What is the initial treatment recommendation for a patient diagnosed with autoimmune encephalitis?

Initial Treatment for Autoimmune Encephalitis

Start high-dose intravenous methylprednisolone (1g daily for 3-5 days) immediately once infection is ruled out, as this is the most commonly used and recommended first-line therapy for autoimmune encephalitis. 1, 2

First-Line Treatment Algorithm

Standard Approach

• Intravenous methylprednisolone (IVMP) is the preferred initial therapy, chosen by 84% of specialists either alone (65%) or in combination with other agents (19%). 1
• Standard dosing is 1-2 mg/kg/day, with pulse dosing at 1g daily for 3-5 days recommended for severe presentations. 2
• Treatment should begin as soon as cerebrospinal fluid results rule out infection and primary CNS lymphoma or neurosarcoidosis are not considerations. 3

When to Use IVIG Instead of Steroids

IVIG (0.4 g/kg/day for 5 days, total 2 g/kg) is preferred over steroids when: 2, 3

• Patient is agitated or combative
• Bleeding disorders or coagulopathy present
• Difficulty with central line placement
• Contraindications to steroids exist (uncontrolled hypertension, uncontrolled diabetes, acute peptic ulcer, or severe behavioral symptoms that worsen with corticosteroids) 1

When to Use PLEX Instead of Steroids

Plasma exchange (5-10 sessions every other day) is preferred when: 2, 3

• Severe hyponatremia present
• High thromboembolic risk (known/suspected cancer, smoking, hypertension, diabetes, hyperlipidemia, hypercoagulable states) 1, 3
• Associated brain or spinal demyelination 3

Combination Therapy for Severe Cases

For severe initial presentations (NMDAR-IgG picture, NORSE, dysautonomia), consider combination therapy from the start: 1, 4

• Steroids plus IVIG, or
• Steroids plus PLEX

A 2025 study from the German Network for Autoimmune Encephalitis Research showed that both IVMP + IVIG and IVMP + PLEX produce significant improvements, though IVMP + PLEX showed slightly greater mRS reduction in anti-NMDAR encephalitis specifically. 5

Special Clinical Scenarios

Steroid-Responsive Conditions Requiring Immediate IVMP

These conditions should receive IVMP as first-line without delay: 1

• Faciobrachial dystonic seizures (suggestive of LGI1-antibody encephalitis)
• Autoimmune encephalitis in the setting of immune checkpoint inhibitors
• Central demyelination
• Autoimmune GFAP astrocytopathy

Immune Checkpoint Inhibitor-Related Encephalitis

Permanently discontinue the checkpoint inhibitor immediately and initiate methylprednisolone at pulse dose (1g/day). 4

• Consider adding IVIG or PLEX if no improvement or worsening after 3 days. 4

Bridging Therapy After Acute Treatment

After completing acute first-line therapy, initiate bridging therapy with: 3

• Gradual oral prednisone taper (most popular choice at 38%), or 6
• Monthly IVIG, or
• Monthly intravenous methylprednisolone

When to Escalate to Second-Line Therapy

Timing of Escalation

Add rituximab or cyclophosphamide if there is no meaningful clinical, radiological, or electrophysiological response after 2-4 weeks of optimized first-line therapy. 2, 4

Criteria for Treatment Failure

• Absence of clinical improvement after 2-4 weeks of high-dose corticosteroids, IVIG, or PLEX 4
• Failure to respond to more than one first-line agent (preferred by 50% of specialists) 4
• Progressive clinical deterioration despite adequate first-line therapy, especially with hemodynamic compromise or severe dysfunction 4

Choice of Second-Line Agent

Rituximab (375 mg/m² IV weekly for 4 doses or 1g on days 1 and 15) is preferred for: 4

• Antibody-mediated autoimmune encephalitis (chosen by 80% of specialists) 2, 4
• Anti-NMDAR, anti-LGI1, or anti-CASPR2 antibodies 4
• Unknown antibodies 4

Cyclophosphamide (0.5-1 g/m² every 3 weeks for 4-6 months) should be considered for: 4

• T-cell mediated autoimmunity 2, 4
• Classical paraneoplastic encephalitis 4

Critical Pitfalls to Avoid

• Do not wait for antibody test results to initiate immunotherapy—delayed treatment worsens outcomes. 4
• Do not underestimate the need for early escalation—32% of specialists add second-line agents after failure of only one first-line agent. 4
• Do not neglect oncological screening—perform CT chest/abdomen/pelvis with contrast, as failure to identify paraneoplastic causes compromises treatment. 1
• Avoid monotherapy with steroids in severe cases—combination therapy should be considered from the start. 4
• Do not discontinue first-line therapy prematurely—continue until patient shows improvement, as second-line agents have delayed onset of action. 7