Autoimmune Encephalitis: Investigations and Causes
Investigations
When autoimmune encephalitis (AE) is suspected, begin immediately with brain MRI with contrast and lumbar puncture, followed by neuronal autoantibody testing in both CSF and serum 1. This structured approach confirms focal/multifocal brain pathology, establishes inflammatory etiology, and identifies specific antibodies.
Step 1: Confirm Brain Pathology
Brain MRI with contrast: Look for patterns consistent with limbic, cortical/subcortical, striatal, diencephalic, brainstem, cerebellar, or meningoencephalitis involvement. Bilateral limbic encephalitis on MRI is sufficient for definite AE diagnosis when viral studies are negative, even without detectable antibodies 1.
EEG: Perform if MRI is negative, patient is encephalopathic, or having frequent seizures. Look for focal slowing, lateralized periodic discharges, or extreme delta brush (seen in NMDAR-antibody encephalitis). EEG helps exclude subclinical status epilepticus and can provide evidence of brain abnormality when MRI is negative 1.
Brain FDG-PET: Reserve for cases with high clinical suspicion but negative MRI and inconclusive initial testing. PET is more sensitive than MRI and can reveal bilateral temporal hypermetabolism (limbic encephalitis) or bilateral occipito-parietal hypometabolism (NMDAR-antibody encephalitis) 1.
Step 2: Confirm Inflammatory Etiology
Lumbar puncture is mandatory and should test for 1:
- Neuronal autoantibodies in CSF (higher sensitivity than serum alone)
- Oligoclonal bands, IgG index, and IgG synthesis rate
- Cell count and protein (to rule out infection initially)
- Viral PCR panels (HSV, VZV, HHV6) to exclude infectious causes
- Cytology if malignancy suspected
Blood tests 1:
- Serum neuronal autoantibodies (test both serum and CSF for maximum sensitivity)
- Additional tests guided by MRI pattern and differential diagnosis (see Table 3 in guidelines for syndrome-specific testing)
Step 3: Cancer Screening
Perform comprehensive malignancy screening in relevant cases 1:
- CT chest, abdomen, pelvis with contrast (first-line)
- Mammogram/breast MRI in women
- Pelvic ultrasound (especially if NMDAR-antibody suspected)
- Testicular ultrasound in men
- Whole body FDG-PET if initial screening negative and clinical suspicion remains high
Common pitfall: Cancer screening is particularly critical in elderly patients, smokers, those with rapid weight loss, and when intracellular antibodies are detected 1.
Causes (Etiological Classification)
Autoimmune encephalitis has four primary etiological categories 1:
1. Idiopathic (Most Common)
- No identifiable trigger
- More common in patients with personal or family history of other autoimmune disorders
- Associated with antibodies against surface antigens (NMDAR, LGI1, CASPR2, GABAR)
2. Paraneoplastic
- Triggered by underlying malignancy
- More common in elderly, smokers, and those with rapid unintentional weight loss
- Classical paraneoplastic syndromes associated with antibodies against intracellular antigens (anti-Hu, anti-Ma2, anti-Yo)
- NMDAR-antibody encephalitis can be paraneoplastic (ovarian teratoma in young women)
- LGI1-antibody encephalitis occasionally associated with thymoma or small cell lung cancer
3. Postinfectious
- Herpes simplex virus (HSV) encephalitis is a recognized trigger, particularly for anti-NMDAR encephalitis 1, 2
- Preceding viral infection, fever, or viral-like prodrome is common 1
- Other viral infections (VZV, HHV6) may trigger autoimmune responses
4. Iatrogenic
- Immune checkpoint inhibitors (ICIs) can cause accelerated paraneoplastic encephalitis in patients with advanced cancer 1
- TNFα inhibitors
- Other immune-modulating therapies
Antibody Classification and Clinical Relevance
Understanding antibody types guides prognosis and treatment 1:
High Clinical Relevance - Surface Antigens:
- NMDAR, AMPAR, LGI1, CASPR2, GABAR A/B, DPPX, glycine receptor
- Generally better response to immunotherapy
- GAD65 (intracellular) in high titers behaves like surface antibodies
Classical Paraneoplastic - Intracellular Antigens:
- Anti-Hu, anti-Ma2, anti-Yo, anti-CV2/CRMP5
- Associated with cell-mediated autoimmunity
- Often irreversible neuronal damage
- Require aggressive cancer screening and treatment
Low Clinical Relevance:
- VGKC, VGCC (may be relevant in other contexts like Lambert-Eaton syndrome)
Critical Diagnostic Considerations
Important caveats 1:
Seronegative disease exists: Up to 30-40% of clinically definite AE cases may be antibody-negative. Diagnosis relies on clinical criteria, MRI/EEG findings, CSF inflammation, and exclusion of alternatives 3.
CSF testing is more sensitive than serum alone: Always test both compartments, but CSF antibodies have higher diagnostic yield 1.
Normal MRI and EEG do not exclude AE: Consider FDG-PET in high suspicion cases with negative conventional studies 1.
Timing matters: Antibody testing may be negative early in disease course; repeat testing if clinical suspicion remains high.
Differential diagnosis is broad: Each anatomical syndrome has specific infectious, inflammatory, and metabolic mimics that must be systematically excluded (see Table 3 for syndrome-specific differentials) 1.