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

Checkpoint Inhibitor Encephalitis Treatment

For checkpoint inhibitor-related encephalitis, immediately hold the checkpoint inhibitor, initiate IV acyclovir empirically until HSV is excluded, and start methylprednisolone 1-2 mg/kg/day IV, escalating to pulse-dose methylprednisolone 1 g IV daily for 3-5 days plus IVIG 2 g/kg over 5 days (0.4 g/kg/day) for severe or progressive cases. 1

Initial Management Algorithm

Immediate Actions (All Grades)

• Hold checkpoint inhibitor therapy immediately upon suspicion of encephalitis 1
• Obtain urgent neurology consultation to confirm diagnosis and guide management 1
• Start empirical IV acyclovir concurrently until CSF PCR results exclude HSV and other viral etiologies 1, 2

Diagnostic Workup Requirements

• MRI brain with or without contrast (may show T2/FLAIR changes typical of autoimmune encephalopathies or limbic encephalitis, or may be normal) 1
• Lumbar puncture with cell count, protein, glucose, Gram stain, culture, HSV PCR, other viral PCRs, cytology, and onconeural antibodies 1, 2
• Screen for autoimmune encephalopathy and paraneoplastic antibodies in blood and CSF 1

Treatment Intensity Based on Severity

Mild to Moderate Cases

• Methylprednisolone 1-2 mg/kg/day IV as initial therapy 1, 3
• Continue empirical IV acyclovir until infectious causes excluded 1, 2
• Monitor closely for progression requiring escalation 1

Severe or Progressive Cases (Critical Escalation Criteria)

Escalate immediately if:

• Symptoms are severe at presentation or rapidly progressing 1
• Oligoclonal bands present in CSF 1
• No improvement or worsening on standard-dose methylprednisolone 1

Escalated regimen:

• Pulse-dose methylprednisolone 1 g IV daily for 3-5 days 1, 3
• PLUS concurrent IVIG 2 g/kg total dose divided over 5 days (0.4 g/kg/day) 1, 3
• This combination should be initiated early in severe cases, not delayed while awaiting antibody results 3

Refractory Disease Management

Second-Line Therapies

If limited or no improvement after pulse corticosteroids plus IVIG:

• Consider rituximab (preferred for antibody-mediated disease) 1, 4
• Consider plasmapheresis (5-10 sessions every other day) 1, 4
• Both options require consultation with neurology 1

Checkpoint Inhibitor Discontinuation

• Permanently discontinue checkpoint inhibitor for encephalitis of any grade 1, 4
• Do not resume therapy even after resolution, as relapse risk is significant 5

Critical Pitfalls and Caveats

Infectious Exclusion is Mandatory

• Never delay empirical IV acyclovir while awaiting diagnostic confirmation—start concurrently with immunosuppression 1, 2
• Bacterial meningitis must also be excluded with empirical antibacterial therapy until CSF culture is negative 1
• HSV encephalitis can be fatal if missed; PCR results take time 2

Diagnostic Challenges

• MRI may be normal in up to 67% of cases, so do not exclude encephalitis based on normal imaging 1, 6
• CSF typically shows lymphocytic pleocytosis (85%) and elevated protein (69-84%), but can be normal 6, 5
• Autoantibodies are present in only 31-47% of cases, so negative antibodies do not exclude diagnosis 6, 5

Treatment Response Patterns

• Most patients (81-86%) improve with corticosteroids alone, but 19-26% require additional immunosuppression with IVIG 6, 5
• Clinical improvement typically begins within 2-4 days of high-dose corticosteroids 7, 8
• Steroid unresponsiveness is rare and should prompt reconsideration of the diagnosis 6
• Relapse can occur during corticosteroid taper (10% of cases), requiring re-escalation 5

Mortality and Long-Term Outcomes

• Mortality during index hospitalization is approximately 19% without aggressive treatment 6
• Long-term neurological sequelae are common even with treatment 5
• Early recognition and prompt initiation of high-dose corticosteroids is essential to prevent complications including hydrocephalus and tonsillar herniation 7

Evidence Quality Note

These recommendations are based on the 2018 American Society of Clinical Oncology Clinical Practice Guideline for management of immune-related adverse events, which represents the highest quality guideline evidence available 1. The specific IVIG dosing (2 g/kg over 5 days) and pulse methylprednisolone regimen (1 g daily for 3-5 days) are consistently recommended across multiple iterations of this guideline 1, 3.