Diagnostic Work-Up and Initial Treatment for Suspected Autoimmune Encephalitis
Begin acute immunotherapy immediately with high-dose intravenous methylprednisolone once basic CSF results exclude infection, without waiting for antibody results, as early treatment significantly improves outcomes. 1
When to Suspect Autoimmune Encephalitis
Suspect autoimmune encephalitis when patients present with acute or subacute onset (less than 3 months) of neuropsychiatric symptoms with a polysyndromic presentation—this multifocal pattern is the clinical hallmark distinguishing it from other conditions. 2, 1 Key red flags include:
- Temporal pattern: Rapid progression over days to weeks, not hyperacute (which suggests stroke) or chronic (which suggests neurodegeneration). 2
- Polysyndromic features: Combination of altered mental status, seizures, psychiatric symptoms, movement disorders, and autonomic instability. 2
- High-risk populations: Known cancer, smokers, elderly with weight loss (paraneoplastic risk), or personal/family history of autoimmune disorders. 2, 1
- Preceding triggers: Viral prodrome, recent HSV encephalitis, or exposure to immune checkpoint inhibitors. 2
Diagnostic Algorithm: Three-Step Approach
The diagnosis follows a systematic three-step process: (1) confirm focal or multifocal brain pathology, (2) establish inflammatory etiology while excluding competing diagnoses, and (3) screen for associated malignancy. 3, 1
Step 1: Confirm Brain Pathology
Brain MRI with and without contrast is the initial imaging modality of choice. 3, 1 Look for:
- Bilateral hippocampal T2/FLAIR hyperintensities (limbic encephalitis pattern)
- Striatal abnormalities
- Cortical/subcortical changes
- Radial perivascular enhancement (GFAP astrocytopathy)
- Punctate brainstem/cerebellar enhancement (CLIPPERS) 2
If MRI is negative but clinical suspicion remains high, proceed with:
- EEG: Essential to exclude subclinical status epilepticus and identify focal abnormalities. Look for focal slowing/seizures, lateralized periodic discharges, or extreme delta brush (characteristic of NMDAR-antibody encephalitis). 2, 3 Note that a normal EEG does not exclude autoimmune encephalitis, particularly in LGI1-antibody encephalitis where patients may have faciobrachial dystonic seizures despite normal EEG. 2, 3
- Brain FDG-PET: More sensitive than MRI in case series; use when MRI is negative or contraindicated. 2, 3
Step 2: Establish Inflammatory Etiology
Lumbar puncture is essential and should be performed urgently. 3, 1 Comprehensive CSF analysis must include:
- Cell count with differential
- Protein, glucose
- IgG index and oligoclonal bands
- IgG synthesis rate
- Viral PCR panel: HSV1/2, VZV, HHV6 (to exclude infectious causes) 2, 3
- Neuronal autoantibodies in CSF 3, 1
Critical timing: Collect blood samples for antibody testing before administering any immunotherapy, IVIG, or plasmapheresis to avoid false results. 3
Serum testing should include:
- Neuronal autoantibody panel: Anti-NMDAR, anti-VGKC, anti-LGI1, anti-CASPR2, anti-GAD65, anti-DPPX 3, 1
- Exclusionary tests: ANA, ENA, antiphospholipid antibodies, lupus anticoagulant 3
- Metabolic/nutritional: Thiamine, ammonia, comprehensive metabolic panel, sodium (hyponatremia common in LGI1-antibody encephalitis) 3
- Infectious: Treponemal antibodies 3
- Toxicology screen 3
Test both serum and CSF because sensitivity varies by antibody type—some antibodies are better detected in serum while others require CSF. 3 Do not skip serum testing even when CSF is available. 3 Do not delay antibody testing if CSF shows normal cell counts, as autoimmune encephalitis can present with normal routine CSF studies. 3
Important caveat: Commercial assays have frequent false negatives, especially in CSF samples. 3 If clinical suspicion remains high despite negative commercial testing, consider sending samples to reference neuroimmunology laboratories.
Step 3: Screen for Associated Malignancy
Cancer screening is essential as autoimmune encephalitis may be paraneoplastic. 3, 1
Initial screening:
- CT chest, abdomen, pelvis with contrast 3
If initial screening is negative:
- Whole body FDG-PET 3
Targeted approach: When clinical presentation strongly suggests specific antibody-tumor associations (e.g., anti-NMDAR encephalitis in young women suggests ovarian teratoma), begin with targeted imaging such as pelvic ultrasound. 3
Initial Treatment
Start acute immunotherapy immediately once infection is ruled out based on basic CSF results—do not wait for antibody results or complete workup. 1 Early treatment is associated with significant improvement in outcomes, with confusion and seizures often improving rapidly. 3, 1
First-Line Treatment
High-dose intravenous methylprednisolone is the first-line treatment (0.5 mg/kg/day prednisone equivalent), followed by short or long oral taper. 3, 1
Alternative first-line options (if steroids contraindicated):
- IVIG: 0.4 g/kg/day for 5 days 3
- Plasma exchange (PLEX): Consider as alternative or in addition to IVIG in non-responders 3, 1
Treatment Monitoring
- Regular monitoring of antibody levels in serum to evaluate treatment efficacy 3, 1
- Periodic neurological evaluation to monitor symptom improvement 3, 1
- Repeat brain MRI after 3-6 months of treatment 3
Expected recovery timeline: Confusion and seizures improve rapidly with immunosuppression, while memory recovery may take months or years. 3
When to Consider Brain Biopsy
Brain biopsy should be considered only if the diagnosis remains uncertain after completing the above workup, particularly when primary CNS lymphoma or neurosarcoidosis cannot be excluded. 3 This is a last resort after exhausting non-invasive diagnostic measures.
Differential Diagnosis by Anatomical Pattern
Tailor additional testing based on MRI anatomical patterns, though comprehensive testing is warranted even with negative MRI. 3 Key differentials include: