How to diagnose autoimmune encephalitis?

Diagnosing Autoimmune Encephalitis

Suspect autoimmune encephalitis in any patient presenting with acute or subacute (less than 3 months) onset of polysyndromic neuropsychiatric symptoms, and immediately initiate a structured three-step diagnostic algorithm: confirm brain pathology, establish inflammatory etiology, and screen for malignancy. 1

When to Suspect Autoimmune Encephalitis Clinically

Temporal Pattern Recognition

• Acute to subacute presentation over less than 3 months is the hallmark - hyperacute presentations suggest vascular causes, while chronic presentations (except LGI1, CASPR2, DPPX, GAD65 antibodies) suggest neurodegenerative disease 1
• Monophasic course is most common in idiopathic cases, while progressive courses occur in paraneoplastic syndromes 1
• Relapses are rare and typically indicate insufficient treatment or premature immunotherapy discontinuation 1

Key Clinical Features to Identify

• Polysyndromic presentation is the clinical hallmark - multifocal brain inflammation produces combinations of cognitive/behavioral changes, seizures, movement disorders, autonomic dysfunction, and speech disturbances 1
• Preceding viral infection, fever, or viral-like prodrome is common 1
• Personal or family history of autoimmune disorders increases risk of idiopathic autoimmune encephalitis 1
• Cancer history, smoking, elderly age, or rapid weight loss increases paraneoplastic risk 1
• Recent exposure to immune checkpoint inhibitors or TNFα inhibitors can trigger autoimmune encephalitis 1

Step 1: Confirm Focal or Multifocal Brain Pathology

Brain MRI with Contrast (First-Line Imaging)

• Obtain standard brain MRI with contrast immediately - this rules out alternative diagnoses and identifies anatomical patterns 1
• Bilateral limbic encephalitis on MRI is sufficient for definite autoimmune encephalitis diagnosis (even without antibodies) when infection is excluded 1
• All other MRI patterns (cortical/subcortical, striatal, diencephalic, brainstem, encephalomyelitis, meningoencephalitis) support possible or probable autoimmune encephalitis 1
• Diffuse or patchy contrast enhancement suggests inflammation, but intense enhancement is unlikely in autoimmune encephalitis 1
• Radial perivascular enhancement suggests GFAP astrocytopathy; punctate brainstem/cerebellar enhancement suggests CLIPPERS 1

EEG (When MRI is Negative or Patient is Encephalopathic)

• Perform EEG to exclude subclinical status epilepticus and confirm focal/multifocal brain abnormality when MRI is negative 1
• Autoimmune encephalitis is a major cause of new onset refractory status epilepticus (NORSE) 1
• Findings suggestive of autoimmune encephalitis: focal slowing/seizures, lateralized periodic discharges, extreme delta brush (NMDAR-antibody encephalitis) 1
• Normal EEG does not exclude autoimmune encephalitis but can support primary psychiatric disorders 1

Brain FDG-PET (When MRI Negative and High Clinical Suspicion)

• Order brain FDG-PET when MRI is negative but clinical suspicion remains high - PET is more sensitive than MRI in case series 1
• Can substitute for MRI when MRI is contraindicated 1

Step 2: Confirm Inflammatory Etiology and Exclude Competing Diagnoses

Lumbar Puncture with Comprehensive CSF Analysis

• Perform lumbar puncture immediately after brain imaging to confirm inflammation and rule out infection 1, 2
• Test CSF for: cell count and differential, protein, glucose, IgG index, IgG synthesis rate, oligoclonal bands 1, 2
• Send CSF PCR for HSV1/2 and VZV to exclude infectious causes (strength of evidence level A) 2
• Test neuronal autoantibodies in CSF: anti-NMDAR, anti-VGKC, anti-LGI1, anti-CASPR2, AMPAR, GABAR A/B, DPPX, glycine receptor, AQP4, MOG, GFAP 1, 2
• Consider CSF cytology in select cases 1

Serum Testing

• Send serum neuronal autoantibody panel in parallel with CSF testing 1, 2
• Order additional blood tests guided by MRI findings and differential diagnosis to exclude metabolic/systemic causes 1

Brain Biopsy (Last Resort)

• Consider brain biopsy only if diagnosis remains uncertain after comprehensive testing and to exclude primary CNS lymphoma or neurosarcoidosis 1

Step 3: Screen for Associated Malignancy

Initial Cancer Screening

• Start with CT chest, abdomen, and pelvis with contrast (or MRI if CT contraindicated) 1
• If negative, add mammogram/breast MRI, pelvic or testicular ultrasound based on antibody profile and cancer risk 1
• Order whole body FDG-PET if initial screening is negative 1

Targeted Screening Approach

• If clinical picture suggests specific neoplasm (e.g., NMDAR-antibody encephalitis suggests ovarian teratoma), start with targeted imaging like pelvic ultrasound 1

Critical Diagnostic Pitfalls to Avoid

Timing Errors

• Do not delay immunotherapy while waiting for antibody results - start treatment once infection is ruled out based on basic CSF results 1, 3
• Chronic presentations (>3 months) should prompt reconsideration of neurodegenerative or other etiologies 1

Antibody Interpretation Errors

• Antibodies to intracellular antigens (classical onconeuronal antibodies) indicate paraneoplastic syndromes 1
• Surface antigen antibodies (NMDAR, LGI1, CASPR2, etc.) have high clinical relevance 1
• VGKC and VGCC antibodies have low clinical relevance for encephalitis diagnosis 1
• GAD65 antibodies are clinically relevant only in high titers 1

Differential Diagnosis Considerations

• For limbic encephalitis: exclude HSV, VZV, HHV6 1
• For cortical/subcortical patterns: exclude ADEM, tumefactive MS, PML, CJD, lupus cerebritis, neurosarcoidosis, lymphoma 1
• For striatal patterns: exclude CJD, West Nile virus, toxic/anoxic injury, hyperglycemic injury 1
• For brainstem patterns: exclude Listeria rhombencephalitis, CLIPPERS, neurosarcoidosis, PML 1

Special Population Considerations

• LGI1 encephalitis commonly presents with hyponatremia (55% of cases) and faciobrachial dystonic seizures that are highly steroid-responsive 3
• CSF changes are uncommon in LGI1 encephalitis unlike other autoimmune encephalitis subtypes 3
• MRI shows medial temporal lobe inflammation in only 60% of LGI1 cases 3