What is the best treatment approach for a patient with uncontrolled seizures, high ANA titer, elevated CRP, and mixed seizure types, with potential autoimmune etiology?

Treatment Approach for Suspected Autoimmune Encephalitis with Refractory Seizures

This patient's 30-year history of uncontrolled seizures with ANA positivity (1:320), elevated CRP, chronic monocytosis, behavioral changes linked to immune triggers, and partial ACTH response strongly suggests autoimmune encephalitis, and should be treated immediately with first-line immunotherapy (high-dose corticosteroids, IVIG, or plasma exchange) without waiting for antibody confirmation, as delay in treatment leads to worse outcomes. 1, 2, 3

Immediate Diagnostic Workup Required

Before initiating treatment, rapidly complete the following evaluation:

• Neurologic consultation immediately 4
• MRI brain with and without contrast looking specifically for T2/FLAIR hyperintensities in limbic regions or other areas characteristic of autoimmune encephalitis 4, 1
• Lumbar puncture with comprehensive CSF analysis including cell count with differential, protein, glucose, oligoclonal bands, IgG index, autoimmune encephalopathy panel, paraneoplastic antibody panel, and viral PCRs (especially HSV) 4, 1
• Serum studies: neuronal autoantibody panel, paraneoplastic panel, thyroid function with TPO and thyroglobulin antibodies, morning cortisol and ACTH, ESR, CBC, comprehensive metabolic panel 4, 1
• EEG to evaluate for subclinical seizures and characteristic patterns 4, 1
• Collect blood samples BEFORE any IVIG or plasma exchange to avoid false antibody results 1, 2

Critical caveat: Normal CSF does not exclude autoimmune encephalitis—antibody testing should still be performed with high clinical suspicion 1, 2

First-Line Immunotherapy (Initiate Immediately)

Do not wait for antibody results to start treatment, as early immunotherapy within 4 weeks of symptom onset confers the best recovery 4, 1, 2, 3

Choose one or combine the following first-line agents:

High-Dose Corticosteroids (Most Common First Choice)

• Intravenous methylprednisolone 1-2 mg/kg/day for standard dosing 4, 3
• OR pulse dosing: methylprednisolone 1g IV daily for 3-5 days for severe cases 4, 3
• Followed by oral corticosteroid taper over at least 4-6 weeks 4, 3

IVIG (Preferred in Specific Situations)

• 0.4 g/kg/day for 5 days (total dose 2 g/kg) 4, 3
• Preferred if patient is agitated/combative, has bleeding disorders, or difficulty with central line placement 3

Plasma Exchange (PLEX)

• 5-10 sessions performed every other day 3
• Preferred for severe hyponatremia, high thromboembolic risk, or associated demyelination 3
• Often used preceding IVIG 2, 3

Combination therapy is frequently employed and recommended 2, 3

Second-Line Immunotherapy

If no meaningful clinical or radiological response after 2-4 weeks of optimized first-line therapy, escalate to second-line agents 3:

• Rituximab is the preferred second-line agent for antibody-mediated autoimmune encephalitis (chosen by 80% of experts) 3
• Cyclophosphamide should be considered for cell-mediated autoimmunity 3
• Both agents have shown good results as rescue therapy 3

Concurrent Supportive Management

Seizure Control

• Continue or optimize antiseizure medications 1, 2
• Consider seizure prophylaxis given the patient's history and EEG abnormalities 4

Monitor for Complications

• Serial monitoring of CRP, ferritin, CBC, comprehensive metabolic panel 4
• Careful correction of hyponatremia if present 1, 2, 3
• Management of dysautonomia (blood pressure fluctuations, cardiac arrhythmias) 1, 2, 3
• Aspiration precautions 4

Understanding the Elevated CRP in This Context

Important distinction: While seizures themselves can transiently elevate CRP, the chronic elevation in this patient suggests underlying autoimmune inflammation rather than seizure-induced changes alone 5, 6, 7

• Seizure-induced CRP elevation is typically mild (<6 mg/dL) and transient 5
• Chronic intractable epilepsy with frequent generalized motor seizures can cause persistently elevated IL-6 and CRP 7
• However, this patient's constellation of findings (ANA positivity, chronic monocytosis, immune-triggered behavioral changes, ACTH response) points toward primary autoimmune etiology 1, 2

Tumor Screening

Given the possibility of paraneoplastic encephalitis:

• Whole-body imaging as indicated by antibody profile 2
• Patients with known cancer or at increased risk (smokers, elderly, rapid weight loss) require aggressive tumor screening 4, 2
• Annual tumor screening for several years, particularly if treatment response is poor or relapses occur 4

Critical Pitfalls to Avoid

• Never delay immunotherapy waiting for antibody results—this is the single most important factor affecting outcomes 1, 2, 3
• Do not assume normal CSF excludes autoimmune encephalitis 1, 2
• Insufficient treatment or rapid interruption causes relapses—taper steroids slowly over 4-6 weeks minimum 4, 2, 3
• Collect blood samples before IVIG/PLEX to avoid false antibody results 1, 2
• Monitor for treatment response at 2-4 weeks—if inadequate, escalate to second-line agents rather than continuing ineffective first-line therapy 3

Long-Term Management

• Serial antibody level monitoring in serum and CSF can guide treatment weaning 2
• Approximately 25-30% of patients may relapse, particularly with NMDA-receptor antibody encephalitis 4
• Relapses often result from insufficient initial treatment or premature discontinuation of immunotherapy 4, 2