What are the clinical presentation, diagnosis, and treatment options for a patient with suspected autoimmune encephalitis?

Autoimmune Encephalitis: Clinical Presentation and Diagnosis

Clinical Presentation

Autoimmune encephalitis typically presents acutely or subacutely over less than 3 months with a polysyndromic constellation of neurological and psychiatric symptoms, distinguishing it from neurodegenerative conditions. 1

Temporal Course and Risk Factors

• Acute to subacute onset (duration <3 months) is the hallmark presentation, with hyperacute presentations suggesting vascular etiology instead 1
• Preceding viral illness or prodrome is common, including fever or viral-like symptoms 1
• High-risk populations include patients with known cancer, smokers, elderly patients with unintentional weight loss (paraneoplastic), or those with personal/family history of autoimmune disorders 1
• Iatrogenic triggers include immune checkpoint inhibitors (causing accelerated paraneoplastic encephalitis), TNFα inhibitors, or post-HSV encephalitis 1

Core Clinical Features (Polysyndromic Presentation)

The diffuse immune reaction produces multifocal brain inflammation resulting in multiple simultaneous symptoms 1:

• Seizures (present in 100% of cases in some series) of varied semiology, including new-onset refractory status epilepticus (NORSE) 1, 2
• Cognitive impairment and behavioral changes including memory deficits, confusion, and psychiatric symptoms 1, 3
• Movement disorders including oromandibular dyskinesia, faciobrachial dystonic seizures (LGI1-antibody), choreiform movements, or dystonia 1, 3
• Autonomic dysfunction including dysautonomia, which indicates severe disease 1
• Speech dysfunction and language disturbances 1
• Decreased level of consciousness or encephalopathy 1

Antibody-Specific Patterns (Though Significant Overlap Exists)

• NMDAR-antibody encephalitis: oromandibular dyskinesia, cognitive/behavioral changes, speech dysfunction, autonomic instability, and extreme delta brush on EEG 1
• LGI1-antibody encephalitis: faciobrachial dystonic seizures, frequent subclinical seizures, and hyponatremia 1
• Paraneoplastic syndromes: progressive course that plateaus after cancer treatment, especially in cerebellar degeneration 1

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Diagnostic Approach

The diagnosis follows a systematic three-step algorithm: (1) confirm focal/multifocal brain pathology, (2) establish inflammatory etiology while excluding competing diagnoses, and (3) screen for associated malignancy. 4

Step 1: Confirm Focal or Multifocal Brain Pathology

Brain MRI (First-Line Imaging)

• Obtain brain MRI with or without contrast to identify characteristic anatomical patterns 1, 4
• Bilateral limbic encephalitis on MRI is sufficient for definite AE diagnosis (in appropriate clinical context with negative viral studies), even without antibody confirmation 1
• Other MRI patterns (cortical/subcortical, striatal, diencephalic, brainstem, encephalomyelitis, meningoencephalitis) support possible/probable AE but require antibody confirmation 1
• Normal MRI does not exclude AE—proceed with additional testing 1
• Specific patterns: radial perivascular enhancement suggests autoimmune GFAP astrocytopathy; punctate brainstem/cerebellar enhancement suggests CLIPPERS 1

EEG (When MRI Negative or Patient Encephalopathic)

• Perform EEG if MRI is negative, patient is encephalopathic, or having frequent seizures 1, 4
• Findings suggestive of AE: focal slowing/seizures, lateralized periodic discharges, extreme delta brush (NMDAR-antibody encephalitis) 1, 4
• Normal EEG does not exclude AE, particularly in LGI1-antibody encephalitis where patients may have faciobrachial dystonic seizures despite normal EEG 1, 4
• Utility: excludes subclinical status epilepticus, provides evidence of focal brain abnormality when MRI negative, helps differentiate from primary psychiatric disorders and CJD 1

Brain FDG-PET (Third-Line Imaging)

• Reserve for cases with negative MRI but high clinical suspicion, or when MRI is contraindicated 1, 4
• More sensitive than MRI in case series, revealing abnormalities at earlier disease stages 1
• Characteristic patterns: bilateral temporal hypermetabolism (limbic encephalitis), bilateral occipito-parietal hypometabolism (NMDAR-antibody encephalitis) 1

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Step 2: Confirm Inflammatory Etiology and Exclude Competing Diagnoses

Lumbar Puncture (Essential)

• Perform lumbar puncture with comprehensive CSF analysis: cell count with differential, protein, glucose, IgG index, oligoclonal bands, IgG synthesis rate, and neuronal autoantibodies 1, 4
• Test CSF viral PCR (HSV1/2, VZV, HHV6) to exclude infectious causes 1, 4
• Normal routine CSF studies do not exclude AE—proceed with antibody testing if clinical suspicion remains high 1
• CSF may be normal in some AE patients, particularly regarding cell counts 1

Neuronal Autoantibody Testing (Critical)

• Test neuronal autoantibodies in BOTH serum and CSF before any immunotherapy administration 4
• Collect samples before IVIG or plasmapheresis to avoid false positive/negative results 1, 4
• Panel should include: anti-NMDAR, anti-VGKC, anti-LGI1, anti-CASPR2, and other relevant antibodies 4
• Sensitivity varies by antibody type and sample source—some antibodies are better detected in serum, others in CSF 4
• Commercial assays have frequent false negatives, especially in CSF samples 4

Exclusionary Blood Tests

Tailor additional testing based on MRI anatomical patterns (Table 3), but perform comprehensive testing even with negative MRI 1, 4:

• Autoimmune workup: ANA, ENA antibodies, antiphospholipid antibodies, lupus anticoagulant, antithyroid antibodies 1, 4
• Infectious workup: HIV, treponemal antibodies (syphilis), viral PCR as indicated 1, 4
• Metabolic/nutritional: vitamin B1/B12 levels, ammonia, comprehensive metabolic panel, hormonal panels when appropriate 1, 4
• Toxicology screen 1, 4
• Monitor sodium levels closely—hyponatremia is common with LGI1-antibody encephalitis 1, 4
• Inflammatory markers and immunoglobulins 1

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Step 3: Screen for Associated Malignancy

Cancer screening is essential in relevant cases, particularly in patients with known cancer, smokers, elderly patients, or those with rapid weight loss. 1

Screening Algorithm

• Initial screening: CT chest, abdomen, and pelvis with contrast (or MRI if CT contraindicated) 1, 4
• If initial screening negative, add: mammogram/breast MRI, pelvic or testicular ultrasound 1, 4
• If screening remains negative: whole body FDG-PET 1, 4
• Targeted approach option: When clinical presentation strongly suggests specific neoplasm (e.g., pelvic ultrasound first if anti-NMDAR encephalitis suspected) 1, 4

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Step 4: Brain Biopsy (Last Resort)

Consider brain biopsy only if diagnosis remains uncertain after completing the above workup, particularly when primary CNS lymphoma or neurosarcoidosis cannot be excluded. 4

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Key Diagnostic Pitfalls and Caveats

Common Errors to Avoid

• Do not delay antibody testing if CSF is normal—AE can present with normal routine CSF studies 1, 4
• Do not rely solely on commercial assays—false negatives are frequent 4
• Do not skip serum testing even when CSF is available—test both samples 4
• Do not wait for antibody results to initiate treatment—once infection is ruled out, start immunotherapy promptly 1
• Do not assume chronic presentations are AE—chronic courses (>3 months) suggest neurodegenerative disease except in LGI1, CASPR2, DPPX, and GAD65-antibody encephalitis 1

Differential Diagnosis Considerations

Tailor differential diagnosis based on anatomical syndrome 1:

• Limbic encephalitis: HSV, VZV, HHV6
• Cortical/subcortical: ADEM, tumefactive MS, PML, CJD, lupus cerebritis, Behçet's, neurosarcoidosis, lymphoma
• Striatal: CJD, West Nile virus, toxic encephalopathy
• Meningoencephalitis: tuberculosis, neurosarcoidosis, Behçet's, bacterial/viral infection, leptomeningeal carcinomatosis

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Treatment Initiation

Once infection is ruled out based on basic CSF results and if biopsy for primary CNS lymphoma or neurosarcoidosis is not a consideration, start acute immunotherapy immediately with high-dose corticosteroids (or IVIG/PLEX if steroids contraindicated). 1

First-Line Treatment Algorithm

Standard Cases

• Intravenous methylprednisolone (IVMP) is first-line treatment, followed by short or long oral taper 1
• High-dose corticosteroids (0.5 mg/kg/day prednisone or methylprednisolone equivalent) 4

Steroid-Responsive Conditions (Prefer Steroids)

Use steroids preferentially in: faciobrachial dystonic seizures (LGI1-antibody), AE with immune checkpoint inhibitors, central demyelination, autoimmune GFAP astrocytopathy, CLIPPERS, steroid-responsive encephalopathy with autoimmune thyroiditis 1

Contraindications to Steroids

Relative contraindications: uncontrolled hypertension, uncontrolled diabetes, acute peptic ulcer, severe behavioral symptoms worsening with corticosteroids 1

Alternative first-line options when steroids contraindicated:

• IVIG (0.4 g/kg/day for 5 days): prefer in agitated patients and those with bleeding disorders 1, 4
• PLEX: prefer in patients with severe hyponatremia, high thromboembolic risk (cancer, smoking, hypertension, diabetes, hyperlipidemia, hypercoagulable states), or associated brain/spinal demyelination 1

Severe Presentations (Combination Therapy from Onset)

Start combination therapy (steroids/IVIG or steroids/PLEX) immediately in: severe NMDAR-antibody presentation, NORSE, severe dysautonomia 1

Second-Line Treatment

• If no improvement by end of initial treatment cycle: add IVIG or PLEX 1
• If no improvement 2-4 weeks after combined acute therapy: start second-line agents (rituximab or cyclophosphamide) 1

Paraneoplastic AE

If tumor present or classical paraneoplastic syndrome: treatment algorithm differs, with consideration of rituximab earlier and experimental therapies (IL-6 inhibitors, bortezomib) for refractory cases 1, 5

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Prognosis and Monitoring

• Early immunosuppressive treatment is associated with significant improvement in outcomes 4
• Confusion and seizures often improve rapidly with immunosuppression, while memory recovery may take months to years 4
• Regular monitoring of antibody levels in serum is essential to evaluate treatment efficacy 4
• Periodic neurological evaluation is necessary to monitor symptom improvement 4
• Repeat brain MRI after 3-6 months of treatment 4
• Relapses are rare and usually result from insufficient treatment or rapid immunotherapy interruption 1