What is the prognosis of autoimmune encephalitis, and how do early first‑line immunotherapy, age, antibody subtype (e.g., anti‑NMDA‑receptor vs anti‑LGI1), and tumor association affect functional recovery and mortality?

Prognosis of Autoimmune Encephalitis

Most patients with autoimmune encephalitis achieve good functional recovery (80% reach mRS 0-2) when treated promptly with immunotherapy, though outcomes vary significantly based on early treatment initiation, age, antibody subtype, and disease severity. 1, 2

Overall Prognosis and Recovery Rates

• Approximately 75-80% of patients achieve complete recovery or good functional outcomes (mRS 0-2) with appropriate immunotherapy, while 20-25% experience persistent sequelae of varying severity 1, 2
• Mortality rates range from 3-5% in treated cohorts, with most deaths occurring in severe cases requiring intensive care 1, 2
• Relapse occurs in approximately 12-28% of patients during long-term follow-up, necessitating maintenance immunotherapy in selected cases 1, 3

Impact of Early First-Line Immunotherapy

Early initiation of first-line immunotherapy (within 2-4 weeks of symptom onset) is the single most important modifiable prognostic factor, as delayed treatment beyond 48 hours after hospital admission significantly worsens outcomes 4, 5, 6

• Response to first-line therapy (corticosteroids, IVIG, or plasma exchange) is itself a strong predictor of good long-term prognosis 6, 2
• Approximately 60% of severe AE patients respond adequately to first-line immunotherapy alone 2
• Patients requiring escalation to second-line therapy (rituximab or cyclophosphamide) within 2-4 weeks of inadequate first-line response have better outcomes than those with delayed escalation 7, 6

Age-Related Prognostic Differences

Infants and young children (≤3 years old) with anti-NMDAR encephalitis have significantly worse prognosis compared to older children and adults, with higher rates of fever, status epilepticus, ICU admission, and persistent neurological sequelae 1

• The elderly (>60-65 years) face higher mortality risk, particularly with HSV encephalitis, though autoimmune encephalitis in this age group (median age 65 years for antibody-mediated AE) can still respond well to immunotherapy if treated promptly 5, 8
• Young to middle-aged adults (median age 35 years) generally have the most favorable prognosis with appropriate treatment 2

Antibody Subtype-Specific Outcomes

Anti-NMDAR Encephalitis

• Anti-NMDAR encephalitis is the most common subtype in patients under 30 years and generally has favorable prognosis with early immunotherapy 4, 1
• Up to 50% of women over age 18 with anti-NMDAR encephalitis have associated ovarian teratomas; tumor removal significantly improves outcomes 4
• Rituximab is the preferred second-line agent for anti-NMDAR encephalitis due to superior efficacy in antibody-mediated disease 4, 7

Anti-LGI1 Encephalitis

• Anti-LGI1 encephalitis is the second most common subtype and typically presents with cognitive changes and distinctive seizure types 8
• This subtype generally responds well to immunotherapy, though specific prognostic data is more limited than for anti-NMDAR encephalitis 9, 8

Other Antibody Subtypes

• Anti-CASPR2, anti-GABABR, and other rare antibody subtypes collectively represent a minority of cases with variable prognosis depending on tumor association and treatment response 1, 8

Tumor Association and Prognosis

Identification and removal of underlying tumors (particularly ovarian teratomas in anti-NMDAR encephalitis) is critical for optimal outcomes, as the tumor often triggers the autoimmune response 4

• Tumor screening with CT chest/abdomen/pelvis should be performed in all patients, with additional imaging (pelvic ultrasound, PET scan) guided by individual risk factors 4
• Annual tumor surveillance should be conducted for several years in patients with proven antibody-associated encephalitis, as tumors may develop after initial presentation 9, 4
• Paraneoplastic cases with intracellular antibodies generally have worse prognosis than those with neuronal surface antibodies 3

Predictors of Poor Prognosis

Several baseline factors predict worse outcomes and should trigger early escalation to second-line therapy:

• Modified Rankin Scale (mRS) ≥4 at worst neurological status 6, 1
• Requirement for intensive care unit admission 6, 1
• Failure to respond to more than one first-line immunotherapy agent 7, 6
• High neutrophil-to-lymphocyte ratio (NLR) at presentation (lower NLR predicts better outcomes) 2
• Progressive clinical deterioration despite adequate first-line therapy 7

Biomarkers for Treatment Response

• High CD19+ B-cell count at baseline predicts favorable response to first-line immunotherapy (OR 1.197,95% CI 1.043-1.496) 2
• Lower neutrophil-to-lymphocyte ratio predicts good long-term prognosis (OR 0.686,95% CI 0.472-0.884) 2

Long-Term Functional Recovery

• Among patients achieving good outcomes, approximately 75% recover completely without residual deficits, while 25% have mild persistent symptoms that do not significantly impact daily function 1
• Cognitive deficits, psychiatric symptoms, and seizures are the most common persistent sequelae in patients with incomplete recovery 9, 8
• Maintenance immunotherapy with oral prednisone taper, monthly IVIG, or monthly IV methylprednisolone reduces relapse risk and improves long-term outcomes 4, 3

Critical Pitfalls to Avoid

• Do not delay immunotherapy while awaiting antibody confirmation—treatment should begin once infection is excluded by basic CSF analysis, as delayed treatment dramatically worsens prognosis 4, 7
• Do not underestimate the need for early escalation to second-line therapy—waiting beyond 2-4 weeks after first-line failure increases morbidity 7, 6
• Do not neglect tumor screening—failure to identify and remove underlying neoplasms compromises treatment efficacy and increases relapse risk 9, 4
• Do not use monotherapy with corticosteroids alone in severe presentations—combination therapy (steroids plus IVIG or plasma exchange) from the outset improves outcomes in critically ill patients 4, 7