Edited by: Noel G. Carlson, The University of Utah, United States
Reviewed by: Pablo Cabezudo-García, Universidad de Málaga, Spain; Xiaoqiu Shao, Capital Medical University, China
This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Identifying the predictors for seizure outcome in autoimmune encephalitis (AE) and investigating how to prevent persistent seizures would have major clinical benefits effectively. Thus, we aimed to perform a systematic review and meta-analysis to examine seizure outcome-related factors in AE patients.
PubMed and EMBASE were systematically searched from inception to 10 June 2022 for studies investigating seizure outcome-related factors in AE. The pooled effect estimates, including standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs), were calculated to estimate the effect of each included factor on the seizure outcome.
A total of 10 studies were included in the meta-analysis. Our pooled results of this meta-analysis showed that five factors were found to increase the risk of persistent seizures in AE patients, including onset with seizures (OR = 2.106, 95% CI = 1.262–3.514,
Our meta-analysis indicated that onset with seizures, status epilepticus, EEG abnormalities, MRI abnormalities, and longer time from clinical onset to immunotherapy were risk factors for persistent seizures in AE patients.
Autoimmune encephalitis (AE) comprises a group of non-infectious inflammatory brain diseases mediated by antibodies that attack surface receptors and ion channels on neurological tissues (
The risk of experiencing persistent seizures or developing chronic epilepsy after resolved AE has been uncertain. A recent prospective cohort study reported that 9.3% of patients experienced seizure recurrence and 3.1% developed chronic epilepsy after the acute phase of AE (
To date, no meta-analysis on seizure outcome-related factors in AE has been performed. Thus, we aimed to perform a systematic review and meta-analysis to investigate the predictors of persistent seizures or chronic epilepsy in AE patients.
This systematic review and meta-analysis were conducted according to the recommendations by the Meta-Analysis of Observational Studies in Epidemiology Group, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines (
PubMed and EMBASE were systematically searched by two independent reviewers (P. L and Q. C) from inception to 10 June 2022 for studies investigating seizure outcome-related factors in autoimmune encephalitis (AE). We used the following search terms: (“autoimmune encephalitis” OR “anti-NMDAR encephalitis” OR “anti-GABABR encephalitis” OR “anti-LGI1 encephalitis”) AND (“epilepsy” OR “seizure”). References of original studies, relevant reviews, and meta-analyses were hand-searched for further supplementation.
Published literature was included if they simultaneously met the following criteria: (1) all involved AE patients were grouped according to seizure outcome; (2) the diagnosis of AE patients was based on definitive diagnostic criteria; (3) sufficient data on predictors for seizure outcome studied in this meta-analysis were reported; and (4) retrospective or prospective cohort studies published in English. Articles were excluded for the following reasons: (1) reviews, meta-analyses, letters, case reports, and conference abstracts; (2) incomplete data; and (3) duplicated articles. If two published studies were based on the same cohort, we chose the study with larger sample size. Divergences in the study selection process were resolved through a discussion in the third part.
Seizure outcome was assessed based on whether the patient experienced persistent seizures and developed epilepsy after the acute phase (
The following data were extracted using a predesigned standard form: name of the first author, publication year, country, sample size, study design, follow-up time, mean age, gender proportion (female), antibody types, and original data. The quality of each selected study was assessed using the Newcastle–Ottawa Scale (NOS) guidelines (
The pooled effect estimates, including standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs), were calculated to estimate the effect of each included factor on the seizure outcome. We measured heterogeneity using the I2 statistic and Q statistic (
A total of 2,352 articles were initially identified after the literature search. In addition, 986 duplicated articles were removed. Then, 1,198 articles were excluded after screening the titles and abstracts, leaving 168 articles with full text available. Eventually, 10 studies were included in the meta-analysis (
Flowchart of the study selection process.
Characteristics of all included studies in our meta-analysis.
Guery et al. ( |
France | 39 | Retrospective cohort | 42 | 63 | 14 (36%) | LGI1 | F1, F4, F5, F6, F7 | 8 |
Zhong et al. ( |
China | 86 | Retrospective cohort | 21 | 48 | 42 (48.8%) | NMDAR, LGI1, GABABR | F1, F2, F3, F4, F5, F6, F7 | 8 |
Gifreu et al. ( |
Spain | 19 | Retrospective cohort | 7.16 | 52.79 | 9 (47.37) | GAD, NMDAR, LGI1 | F1, F2, F4, F6, F7 | 7 |
Chen et al. ( |
China | 111 | Retrospective cohort | > 6 | 36.8 | 61 (55%) | NMDAR, LGI1,GABABR,GAD-65, Caspr2 | F1, F2, F3, F4, F6, F7 | 7 |
Lin et al. ( |
China | 70 | Retrospective cohort | >24 | 60 | 21 (30%) | LGI1 | F1, F2, F4, F5, F6 | 8 |
Wang et al. ( |
China | 56 | Retrospective cohort | >12 | _ | 27 (48.2%) | NMDAR, LGI1, GABABR | F1, F2, F3, F4, F5, F6 | 8 |
Shen et al. ( |
China | 80 | Prospective cohort | 30.5 | 36.4 | 36 (45.0%) | NMDAR, LGI1, GABABR | F1, F2, F4, F5, F6 | 8 |
Zhang et al. ( |
China | 52 | Retrospective cohort | 30 | 46 | 23 (44.2) | NMDAR, LGI1, GABABR | F1, F2, F3, F4, F5, F6 | 7 |
Qu et al. ( |
China | 62 | Retrospective cohort | 48 | 6.5 | 31 (50.%) | NMDAR | F1, F2, F3, F4, F5, F6, F7 | 7 |
Casciato et al. ( |
Italy | 33 | Retrospective cohort | 19 | 61.2 | 14 (42.4%) | NMDAR, LGI1,GAD-65, Caspr2, SOX1 | F5, F6 | 7 |
Risk factors: F1, age at onset; F2, gender (female); F3, onset with seizures; F4, status epilepticus; F5, EEG abnormality; F6, MRI abnormality; F7, time from clinical onset to immunotherapy.
Data were extracted in AE patients with or without persistent seizures from 10 studies. Here, we only presented the factors with a relatively large population (reported in at least three studies) to lower the error of estimates. Thus, seizure outcome-related factors in the meta-analysis included age at onset, sex proportion (female), onset with seizures, status epilepticus, EEG abnormalities, MRI abnormalities, and time from clinical onset to immunotherapy (
Pooled analysis of each included risk factor for persistent seizures in this meta-analysis.
Age at onset (years) | 9 | 575 | 0.119 | 0.174–0.413 | 0.426 | 53.40% | 0.028 | Random |
Female | 8 | 536 | 1.13 | 0.762–1.675 | 0.543 | 0% | 0.927 | Fixed |
Onset with seizures | 5 | 367 | 2.106 | 1.262–3.514 | 0.004 | 8.90% | 0.355 | Fixed |
Status epilepticus | 9 | 575 | 3.017 | 1.995–4.563 | < 0.001 | 0% | 0.553 | Fixed |
EEG abnormality | 9 | 497 | 1.581 | 1.016–2.46 | 0.042 | 46.10% | 0.062 | Fixed |
MRI abnormality | 10 | 608 | 1.544 | 1.044–2.283 | 0.03 | 0% | 0.823 | Fixed |
Time from clinical onset to immunotherapy | 5 | 317 | 1.887 | 0.598–3.156 | 0.004 | 93.80% | < 0.001 | Random |
A total of nine studies representing 575 participants were about the age at onset. Meta-analysis results suggested no statistically significant difference in terms of age at onset between patients with and without persistent seizures (SMD = 0.119, 95% CI = −0.174–0.413,
A total of eight studies involving 536 participants were about gender proportion. Meta-analysis results showed no statistically significant difference in sex proportion between the persistent seizure group and the seizure remission group (OR = 1.13, 95% CI = 0.762–1.675,
A total of five studies involving 367 participants were about the onset with seizures. Meta-analysis results showed that onset with seizures increased the risk of persistent seizures in AE patients (OR = 2.106, 95% CI = 1.262–3.514,
A total of nine studies involving 575 participants were about status epilepticus. Meta-analysis results showed that the risk of persistent seizures significantly increased in AE patients who experienced status epilepticus at the acute phase (OR = 3.017, 95% CI = 1.995–4.563,
A total of nine studies involving 497 participants were about EEG abnormalities. Meta-analysis results showed that EEG abnormalities increased the risk of persistent seizures in AE patients (OR = 1.581, 95% CI = 1.016–2.46,
A total of 10 studies involving 608 participants were about MRI abnormalities. Meta-analysis results showed that MRI abnormalities were associated with an increased risk of persistent seizures in AE patients (OR = 1.544, 95% CI = 1.044–2.283,
Forest plot of the association between MRI abnormalities and persistent seizures.
Funnel plot suggests no obvious publication bias.
A total of five studies involving 317 participants were about the time from clinical onset to immunotherapy. Meta-analysis results showed that patients in the persistent seizure group were prone to experience a longer time from clinical onset to immunotherapy than those in the seizure remission group (SMD = 1.887, 95% CI = 0.598–3.156,
This systematic review involved extensive analysis and shed new light on early predictors of persistent seizures in AE. Seven factors were available for meta-analysis. We found that onset with seizures, status epilepticus, EEG abnormalities, MRI abnormalities, and longer time from clinical onset to immunotherapy was associated with an increased risk of persistent seizures in AE patients. In contrast, there was no evidence that age at onset and sex affected seizure outcomes.
Prior literature has reported that onset with seizures and status epilepticus occurrence were associated with a poor seizure outcome (
Interictal epileptiform discharges (IEDs) were an important risk factor for poor seizure outcomes in patients with anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis, particularly in those with anti-NMDAR encephalitis (
However, our meta-analysis showed that abnormal EEG findings had a negative impact on seizure outcomes, and there was no significant heterogeneity among the included studies. The exact mechanism remains uncertain. One of the possible mechanisms was intrinsic disease severity. Evidence also suggests that EEG abnormalities may predict an increased risk of seizure recurrence and the development of drug-resistant epilepsy in newly diagnosed epilepsy (
According to the literature, the administration of immunotherapy was significantly associated with seizure outcome, and delay of immunotherapy initiation was also related to the development of drug-resistant epilepsy (
This meta-analysis had several limitations. First, we could not perform subgroup analysis by antibody type due to the unconformity of original studies and the limited sample size. Second, some potential risk factors for persistent seizures were not analyzed when one or two studies reported them. For, example, Zhong et al. recently reported that a larger number of ASMs was related to an increased risk of persistent seizures (
A systematic review and meta-analysis were performed to investigate AE patients' seizure outcome-related factors. The results indicated that onset with seizures, status epilepticus, EEG abnormalities, MRI abnormalities, and longer time from clinical onset to immunotherapy were risk factors for persistent seizures in these patients. The numerous proposed predictors could help to treat physicians formulate prevention strategies for the development of epilepsy. In clinical practice, we should prioritize immunotherapy to control acute seizures as soon as possible and improve seizure outcomes after the acute phase.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
WL guided the design of the study and reviewed the manuscript. PL designed the study, screened the literature, extracted data, performed the statistical analysis, and wrote the manuscript. RZ and QC supported the screening of the literature and extracted the data. QC supported the visualization of the results. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
We sincerely thank the originator of the Newcastle–Ottawa Scale.