Autoimmune Encephalitis (Anti-NMDA Receptor Encephalitis)
This clinical presentation—a young woman with high fever, refractory seizures unresponsive to multiple antiepileptic drugs and benzodiazepines, and CSF showing mild lymphocytic pleocytosis (6 cells) with mildly elevated protein (80 mg/dL)—is most consistent with autoimmune encephalitis, specifically anti-NMDA receptor encephalitis, and requires immediate immunosuppressive therapy with high-dose intravenous corticosteroids, IVIG, or plasma exchange, alongside urgent ovarian imaging to exclude teratoma. 1
Why Autoimmune Encephalitis is Most Likely
Refractory seizures (status epilepticus) that fail to respond to multiple antiepileptic drugs (topiramate, levetiracetam, lacosamide) and IV benzodiazepines are a hallmark of autoimmune encephalitis, particularly anti-NMDA receptor encephalitis. 1
Young female demographic (23 years old) is the classic presentation for anti-NMDA receptor encephalitis, which predominantly affects women of childbearing age. 1
Mild CSF abnormalities with lymphocytic pleocytosis (6 cells) and mildly elevated protein (80 mg/dL) are characteristic of autoimmune encephalitis. In contrast to infectious causes, the CSF abnormalities are often subtle or even normal in autoimmune encephalitis. 1, 2
Fever with seizures in this context suggests an inflammatory CNS process, and when seizures are refractory to standard antiepileptic therapy, autoimmune encephalitis must be considered immediately. 1, 3
Critical Immediate Management
First-Line Immunotherapy (Start Within Hours)
High-dose intravenous methylprednisolone (1 gram daily for 3-5 days) should be initiated immediately. 1
IVIG (0.4 g/kg daily for 5 days) can be used as an alternative or in combination with corticosteroids. 1
Plasma exchange (5-7 exchanges over 10-14 days) should be considered if there is no response to corticosteroids and IVIG within 10-14 days. 1
Treatment started within 4 weeks of symptom onset confers the best recovery, making early recognition and intervention critical. 1
Concurrent Empiric Antimicrobial Coverage (Until Exclusion)
While autoimmune encephalitis is most likely, you must not miss infectious causes that require immediate treatment:
IV acyclovir (10 mg/kg every 8 hours) should be started immediately to cover HSV encephalitis until HSV PCR returns negative. HSV encephalitis can present with seizures and mild CSF pleocytosis, and 5-10% of cases have completely normal initial CSF. 2, 4
Broad-spectrum antibiotics (ceftriaxone 2g IV q12h + vancomycin 15-20 mg/kg IV q8-12h + ampicillin 2g IV q4h) should be given to cover bacterial meningitis, including Listeria, until bacterial cultures are negative at 48-72 hours. 2
Essential Diagnostic Workup
Autoimmune Panel (Send Immediately)
Serum and CSF autoimmune encephalitis antibody panel including anti-NMDA receptor, anti-LGI1, anti-CASPR2, anti-GABA-B, and anti-AMPA receptor antibodies. 1, 2
CSF-specific IgM antibodies for anti-NMDA receptor are diagnostic and can be detected in CSF even when serum is negative. 1
Tumor Screening (Urgent)
Pelvic ultrasound or CT/MRI to screen for ovarian teratoma, which is present in approximately 50% of young women with anti-NMDA receptor encephalitis. 1
Annual tumor screening should be conducted for several years if initial imaging is negative, as teratomas can develop later. 1
Infectious Workup (To Exclude Mimics)
CSF HSV-1/2, VZV, and enterovirus PCR with sensitivity >95% for HSV. 2
CSF bacterial culture and Gram stain. 2
Brain MRI with contrast to evaluate for temporal lobe involvement (HSV), autoimmune patterns, or other parenchymal abnormalities. MRI is abnormal in only 30% of autoimmune encephalitis cases, showing FLAIR or T2 signal changes in medial temporal lobes, periventricular regions, or cerebellum. 1, 2
EEG to assess for nonconvulsive status epilepticus and to document epileptic activity, which is present in only 30% of autoimmune encephalitis cases. 1
Key Differential Diagnoses to Exclude
HSV Encephalitis
- Would typically show temporal lobe involvement on MRI and hemorrhagic changes, though MRI can be normal early. 2
- CSF may be normal initially in 5-10% of cases, requiring repeat lumbar puncture at 24-48 hours if HSV PCR is negative but suspicion remains high. 2, 4
- Lymphocytic pleocytosis is typical, but CSF protein is usually more elevated (>100 mg/dL) than in this case. 4
Tuberculous Meningitis
- Would show CSF/plasma glucose ratio <0.5** and **markedly elevated protein (>100 mg/dL). 5
- Subacute course >3 weeks is typical, not acute presentation with high fever. 5
- This patient's normal CSF glucose (implied by protein 80 mg/dL without mention of low glucose) makes TB meningitis unlikely. 5
Japanese Encephalitis (If Endemic Exposure)
- Would show lymphocytic pleocytosis with moderately elevated protein, similar to this case. 1
- Seizures are common, especially in children, and parkinsonian features may be present. 1
- However, no specific treatment exists for Japanese encephalitis beyond supportive care, making this diagnosis less actionable. 1
Critical Pitfalls to Avoid
Do not delay immunotherapy while awaiting antibody results. Treatment should begin based on clinical suspicion when seizures are refractory and CSF shows mild lymphocytic pleocytosis. 1
Do not stop empiric acyclovir and antibiotics prematurely. Continue until HSV PCR is negative and bacterial cultures are negative at 48-72 hours. 2
Do not miss ovarian teratoma. Failure to identify and remove the tumor significantly worsens outcomes in anti-NMDA receptor encephalitis. 1
Recognize that 25% of patients relapse after initial treatment, requiring extended immunosuppression and tumor surveillance. 1
Second-Line Immunotherapy (If No Response to First-Line)
Rituximab (375 mg/m² weekly for 4 weeks) should be considered if there is no response to corticosteroids, IVIG, and plasma exchange within 2-4 weeks. 1
Cyclophosphamide (750 mg/m² monthly) is an alternative second-line agent. 1