What are the diagnostic criteria for autoimmune encephalitis?

Diagnostic Criteria for Autoimmune Encephalitis

Autoimmune encephalitis diagnosis requires a structured three-step approach: first, confirm focal or multifocal brain pathology; second, demonstrate inflammatory etiology while excluding competing diagnoses; and third, screen for associated neoplasm. 1

Step 1: Confirm Focal or Multifocal Brain Pathology

The initial diagnostic step establishes objective evidence of brain involvement:

• Brain MRI with or without contrast is the primary modality

  • Bilateral limbic encephalitis on MRI is sufficient for definite AE diagnosis (even without antibodies) when viral studies are negative 1
  • Other patterns (cortical/subcortical, striatal, diencephalic, brainstem, encephalomyelitis, meningoencephalitis) support possible or probable AE 1
  • MRI may be normal in some cases—this does not exclude AE 1

• EEG when MRI is negative, patient is encephalopathic, or having frequent seizures

  • Can confirm focal/multifocal brain abnormality when imaging is negative
  • Identifies subclinical status epilepticus
  • Supportive findings: focal slowing/seizures, lateralized periodic discharges, extreme delta brush (NMDAR encephalitis) 1
  • Normal EEG does not exclude AE 1

• Brain FDG-PET if MRI negative and diagnosis remains uncertain

  • More sensitive than MRI in case series
  • Can substitute for MRI when contraindicated 1

Step 2: Confirm Inflammatory Etiology and Exclude Alternatives

This step differentiates autoimmune from infectious or other causes:

Lumbar Puncture (CSF Analysis)

• Neuronal autoantibodies (CSF and serum)
• Infectious studies to exclude viral encephalitis (HSV, VZV, HHV6)
• Inflammatory markers: IgG index, oligoclonal bands
• CSF pleocytosis (≥5 WBC/mm³) supports diagnosis but absence does not exclude it 1
• Cytology in selected cases

Blood Tests

• Serum neuronal autoantibodies
• Additional testing guided by MRI findings and differential diagnosis 1

Brain Biopsy

• Reserved for cases where diagnosis remains uncertain after comprehensive workup 1

Clinical Criteria Framework

For possible AE, patients must have:

• Altered mental status (decreased consciousness, lethargy, or personality change) lasting ≥24 hours with no alternative cause identified
• Plus at least 2 of the following minor criteria: 2
  • Documented fever ≥38°C within 72 hours before or after presentation
  • Generalized or partial seizures not fully attributable to preexisting seizure disorder
  • New onset focal neurologic findings
  • CSF WBC count ≥5/mm³
  • Brain parenchymal abnormality on neuroimaging suggestive of encephalitis
  • EEG abnormality consistent with encephalitis

For probable or confirmed AE:

• ≥3 minor criteria required 2
• Confirmed AE requires one of:
  • Pathologic confirmation of brain inflammation
  • Defined evidence of acute infection with microorganism strongly associated with encephalitis
  • Laboratory evidence of autoimmune condition strongly associated with encephalitis 2

Step 3: Screen for Associated Neoplasm

Once AE is diagnosed, systematic cancer screening is essential:

• CT chest, abdomen, pelvis (initial screen)
• Mammogram/breast MRI (women)
• Pelvic or testicular ultrasound (as appropriate)
• Body PET if initial screen negative 1

Clinical pearl: If clinical picture strongly suggests specific antibody (e.g., anti-NMDAR), targeted screening can begin (pelvic ultrasound for ovarian teratoma) 1

Antibody Classification and Clinical Relevance

The 2021 guidelines classify antibodies by clinical significance 1:

High clinical relevance (definite AE when positive):

• Surface antigens: NMDAR, AMPAR, LGI1, CASPR2, GABA-A/B receptors, DPPX, glycine receptor
• Other highly relevant: AQP4, MOG, GFAP (with typical radial perivascular enhancement)
• High-titer GAD65 (intracellular but clinically relevant in high titers)

Low clinical relevance:

• VGKC, VGCC (may be relevant in other presentations like Lambert-Eaton syndrome)

Critical Pitfalls to Avoid

1. Do not rely solely on antibody testing—diagnosis is clinical with antibody support 1
2. CSF pleocytosis absence does not exclude AE, especially in immunocompromised patients or early disease 2
3. Normal MRI occurs in AE—proceed with EEG or PET if clinical suspicion high 1
4. Seronegative AE exists—apply clinical criteria rigorously and exclude alternatives 1
5. Red flags for misdiagnosis: insidious onset, nonspecific antibodies only, failure to meet clinical criteria 3