Risk of Epilepsy and Factors Associated With Time to Seizure Remission in Anti-LGI1 Encephalitis: Long-Term Outcome in 236 Patients

Abstract

Background and objectives: Autoimmune encephalitis (AIE) with anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies typically manifests with subacute cognitive deficits, seizures, and psychiatric symptoms, mostly in older adults. Immunotherapy (IT) leads to the cessation of seizures in most patients, yet some develop AIE-associated epilepsy (AEAE) and persistent cognitive deficits. The aim of this large multicentric retrospective observational cohort study was to assess long-term outcomes of patients with anti-LGI1 encephalitis regarding seizures and AEAE and to identify associated factors.

Methods: We included patients with anti-LGI1 encephalitis from 3 national referral centers/consortia meeting the following inclusion criteria: (I) definite LGI1 limbic encephalitis (Graus criteria); (II) occurrence of seizures; and (III) follow-up period ≥24 months. We aimed to (1) determine the risk of seizure recurrence (ROSR) on remission, (2) investigate clinical and paraclinical biomarkers for an effect on time to seizure remission using Cox proportional hazard modeling (n = 188), and (3) assess the risk of AEAE and determine associated factors (n = 236).

Results: AEAE was observed in 5.9% (16/271) of the full cohort. Both AEAE (16/16 vs 129/215, p = 0.001) and longer time to seizure remission (OR 1.36 per year, p = 0.025) were associated with persistent cognitive impairment. Patients with pilomotor seizures had a lower rate of seizure remission (hazard ratio [HR] 0.58, 95% CI 0.55-0.60, p < 0.001) while patients under IT administration had a higher rate of seizure remission over time (HR 12.4, 95% CI 9.67-16.0, p < 0.001). In addition, patients receiving second-line IT tended to achieve earlier seizure remission (log-rank test, p = 0.019). The ROSR at 12, 60, and 120 months on seizure remission was 9% (95% CI 4.5%-13%), 20% (95% CI 11%-28%), and 53% (95% CI 14%-74%), respectively.

Discussion: In conclusion, our results demonstrate that AEAE in anti-LGI1 encephalitis is rare and suggest that the diagnosis of epilepsy is inappropriate in patients reaching seizure remission because of a relatively low ROSR. Accordingly, on seizure remission, the diagnosis of acute symptomatic seizures would be appropriate. Moreover, we validate and quantify the importance of IT for seizure remission and identify biomarkers associated with lower rates of seizure remission. Late remission of seizures and AEAE were associated with persistent cognitive impairment.

Figure 1. Composition of the Study Population

Flowchart illustrating the inclusion and composition of patients included in the study.

Figure 2. Kaplan-Meier Plot for Seizure Remission Comparing Patients Who Did or Did Not Receive Second-Line Immunotherapy (IT)

Primary Cohort. p Value based on corresponding log-rank test. Risk table below plot. For better readability, the x-axis is cut at 76 months. A plot showing all events is available in eFigure 2A.

Figure 3. Time to Seizure Freedom and Initiation of Immunotherapy (IT)

(A) Bar chart illustrating the occurrence of seizures in each patient of the German and French cohort throughout the course of the disease, filtered for 187 of 188 patients (99%) who received immunotherapy (IT) at some point. The vertical line at t = 0 months indicates the time of IT initiation. Time with first symptoms besides seizures is indicated in brown, seizures in orange, seizure freedom in light blue and seizure freedom without ASMs in light green, sorted by time with seizures after starting IT. For periods with a duration of (rounded) 0 months, 0.5 months were added for visualization. Seizure-free intervals <6 months were not assessed. ASM = antiseizure medication. (B) Histogram of the time of (first) seizure freedom relative to the time of first IT administration (t = 0 months). Note that some patients are not shown for better readability (n = 2 with seizure freedom 5 months before and n = 14 more than 25 months after IT initiation). (C) Jitter plot of the time of first IT administration and the time to seizure freedom (relative to first symptoms; jitter of 0.2 in all directions to reduce overlap, opacity: 0.5). For better readability, some patients are not shown (n = 5 with seizure freedom after more than 53 months and n = 4 with IT initiation more than 20 months after seizures started). eFigure 3 includes corresponding plots for (B) and (C) showing all patients.

Figure 4. Risk of Seizure Recurrence

The risk of seizure recurrence (ROSR) (and its 95% CI shaded area) is calculated by subtracting the Kaplan-Meier estimate (KM) for the event of seizure recurrence (and its CI) from 1 (ROSR = 1–KM), filtered for 180 of 188 patients (96%) who reached seizure remission (≥6 months of seizure freedom) once. Risk table below plot. A gray dashed line marks a ROSR of 60%. Note that the point estimate of the ROSR does not surpass this threshold at any time point. For better readability, the x-axis is cut at 100 months because no further patients reach the event of seizure recurrence after this time point (only censored data after 100 months). Accordingly, the ROSR remains 53% (95% CI 14%–74%) from 97 months until the last censoring at 154 months.