What is the management of checkpoint inhibitor-induced encephalopathy?

Management of Checkpoint Inhibitor-Induced Encephalopathy

For checkpoint inhibitor-induced encephalopathy, permanently discontinue the immune checkpoint inhibitor (ICI) and immediately administer high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day IV), with consideration of pulse-dose steroids (1g/day for 3-5 days) for severe cases or those not responding to initial treatment. 1

Diagnostic Evaluation

When encephalopathy is suspected, a thorough neurological evaluation should be performed:

• Neurological consultation - Essential for all grade 2 or higher neurological immune-related adverse events (irAEs) 1

• Brain MRI with and without contrast - May reveal T2/FLAIR changes typical of autoimmune encephalopathies or limbic encephalitis 1

• Lumbar puncture with comprehensive CSF analysis:

  • Cell count, protein, glucose
  • Oligoclonal bands
  • Viral PCRs
  • Cytology (to rule out leptomeningeal metastasis)
  • Onconeural antibodies
  • Autoimmune encephalitis panel 1

• Blood tests:

  • B12, HIV, rapid plasma reagin
  • ANA, Ro/La, TSH
  • Aquaporin-4 IgG
  • Paraneoplastic panel 1

• EEG to rule out seizure activity 1

Management Algorithm

Grade 1 (Mild symptoms)

• Hold ICI and initiate diagnostic work-up
• Consider permanent discontinuation if symptoms worsen or do not improve 1

Grade 2 (Moderate symptoms, limiting instrumental ADLs)

• Hold ICI
• Start methylprednisolone 0.5-1.0 mg/kg/day PO or IV once infection has been excluded
• Consider permanent discontinuation if symptoms worsen or do not improve 1

Grade 3-4 (Severe symptoms or life-threatening consequences)

1. Permanently discontinue ICI 1
2. Start high-dose corticosteroids:
   • Methylprednisolone 1-2 mg/kg/day IV 1
   • For severe or progressing symptoms, consider pulse-dose steroids (methylprednisolone 1g IV daily for 3-5 days) 1
3. Administer prophylactic antibiotics to prevent opportunistic infections 1
4. Consider additional immunomodulatory therapy if no improvement or worsening after 3 days:
   • IVIG (2 g/kg over 5 days) 1
   • Plasmapheresis 1
5. For refractory cases with positive autoimmune encephalopathy or paraneoplastic antibodies:
   • Consider rituximab in consultation with neurology 1

Special Considerations

• Rule out infection: Empiric antiviral therapy (IV acyclovir) should be administered until CSF viral PCR results are negative 1

• ICU admission: Patients with grade 4 toxicity (life-threatening) should be admitted to the intensive care unit 1

• Steroid tapering: Corticosteroids should be tapered gradually over at least 4-6 weeks following acute management 1

• Monitoring: Close neurological monitoring is essential during treatment and recovery

Prognostic Factors

Recent evidence suggests that certain presentations of checkpoint inhibitor-induced encephalopathy carry worse prognosis:

• Encephalopathy without evidence of CNS inflammation has been associated with higher mortality 2
• Most deaths occur during the first month of symptom onset, highlighting the importance of early and aggressive intervention 2

Pitfalls and Caveats

• Delayed diagnosis: Neurological irAEs may present with nonspecific symptoms that can be mistaken for other conditions. Maintain a high index of suspicion in any patient receiving ICIs who develops new neurological symptoms.

• Inadequate initial treatment: Starting with insufficient corticosteroid doses may lead to irreversible neurological damage. Don't hesitate to use high-dose steroids early.

• Premature steroid tapering: Rapid tapering of corticosteroids can lead to symptom recurrence. Follow a gradual taper over at least 4-6 weeks.

• Missing concurrent irAEs: Patients with neurological irAEs may have concurrent immune-related toxicities affecting other organ systems, particularly myocarditis, which significantly increases mortality risk 2.

• Resumption of ICI therapy: Generally, ICIs should be permanently discontinued after grade 3-4 neurological toxicity. Resumption carries significant risk of recurrence or worsening of neurological symptoms.