Autoimmune Encephalitis in the ICU: Recognition, Diagnosis, and Management of Anti-NMDA Receptor and Other Antibody-Mediated Syndromes

Dr Neeraj Manikath , claude.ai

Abstract

Autoimmune encephalitis represents a paradigm shift in neuropsychiatric medicine, transforming previously "untreatable" psychiatric presentations into potentially reversible neurological conditions. This review focuses on the critical care management of autoimmune encephalitis, with particular emphasis on anti-NMDA receptor encephalitis and other antibody-mediated syndromes that frequently masquerade as primary psychiatric illness. We discuss clinical recognition patterns, diagnostic strategies, and management approaches specifically relevant to the intensive care setting. The increasing recognition of these syndromes has profound implications for emergency medicine, critical care, and psychiatric practice, as timely diagnosis and treatment can mean the difference between full recovery and permanent disability or death.

Keywords: autoimmune encephalitis, anti-NMDA receptor encephalitis, critical care, psychiatric emergency, immunotherapy

Introduction

The landscape of neuropsychiatric emergencies has been revolutionized by the recognition of autoimmune encephalitis syndromes. What was once attributed to primary psychiatric illness, drug intoxication, or idiopathic encephalitis is now understood to represent a spectrum of antibody-mediated brain disorders with specific therapeutic implications. The critical care physician sits at the nexus of this diagnostic challenge, as these patients frequently present with altered mental status, behavioral disturbances, seizures, and autonomic instability requiring intensive monitoring and support.

Anti-NMDA receptor encephalitis, first described by Dalmau et al. in 2007¹, has become the prototype for understanding autoimmune encephalitis. However, the expanding spectrum now includes over 20 distinct antibody-associated syndromes, each with characteristic clinical features, associated malignancies, and treatment responses². The critical care setting presents unique challenges in recognition and management, as the acute presentation often obscures the underlying autoimmune process.

Clinical Presentation and Recognition

The Autoimmune Encephalitis Spectrum

Autoimmune encephalitis encompasses two broad categories: those associated with antibodies against intracellular antigens (often paraneoplastic) and those targeting cell surface or synaptic proteins (frequently non-paraneoplastic)³. The latter group, including anti-NMDA receptor encephalitis, typically presents with more acute onset and better treatment responsiveness.

Anti-NMDA Receptor Encephalitis: The Great Mimicker

Anti-NMDA receptor encephalitis classically progresses through distinct phases, though presentation in the ICU may capture patients at any stage⁴:

Phase 1 (Prodromal, Days 1-14):

Viral-like symptoms (fever, headache, malaise)
Behavioral changes and psychiatric symptoms
Often mistaken for viral encephalitis or psychiatric emergency

Phase 2 (Psychotic, Days 2-21):

Prominent psychiatric symptoms (psychosis, agitation, paranoia)
Sleep disturbances and insomnia
Cognitive dysfunction and memory impairment
Frequently leads to psychiatric hospitalization

Phase 3 (Unresponsive, Days 10-35):

Decreased responsiveness and catatonic features
Seizures (often refractory)
Movement disorders (orofacial dyskinesias, choreoathetosis)
Autonomic instability

Phase 4 (Hyperkinetic, Variable timing):

Severe dyskinesias and abnormal movements
Central hypoventilation requiring mechanical ventilation
Temperature dysregulation
This phase often necessitates ICU admission

Phase 5 (Recovery, Weeks to months):

Gradual improvement in reverse order of symptom onset
Long-term cognitive and behavioral sequelae possible

🔹 PEARL: The "Rule of 4s" for Anti-NMDA Receptor Encephalitis

4 Core Features: Psychiatric symptoms, seizures, movement disorders, autonomic dysfunction
4 Demographics: Young females (though any age/sex possible)
4 Weeks: Typical progression from onset to ICU admission
4 Phases: Prodromal → Psychotic → Unresponsive → Hyperkinetic

Other Autoimmune Encephalitis Syndromes in the ICU

LGI1 (Leucine-Rich Glioma-Inactivated 1) Encephalitis

Classic triad: Faciobrachial dystonic seizures, cognitive decline, hyponatremia
ICU relevance: Severe hyponatremia may precipitate altered mental status
Demographics: Older adults (>50 years)
Treatment response: Excellent with early immunotherapy⁵

CASPR2 (Contactin-Associated Protein-2) Encephalitis

Features: Limbic encephalitis, peripheral nerve hyperexcitability, Morvan's syndrome
ICU relevance: Autonomic dysfunction and cardiac arrhythmias
Association: Thymoma in ~50% of cases

GABAB Receptor Encephalitis

Features: Refractory seizures, limbic encephalitis
ICU relevance: Status epilepticus common
Association: Small cell lung cancer in ~50% of cases⁶

AMPA Receptor Encephalitis

Features: Limbic encephalitis with prominent psychiatric symptoms
Association: Ovarian teratoma, lung, breast, or thymic tumors

🔹 CLINICAL HACK: The "Autoimmune Encephalitis Red Flags" Checklist

HIGH SUSPICION when ≥3 present:

[ ] Young adult with rapid-onset psychiatric symptoms
[ ] Movement disorders (especially orofacial dyskinesias)
[ ] Refractory seizures or status epilepticus
[ ] Autonomic instability without clear cause
[ ] CSF pleocytosis with normal/low glucose
[ ] MRI with limbic or multifocal abnormalities
[ ] Poor response to standard psychiatric medications

Diagnostic Approach

When to Suspect Autoimmune Encephalitis

The diagnosis of autoimmune encephalitis requires a high index of suspicion, particularly in the ICU setting where acute management often takes precedence over diagnostic workup. Key clinical scenarios warranting consideration include:

Rapid-onset psychiatric symptoms in previously healthy individuals
Treatment-refractory seizures, especially with psychiatric features
Movement disorders in the setting of altered mental status
Unexplained autonomic dysfunction
Catatonia unresponsive to benzodiazepines or ECT
"Viral encephalitis" with atypical features or poor recovery

🔹 OYSTER: The "Psychiatric Emergency" Trap

Common Pitfall: Young adults presenting with acute psychosis are often assumed to have primary psychiatric illness or substance use. Clinical Clue: Look for neurological "red flags" - seizures, movement disorders, or autonomic dysfunction suggest organic etiology. Action: Maintain high suspicion for autoimmune encephalitis in any acute psychiatric presentation with neurological features.

Laboratory Investigations

Cerebrospinal Fluid Analysis:

Essential in all suspected cases
Typical findings: lymphocytic pleocytosis (median 25 cells/μL), elevated protein, normal glucose
Oligoclonal bands present in ~60% of cases⁷
Pearl: Normal CSF does not exclude autoimmune encephalitis

Serum and CSF Antibody Testing:

Both serum and CSF should be tested
CSF antibodies more specific for CNS involvement
Commercial panels available (Mayo Clinic, Oxford Autoimmune Neurology)
Important: Antibody testing should not delay empirical treatment

Neuroimaging:

MRI findings variable and often non-specific
T2/FLAIR hyperintensities in limbic regions common
Anti-NMDA: Often normal or subtle changes
LGI1: Classic hippocampal hyperintensities
CASPR2: May show basal ganglia involvement

Electroencephalography:

Abnormal in >90% of cases
"Extreme delta brush" pattern pathognomonic for anti-NMDA receptor encephalitis⁸
Non-convulsive status epilepticus common
Pearl: Continuous EEG monitoring recommended in ICU patients

🔹 CLINICAL HACK: The "Extreme Delta Brush" Sign

This EEG pattern consists of 1-3 Hz delta waves with superimposed 20-30 Hz beta activity and is virtually pathognomonic for anti-NMDA receptor encephalitis. Its presence should trigger immediate antibody testing and consideration of empirical immunotherapy.

Tumor Screening

The association between autoimmune encephalitis and underlying neoplasms varies by syndrome and demographic factors:

Anti-NMDA Receptor Encephalitis:

Ovarian teratoma in ~50% of females >18 years
Lower tumor association in children and males
Screening: Pelvic/abdominal CT/MRI, transvaginal ultrasound

LGI1 and CASPR2:

Thymoma association, especially with CASPR2
Screening: Chest CT

GABAB and AMPA:

High tumor association (>50%)
Comprehensive malignancy screening indicated

GAD65:

Low acute tumor risk
Associated with other autoimmune conditions

Management in the ICU Setting

First-Line Immunotherapy

Early immunotherapy is crucial for optimal outcomes. The standard first-line regimen includes⁹:

Methylprednisolone:

1g IV daily × 5 days, followed by oral prednisolone taper
Alternative: IV dexamethasone 0.15 mg/kg/day

Intravenous Immunoglobulin (IVIG):

0.4 g/kg/day × 5 days
Monitor renal function and consider pre-medication

Plasma Exchange (PLEX):

5-7 exchanges over 10-14 days
Alternative to IVIG, not necessarily additive
Consider in severe cases or IVIG intolerance

🔹 PEARL: The "72-Hour Rule"

Patients who show no improvement after 72 hours of first-line immunotherapy should be considered for second-line agents. Early escalation correlates with better long-term outcomes.

Second-Line Immunotherapy

For patients not responding to first-line therapy within 2-4 weeks:

Rituximab:

375 mg/m² weekly × 4 doses
Monitor for infusion reactions and opportunistic infections
Particularly effective in anti-NMDA receptor encephalitis¹⁰

Cyclophosphamide:

750 mg/m² monthly × 6 doses
Requires careful monitoring for cytopenias and infections
Consider in refractory cases

Supportive Care Considerations

Seizure Management:

Standard anticonvulsants often ineffective
Consider levetiracetam or lacosamide as first-line
Avoid phenytoin due to cognitive side effects
Status epilepticus may require anesthetic agents

Autonomic Dysfunction:

Temperature regulation issues common
Cardiac monitoring for arrhythmias
Avoid overhydration in hyponatremic patients

Movement Disorders:

Avoid neuroleptics (may worsen symptoms)
Benzodiazepines for acute agitation
Consider clonazepam for choreiform movements

Respiratory Support:

Central hypoventilation may develop
Early intubation for airway protection
Prolonged mechanical ventilation often required

🔹 CLINICAL HACK: The "Neuroleptic Trap"

Avoid typical and atypical antipsychotics in suspected autoimmune encephalitis, as they may worsen movement disorders and delay recovery. Use benzodiazepines and environmental modifications for behavioral control.

Prognosis and Long-term Outcomes

The prognosis of autoimmune encephalitis varies significantly by syndrome and treatment timing:

Anti-NMDA Receptor Encephalitis:

70-80% achieve good functional recovery¹¹
Recovery often takes 18-24 months
Earlier treatment correlates with better outcomes
Relapses occur in ~10-25% of cases

LGI1 Encephalitis:

Excellent prognosis with early treatment
Cognitive deficits may persist
Low relapse rate

Paraneoplastic Syndromes:

Prognosis largely depends on tumor control
Often limited recovery potential
Stabilization rather than improvement may be the goal

Factors Associated with Poor Prognosis:

Delayed diagnosis and treatment (>4 weeks)
Need for ICU admission
Absence of underlying tumor (paradoxically worse in some syndromes)
Development of severe autonomic dysfunction
Age >45 years (for anti-NMDA receptor encephalitis)

🔹 PEARLS AND PITFALLS SUMMARY

Diagnostic Pearls:

The "4-3-2-1 Rule": 4 symptom domains (psychiatric, seizures, movements, autonomic), 3 phases of illness, 2 diagnostic tests (CSF + antibodies), 1 treatment approach (early immunotherapy)
CSF Trinity: Pleocytosis + elevated protein + normal glucose = think autoimmune
EEG Gold Standard: Extreme delta brush pattern is pathognomonic for anti-NMDA receptor encephalitis

Management Pearls:

Time is Brain: Early immunotherapy (within 4 weeks) dramatically improves outcomes
First-line Trinity: Steroids + IVIG/PLEX + tumor removal (if present)
Avoid the "Psych Trap": Don't delay medical workup for apparent psychiatric presentations

Common Pitfalls:

Anchoring on psychiatric diagnosis in young adults with acute behavioral changes
Waiting for antibody results before initiating treatment
Using antipsychotics which may worsen movement disorders
Inadequate tumor screening based on age and antibody type

Future Directions and Emerging Concepts

The field of autoimmune encephalitis continues to evolve rapidly. Emerging areas include:

Novel Antibody Targets:

DPPX, IgLON5, and other newly identified antigens
Better understanding of antibody pathogenicity

Biomarkers:

Neurofilament light chain as severity marker
Cytokine profiles for treatment monitoring

Treatment Optimization:

Personalized immunotherapy based on antibody type
Novel agents (tocilizumab, bortezomib)
Maintenance therapy strategies

Pediatric Considerations:

Age-specific presentation patterns
Long-term developmental outcomes
School and cognitive rehabilitation

Conclusion

Autoimmune encephalitis represents one of the most significant advances in neuropsychiatric medicine, offering hope for recovery in conditions previously considered untreatable. For the critical care physician, recognition of these syndromes requires a paradigm shift from purely supportive care to active immunomodulatory intervention. The key to successful management lies in maintaining a high index of suspicion, particularly in young adults with rapid-onset neuropsychiatric symptoms, and initiating empirical immunotherapy while pursuing definitive diagnostic testing.

The mantra "time is brain" applies equally to autoimmune encephalitis as it does to stroke. Early recognition and aggressive immunotherapy can mean the difference between full recovery and permanent disability. As our understanding of these conditions continues to evolve, the critical care physician will play an increasingly important role in the acute management and long-term outcomes of patients with autoimmune encephalitis.

Key Clinical Action Points

Suspect autoimmune encephalitis in any rapid-onset neuropsychiatric syndrome
Screen systematically with CSF analysis, EEG, MRI, and antibody testing
Start empirical immunotherapy early (don't wait for antibody results)
Search for underlying tumors based on syndrome and demographics
Support with appropriate ICU monitoring and symptomatic management
Escalate to second-line therapy if no improvement in 72 hours
Plan for prolonged recovery and potential long-term sequelae

References

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Conflicts of Interest: None declared Funding: None

Tuesday, September 9, 2025