How should autoimmune encephalitis be diagnosed and managed, including first‑line and second‑line therapies?

Autoimmune Encephalitis: Diagnosis and Management

Diagnostic Approach

Start immunotherapy with high-dose intravenous methylprednisolone (IVMP) immediately once infection is ruled out by basic CSF analysis, without waiting for antibody results. 1

Essential Diagnostic Workup

Perform these investigations in parallel while initiating treatment:

• Brain MRI and/or EEG to identify focal or multifocal abnormalities 1
• Lumbar puncture to confirm inflammatory etiology and exclude infection/malignancy. Test for:
  • Oligoclonal bands
  • IgG index and synthesis rate
  • Neuronal autoantibodies in CSF 1
• Serum testing for neuronal autoantibodies and alternative causes 1
• Brain FDG-PET when clinical suspicion is high but other studies are uninformative 1
• Cancer screening with CT chest/abdomen/pelvis with contrast. If negative, add mammogram/breast MRI, pelvic ultrasound, or whole-body FDG-PET based on antibody type and risk factors 1

First-Line Treatment Algorithm

Standard Cases

Begin with IVMP followed by oral taper unless contraindications exist 1. Relative contraindications include uncontrolled hypertension, uncontrolled diabetes, acute peptic ulcer, or severe behavioral symptoms worsening with steroids 1.

If steroids are contraindicated: Use IVIG or plasma exchange (PLEX) as initial therapy 1.

Choosing Between IVIG and PLEX When Adding to Steroids

Use IVIG first in:

• Agitated patients
• Bleeding disorders 1

Use PLEX first (5-10 sessions every other day) in:

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

Severe Presentations

Start combination therapy (steroids + IVIG or steroids + PLEX) immediately from the beginning in patients with:

• Severe NMDAR-antibody presentation
• New-onset refractory status epilepticus (NORSE)
• Severe dysautonomia 1

This approach is recommended despite limited high-quality evidence, as 28% of expert clinicians favor this strategy for severe NMDAR encephalitis 1.

Second-Line Treatment

If no clinical, radiological, or electrophysiological improvement occurs by the end of first-line treatment, add IVIG or PLEX to the regimen 1. If already using combination first-line therapy, proceed to second-line agents.

When to Initiate Second-Line Agents

Start second-line therapy 2-4 weeks after completion of combined acute therapy if no meaningful improvement occurs 1.

Choosing Second-Line Agents

Use rituximab for antibody-mediated autoimmunity (e.g., NMDAR-antibody encephalitis, surface antigen antibodies) 1. This is preferred by 80% of expert clinicians for unknown antibody scenarios 1.

Use cyclophosphamide for cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome with antibodies against intracellular antigens) 1.

Rationale: Rituximab is less toxic than cyclophosphamide and preferentially used, though it primarily targets B-cells. However, it indirectly suppresses T-cell activity by reducing B-cell drive to T-cells 1.

Refractory Cases

For patients failing conventional second-line therapies, consider experimental approaches:

• IL-6 inhibitors (tocilizumab) 1, 2, 3
• Bortezomib (plasma cell-depleting agent) 1, 2, 3

These have minimal supporting evidence but represent options when standard therapies fail 1.

Bridging/Maintenance Therapy

After acute treatment, initiate bridging therapy with:

• Gradual oral prednisone taper, OR
• Monthly intravenous immunoglobulin, OR
• Monthly intravenous methylprednisolone 1

This prevents relapses, particularly in NMDAR-antibody encephalitis where untreated patients have higher relapse risk 4.

Critical Pitfalls to Avoid

1. Do not delay treatment waiting for antibody results - commercial panels often take weeks and may be negative despite true AE 1
2. Do not use PLEX in agitated patients - it's less suitable due to need for cooperation and line placement 1
3. Do not overlook tumor screening - perform comprehensive cancer workup as many AE cases are paraneoplastic 1
4. Do not use sequential therapy in severe presentations - start combination first-line therapy immediately 1
5. Do not stop immunotherapy abruptly - wean carefully with serial antibody level monitoring to prevent relapses 4

Special Considerations

Steroid-responsive conditions requiring immediate IVMP:

• Faciobrachial dystonic seizures (LGI1-antibody encephalitis)
• AE with immune checkpoint inhibitors
• Autoimmune GFAP astrocytopathy
• Steroid-responsive encephalopathy with autoimmune thyroiditis 1

These conditions should receive steroids preferentially over other first-line options 1.