The Baffling Brain: Autoimmune Encephalitis

A Critical Care Perspective on Diagnosis and Management

Dr Neeraj Manikath , claude.ai

Abstract

Autoimmune encephalitis (AE) represents a paradigm shift in our understanding of neuropsychiatric disorders, bridging the gap between neurology, psychiatry, and critical care medicine. Once considered rare, AE is now recognized as a leading cause of non-infectious encephalitis, particularly in younger patients. This review explores the diagnostic challenges, antibody-specific clinical syndromes, and evidence-based therapeutic strategies essential for critical care physicians managing these complex patients.

Introduction

The recognition of autoimmune encephalitis has revolutionized our approach to patients presenting with acute behavioral changes, seizures, and altered consciousness. Since the landmark description of anti-NMDA receptor encephalitis in 2007, the spectrum of autoimmune encephalopathies has expanded dramatically, with over 20 distinct antibody-associated syndromes now identified. In the intensive care unit, these patients often present with refractory status epilepticus, severe autonomic instability, or profound coma, making early recognition and treatment imperative for favorable outcomes.

The true incidence of AE rivals that of infectious encephalitis, with studies suggesting rates of 0.8-1.0 per 100,000 person-years. However, diagnostic delays remain common, with many patients initially misdiagnosed as having primary psychiatric illness or viral encephalitis. For the critical care physician, understanding the protean manifestations of AE and maintaining a high index of suspicion can be life-saving.

The Masqueraders: Differentiating from Psychiatric Illness, Viral Encephalitis, and Neurodegenerative Disease

The Psychiatric Mimicry Dilemma

Clinical Pearl: Any patient presenting with new-onset psychiatric symptoms accompanied by seizures, movement disorders, or autonomic instability should raise suspicion for AE, not primary psychiatric illness.

The overlap between AE and primary psychiatric disorders presents one of the most challenging diagnostic conundrums. Studies indicate that up to 77% of anti-NMDA receptor encephalitis patients are initially referred to psychiatry services. Key distinguishing features include:

Red Flags for AE over Primary Psychiatric Illness:

Rapid progression (days to weeks vs. months to years)
Associated neurological symptoms: seizures (60-80% in NMDA-AE), movement disorders, autonomic instability
Age of onset: first psychiatric episode after age 30 warrants heightened suspicion
Treatment resistance: failure to respond to appropriate psychiatric medications
Cognitive dysfunction: profound memory deficits disproportionate to mood symptoms
Sleep disturbances: insomnia with oneiric stupor (dream-like state while awake)

Oyster: The presence of "psychiatry-plus" features (psychiatric symptoms plus seizures, movement disorders, or dysautonomia) should virtually exclude primary psychiatric diagnosis until AE is ruled out.

Viral Encephalitis: The Great Imitator

Herpes simplex encephalitis (HSE) remains the most important infectious differential, given its treatable nature and devastating consequences if missed. However, several clinical and investigational clues can help differentiate these entities:

Feature	Viral Encephalitis (HSE)	Autoimmune Encephalitis
Onset	Acute (hours-days)	Subacute (days-weeks)
Fever	High-grade, prominent	Low-grade or absent
CSF pleocytosis	>100 cells (often >500)	<100 cells (typically <50)
CSF protein	Markedly elevated	Normal to mildly elevated
MRI findings	Temporal lobe hemorrhagic necrosis	Variable; often normal initially
Focal deficits	Early aphasia, hemiparesis	Movement disorders, psychiatric

Critical Care Hack: In unclear cases, empiric acyclovir should always be initiated until HSV PCR returns negative. However, don't let normal MRI or negative HSV PCR exclude AE—both conditions can coexist, and HSV encephalitis may trigger parainfectious AE.

Neurodegenerative Disease Considerations

In older patients, rapidly progressive dementia (RPD) syndromes, particularly Creutzfeldt-Jakob disease (CJD), enter the differential. Distinguishing features include:

Favoring AE:

Prominent behavioral or psychiatric features early
Responsiveness to immunotherapy
Specific antibody positivity
MRI: FLAIR hyperintensity in medial temporal lobes, cerebellum, or brainstem

Favoring CJD:

Prominent myoclonus
Visual symptoms early
DWI hyperintensity in cortical ribbon or basal ganglia
Elevated CSF 14-3-3 protein or RT-QuIC positivity

Pearl: LGI1 antibody-associated encephalitis can present as RPD in patients >50 years, but responds dramatically to immunotherapy—making this a critical diagnosis not to miss.

Antibody Profiles: Anti-NMDA, LGI1, CASPR2 - Clinical Pearls for Each

Anti-NMDA Receptor Encephalitis

Epidemiology: Most common AE in patients <30 years; female predominance (4:1)

Classic Clinical Progression:

Prodromal phase (days): flu-like symptoms, headache, fever
Psychiatric phase (1-2 weeks): psychosis, agitation, bizarre behavior
Neurological phase (2-4 weeks): seizures, movement disorders, decreased consciousness
Hyperkinetic phase: orofacial dyskinesias, choreoathetosis, autonomic instability
Recovery phase (months): gradual improvement, often with amnesia for acute illness

Pathognomonic Movement Disorder: Orofacial dyskinesias with limb choreoathetosis occurring in a comatose patient is virtually diagnostic.

Critical Care Pearl: Autonomic instability can be severe—expect cardiovascular lability (hypertension/hypotension, brady/tachycardia), hyperthermia, and hypoventilation requiring mechanical ventilation in 75% of ICU patients.

Tumor Association: Ovarian teratoma in 30-60% of females (age 12-45 years). Always screen with pelvic ultrasound/CT—tumor removal significantly improves outcomes.

Pediatric Oyster: Children <12 years often present with movement disorders and seizures without prominent psychiatric features, and have lower rates of tumor association.

LGI1 (Leucine-Rich Glioma-Inactivated 1) Antibody Encephalitis

Epidemiology: Median age 60 years; male predominance (2:1)

Signature Clinical Features:

Faciobrachial dystonic seizures (FBDS): Pathognomonic brief (<3 seconds) focal seizures involving ipsilateral face and arm, occurring up to 100 times daily
Severe hyponatremia: Present in 60%, often <125 mEq/L (SIADH mechanism)
Cognitive impairment: Prominent amnesia and temporal lobe seizures
REM sleep behavior disorder

Critical Pearl: FBDS precedes cognitive decline by weeks to months. Early recognition and treatment can prevent progression to severe encephalitis. FBDS often do not respond to traditional antiepileptic drugs but respond dramatically to immunotherapy.

Diagnostic Hack: The triad of FBDS + hyponatremia + medial temporal lobe T2 hyperintensity on MRI is virtually pathognomonic for LGI1-AE.

Tumor Association: Only 5-10% (small cell lung cancer, thymoma)—much lower than NMDA-AE

CASPR2 (Contactin-Associated Protein-2) Antibody Encephalitis

Epidemiology: Similar to LGI1 (older males), often overlapping clinical features

Clinical Syndrome (Morvan Syndrome spectrum):

Neuromyotonia (continuous muscle fiber activity)
Neuropathic pain
Autonomic dysfunction (hyperhidrosis, constipation)
Insomnia (profound, with oneiric stupor)
Cognitive impairment
Weight loss

Distinguishing from LGI1:

Peripheral nerve involvement: neuropathic pain, neuromyotonia
Severe insomnia more prominent than in LGI1
Hyponatremia less common
FBDS absent

Pearl: CASPR2 antibodies may overlap with voltage-gated potassium channel (VGKC) complex antibodies. However, true pathogenic antibodies target CASPR2 or LGI1 proteins—not the VGKC complex itself. Always request specific antibody testing.

Tumor Association: 20-40% (thymoma, small cell lung cancer)

The Diagnostic Triad: Clinical Presentation, MRI Brain, and Autoimmune Antibody Panels

Clinical Criteria for Possible AE

The 2016 consensus criteria establish a framework for diagnosis even before antibody results are available:

Three Major Criteria (all required):

Subacute onset (<3 months) of working memory deficits, altered mental status, or psychiatric symptoms
At least one of: new focal CNS findings, seizures, CSF pleocytosis, MRI features suggestive of encephalitis
Reasonable exclusion of alternative causes

Oyster: Don't wait for antibody results to initiate treatment. Seronegative AE exists in 10-30% of cases with compatible clinical syndrome. When clinical suspicion is high, treat empirically.

MRI Brain: What to Look For

NMDA Receptor Encephalitis:

Normal in 50% during initial presentation
When abnormal: T2/FLAIR hyperintensity in cortical/subcortical regions, medial temporal lobes, cerebellum, brainstem
Pearl: Normal MRI does not exclude diagnosis

LGI1 Encephalitis:

Medial temporal lobe T2/FLAIR hyperintensity (80%)
Often bilateral, asymmetric
May show hippocampal atrophy in chronic cases
Basal ganglia enhancement occasionally seen

CASPR2 Encephalitis:

Similar to LGI1 but less frequent
May show cerebellar atrophy

Critical Care Hack: Always perform MRI with gadolinium contrast and include FLAIR, DWI, and T1 post-contrast sequences. Leptomeningeal enhancement may be seen in severe cases.

Autoimmune Antibody Panels: Serum and CSF

Testing Strategy:

Both serum AND CSF should be tested—some antibodies are exclusively or predominantly detected in CSF (especially NMDA receptor antibodies)
First-line panel should include: NMDA, LGI1, CASPR2, AMPA, GABA-B, GABA-A receptors
Consider expanded panels for atypical presentations: GAD65, mGluR5, DPPX

Interpretation Pearls:

Serum-only positivity (especially at low titers): consider false positive or paraneoplastic syndrome without encephalitis
CSF positivity (with or without serum): highly specific for true AE
Low VGKC titers without LGI1/CASPR2: often non-specific; less likely to respond to immunotherapy

Critical Care Oyster: Commercial antibody panels may take 1-2 weeks. CSF parameters can guide early treatment:

Lymphocytic pleocytosis (5-100 cells)
Protein mildly elevated or normal
Glucose normal
Oligoclonal bands present in 60%
Negative HSV/VZV PCR

First-Line Immunotherapy: Pulse Steroids, IVIG, and Plasmapheresis

Treatment Principles

Time is brain: Early immunotherapy (within 4 weeks of symptom onset) correlates with better outcomes. In the ICU, don't delay treatment while awaiting antibody confirmation in patients meeting clinical criteria for possible AE.

Methylprednisolone Pulse Therapy

Regimen: 1000 mg IV daily for 3-5 days, followed by oral prednisone taper (1 mg/kg/day, taper over 6-8 weeks)

Mechanism: Broad immunosuppression, reduced inflammation, decreased antibody production

Pearls:

First-line for most AE subtypes
Monitor for hyperglycemia, hypertension, psychosis (can worsen psychiatric symptoms initially)
Consider stress dose steroids during taper if adrenal suppression suspected

Intravenous Immunoglobulin (IVIG)

Regimen: 0.4 g/kg/day for 5 days (total 2 g/kg)

Mechanism: Antibody neutralization, complement inhibition, immune modulation

Advantages:

Excellent safety profile
Can be combined with steroids
Preferred in patients with active infection concerns

Pearls:

Administer slowly in patients with cardiac or renal dysfunction
Monitor for aseptic meningitis (headache, fever post-infusion)
May cause hemolysis in patients with blood group antibodies

Plasma Exchange (PLEX)

Regimen: 5-7 exchanges over 10-14 days (1-1.5 plasma volumes per exchange)

Mechanism: Direct removal of pathogenic antibodies

Indications:

Severe, rapidly progressive cases
Failure to respond to steroids/IVIG
Refractory status epilepticus

Critical Care Pearls:

Requires central venous access—consider tunneled catheter if prolonged therapy anticipated
More effective than IVIG in severe NMDA receptor encephalitis (retrospective data)
Replace with albumin (preferred) or FFP
Monitor for hypocalcemia, hypotension, line infections

Hack: In mechanically ventilated patients with refractory AE, consider immunoadsorption where available—more selective than PLEX, removes IgG while sparing clotting factors and albumin.

Combination vs. Sequential Therapy

Recommended First-Line Approach:

Mild to moderate cases: Methylprednisolone + IVIG
Severe cases (ICU, coma, refractory seizures): Methylprednisolone + PLEX, or triple therapy (steroids + IVIG + PLEX)

Pearl: Response to first-line therapy should be assessed at 10-14 days. If no improvement or worsening occurs, escalate to second-line agents—don't wait.

Second-Line and Long-Term Management: Rituximab and Cyclophosphamide

Indications for Second-Line Therapy

Failure to improve after 10-14 days of first-line therapy
Relapse despite first-line treatment
Severe presentation requiring aggressive immunosuppression
Known high-relapse antibodies (LGI1, CASPR2)

Rituximab (Anti-CD20 Monoclonal Antibody)

Regimen:

Induction: 375 mg/m² IV weekly × 4 doses, OR 1000 mg IV × 2 doses (2 weeks apart)
Maintenance: Consider 6-12 monthly dosing for 1-2 years in relapsing cases

Mechanism: B-cell depletion, reducing antibody-producing cells

Advantages:

Generally well-tolerated
Preferred in younger patients, women of childbearing age
Lower toxicity than cyclophosphamide

Monitoring:

Pre-infusion: Hepatitis B screening (risk of reactivation)
CD19/CD20 counts to confirm B-cell depletion
IgG levels (risk of hypogammaglobulinemia with prolonged use)

Pearls:

Increasingly used as first-line in NMDA receptor encephalitis, especially after tumor removal
May take 4-8 weeks to see clinical effect
Premedicate with acetaminophen, antihistamines, and consider corticosteroids to reduce infusion reactions

Cyclophosphamide

Regimen:

IV: 750 mg/m² monthly for 6 months
Oral: 2 mg/kg/day (less commonly used due to bladder toxicity)

Mechanism: Alkylating agent, broad immunosuppression

Indications:

Severe, refractory cases failing rituximab
Older patients (>45 years) where fertility preservation not a concern
Rapid clinical deterioration

Critical Toxicities:

Hemorrhagic cystitis: Prevent with mesna and aggressive hydration
Bone marrow suppression: Monitor CBC weekly
Infertility: Counsel patients; consider fertility preservation
Opportunistic infections: PCP prophylaxis mandatory (trimethoprim-sulfamethoxazole)

Pearl: Cyclophosphamide is more toxic but may be more effective in severe, treatment-refractory cases. Risk-benefit must be carefully weighed.

Long-Term Management and Relapse Prevention

Relapse Rates:

NMDA receptor encephalitis: 12-25%
LGI1 encephalitis: 20-30%
CASPR2 encephalitis: 20-35%

Strategies:

Tumor surveillance: Regular imaging if paraneoplastic; removal significantly reduces relapse
Maintenance immunosuppression: Consider for 1-2 years in antibody-positive patients, especially with relapses
- Rituximab 6-12 monthly
- Mycophenolate mofetil 1000-2000 mg/day
- Azathioprine 2-3 mg/kg/day
Long-term steroid taper: Slow taper over 6-12 months, monitoring for relapse

Critical Care Oyster: Serum antibody titers do not reliably predict relapse and should not guide treatment decisions. Clinical monitoring is paramount.

Conclusion

Autoimmune encephalitis represents a treatable cause of catastrophic neurological illness, but early recognition and aggressive immunotherapy are essential for optimal outcomes. For the critical care physician, maintaining a high index of suspicion in patients with unexplained encephalopathy, new-onset psychiatric symptoms with neurological features, or refractory status epilepticus can be life-saving. The key is recognizing the "psychiatry-plus" syndrome, initiating empiric therapy based on clinical criteria, and escalating treatment aggressively in non-responders. With prompt diagnosis and treatment, the majority of patients can achieve substantial recovery, even from profound coma—a truly rewarding outcome in critical care medicine.

Key References

Graus F, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15(4):391-404.
Dalmau J, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7(12):1091-1098.
Titulaer MJ, 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.
Irani SR, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69(5):892-900.
Lee WJ, et al. Rituximab in autoimmune encephalitis: Clinical outcomes and predictive factors. Ann Clin Transl Neurol 2021;8(2):340-351.
Dubey D, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83(1):166-177.
van Sonderen A, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology 2016;87(5):521-528.
Nosadini M, et al. Use and safety of immunotherapeutic management of N-methyl-d-aspartate receptor antibody encephalitis: a meta-analysis. JAMA Neurol 2021;78(11):1333-1344.

Word Count: 2,000 words

learningmedicine

Wednesday, October 29, 2025