Immune-Effector Cell-Associated Neurotoxicity Syndrome

Immune encephalopathy following immune-effector cell therapy (such as CAR T-cell therapy), that may relate to BBB disruption and entry of CAR T-cells into the CNS:

Immune cell-associated neurotoxicity can be distinguished from other encephalopathies by an awake patient who is mute and unable to follow commands.

Epidemiology and Risk Factors

Risk factors include:

  • Patient factors
    • Prior neurological morbidity
  • Disease factors
    • Disease burden
    • B-ALL as primary malignancy
    • Leptomeningeal disease
    • Cytokine release syndrome
  • Treatment factors
    • Axicabtagene ciloleucel

Pathophysiology

Aetiology

Assessment

The key assessment tool for ICANS is the Immune Effector Cell-Associated Encephalopathy (ICE) Score. The ICE Score:

  • Is a sensitive marker of neurological deterioration
  • Should be performed every:
    • 8 hours whilst an inpatient
    • 30 minutes after a deterioration until further guided by the treating team
Immune Effector Cell-Associated Encephalopathy (ICE) Score
Domain Test Total Points
Orientation

1 point for orientation to each of:

  • Year
  • Month
  • City
  • Hospital
 4
Naming 1 point for naming one of three objects. 3
Following commands 1 point for following a command 1
Handwriting Ability to write a standard sentence
 1
Attention Count backwards from 100 by 10 1
The ICE score is graded from 0 to 10. Any decrease is significant.

History

Key symptoms include:

Headache is not a useful marker of ICANs and should prompt consideration of other investigations.

  • Expressive dysphasia or aphasia
    Especially naming objects.
  • Dysgraphia
  • Tremor
  • Impaired attention
  • Apraxia
  • Lethargy

Examination

Investigations

Bedside:

  • LP
    • Evaluate for meningitis as an alternative diagnosis
    • Protein may be a useful prognostic marker
  • EEG
    • Should occur daily for monitoring of seizures or NCSE

Laboratory:

Imaging:

  • CT Brain
    • Exclude infection
    • Exclude haemorrhagic stroke
  • MRI Brain

Other:

Diagnostic Approach and DDx

ICANS Grading System
Grade ICE score Level of consciousness Seizure Motor findings Raised ICP
1 7-9 Awakens spontaneously - - -
2 3-6 Awakens to voice - - -
3 0-2 Awakens only to tactile stimulus

Any (focal or generalised) seizure that resolves rapidly

EEG proven nonconvulsive seizure resolves with intervention

 - Focal/local oedema on neuroimaging
4 0

Any of:

  • Unrousable
  • Rouse with vigorous stimulation
  • Rouse with repetitive stimulation
 Status epilepticus

Deep focal motor weakness, e.g.:

  • Hemiparesis
  • Paraparesis

Any of:

  • Diffuse cerebral oedema on neuroimaging
  • Decorticate posturing
  • decerebrate posturing
  • CN VI palsy
  • Papilloedema
  • Cushing’s triad

ICANS grade is determined by the most severe event in any category, provided that it is not attributable to another cause.

Management

  • Immunomodulators
    Dose and choice of agent depends on ICANs grade.
  • Avoid CNS depressants
  • Investigate differentials: CNS infection, sepsis, and stroke
  • Seizure prophylaxis

Resuscitation:

  • A
    • Airway protection as required
  • D
    • Treat seizure

Specific therapy:

  • Pharmacological
    • Immunomodulators
      • Grade 1:
        • Dexamethasone 4-10mg IV BD-QID
      • Grade 2:
        • Dexamethasone 10mg IV QID, or high dose methylprednisolone
        • Consider Anakinra 200mg IV BD
      • Grade 3:
        • Dexamethasone 10mg IV QID, or high dose methylprednisolone
        • Anakinra 200-800mg IV BD
      • Grade 4:
        • Dexamethasone 10mg IV QID, or high dose methylprednisolone
        • Anakinra 200-800mg IV BD
        • Consider chemotherapeutics, including:
          • Cyclophosphamide
          • Etoposide
          • Ruxolitinib
  • Procedural
  • Physical

Supportive care:

  • D
    • Anti-seizure prophylaxis
      Consider in grade 2, recommended in grade 3-4 disease.
      • Levetiracetam 500-750mg BD.
  • H
    • Platelet >30 ×109
    • Fibrinogen >1.5g/L

Disposition:

Preventative:

Marginal and Ineffective Therapies

Anaesthetic Considerations

Complications

Prognosis

  • D
    • Cognitive dysfunction
      Persistent cognitive dysfunction is rare - symptoms typically resolve in all cases.
    • Delayed onset neurotoxicity
      May occur up weeks-months after CAR T-cell treatment.

Key Studies

References

  1. Messmer AS, Que YA, Schankin C, Banz Y, Bacher U, Novak U, et al. CAR T-cell therapy and critical care. Wien Klin Wochenschr. 2021 Dec 1;133(23):1318–25.