Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis

Abstract

Objective: This nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABA_BR) encephalitis.

Methods: Anti-LGI1, anti-NMDAR, and anti-GABA_BR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.

Results: Of 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABA_BR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27-160), and 28 days from start of immunotherapy (IQR 9-71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis.

Conclusion: Epilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.

Figure 1. Timelines (in days) of anti–leucine-rich glioma-inactivated 1 encephalitis patients with epileptic seizures

The percentages shown on the left correspond to patients (1) reaching seizure freedom after the use of immunotherapy (green), (2) reaching seizure freedom probably after the use of immunotherapy (triple green), (3) reaching seizure freedom after the use of antiepileptic drugs (AEDs) (red), (4) reaching seizure freedom probably after the use of AEDs (double red), (5) who could not be categorized (gray stripes), and (6) who did not reach seizure freedom (black dots). If patients were treated with another immunomodulating treatment >1 month after the initial treatment (for example, IV immunoglobulin after prednisolone), this is shown as a new blue square. Treatment with an additional AED or dosage increase after >1 month is shown as a second purple diamond. Relapses are only shown if patients had seizures. Median time of follow-up from onset was 33 months (interquartile range [IQR] 19–52, range 8–119). Median time of seizure freedom was 23 months (IQR 14–40, range 4–102). The median interval between start of AEDs and start of immunotherapy was 57 days (IQR 27–152). **Timeline of the only patient who developed epilepsy after resolved encephalitis. The symbols in this timeline are not fitted to scale. The onset of seizures was in 2009, the patient was treated with prednisone (and AEDs), leading to reversibility of cognitive signs, but he still has temporal epilepsy. IT = immunotherapy.

Figure 2. Timelines (in days) of anti–NMDA receptor encephalitis patients with epileptic seizures

See legend of figure 1. Median time of follow-up was 37 months (interquartile range [IQR] 15–59, range 1–149). Median time of seizure freedom was 31 months (IQR 15–58, range 4–129). The median interval between start of antiepileptic drugs (AEDs) and start of immunotherapy was 14 days (IQR 4–24). IT = immunotherapy.

Figure 3. Timelines (in days) of anti–gamma-aminobutyric acid B-receptor encephalitis patients with epileptic seizures

See legend of figure 1. Median time of follow-up was 15 months (interquartile range [IQR] 9–21, range 0–109). Median time of seizure freedom was 15 months (IQR 9–20, range 5–100). The median interval between start of antiepileptic drugs (AEDs) and start of immunotherapy was 10 days (IQR 7–28). IT = immunotherapy.

Figure 4. Evaluation of the patients at risk to develop epilepsy after resolved encephalitis at 6, 12, and 24 months after the initiation of immunotherapy

The figure shows the cumulative percentages of the patients who reached or did not reach seizure freedom and the use of antiepileptic drugs (AEDs). Patients with a relapse less than 3 months before the time point at 6, 12, or 24 months, or with a relapse at 6, 12, or 24 months, are also shown in the figure. Fourteen patients developed a relapse with epileptic seizures within 24 months after the start of immunotherapy, in 7 of them despite continuous AED treatment. At relapse, the median seizure duration was 12 days (interquartile range [IQR] 4–29, range 3–92). Eleven of these 14 patients became seizure-free within days or weeks after restarting immunotherapy, 2 patients became seizure-free after 3 months, and 1 patient developed epilepsy after resolved encephalitis.

Figure 5. Response percentages of most prescribed antiepileptic drugs (AEDs) and side effects

Response percentages of most prescribed AEDs and side effects in patients with (A) anti–gamma-aminobutyric acid B-receptor (GABABR), (B) anti–NMDA receptor (NMDAR), or (C) anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis, (D) focal seizures in patients with anti-LGI1 encephalitis, and (E) faciobrachial dystonic seizures (FBDS) in patients with anti-LGI1 encephalitis.“Some effect” was scored if noted specifically as a considerable reduction of seizures. In some patients, responses to specific AEDs were not assessable, due to concomitant use of immunotherapy or missing data. *A total of 20/21 patients with anti-GABA_BR encephalitis were treated with levetiracetam (LEV) (n = 16) or valproic acid (VPA) (n = 15), 11 patients were treated with both LEV and VPA. Responses of 2 patients treated with LEV were not assessable. **A total of 40/42 patients with anti-NMDAR encephalitis were treated with LEV (n = 28), VPA (n = 24), or carbamazepine (CBZ) (n = 10); in 17 patients, these AEDs were combined. Responses of seizures of 2 patients treated with VPA, 7 patients treated with LEV, and 4 patients treated with CBZ were not assessable. ***A total of 37 patients with anti-LGI1 encephalitis were treated with LEV (n = 29), VPA (n = 19), or CBZ (n = 22); in 25 patients, combinations of these AEDs were used. Responses of seizures of 4 patients treated with VPA, 6 patients treated with LEV, and 1 patient treated with CBZ were not assessable. Comparing patients treated with both LEV and CBZ (most prescribed, n = 15), CBZ was more effective (p = 0.031). In the LGI1 group, only 4 patients were treated with oxcarbazepine, 1 patient reached seizure freedom, 1 patient showed some effect, and 2 had no effect. Treatment responses of patients with anti-LGI1 encephalitis are also shown for focal seizures (D) and FBDS (E). FBDS hardly responded to VPA, LEV, or CBZ, while focal seizures responded somewhat better to carbamazepine.