What biomarkers are used in the diagnosis and management of autoimmune antibody negative encephalitis in patients with no detected common autoimmune antibodies?

Biomarkers in Autoimmune Antibody-Negative Encephalitis

In antibody-negative autoimmune encephalitis, the key biomarkers are CSF inflammatory markers (elevated IgG index and oligoclonal bands), characteristic MRI patterns showing focal/multifocal brain abnormalities, and EEG findings demonstrating focal or multifocal dysfunction—all used to confirm inflammatory etiology when neuronal autoantibodies are absent. 1

CSF Inflammatory Biomarkers

CSF analysis remains the cornerstone for diagnosing antibody-negative cases, even when neuronal autoantibodies are not detected. 1

• IgG index elevation serves as a critical biomarker indicating intrathecal antibody synthesis 1
• Oligoclonal bands in CSF (absent in serum) demonstrate CNS-specific immune activation 1
• IgG synthesis rate provides quantitative assessment of intrathecal inflammation 1
• CSF pleocytosis (elevated white blood cell count) supports inflammatory etiology, though notably routine CSF studies may be normal in some AE patients and this does not exclude the diagnosis 1

Critical caveat: The American Academy of Neurology explicitly recommends against delaying diagnosis if CSF shows normal cell counts, as autoimmune encephalitis can present with normal routine CSF studies. 2

Neuroimaging Biomarkers

MRI patterns serve as powerful diagnostic biomarkers when antibodies are absent. 1

• Bilateral limbic encephalitis on MRI is the only imaging finding sufficient to diagnose definite AE in the correct clinical setting (e.g., negative CSF viral studies) even without detectable antibodies 1
• Radial perivascular enhancement suggests autoimmune GFAP astrocytopathy 1
• Cortical/subcortical, striatal, diencephalic, brainstem, or meningoencephalitis patterns support possible or probable AE diagnosis 1
• Diffuse or patchy contrast enhancement suggestive of inflammation may be present, though intense enhancement is unlikely 1

FDG-PET Metabolic Biomarkers

When MRI is negative but clinical suspicion remains high, FDG-PET provides metabolic biomarkers. 1

• Bilateral temporal hypermetabolism indicates seropositive or seronegative limbic encephalitis 1
• Bilateral occipito-parietal hypometabolism suggests NMDAR-antibody encephalitis pattern (even when antibodies are negative) 1
• FDG-PET may reveal brain abnormalities at an earlier stage than MRI 1

Important limitation: Immunosuppressants, anesthetics, antiseizure medications, and seizures themselves can alter cortical metabolism, reducing specificity. 1

Electrophysiological Biomarkers

EEG provides functional evidence of brain involvement when other tests are equivocal. 1

• Focal or multifocal slowing confirms brain abnormality when MRI is negative 1
• Subclinical status epilepticus detection in encephalopathic patients 1
• Epileptiform activity supports diagnosis, particularly in new onset refractory status epilepticus (NORSE) 1

Exclusionary Biomarkers

Testing to rule out mimics is essential before confirming antibody-negative AE. 2

• Viral PCR (HSV1/2, VZV) must be negative to exclude infectious causes 2
• Sodium levels should be monitored (hyponatremia common in LGI-1 encephalitis, though this typically has positive antibodies) 2
• Antinuclear antibodies, extractable nuclear antigens, antiphospholipid antibodies exclude other autoimmune conditions 2
• Metabolic panel, ammonia, vitamin B1/B12, thyroid antibodies rule out metabolic/nutritional causes 1, 2

Diagnostic Algorithm for Antibody-Negative Cases

Step 1: Confirm focal/multifocal brain pathology with MRI (with/without contrast), then EEG if MRI negative, then brain PET if diagnosis uncertain. 1

Step 2: Perform lumbar puncture testing CSF for inflammatory markers (IgG index, oligoclonal bands), cell count, protein, glucose, and comprehensive viral exclusion. 1

Step 3: Send blood exclusionary tests guided by MRI pattern, but comprehensive testing warranted even with negative MRI. 2

Step 4: If diagnosis remains uncertain after comprehensive antibody testing (both serum and CSF using cell-based AND tissue-based assays), consider brain biopsy. 1, 3

Critical Testing Considerations

Comprehensive antibody testing is mandatory before labeling a case as antibody-negative. 3

• A 2023 study found that of 33 patients initially classified as possible antibody-negative AE, 5 (15%) were found to have antibodies when comprehensive testing (combining cell-based and tissue-based assays) was performed 3
• Commercial assays alone have frequent false negatives, especially in CSF samples 2
• Both serum and CSF should be tested, as sensitivity varies by antibody type 2

True antibody-negative AE is rare: Only 1.5% of 2,250 patients tested met criteria for possible antibody-negative AE, and after comprehensive testing and strict application of diagnostic criteria, only 10 patients had probable/definite antibody-negative AE/LE/ADEM. 3

Prognostic Biomarkers

Once diagnosed, certain biomarkers predict treatment response. 3

• In the antibody-negative cohort, 50% of patients improved with immunotherapy, 10% stabilized, 10% worsened, and 30% died (all deaths related to encephalitis) 3
• Early immunosuppressive treatment correlates with improved outcomes 2
• Serial inflammatory marker measurements may help monitor treatment response 4