EEG if available)
 * Only if associated with cytokine-release syndrome, consider anti-IL-6 therapy (tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV)

Grade 2

 * All measures for Grade 1
 * Only if associated with cytokine-release syndrome, give anti-IL-6 therapy (tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV)
 * If refractory to anti-IL-6 therapy or if no cytokine release syndrome, consider dexamethasone 10 mg IV q6h or methylprednisolone 1 mg/kg IV q12h
 * Consider transfer to ICU

Grade 3

 * All measures for Grade 1
 * Transfer to ICU
 * Only if associated with cytokine-release syndrome, give anti-IL-6 therapy (tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV) if not given previously
 * If refractory to anti-IL-6 therapy or if no cytokine release syndrome, consider dexamethasone 10 mg IV q6h or methylprednisolone 1 mg/kg IV q12h (if not given previously). This is more recommended for axicabtagene-ciloleucel CAR construct than for other CAR-T cell therapies.
 * Treat elevated ICP if necessary (see below)
 * Consider repeat neuroimaging every 2-3 days

Grade 4

 * All measures for Grade 1
 * Transfer to ICU
 * If associated with cytokine-release syndrome, give anti-IL-6 therapy (tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV) if not given previously
 * Consider high-dose corticosteroids until improvement to grade 1. Methylprednisolone 1g IV daily x3 days, then 250 mg IV q12h x2 days, then 125 mg IV q12h x2 days, then 60 mg IV q12h x2 days, and taper from there. This is more recommended for axicabtagene-ciloleucel CAR construct than for other CAR-T cell therapies.
 * Treat elevated ICP if necessary (see below)
 * Treat status epilepticus if necessary (see below)
 * If refractory, consider additional treatments including:
 * Cyclophosphamide or other immunosuppressive agents
 * Anakinra
 * Suicide/elimination gene activation

Management of elevated ICP

 * Stage 1 or 2 papilledema, CSF opening pressure <20 mmHg, no cerebral edema
 * Acetazolamide 1000 mg IV, then 250-1000 mg IV q12h (adjust dose based on renal function and acid-base balance, monitored 1-2 times per day)
 * Stage 3-5 papilledema, cerebral edema, or CSF opening pressure of ≥20
 * Methylprednisolone 1g IV daily (as for grade 4 encephalopathy, above)
 * Head of bed @ 30 degrees
 * Consider hyperventilation to pCO2 28-30 mmHg. This is per recommendations but I suspect is misguided.
 * Hyperosmolar therapy with either:
 * Mannitol
 * Dose: 0.5-1 g/kg IV, then 0.25-1 g/kg IV every 6 hours
 * Monitoring: BMP and serum osms q6h, hold for osm gap ≥40 or for serum osms ≥320 mOsm/kg
 * Hypertonic saline (3%)
 * Dose: 250 mL IV bolus, then 50-75 mL/hr
 * Monitoring: BMP q4h, hold for Na ≥ 155 mEq/L
 * Hypertonic saline (23.4%) -- for imminent herniation
 * Dose: 30 mL IV
 * If an Ommaya reservoir is present, drain CSF to target opening pressure <20 mmHg

Management of seizures
Although Neepalu et al. make specific recommendations, these are not based on anything and usual treatment for seizures should be pursued. Of note, favored agent is levetiracetam and lorazepam, with phenobarbital as second line.