What are the causes and treatment options for autoimmune encephalitis?

Causes of Autoimmune Encephalitis

Autoimmune encephalitis is primarily caused by immune-mediated inflammation triggered by viral infections, malignancies, immune checkpoint inhibitors, and idiopathic mechanisms that lead to antibody production against neuronal antigens. 1

Etiological Classification

1. Idiopathic Causes

• Spontaneous autoimmune reactions without identifiable triggers
• More common in patients with personal or family history of other autoimmune disorders 1
• Often results in a monophasic disease course 1

2. Paraneoplastic Causes

• Associated with underlying malignancies:
  • Small cell lung cancer
  • Thymoma
  • Gynecological malignancies
  • Breast cancer
  • Seminoma 2
  • Ovarian teratomas (especially in anti-NMDAR encephalitis) 1
• Risk factors include:
  • Advanced age
  • Smoking history
  • Unintentional weight loss 1
• Often presents with a progressive course that plateaus after cancer treatment 1

3. Post-infectious Triggers

• Herpes simplex virus (HSV) encephalitis is a well-established trigger 1
  • Up to 24.5% of HSV encephalitis patients develop NMDAR antibodies within 3 months 1
• Other viral infections associated with autoimmune encephalitis:
  • Varicella zoster virus
  • Epstein-Barr virus
  • Influenza A virus 1
• Typically presents with viral-like prodrome or fever before neurological symptoms 1

4. Iatrogenic/Medication-Induced

• Immune checkpoint inhibitors (ICIs) used in cancer treatment
  • Can cause accelerated paraneoplastic encephalitis in advanced cancer patients 1, 2
  • Expands the range of affected patients to include those with melanoma and renal cell carcinoma 2
• TNFα inhibitors 1
• Symptoms typically appear within 3 months of treatment initiation 2

Serological Classification

1. Antibodies to Intracellular Antigens

• Classical onconeuronal antibodies
• Strongly associated with underlying malignancies 1

2. Antibodies to Surface Antigens (High Clinical Relevance)

• NMDAR (N-methyl-D-aspartate receptor) - most common cause of autoimmune encephalitis in patients <30 years 1
• AMPAR
• LGI1
• CASPR2
• GABAR A/B
• DPPX
• Glycine receptor
• AQP4
• MOG
• GFAP 1

3. Antibodies to Surface Antigens (Low Clinical Relevance)

• VGKC
• VGCC 1

Clinical Presentation Patterns

Autoimmune encephalitis typically presents with:

• Acute or subacute onset (duration <3 months) 1
• Polysyndromic presentation (clinical hallmark) 1
• Multifocal brain inflammation with possible involvement of meninges, spinal cord, and peripheral nervous system 1

Chronic presentations are primarily seen in:

• LGI1-antibody encephalitis
• CASPR2-antibody encephalitis
• DPPX-antibody encephalitis
• GAD65-antibody encephalitis 1

Diagnostic Approach

1. Brain MRI with contrast

   • Look for bilateral limbic encephalitis (sufficient for definite AE diagnosis with negative CSF viral studies) 1, 3
   • Other patterns: cortical/subcortical, striatal, diencephalic, brainstem changes 1
   • May be normal in up to 20% of cases 3

2. CSF Analysis

   • Collect 8-15 mL total CSF in 3-4 sequential tubes 3
   • Test for cell count, protein, glucose, and neural autoantibody panel 3

3. Antibody Testing

   • Test both serum and CSF (70-80% detection rate) 3
   • Some antibodies more sensitive in CSF (NMDAR, GFAP)
   • Others more sensitive in serum (onconeuronal, LGI1, AQP4) 3

4. Additional Testing

   • FDG-PET scan when other tests inconclusive 3
   • Screen for associated neoplasms 3
   • Exclude other etiologies with serum studies 3

Treatment Approach

1. First-line Immunotherapy

   • IV corticosteroids (70-80% response rate)
   • IVIG (60-70% response rate)
   • Plasma exchange (50-60% response rate) 3
   • Can be combined in severe cases 4

2. Second-line Agents (for unresponsive cases)

   • Rituximab
   • Cyclophosphamide 4

3. Refractory Cases

   • Cytokine-based drugs (tocilizumab, interleukin-2/basiliximab, anakinra, tofacitinib)
   • Plasma cell-depleting agents (bortezomib, daratumumab)
   • Treatments targeting intrathecal immune cells (intrathecal methotrexate, natalizumab) 4

Important Clinical Considerations

• Relapses are rare in autoimmune encephalitis (unlike MS) and often result from insufficient treatment or rapid immunotherapy interruption 1
• Autoimmune encephalitis should be considered in patients with viral encephalitis who show slow response to antivirals or develop recrudescent symptoms 1
• Early immunotherapy is critical for favorable outcomes - don't delay while waiting for antibody results 3
• Anti-NMDAR encephalitis is now recognized as the most common cause of encephalitis in patients <30 years of age 1