What is the recommended treatment for checkpoint inhibitor‑related encephalitis?

Treatment of Checkpoint Inhibitor-Related Encephalitis

For checkpoint inhibitor encephalitis, immediately discontinue immunotherapy and initiate high-dose intravenous methylprednisolone (1-2 mg/kg/day or pulse-dose 1 gram daily for 3-5 days), with addition of IVIG or plasmapheresis if no improvement occurs within 3 days. 1

Severity-Based Treatment Algorithm

Grade 1 (Mild Symptoms)

• Hold checkpoint inhibitor and monitor closely for symptom progression over one week 1
• Consider permanent discontinuation if symptoms worsen or fail to improve 1
• Intervention not indicated if truly asymptomatic 1

Grade 2 (Moderate Symptoms, Limiting Instrumental ADLs)

• Permanently discontinue checkpoint inhibitor 1
• Initiate prednisone 0.5-1 mg/kg/day orally once infection is excluded 1
• Obtain urgent neurology consultation 1
• Taper steroids over at least 4-6 weeks following symptom improvement 1

Grade 3-4 (Severe/Life-Threatening)

• Permanently discontinue checkpoint inhibitor immediately 1
• Admit to hospital with ICU-level monitoring capability 1
• Initiate methylprednisolone 1-2 mg/kg/day IV or pulse-dose 1 gram daily for 3-5 days 1
• Add IVIG (2 g/kg over 5 days) or plasmapheresis if no improvement or worsening after 3 days 1
• Consider prophylactic antibiotics during high-dose immunosuppression 1

Essential Diagnostic Workup

Before initiating treatment, rapidly exclude alternative diagnoses:

• Neurology consultation (mandatory for all grades ≥2) 1
• MRI brain with and without contrast to evaluate for inflammatory changes, metastases, or demyelination 1
• Lumbar puncture with comprehensive CSF analysis: cell count, protein, glucose, oligoclonal bands, IgG index, autoimmune encephalitis panel (including NMDAR, LGI1, CASPR2, AMPAR, GABA-B receptor), paraneoplastic antibodies (anti-Hu, anti-CRMP5-CV2), viral PCRs (especially JCV to exclude PML) 1, 2, 3
• Serum studies: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG, thyroid peroxidase antibodies, morning cortisol and ACTH, paraneoplastic panel 1
• EEG to evaluate for subclinical seizures 1

Research data shows CSF abnormalities are common: lymphocytic pleocytosis in 77-85% and elevated protein in 69-84% of cases 2, 3. However, brain MRI is abnormal in only 33-65% of patients, so normal imaging does not exclude the diagnosis 2, 3.

Steroid-Refractory Disease Management

If no improvement after 3 days of high-dose corticosteroids:

• Add IVIG (0.4 g/kg/day for 5 days, total 2 g/kg) concurrently with continued steroids 1, 2
• Consider plasmapheresis as alternative to IVIG (note: plasmapheresis immediately after IVIG will remove immunoglobulin) 1
• Initiate rituximab if positive for autoimmune encephalopathy antibodies or limited improvement (375 mg/m² weekly for 4 weeks or two 1000 mg doses separated by 2 weeks) 1, 4, 2
• Consider cyclophosphamide for refractory cases unresponsive to rituximab 4

Research evidence demonstrates that 94% of patients receive corticosteroids, but 26-36% require additional IVIG and 12-29% require rituximab for adequate disease control 2, 3. Mortality is approximately 10-19% in severe cases 3.

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting antibody results—only 31-47% of patients test positive for known autoantibodies 2, 3
• Do not attribute symptoms to disease progression without contrast MRI and CSF cytology to exclude leptomeningeal carcinomatosis 1
• Exclude HSV encephalitis before initiating immunosuppression 1
• Avoid medications that worsen neurological symptoms: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, macrolides 1
• Do not use standard-dose corticosteroids for severe presentations—pulse-dose methylprednisolone is required 1

Steroid Tapering and Long-Term Management

• Taper corticosteroids gradually over at least 4-6 weeks following acute symptom resolution 1
• Monitor for relapse during taper—approximately 10% of patients experience clinical relapse after completing corticosteroid taper 3
• Serial antibody level monitoring in serum and CSF can guide tapering decisions 1

Prognosis and Checkpoint Inhibitor Resumption

• Most patients (81%) achieve clinical improvement with appropriate immunotherapy 3
• Checkpoint inhibitor resumption is generally not recommended—only 5-7% of patients in published series resumed therapy, with 43% experiencing relapse 3
• Despite discontinuation of immunotherapy, anti-cancer response persists in 77-85% of patients at 6 months post-treatment initiation 2