Caspr2 Antibody Positive Encephalitis: Treatment and Workup
Start high-dose corticosteroids immediately once infection is ruled out, followed by IVIG or plasma exchange if no improvement, with rituximab as second-line therapy for antibody-mediated disease. 1
Diagnostic Workup
Initial Investigations
- Brain MRI: Look for medial temporal lobe T2/FLAIR hyperintensities or hippocampal abnormalities (present in ~53% of cases) 2
- EEG: Assess for slow wave background activity (abnormal in ~87% of pediatric cases, 40% overall) 2, 3
- Lumbar puncture: Test CSF for:
- Cell count, protein, oligoclonal bands, IgG index
- CASPR2 antibodies in CSF (positive in ~50% of cases) 2
- Rule out infectious causes
- Serum CASPR2 antibody titer: A titer ≥1:200 has 85% sensitivity and 81% specificity for true autoimmune encephalitis 4. Lower titers may represent false positives, especially in refractory epilepsy or behavioral disorders 3
Cancer Screening
Perform CT chest/abdomen/pelvis with contrast to screen for thymoma (present in 21.8% of cases) and other malignancies 1, 2. Thymoma is the most commonly associated tumor with CASPR2 encephalitis. If initial screening is negative but clinical suspicion remains high, consider whole-body FDG-PET (abnormal in 85.7% when performed) 2.
Important Diagnostic Pitfall
Beware of false-positive CASPR2 antibodies: Up to 42% of pediatric cases with low titers, normal MRI/EEG/CSF, and refractory epilepsy or behavioral symptoms may be false positives 3. The combination of high antibody titer (≥1:200) plus encephalitic MRI findings has very high specificity (100%) for true autoimmune encephalitis 4.
Treatment Algorithm
First-Line Immunotherapy
Step 1: High-dose corticosteroids (methylprednisolone 1g IV daily × 3-5 days) once infection is excluded 1
- Alternative if steroids contraindicated: IVIG or plasma exchange
- CASPR2 encephalitis is noted as steroid-responsive 1
Step 2: Add IVIG or plasma exchange if no improvement after initial corticosteroid cycle 1
- IVIG: Preferred in agitated patients or those with bleeding disorders
- Plasma exchange (5-10 sessions): Preferred if severe hyponatremia, high thromboembolism risk, or associated demyelination 1
- Recent data shows no significant outcome difference between IVIG and plasma exchange for CASPR2 encephalitis 5
Second-Line Immunotherapy
If no clinical or radiological improvement 2-4 weeks after combined first-line therapy, initiate rituximab 1
- Rituximab is the preferred second-line agent for CASPR2 encephalitis because it is antibody-mediated (IgG4 predominant) 1, 6
- Dosing: 375 mg/m² weekly × 4 weeks OR 1000 mg × 2 doses, 2 weeks apart 1
- Cyclophosphamide is reserved for suspected cell-mediated/paraneoplastic syndromes 1
- Rituximab has been successfully used in refractory cases 3
Bridging/Maintenance Therapy
Start bridging therapy with gradual oral prednisone taper or monthly IVIG/IV methylprednisolone 1
- This prevents relapses during the recovery phase
- Monitor for disease recurrence (occurs in ~13-29% of cases) 7, 2
Clinical Features to Recognize
The most common presentations include:
- Limbic encephalitis (38.7-73%): Memory impairment, confusion, seizures 7, 2
- Seizures (53%): Often refractory 7
- Peripheral nerve hyperexcitability (37.7%): Neuromyotonia, fasciculations, cramps 2
- Morvan syndrome (22.7%): Insomnia, autonomic dysfunction, neuromyotonia 2
- Behavioral/psychiatric symptoms (20%): Psychosis, agitation 7
- Cerebellar symptoms (13-15%): Ataxia 7, 2
Prognosis
Most patients (75-84%) achieve good functional outcomes (mRS 0-2) with immunotherapy 7, 4. Treatment should be initiated early without waiting for antibody confirmation when clinical suspicion is high. Patients who receive immunotherapy have significantly better outcomes than untreated patients 5. Watch for hippocampal atrophy on follow-up MRI, which can develop even with treatment 4.