What is the diagnostic approach for a patient suspected of having autoimmune encephalitis?

Diagnostic Approach to Autoimmune Encephalitis

The diagnosis of autoimmune encephalitis requires a systematic three-step approach: (1) confirm focal or multifocal brain pathology, (2) establish inflammatory etiology while excluding competing diagnoses, and (3) screen for associated malignancy. 1

Step 1: Confirm Focal or Multifocal Brain Pathology

Brain MRI with or without contrast is the initial imaging modality of choice to evaluate for characteristic patterns including hippocampal, striatal, or other regional abnormalities. 1, 2

• EEG should be performed if MRI is negative, if the patient is encephalopathic, or if frequent seizures are occurring. 1 EEG serves dual purposes: confirming focal/multifocal brain abnormality when MRI is unrevealing, and excluding subclinical status epilepticus. 1

• Brain FDG-PET is reserved for cases where MRI is negative but clinical suspicion remains high, or when MRI is contraindicated. 1 Case series demonstrate that FDG-PET can be more sensitive than MRI in detecting focal abnormalities. 1

Key EEG Findings

• Focal slowing or seizures, lateralized periodic discharges, and extreme delta brush (particularly in NMDAR-antibody encephalitis) suggest autoimmune encephalitis. 1
• A normal EEG does not exclude autoimmune encephalitis, especially in LGI1-antibody encephalitis where patients may have classical faciobrachial dystonic seizures despite normal EEG. 1

Step 2: Confirm Inflammatory Etiology and Exclude Competing Diagnoses

Lumbar puncture is essential and should include comprehensive CSF analysis: cell count with differential, protein, glucose, IgG index, oligoclonal bands, and neuronal autoantibodies. 1, 2 Do not delay antibody testing even if CSF cell counts are normal, as autoimmune encephalitis can present with normal routine CSF studies. 2

Critical Testing Strategy

Both serum and CSF neuronal autoantibodies must be tested simultaneously because sensitivity varies by antibody type. 2 The panel should include anti-NMDAR, anti-VGKC, anti-LGI1, anti-CASPR2, anti-GABABR, and anti-AMPAR antibodies. 2

• Collect blood samples before administering any immunotherapy (IVIG or plasmapheresis) to avoid false positive or false negative results. 2

• Commercial assays have significant limitations: false negatives occur in approximately 9% of serum samples and 29% of CSF samples, particularly for GABABR (39% false negative rate), LGI1 (17%), and AMPAR (11%) antibodies. 3 If clinical suspicion is high and commercial testing is negative, request more comprehensive antibody studies. 3

Essential Exclusionary Blood Tests

The following tests should be ordered to rule out competing etiologies 2:

• Infectious workup: PCR for HSV1/2 and VZV (strength of evidence A), treponemal antibodies
• Autoimmune panel: ANA, ENA antibodies, antiphospholipid antibodies, lupus anticoagulant
• Metabolic/nutritional: Comprehensive metabolic panel, vitamin B1 (thiamine), ammonia, hormonal panels when indicated
• Toxicology screen
• Sodium level (hyponatremia is common with LGI1-antibody encephalitis) 2

Tailor additional blood tests based on MRI anatomical patterns, though comprehensive testing is warranted even with negative MRI. 2

Step 3: Screen for Associated Neoplasm

Cancer screening should begin with CT chest, abdomen, and pelvis with contrast. 1 If initial screening is negative, proceed systematically:

• Mammogram or breast MRI
• Pelvic or testicular ultrasound
• Whole body FDG-PET if initial screening remains negative 1

A targeted screening approach may be implemented when clinical presentation strongly suggests a specific neoplasm (e.g., starting with pelvic ultrasound if anti-NMDAR encephalitis is suspected). 1

Diagnostic Algorithm Application

The Graus criteria provide a framework for categorizing likelihood (possible, probable, definite autoimmune encephalitis), but sensitivity is time-dependent and specificity relies heavily on microbiological test results. 4 In the acute setting within the first week of presentation, sensitivity is only 58% with very low specificity (8%) for possible autoimmune encephalitis. 4

Clinical Discriminators

Key clinical features that differentiate autoimmune from infectious encephalitis include 4:

• Headache and fever are more common in infectious encephalitis
• Epileptic seizures are more common in autoimmune encephalitis
• CSF cell count tends to be lower in autoimmune encephalitis

Common Diagnostic Pitfalls

• Anti-CASPR2 and anti-LGI1-associated autoimmune encephalitis can mimic infectious presentations. 4
• Do not rely solely on commercial assays, as false negatives are frequent, especially in CSF samples. 2, 3
• Do not skip serum testing even when CSF is available, as some antibodies are better detected in serum. 2
• Do not delay immunotherapy while awaiting antibody results if autoimmune etiology is considered likely, even if diagnostic criteria are not yet fulfilled. 4, 5

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. 1