What is the treatment for autoimmune encephalitis?

Treatment of Autoimmune Encephalitis

The treatment of autoimmune encephalitis should begin with first-line immunotherapy consisting of high-dose corticosteroids, intravenous immunoglobulin (IVIG), or plasma exchange (PLEX), followed by second-line agents such as rituximab or cyclophosphamide in refractory cases. 1

First-Line Treatment Options

Initial Approach

• Once infection is ruled out based on cerebrospinal fluid results and when primary CNS lymphoma or neurosarcoidosis is not a consideration, start acute immunotherapy immediately 1
• High-dose corticosteroids (intravenous methylprednisolone) are the most commonly used first-line therapy, selected by 84% of experts for general autoimmune encephalitis presentations 1
• Standard dosing for methylprednisolone is 1-2 mg/kg/day, with consideration of pulse dosing at 1g daily for 3-5 days in severe cases 1
• If corticosteroids are contraindicated or ineffective, proceed with IVIG or PLEX 2

IVIG vs. PLEX Selection

• IVIG is preferred for patients who are agitated or combative, have bleeding disorders, or have difficulty with central line placement 2, 1
• IVIG is typically administered at 0.4 g/kg/day for 5 days (total dose 2 g/kg) 2
• PLEX is preferred for patients with severe hyponatremia, high thromboembolic risk, or associated brain/spinal demyelination 2, 1
• PLEX typically involves 5-10 sessions performed every other day 2, 1
• A small retrospective study showed better outcomes in NMDAR-antibody encephalitis when both corticosteroids and PLEX were used compared to corticosteroids alone 1

Combination First-Line Therapy

• For severe initial presentations (e.g., NMDAR-antibody encephalitis, new-onset refractory status epilepticus, severe dysautonomia), consider combination therapy with steroids plus IVIG or steroids plus PLEX from the beginning 1, 2
• In the AEACN survey, combination therapy was selected by 28% of responders for NMDAR-antibody encephalitis and 19% for unspecified autoimmune encephalitis 1
• More commonly, combination therapy is done sequentially if there is no meaningful response to the initial agent 1

Second-Line Treatment

When to Escalate Therapy

• If there is no meaningful clinical or radiological response to optimized first-line therapy after 2-4 weeks, add a second-line agent 1
• In a survey of experts, 32% indicated adding a second-line agent if there was no response to one first-line agent, while 50% would add a second-line agent only after failure of more than one first-line agent 1
• Early treatment and escalation to second-line therapy in refractory cases improves outcomes 3

Second-Line Agent Selection

• Rituximab is the preferred second-line agent for antibody-mediated autoimmune encephalitis (e.g., NMDAR-antibody encephalitis), chosen by 80% of experts in cases with unknown antibodies 1
• Cyclophosphamide should be considered for cell-mediated autoimmunity (e.g., classical paraneoplastic syndromes) 1
• Both rituximab and cyclophosphamide have shown good results as second-line agents for rescue therapy in autoimmune encephalitis 1
• Rituximab is generally less toxic than cyclophosphamide and therefore preferred by most clinicians, although it may not be as effective for cell-mediated inflammation 1

Refractory Cases and Third-Line Options

• If no clear objective or subjective evidence of improvement with conventional second-line therapies, consider novel approaches 1, 4
• Potential third-line options include:
  • Tocilizumab (IL-6 inhibitor) 1, 4, 3
  • Bortezomib (proteasome inhibitor) 1, 4, 3
  • Interleukin-2/basiliximab 4
  • Anakinra 4
  • Tofacitinib 4
  • Intrathecal methotrexate 4, 5
  • Natalizumab 4
• Evidence for these agents is mostly based on case reports or small case series 4, 5

Bridging and Maintenance Therapy

• After acute treatment, start bridging therapy with one of the following 1:
  • Gradual oral prednisone taper
  • Monthly IVIG
  • Monthly intravenous methylprednisolone
• Early aggressive treatment is associated with better functional outcomes and fewer relapses 6, 7

Special Considerations

• For immune checkpoint inhibitor-related autoimmune encephalitis, permanently discontinue the checkpoint inhibitor 1
• For encephalitis with positive autoimmune encephalopathy or paraneoplastic antibody and limited improvement, consider rituximab or plasmapheresis in consultation with neurology 1
• When present, associated tumors should be removed as part of the treatment approach 7
• Patients given immune therapy do better and relapse less than patients given no treatment 7

Treatment Algorithm

1. Rule out infection and other etiologies
2. Start first-line therapy:
   • High-dose corticosteroids (IV methylprednisolone 1-2 mg/kg/day or pulse 1g daily for 3-5 days)
   • If contraindicated or ineffective, use IVIG (2 g/kg over 5 days) or PLEX (5-10 sessions)
   • For severe presentations, consider combination therapy
3. If no improvement after 2-4 weeks of optimized first-line therapy:
   • Add rituximab for antibody-mediated disease
   • Add cyclophosphamide for cell-mediated disease
4. For refractory cases, consider third-line options like tocilizumab or bortezomib
5. Implement bridging therapy with oral prednisone taper, monthly IVIG, or monthly IV methylprednisolone 1