Treatment of Autoimmune Encephalitis
Start high-dose intravenous corticosteroids immediately once infection is ruled out, with methylprednisolone 1-2 mg/kg/day or pulse dosing at 1g daily for 3-5 days as the first-line treatment for autoimmune encephalitis. 1, 2
Initial Treatment Strategy
First-Line Immunotherapy Options
The cornerstone of acute management involves three primary modalities that should be initiated promptly once cerebrospinal fluid excludes infection and primary CNS lymphoma or neurosarcoidosis are not considerations 3, 1:
High-dose corticosteroids are the most commonly used first-line therapy 2:
- Standard dosing: intravenous methylprednisolone 1-2 mg/kg/day 1, 2
- Pulse dosing for severe cases: 1g daily for 3-5 days 1, 2
IVIG should be used instead of steroids in specific clinical scenarios 3, 1:
- Patients who are agitated or combative 3, 1
- Bleeding disorders or coagulopathy present 3, 1
- Difficulty with central line placement 3
- Contraindications to corticosteroids 1
- Dosing: 0.4 g/kg/day for 5 days (total 2 g/kg) 3, 2
PLEX should be chosen as first-line when 3, 1:
- Severe hyponatremia is present 3, 1
- High thromboembolic risk exists 3, 1
- Associated brain or spinal demyelination 3, 1
- Protocol: 5-10 sessions performed every other day 3, 2
Combination Therapy for Severe Presentations
For severe initial presentations, combine steroids plus IVIG or steroids plus PLEX from the beginning rather than sequential monotherapy. 3, 1 This aggressive upfront approach is critical because prompt treatment reduces long-term morbidity and mortality 4.
Treatment Escalation Algorithm
When to Escalate
Add IVIG or PLEX if no clinical, radiological, or electrophysiological improvement occurs after initial corticosteroid treatment. 3, 1 The typical timeframe for assessing response is 2-4 weeks before escalating to second-line agents 2.
Second-Line Immunotherapy
Rituximab is the preferred second-line agent for antibody-mediated autoimmune encephalitis, chosen by 80% of experts even in cases with unknown antibodies 2. This preference reflects rituximab's mechanism of B-cell depletion, which is appropriate for antibody-mediated pathology 2.
Cyclophosphamide should be considered for cell-mediated autoimmunity rather than antibody-mediated disease 1, 2. Both agents have demonstrated good results as rescue therapy 2.
The evidence supporting second-line agents comes from retrospective observations showing that approximately half or more patients require escalation beyond first-line therapy 5. While controlled trial data remain limited, accumulated clinical experience supports their use 6, 5.
Bridging and Maintenance Therapy
After acute treatment, initiate bridging therapy with one of the following 3:
This maintenance approach helps prevent relapses, which occur in a significant proportion of patients 7.
Special Populations and Contexts
Immune Checkpoint Inhibitor-Related Encephalitis
Permanently discontinue the checkpoint inhibitor immediately in cases of ICI-related autoimmune encephalitis 1, 2. High-dose intravenous corticosteroids with ICI discontinuation is the standard approach for higher-grade neurologic immune-related adverse events 4. Additional immunosuppressive therapy with IVIG, plasmapheresis, rituximab, or cyclosporine may be required for rapidly progressive or steroid-refractory cases 4.
Refractory Cases
A minority of patients remain refractory to both first- and second-line therapies 6, 5. For these challenging cases, emerging options include cytokine-based drugs (tocilizumab, interleukin-2/basiliximab), plasma cell-depleting agents (bortezomib, daratumumab), and treatments targeting intrathecal immune cells (intrathecal methotrexate, natalizumab) 6. However, evidence for these agents is limited to case reports and small series 6.
Critical Pitfalls to Avoid
Do not delay immunotherapy while waiting for antibody test results 1. Commercial antibody panels often have prolonged turnaround times and are inherently limited given the ever-growing number of identified antibodies and likelihood of T-cell mediated pathogenesis in some cases 4. Treatment decisions must be made based on clinical presentation, with long-term management modified according to antibody results if identified 4.
Do not fail to screen for underlying malignancy, as this may miss paraneoplastic causes 1. Cancer screening with contrast-enhanced CT of chest, abdomen, and pelvis should be performed in relevant cases 1.
Recognize that median time to onset of neurologic symptoms is approximately 6 weeks, with median time to resolution around 8 weeks 4. This timeline helps set realistic expectations for treatment response.
Supportive Care Essentials
Beyond immunotherapy, comprehensive supportive management is essential 1:
- Manage seizures with appropriate antiepileptic medications 1
- Monitor and treat blood pressure and heart rate fluctuations in dysautonomia; consider temporary pacemaker for severe dysrhythmia 1
- Implement fluid restriction for hyponatremia related to inappropriate antidiuretic hormone secretion 1
- Monitor intracranial pressure in cases with massive inflammation and brain edema 1