Autoimmune Encephalitis in the ICU: Recognition, Management, and Outcomes in Critical Care

Dr Neeraj Manikath , claude.ai

Abstract

Background: Autoimmune encephalitis (AE) represents a group of inflammatory brain disorders mediated by antibodies against neuronal surface antigens, intracellular proteins, or synaptic receptors. Critical care management of AE has evolved significantly, with early recognition and aggressive immunotherapy being paramount to favorable outcomes.

Objective: To provide critical care physicians with evidence-based strategies for diagnosis, treatment, and management of autoimmune encephalitis in the intensive care unit setting.

Methods: Comprehensive review of current literature, guidelines, and expert consensus statements on autoimmune encephalitis management in critical care.

Key Findings: Early initiation of first-line immunotherapy (methylprednisolone 1g IV + IVIG 0.4g/kg × 5 days) within 72 hours of presentation significantly improves neurological outcomes. Second-line therapy with rituximab should be considered by day 3 if no clinical response to first-line treatment is observed.

Keywords: Autoimmune encephalitis, critical care, immunotherapy, NMDA receptor, anti-NMDAR, intensive care unit

Introduction

Autoimmune encephalitis has emerged as a leading cause of acute encephalitis in children and young adults, with an estimated incidence of 13.7 per 100,000 person-years¹. The critical care management of AE requires rapid recognition, prompt immunosuppression, and careful monitoring for complications. Unlike infectious encephalitis, AE is potentially reversible with appropriate treatment, making early diagnosis and intervention crucial for optimal outcomes.

The most common form, anti-NMDA receptor encephalitis, was first described by Dalmau et al. in 2007² and has since become the prototype for understanding autoimmune encephalitis pathophysiology and treatment approaches. However, the ICU management extends beyond anti-NMDAR encephalitis to include various other antibody-mediated syndromes, each with unique clinical presentations and treatment considerations.

Clinical Presentation and Recognition

Classic Prodromal Phase (Days 1-14)

Viral-like symptoms: Fever (60-70%), headache, nausea, vomiting
Psychiatric manifestations: Anxiety, depression, psychosis, behavioral changes
Sleep disturbances: Insomnia, hypersomnia, sleep-wake cycle disruption

Pearl: The psychiatric prodrome often leads to initial psychiatric admission, delaying appropriate neurological evaluation and treatment.

Acute Neurological Phase (Days 7-21)

Movement disorders: Orofacial dyskinesias, dystonia, choreoathetosis, catatonia
Seizures: Present in 75-80% of cases, often refractory to standard antiepileptic drugs³
Cognitive impairment: Memory deficits, executive dysfunction, speech disturbances
Autonomic instability: Hyperthermia, blood pressure fluctuations, cardiac arrhythmias

Oyster: Movement disorders in young patients with altered mental status should raise suspicion for autoimmune encephalitis, not just infectious causes.

Severe ICU Phase (Days 14-28)

Decreased consciousness: Stupor, coma (requires ICU admission)
Respiratory failure: Central hypoventilation, aspiration pneumonia
Status epilepticus: Refractory seizures requiring continuous EEG monitoring
Severe autonomic dysfunction: Temperature instability, hemodynamic compromise

Diagnostic Approach in the ICU

Immediate Assessment (Within 2 Hours)

Comprehensive history: Focus on recent infections, vaccinations, travel, substance use
Physical examination: Neurological assessment, search for tumors (especially ovarian teratoma in young women)
Initial investigations:
- Complete blood count, comprehensive metabolic panel
- Inflammatory markers (ESR, CRP, procalcitonin)
- Toxicology screen, vitamin B12, thiamine levels

Critical Care Hack: Obtain CSF before starting immunotherapy but don't delay treatment beyond 6 hours if LP is contraindicated.

Cerebrospinal Fluid Analysis

Standard CSF studies:

Cell count and differential
Protein and glucose levels
Gram stain and bacterial cultures
HSV PCR, enterovirus PCR, West Nile virus PCR

Specialized CSF antibody panels:

Anti-NMDAR antibodies (most common)
Anti-LGI1, anti-CASPR2 (limbic encephalitis)
Anti-AMPAR, anti-GABABR antibodies
Anti-GAD, anti-amphiphysin (paraneoplastic)

Pearl: CSF antibody results take 5-10 days; initiate empirical immunotherapy based on clinical suspicion rather than waiting for confirmatory results.

Neuroimaging

MRI brain with contrast: May show T2/FLAIR hyperintensities in medial temporal lobes, frontal cortex, or cerebellum⁴
Normal MRI in 50% of anti-NMDAR cases
FDG-PET: May show characteristic patterns of hypermetabolism followed by hypometabolism

Electroencephalography

Continuous EEG monitoring: Essential for seizure detection and management
Characteristic patterns: Delta activity, extreme delta brush pattern (pathognomonic for anti-NMDAR encephalitis)⁵

First-Line Immunotherapy Protocol

Standard Regimen

Methylprednisolone:

Dosing: 1000mg IV daily × 5 days
Follow with oral prednisone 1mg/kg (max 60mg) with slow taper over 6-8 weeks

Intravenous Immunoglobulin (IVIG):

Dosing: 0.4g/kg/day × 5 days (total 2g/kg)
Monitor for fluid overload, especially in elderly patients
Pre-medication with acetaminophen and diphenhydramine

Critical Care Hack: Start both agents simultaneously rather than sequentially to maximize early immunosuppressive effect.

Alternative: Plasma Exchange (PLEX)

Indication: When IVIG contraindicated (IgA deficiency, heart failure)
Protocol: 5-7 exchanges over 10-14 days
Volume: 1-1.5 plasma volumes per exchange

Monitoring During First-Line Therapy

Daily neurological assessments using standardized scales
Continuous cardiac monitoring for arrhythmias
Blood glucose monitoring (steroid-induced hyperglycemia)
Infection surveillance and prophylaxis

Second-Line Immunotherapy

Rituximab Protocol

Timing: Initiate by day 3 if no clinical improvement with first-line therapy

Dosing regimens:

Weekly protocol: 375mg/m² IV weekly × 4 weeks
Intensive protocol: 1000mg IV on days 1 and 15

Pre-medication:

Methylprednisolone 125mg IV
Diphenhydramine 25mg IV
Acetaminophen 650mg PO

Pearl: Earlier initiation of rituximab (day 3 vs day 14) correlates with better functional outcomes at 2 years⁶.

Cyclophosphamide

Indication: Refractory cases or when rituximab contraindicated Dosing: 750mg/m² IV monthly × 6 months Monitoring: CBC, urinalysis, consider mesna for hemorrhagic cystitis prophylaxis

ICU Management Considerations

Seizure Management

First-line AEDs:

Levetiracetam: 500-1000mg IV BID (preferred due to fewer drug interactions)
Valproic acid: 15-20mg/kg loading dose, then 10-15mg/kg BID

Status epilepticus protocol:

Lorazepam 0.1mg/kg IV (max 4mg)
Fosphenytoin 20mg PE/kg IV
Continuous infusions: midazolam, propofol, or pentobarbital

Oyster: Traditional AEDs may be less effective in autoimmune encephalitis; early aggressive immunotherapy is more important than escalating AED therapy.

Respiratory Management

Indications for intubation: GCS ≤8, respiratory failure, refractory status epilepticus
Ventilator settings: Lung-protective strategies, avoid hyperventilation
Extubation readiness: Improved mental status, adequate cough reflex, stable hemodynamics

Autonomic Dysfunction Management

Hyperthermia:

Target core temperature <38.5°C
Cooling blankets, ice packs, intravascular cooling devices
Avoid antipyretics if fever is centrally mediated

Hemodynamic instability:

Fluid resuscitation for hypotension
Vasopressors: norepinephrine preferred over dopamine
Continuous cardiac monitoring for arrhythmias

Critical Care Hack: Use dexmedetomidine for sedation in mechanically ventilated patients - it provides sedation without respiratory depression and may have neuroprotective effects.

Tumor Screening and Management

High-Risk Demographics

Women 12-45 years: Screen for ovarian teratoma (60% association with anti-NMDAR)
Men >50 years: Screen for lung, testicular, or thymic tumors
Children <12 years: Lower tumor association (5-10%)

Screening Protocol

Initial imaging:

CT chest/abdomen/pelvis with contrast
Pelvic ultrasound in females
Testicular ultrasound in males >12 years

Advanced imaging if initial negative:

MRI pelvis in women
FDG-PET scan for occult malignancy

Pearl: Tumor removal often leads to rapid clinical improvement and reduces relapse risk, making aggressive tumor screening essential.

Complications and Management

Infectious Complications

Risk factors:

High-dose corticosteroids
Prolonged ICU stay
Mechanical ventilation
Central venous catheters

Prevention strategies:

PCP prophylaxis with trimethoprim-sulfamethoxazole
Antifungal prophylaxis in high-risk patients
Early removal of unnecessary devices

Medication-Related Complications

IVIG-related:

Aseptic meningitis (2-3% incidence)
Hemolysis in patients with blood group incompatibility
Acute kidney injury
Venous thromboembolism

Rituximab-related:

Infusion reactions (30-40% first infusion)
Progressive multifocal leukoencephalopathy (rare, <1:10,000)
Reactivation of hepatitis B

Prognostic Factors and Outcomes

Favorable Prognostic Factors

Age <30 years
Early treatment initiation (<30 days from symptom onset)
Absence of ICU admission
Associated tumor with successful removal
Good response to first-line therapy

Oyster: Patients may continue to improve for up to 24 months after treatment initiation, so don't abandon hope if initial response is slow.

Poor Prognostic Factors

Delayed diagnosis and treatment (>30 days)
Requirement for ICU admission
Need for mechanical ventilation
Male gender (in anti-NMDAR encephalitis)
Presence of status epilepticus

Outcome Measures

Modified Rankin Scale (mRS) at 24 months:

Good outcome (mRS 0-2): 70-80% of patients
Moderate disability (mRS 3-4): 15-20%
Severe disability/death (mRS 5-6): 5-10%

Relapse Prevention and Long-term Management

Relapse Risk Factors

No tumor found/removed
Incomplete response to initial therapy
CSF antibody persistence at 1 year
Previous relapse history

Maintenance Immunotherapy

Indications:

Incomplete response to acute therapy
Relapse within 2 years
Persistently positive CSF antibodies

Agents:

Mycophenolate mofetil: 1000mg PO BID
Azathioprine: 2-3mg/kg/day PO
Rituximab: 1000mg IV every 6 months

Special Populations

Pediatric Considerations

Lower steroid doses: Methylprednisolone 30mg/kg/day (max 1000mg)
IVIG dosing: Same weight-based dosing as adults
Tumor association: Lower in children <12 years (5-10%)
Prognosis: Generally better than adults

Pregnancy

Preferred agents: Corticosteroids, IVIG
Avoid: Rituximab, cyclophosphamide, mycophenolate
Delivery timing: Consider early delivery if severe disease

Elderly Patients

Increased complications: Higher infection risk, slower recovery
Modified protocols: Lower steroid doses, careful fluid management with IVIG
Tumor screening: More aggressive due to higher malignancy association

Quality Improvement and System Considerations

Early Recognition Protocols

ED screening tools:

Autoimmune Encephalitis Score⁷
Clinical criteria for empirical treatment
Rapid neurology consultation protocols

ICU Care Bundles

Hour 1: Blood cultures, CSF studies, empirical acyclovir
Hour 6: Neurology consultation, continuous EEG
Hour 12: Tumor screening imaging
Day 1: First-line immunotherapy initiation
Day 3: Second-line therapy if no improvement

Critical Care Hack: Develop institutional protocols for autoimmune encephalitis to ensure consistent, evidence-based care and reduce time to treatment.

Emerging Therapies and Future Directions

Novel Immunotherapies

Tocilizumab: IL-6 receptor antagonist showing promise in refractory cases⁸
Bortezomib: Proteasome inhibitor for plasma cell depletion
CAR-T cell depletion: Experimental therapy for B-cell mediated autoimmunity

Biomarkers

Neurofilament light chain: Correlates with neuronal damage severity
HMGB1: Potential inflammatory marker for disease monitoring
Cytokine panels: May predict treatment response

Neuroprotective Strategies

Hypothermia protocols: For severe cases with refractory hyperthermia
Antioxidant therapy: N-acetylcysteine, vitamin C
NMDA receptor modulators: Memantine for receptor dysfunction

Conclusions

Autoimmune encephalitis represents a medical emergency requiring prompt recognition and aggressive treatment in the ICU setting. The combination of methylprednisolone 1g IV and IVIG 0.4g/kg × 5 days remains the cornerstone of first-line therapy, with rituximab initiation recommended by day 3 if no clinical improvement is observed.

Critical care management extends beyond immunotherapy to include comprehensive supportive care, complication prevention, and systematic tumor screening. Early treatment initiation within the first week of symptom onset remains the strongest predictor of favorable outcomes.

The evolving understanding of autoimmune encephalitis pathophysiology continues to inform treatment strategies, with emerging therapies offering hope for patients with refractory disease. ICU physicians must maintain high clinical suspicion, implement standardized treatment protocols, and collaborate closely with neurology and immunology specialists to optimize patient outcomes.

Key Clinical Pearls and Oysters

🔷 Pearls (Remember These):

"The 72-hour rule": Start first-line immunotherapy within 72 hours for optimal outcomes
"Don't wait for CSF": Begin empirical treatment if LP delayed beyond 6 hours
"Day 3 decision": Initiate rituximab by day 3 if no improvement with first-line therapy
"Movement = autoimmune": New-onset movement disorders in young patients suggest AE
"Normal MRI doesn't exclude": 50% of anti-NMDAR cases have normal brain MRI

🦪 Oysters (Don't Get Caught):

"Psychiatric first impression": Initial psychiatric symptoms often delay neurological workup
"AED resistance": Traditional antiepileptic drugs less effective than immunotherapy
"Slow recovery expectation": Improvement continues up to 24 months post-treatment
"False negative serum": CSF antibodies more sensitive than serum testing
"Steroid sparing illusion": Don't reduce steroids too quickly to avoid rebound inflammation

🔧 Critical Care Hacks:

"Dual therapy start": Begin methylprednisolone + IVIG simultaneously, not sequentially
"Dexmedetomidine preference": Best sedation choice for mechanically ventilated AE patients
"Bundle approach": Use time-driven protocols to ensure rapid diagnosis and treatment
"Tumor urgency": Aggressive tumor screening within 48 hours, especially in young women
"Continuous EEG mandate": Essential for seizure detection and treatment monitoring

References

Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177.
Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25-36.
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
Finke C, Kopp UA, Prüss H, et al. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2012;83(2):195-198.
Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79(11):1094-1100.
Balu R, McCracken L, Lancaster E, et al. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019;92(3):e244-e252.
Dubey D, Singh J, Britton JW, et al. Predictive models for diagnosis and prognosis of autoimmune encephalitis. Brain. 2020;143(5):1424-1435.
Lee WJ, Lee ST, Byun JI, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016;86(18):1683-1691.

This review article is intended for educational purposes and should not replace clinical judgment. Treatment decisions should always be individualized based on patient-specific factors and institutional protocols.

Saturday, August 16, 2025