Diagnostic Criteria and Treatment Options for Seronegative Autoimmune Encephalitis
Seronegative autoimmune encephalitis requires a clinical diagnosis based on specific criteria when no identifiable antibodies are present, and early immunotherapy is essential for improved outcomes despite negative antibody testing.
Diagnostic Criteria
Major Criterion (Required)
- Altered mental status (decreased consciousness, lethargy, or personality change) lasting ≥24 hours with no alternative cause identified 1
Minor Criteria (≥3 required for probable/confirmed seronegative autoimmune encephalitis)
- Documented fever ≥38°C within 72 hours before or after presentation 1
- New onset seizures not attributable to preexisting seizure disorder 1
- New focal neurological findings 1
- CSF white blood cell count ≥5/cubic mm 1
- Brain MRI abnormalities suggestive of encephalitis 1
- EEG abnormalities consistent with encephalitis and not attributable to another cause 1
Additional Supportive Features
- Polysyndromic presentation (a clinical hallmark of autoimmune encephalitis) 1
- Preceding viral infection, fever, or viral-like prodrome 1
- Personal or family history of autoimmune disorders 1
- Rapid onset with progression over days to weeks 1
- Exclusion of infectious, toxic, metabolic, and neoplastic causes 1
Diagnostic Algorithm
Step 1: Confirm focal or multifocal brain pathology
- Brain MRI with and without contrast (may be normal in early stages) 1
- EEG if MRI is negative or if patient is encephalopathic/having seizures 1
- Brain FDG-PET if MRI is negative and diagnosis remains uncertain (can be more sensitive than MRI) 1
Step 2: Confirm inflammatory etiology
- Lumbar puncture with CSF analysis including:
- Serum autoantibody testing (despite expected negative results) 1
- Brain biopsy if diagnosis remains uncertain after initial testing 1
Step 3: Screen for associated neoplasm
- CT chest, abdomen, and pelvis 1
- Mammogram/breast MRI in women 1
- Pelvic or testicular ultrasound 1
- Body PET if initial screen negative 1
Treatment Approach
First-Line Immunotherapy
- High-dose corticosteroids (methylprednisolone 1g/day for 3-5 days) 2, 3
- Intravenous immunoglobulin (IVIG) (2g/kg divided over 2-5 days) 2, 3
- Plasma exchange (5-7 exchanges over 10-14 days) if poor response to steroids/IVIG 2, 4
Second-Line Immunotherapy (if inadequate response to first-line)
- Rituximab (anti-CD20 monoclonal antibody) 2, 4
- Cyclophosphamide 2
- Tocilizumab (IL-6 receptor antagonist) for refractory cases 2
Treatment Duration and Monitoring
- Continue immunotherapy for at least 6 months in patients with persistent disease 2
- Monitor response using modified Rankin Scale and Clinical Assessment Scales in Autoimmune Encephalitis 2
- Consider maintenance immunotherapy in patients with relapsing disease 2
Prognostic Factors (RAPID Score)
The following factors are associated with poorer 2-year outcomes in seronegative autoimmune encephalitis 2:
- Refractory status epilepticus 2
- Age of onset ≥60 years 2
- Probable autoimmune encephalitis subtype (vs. limbic encephalitis or ADEM) 2
- Infratentorial involvement 2
- Delay of immunotherapy ≥1 month 2
Important Considerations and Pitfalls
- Don't delay treatment: Initiate immunotherapy when there is strong clinical suspicion, even without antibody confirmation 3, 4
- Watch for super-refractory status epilepticus: This is a common presentation of seronegative autoimmune encephalitis 3
- Consider post-infectious triggers: Autoimmune encephalitis may develop following viral infections (HSV, VZV, EBV) 5
- Monitor for brain atrophy: Development of cerebellar atrophy on follow-up MRIs indicates poor outcomes 2
- Be aware of psychiatric presentations: Pure neuropsychiatric features can occur with normal brain MRI 6
- Recognize that seronegative cases may have better response to first-line therapy than seropositive cases 4
- Consider that antibodies may be discovered later: Some currently "seronegative" cases may be found to have novel antibodies in the future 7