What are the diagnostic approaches and treatment options for autoimmune encephalitis?

Diagnostic Approach and Treatment of Autoimmune Encephalitis

A comprehensive diagnostic workup including brain MRI, CSF analysis, EEG, and autoantibody testing is essential for diagnosing autoimmune encephalitis, followed by prompt immunotherapy with corticosteroids as first-line treatment to reduce morbidity and mortality. 1

Clinical Presentation

Autoimmune encephalitis (AE) presents with various neurological and psychiatric manifestations depending on the anatomical regions involved:

• Limbic encephalitis: Memory deficits, confusion, seizures
• Cortical/subcortical encephalitis: Cognitive impairment, seizures, focal neurological deficits
• Striatal encephalitis: Movement disorders, psychiatric symptoms
• Diencephalic encephalitis: Sleep disturbances, autonomic dysfunction
• Brainstem encephalitis: Cranial nerve abnormalities, ataxia
• Cerebellar encephalitis: Ataxia, dysarthria
• Meningoencephalitis: Headache, fever, altered mental status
• Encephalomyelitis: Combined brain and spinal cord symptoms 1

Diagnostic Algorithm

Step 1: Confirm Brain Pathology Suggestive of AE

1. Brain MRI with and without contrast

   • Look for bilateral limbic encephalitis (sufficient for definite AE diagnosis when CSF viral studies are negative)
   • Other patterns: cortical/subcortical, striatal, diencephalic, brainstem abnormalities 1, 2

2. EEG

   • Perform if MRI is negative or patient has encephalopathy/seizures
   • Look for focal slowing, lateralized periodic discharges, extreme delta brush (in NMDAR encephalitis)
   • Rule out subclinical status epilepticus 1, 2

3. Brain FDG-PET

   • Consider when MRI is negative but clinical suspicion remains high
   • More sensitive than MRI in some cases
   • Common patterns: bilateral temporal hypermetabolism or bilateral occipito-parietal hypometabolism 1, 2

Step 2: Confirm Inflammatory Etiology and Rule Out Alternatives

1. Lumbar Puncture and CSF Analysis

   • Cell count and differential
   • Protein, glucose, CSF/serum glucose ratio
   • IgG index, IgG synthesis rate, oligoclonal bands
   • Neuronal autoantibodies panel (test before immunotherapy)
   • Rule out infectious causes (viral PCR, bacterial cultures) 1, 2

2. Blood Tests

   • Neuronal autoantibody panel (collect before IVIg or PLEX)
   • Antithyroid antibodies
   • Inflammatory markers
   • Antinuclear antibodies
   • Immunoglobulins 1, 2

3. Brain Biopsy

   • Consider if diagnosis remains uncertain after initial testing 1

Step 3: Screen for Associated Neoplasm

1. CT chest, abdomen, and pelvis with contrast (or MRI if CT contraindicated)
2. Mammogram/breast MRI in relevant cases
3. Pelvic or testicular ultrasound in relevant cases
4. Whole body FDG-PET if initial screen negative 1

Treatment Algorithm

First-Line Therapy

1. High-dose corticosteroids (IV methylprednisolone)

   • Start once infection is ruled out
   • Relative contraindications: uncontrolled hypertension, diabetes, acute peptic ulcer, severe behavioral symptoms that worsen with steroids 1

2. Intravenous Immunoglobulin (IVIG)

   • Consider if steroids are contraindicated or ineffective
   • Preferred in agitated patients and those with bleeding disorders 1

3. Plasma Exchange (PLEX)

   • 5-10 sessions every other day
   • Consider first in patients with severe hyponatremia, high thromboembolic risk, or associated demyelination
   • Less suitable for agitated patients 1

4. Combined First-Line Therapies

   • Consider in severe presentations (e.g., NMDAR-antibody encephalitis, new-onset refractory status epilepticus, severe dysautonomia) 1

Second-Line Therapy

1. Rituximab

   • Consider in known or suspected antibody-mediated autoimmunity (e.g., NMDAR-antibody encephalitis)
   • If no improvement 2-4 weeks after combined first-line therapy 1

2. Cyclophosphamide

   • Consider in known or suspected cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome) 1

3. Experimental Therapies

   • Consider tocilizumab or bortezomib if no improvement with conventional second-line therapies 1

Maintenance Therapy

• Gradual oral prednisone taper or
• Monthly IVIG or
• Monthly IV methylprednisolone 1

Common Pitfalls and Caveats

1. Delayed Diagnosis

   • Don't wait for antibody results to start treatment if clinical suspicion is high
   • Initiate immunotherapy promptly after ruling out infection 1

2. Misdiagnosis

   • Consider differential diagnoses including infectious encephalitis, metabolic encephalopathy, and primary psychiatric disorders
   • Use Table 3 in the guidelines for specific differential diagnoses by anatomical syndrome 1

3. Inadequate Cancer Screening

   • Thorough cancer screening is essential, especially for paraneoplastic syndromes
   • Consider additional testing if initial screen is negative 1

4. Antibody Testing Interpretation

   • Some antibodies are more sensitive in serum, others in CSF
   • GAD65 antibodies are clinically relevant at high titers but usually irrelevant at low titers 2
   • Collect samples before immunotherapy to avoid false results 2

5. Treatment Response Assessment

   • Monitor clinical, radiological, and electrophysiological improvement
   • Consider escalating therapy if no improvement after initial treatment 1

By following this structured approach to diagnosis and treatment, clinicians can improve outcomes for patients with autoimmune encephalitis through early recognition and appropriate management.