When should autoimmune encephalitis be suspected and how is it diagnosed and treated in patients presenting with seizures, altered mental status, memory deficits, or psychiatric symptoms?

When to Suspect Autoimmune Encephalitis

Suspect autoimmune encephalitis in any patient presenting with subacute onset (developing over days to weeks, typically within 6 weeks) of altered mental status, memory deficits, or psychiatric symptoms combined with seizures, movement disorders, or focal neurological findings—particularly when the presentation is polysyndromic and multifocal. 1, 2

Clinical Red Flags That Should Trigger Suspicion

Core Presentation Pattern

• Altered mental status lasting ≥24 hours (decreased consciousness, lethargy, personality change, or behavioral changes) with subacute onset is the cardinal feature 1
• Polysyndromic presentation affecting multiple brain regions simultaneously is a clinical hallmark that distinguishes AE from other conditions 1
• Rapid progression over days to weeks (not insidious over months) in a previously healthy individual 1, 3

Specific Clinical Syndromes to Recognize

• Limbic encephalitis: Memory deficits, confusion, psychiatric symptoms, and seizures 1
• New-onset refractory status epilepticus (NORSE): Particularly in patients without prior epilepsy history 4, 5
• Seizures with prominent psychiatric features: Psychosis, behavioral changes, or cognitive dysfunction accompanying seizures 4, 5
• Faciobrachial dystonic seizures: Brief, frequent dystonic posturing of arm and face—highly specific for LGI1 encephalitis 6
• Movement disorders: Orofacial dyskinesias, choreoathetosis, or other abnormal movements 1, 4
• Autonomic instability: Cardiac arrhythmias, hypoventilation, hyperthermia, or blood pressure fluctuations 1, 4

High-Risk Patient Populations

• Cancer patients or high-risk individuals (smokers, elderly, unintentional weight loss) suggest paraneoplastic AE 1
• Patients on immune checkpoint inhibitors can develop accelerated autoimmune encephalitis 1
• Personal or family history of autoimmune disease increases risk of idiopathic AE 1
• Recent viral infection or HSV encephalitis may trigger post-infectious AE 1, 4

Diagnostic Workup Algorithm

Step 1: Confirm Encephalitis Criteria

At least 2 of the following minor criteria are required (3 or more for probable/confirmed encephalitis): 1

• Documented fever ≥38°C within 72 hours of presentation
• Generalized or partial seizures not attributable to preexisting disorder
• New focal neurological findings
• CSF white blood cell count ≥5/mm³
• Brain imaging abnormality suggestive of encephalitis
• EEG abnormality consistent with encephalitis

Step 2: Brain MRI with Contrast

• Order immediately to rule out alternative diagnoses and identify patterns suggestive of AE 1
• Bilateral limbic T2/FLAIR hyperintensities are sufficient for definite AE diagnosis when infection is excluded 1
• Normal MRI does not exclude AE—occurs in 40-60% of cases, particularly LGI1 encephalitis 6, 5
• Consider brain FDG-PET when MRI is negative but clinical suspicion remains high 1, 4

Step 3: Lumbar Puncture (Once Infection Ruled Out by Basic Parameters)

• CSF analysis including: cell count, protein, glucose, oligoclonal bands, IgG index, IgG synthesis rate 1
• CSF neuronal autoantibodies: More sensitive than serum for NMDAR antibodies 4
• Test both CSF and serum for autoantibodies when possible 4
• CSF pleocytosis present in only ~60% of AE cases—normal CSF does not exclude diagnosis 1, 6

Step 4: Serum Testing

• Neuronal autoantibodies in serum: Including NMDAR, LGI1, CASPR2, AMPAR, GABA-B receptor, GAD65 1
• Thyroid antibodies: Elevated in some cases but low specificity 7
• Rule out metabolic/systemic causes guided by clinical presentation 1

Step 5: EEG

• Obtain if patient is encephalopathic, having seizures, or MRI is negative 1
• Look for focal slowing, lateralized periodic discharges, or "extreme delta brush" pattern (suggestive of NMDAR encephalitis) 4
• Normal EEG does not exclude AE 4

Step 6: Cancer Screening (When Appropriate)

• CT chest/abdomen/pelvis with contrast in patients with cancer risk factors or antibodies associated with malignancy 1
• Pelvic ultrasound or testicular ultrasound for NMDAR-positive patients (ovarian teratoma association) 4
• Whole-body FDG-PET if initial screening negative and suspicion remains 1

Treatment Approach

Critical Timing Principle

Start immunotherapy immediately once infection is ruled out by basic CSF parameters—do not wait for antibody results, as delays worsen outcomes. 1, 6

First-Line Immunotherapy

• High-dose IV methylprednisolone (1 gram daily for 3-5 days) is the preferred initial treatment 1, 6
• Alternative first-line options: IVIG or plasma exchange (PLEX) if steroids contraindicated 1
• PLEX preferred in patients with severe hyponatremia (common in LGI1 encephalitis), high thromboembolic risk, or associated demyelination 1, 6
• IVIG preferred in agitated patients or those with bleeding disorders 1

Severe Presentations Require Combination Therapy from Onset

Start combined steroids plus IVIG or steroids plus PLEX immediately in: 1

• Severe NMDAR encephalitis presentations
• New-onset refractory status epilepticus (NORSE)
• Severe dysautonomia
• Rapidly progressive cases

Second-Line Therapy (If No Improvement After 2-4 Weeks)

• Rituximab for antibody-mediated autoimmunity (NMDAR, LGI1, etc.) 1, 6
• Cyclophosphamide for cell-mediated autoimmunity (classical paraneoplastic syndromes) 1

Maintenance/Bridging Therapy

• Gradual oral prednisone taper or monthly IV methylprednisolone or IVIG 1

Critical Pitfalls to Avoid

Diagnostic Pitfalls

• Overreliance on antibody testing: 33% of true AE cases are seronegative; clinical criteria are paramount 8, 3
• Misinterpreting positive serum antibodies: Low-titer or non-specific antibodies (VGKC, thyroid antibodies) are common false positives—50% of misdiagnosed cases had this issue 7
• Confusing functional/psychiatric symptoms with encephalopathy: 38% of misdiagnosed cases involved this error 7
• Insidious onset (>3 months): This argues against AE and suggests neurodegenerative disease or primary psychiatric disorder 3, 7
• Ignoring failure to meet diagnostic criteria: 72% of misdiagnosed AE patients did not fulfill established criteria 7

Treatment Pitfalls

• Delaying immunotherapy while awaiting antibody results: Treatment should begin once infection excluded 1, 6
• Inadequate hyponatremia management: Present in 55% of LGI1 cases; requires careful monitoring and correction 6
• Failing to screen for malignancy: Particularly in older patients, smokers, or those with weight loss 1
• Unnecessary immunotherapy in misdiagnosed cases: Causes harm in 20% of misdiagnosed patients 7

Special Considerations for Specific Antibodies

• LGI1 encephalitis: Faciobrachial dystonic seizures are steroid-responsive; early treatment prevents cognitive decline 6
• NMDAR encephalitis: Often requires aggressive combination therapy; screen for ovarian teratoma 4
• Post-HSV encephalitis: NMDAR antibodies detected in ~30% of HSV cases—interpret in clinical context 4