Risk factors for cognitive impairment in patients with epilepsy: a systematic review and meta-analysis protocol

doi:10.21203/rs.3.rs-2621091/v1

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Risk factors for cognitive impairment in patients with epilepsy: a systematic review and meta-analysis protocol

https://doi.org/10.21203/rs.3.rs-2621091/v1

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Introduction Epilepsy is a common neurological disease affecting at least 50 million people globally. Cognitive impairment is a recognised comorbidity in patients with epilepsy (PWE) and is associated with low quality of life. A large number of studies have investigated the relevant risk factors of cognitive impairment in PWE, while these results were not consistent. The main aim of our study is to review the risk factors that increase the likelihood of cognitive impairment in PWE.

Methods and analysis We will search the literature that reported risk factors for cognitive impairment in PWE in the following online databases from inception to October 2022: China National Knowledge Infrastructure, Wan Fang database, VIP, the Chinese clinical trial registry, China Biology Medicine disc, PubMed, the Cochrane Central Register of Controlled Trials, Embase, and Web of science. Two independent authors will screen the eligible literature according to the inclusion and exclusion criteria. Data extraction will also be conducted by two independent authors, and discrepancies will be solved by a third author. We will use the software Revman 5.4 and Stata 15.1 to perform data synthesis, sensitivity analysis, and meta-regression. If data are sufficient, we will also perform the subgroup analysis. The quality of evidence will be evaluated by the Grading of Recommendations Assessment, Development and Evaluation(GRADE).

Discussion Our study can assist clinicians in better understanding and managing this disease through reviewing the risk factors of cognitive impairment in PWE. We also expect this study can provide reliable evidence for this unanswered research question and promote the development of the prevention and treatment of cognitive impairment in PWE.

Registration number CRD 42022365184.

Risk factors

cognitive impairment

epilepsy

meta-analysis

Epilepsy is a chronic neurological disorder characterized by unprovoked recurrent seizures, affecting at least 50 million people globally.[1] Except for the epileptic seizures themselves, patient also suffer from the neurobiological cognitive, psychological, and social consequences caused by epileptic seizures.[2] Cognitive impairment is a long-standing comorbidity associated with epileptic seizures and persistent over time.[3] It was reported that nearly 65% of patients with epilepsy (PWE) had cognitive impairment, which usually involved several domains, such as memory, executive function, verbal functions, visual motor ability, visual-spatial ability, and so on.[4–7]

In the past, people put more attention to reduce the frequency of epileptic seizures, and neglected the influence of cognitive impairment in PWE. Recent studies have shown that cognitive impariment was already observed in newly diagnosed epileptic patients.[8] About 49.4% of newly diagnosed and untreated people with epilepsy had impairments in attention and executive function, and 47.8% of them reported memory deficits.[9, 10] The high prevalence of cognitive impairment at early course of epilepsy calls for early neuropsychological screening after diagnosing epilepsy or before treatment initiation, so as to monitor the course of the underlying disease and adjust treatment accordingly.[11] Cognitive impariment has a detrimental impact on daily life for PWE. Some patients even ranked cognitive impariment as the biggest problem except for seizures, since memory difficulties often led to some embarrassing situations, for example, forgetting the agreements with other people, especially names and numbers, that severely affected their capacity to work. Additionally, memory difficulties can also make them miss the medication time.[12] Therefore, identifying potential risk factors for cognitive impairment in PWE can help guide treatment choice and improve the quality of daily life.

Cognitive impairment in PWE is a consequence of the combination of several factors. Generally, chronic and frequent epileptic seizures, especially status epilepticus, can cause a progressive cognitive decline by oxidative stress, neuronal loss, neuroinflammation in the brain.[13, 14] However, some studies suggested that cognitive impairment can be observed before the onset of epilepsy. This opinion supported that the underlying etiology of epilepsy may be a significant contributor to cognitive impairment.[15] Additionally, frequent interictal epileptiform discharges are strongly associated with cognitive impairment in children and adults.[16, 17] Nevertheless, whether both interictal epileptiform discharges in waking and sleeping can also be able to affect cognitive impairment have not yet reached consensus.[18] Though the use of AEDs is also considered to play a significant role in cognitive impairment, Emma Foster et al. supported that individual AEDs were not independently associated with cognitive impairment.[19, 20] Before using AEDs, low educational level, stroke or brain surgery etiology, and anxious symptoms are also the influence factors for cognitive impairment. However, this result require larger sample size studies to verify.[21, 22] Overall, despite some studies have achieved agreements on the risk factors for cognitive impairment in PWE, several controversies with respect to some risk factors remains. Therefore, it is crucial to review the related risk factors of cognitive impairment in PWE, and accordingly seek interventions as soon as possible.

To our knowledge, there has been no systematic review reported this topic. Therefore, this study will perform a comprehensive review and meta-analysis to provide more precise and reliable evidence on risk factors for cognitive impairment in epilepsy.

The protocol was developed in conformity with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols Guidelines.[23] We have registered the protocol in PROSPERO (CRD 42022365184).

Patients and public involvement

This study does not involve patients and the public.

Case and control populations

Participants who are diagnosed with epilepsy and cognitive impairment serve as the case group. And populations with epilepsy but do not have cognitive impairment serve as the control group. The definition of epilepsy is two unprovoked seizures occurring more than 24 hours apart; only one unprovoked seizure, but the risk of recurrence is over 60% within the next 10 years; or diagnosed with an epilepsy syndrome.[24] The evaluation of cognitive impairment can be confirmed by Montreal Cognitive Assessment (MoCA), Mini-mental State Examination (MMSE), and other assessment tools of intelligence, such as language, memory, executive function, motor or processing speed.

Outcome measurements

The outcome indicators include all potential risk factors that are relevant to cognitive impairment in PWE, for example the frequency of seizure, AEDs, as well as disease duration, and so on. We will record all the risk factors mentioned in the included literature, and finally make reasonable screening and evaluation.

Search strategy

Two investigators will independently search all literature that reported risk factors of cognitive impairment in PWE from the following digital databases from inception to October 1, 2022: China National Knowledge Infrastructure, VIP, China Biology Medicine disc, the Chinese clinical trial registry, Wan Fang database, PubMed, the Cochrane Central Register of Controlled Trials, Embase, and Web of Science, without language and country limitations. The detailed search strategies for the Medline database are shown in Table 1, and they can be appropriately adjusted according to other databases’ requirements. Additionally, we will check the references of the included studies to find any related literature. We will contact the original author, if can not access the full text. Any disagreements will be solved through discussion by a third author. The software NoteExpress v3.2 will be used to manage all retrieved literature.

Table 1 The search strategies for the Medline database

Number	Searches
#1	"Epilepsy"[MeSH Terms]
#2	"Epilepsies"[Title/Abstract] OR "seizure disorder"[Title/Abstract] OR "seizure disorders"[Title/Abstract] OR "awakening epilepsy"[Title/Abstract] OR "epilepsy awakening"[Title/Abstract] OR "epilepsy cryptogenic"[Title/Abstract] OR "cryptogenic epilepsies"[Title/Abstract] OR "cryptogenic epilepsy"[Title/Abstract] OR "epilepsies cryptogenic"[Title/Abstract] OR "Aura"[Title/Abstract] OR "Auras"[Title/Abstract] OR "Seizures"[Title/Abstract] OR "epilepsies partial"[Title/Abstract] OR "epileptic syndromes"[Title/Abstract]
#3	#1 OR #2
#4	"Cognition Disorders"[MeSH Terms]
#5	"disorder cognition"[Title/Abstract] OR "disorders cognition"[Title/Abstract]
#6	#4 OR #5
#7	"Cognitive Dysfunction"[MeSH Terms]
#8	"cognitive dysfunctions"[Title/Abstract] OR "dysfunction cognitive"[Title/Abstract] OR "dysfunctions cognitive"[Title/Abstract] OR "cognitive impairments"[Title/Abstract] OR "cognitive impairment"[Title/Abstract] OR "impairment cognitive"[Title/Abstract] OR "impairments cognitive"[Title/Abstract] OR "mild cognitive impairment"[Title/Abstract] OR "cognitive impairment mild"[Title/Abstract] OR "cognitive impairments mild"[Title/Abstract] OR "impairment mild cognitive"[Title/Abstract] OR "impairments mild cognitive"[Title/Abstract] OR "mild cognitive impairments"[Title/Abstract] OR "mild neurocognitive disorder"[Title/Abstract] OR "disorder mild neurocognitive"[Title/Abstract] OR "disorders mild neurocognitive"[Title/Abstract] OR "mild neurocognitive disorders"[Title/Abstract] OR "neurocognitive disorder mild"[Title/Abstract] OR "neurocognitive disorders mild"[Title/Abstract] OR "cognitive decline"[Title/Abstract] OR "cognitive declines"[Title/Abstract] OR "decline cognitive"[Title/Abstract] OR "Mental Deterioration"[Title/Abstract] OR "Deterioration, Mental"[Title/Abstract]
#9	#7 OR #8
#10	"risk factor"[Title/Abstract] OR "association"[Title/Abstract] OR "relative risk"[Title/Abstract] OR "OR"[Title/Abstract]
#11	#6 OR #9
#12	#3 AND #10 AND #11

Inclusion and exclusion criteria

Inclusion criteria: 1) The types of included articles are prospective, retrospective cohort study, and case-control study; 2) All participants must be diagnosed with epilepsy, and participants in case group must be accompanied by cognitive impairment regardless of age, gender, region, and severity level; 3) Exposure factors are the risk factors associated with cognitive impairment in PWE.

Exclusion criteria: 1) The sample size of the study is less than 50 cases; 2) Literature reviews, conference abstracts, guidelines, case reports, animal experiments, and duplicate publications will be excluded; 3) Full text or complete data cannot be obtained.

Study selection

Two authors will screen all retrieved articles according to the inclusion and exclusion criteria. The duplicated studies will be removed by the software NoteExpress. Then they will select eligible literature by reading abstracts and titles or full-text when necessary. The disagreements in this process will be solved via consultation with a third author. The procedure for selecting articles is shown in Figure 1.

Data extraction

Two researchers will independently extract data from each eligible study. The detailed information is as follows: first authors’ surname, time of publication, study sample size, participants’ age and gender, study population type, seizure type, disease duration, and related risk factors. If any data is missing, we will contact the original author.

Assessment of bias risk

Two investigators will independently evaluate the risk of bias using the Newcastle-Ottawa Scale (NOS). This scale is categorized into three domains of selection, comparability and outcome (cohort studies) or exposure (case-control studies). Each item will be assessed via the assignment of the star.[25] Any controversial issues can be solved by a discussion with a third author.

Data synthesis

The included risk factors must be analyzed by multiple-factor logistic regression. And they must be reported by more than three articles to ensure that a meta-analysis can be conducted. Otherwise, these articles will be analyzed by systematic review. Additionally, the raw data require to provide the odds ratio (OR) and 95% confidence interval (CI). We will use the software Revman 5.4 and Stata 15.1 to analyze all statistical data. The OR will be calculated for each risk factor, and the confidence interval (CI) is 95%. Heterogeneity between the studies will be assessed through the Q statistic and I² index. When I²≤50%, it indicates that the heterogeneity is not obvious, and we can adopt a fixed-effects model to estimate all pooled results. Otherwise, the random-effects model will be used. The subgroup analysis will be conducted based on the type of epilepsy and study population type. Except for that, we will undertake sensitivity analysis to assess the influence of a single study on the pooled effect size by removing one study each time. Meta-regression analysis will be performed to test the source of heterogeneity when the number of studies is over 10 in meta-analysis. The publication bias between studies will be evaluated by visual inspection funnel plot and quantitative detection Egger’s test when over 10 studies are included in the meta-analysis. P value > 0.05 indicates that the publication bias is not significant. If the data is ambiguous or missing, we will contact the original author by email for more information.

Assessment of evidence quality

The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) toll based on five domains: risk of bias, consistency, directness, precision, and publication bias (https://www.gradepro.org/). Quality assessment result is rated as high, moderate, low, or very low.[26] Two independent authors will participate in this assessment and reach a consensus by discussion to guide the strength of the evidence.

Our study aims to evaluate the available published data on the risk factors of cognitive impairment in PWE. Epilepsy is an intractable neurological disease, and the occurrence of cognitive impairment also makes a tremendous difference in the quality of life for PWE.[27] The purpose of this study is to review the risk factors of cognitive impairment in PWE, which can assist clinicians in better understanding and managing this disease. Additionally, we expect the study to provide reliable evidence for this unanswered research question and promote the development of the prevention and treatment of cognitive impairment in PWE.

The underlying pathogenic mechanisms of cognitive impairment in PWE are not yet fully elucidated. Though studies have shown that multiple risk factors are associated with the development and progression of cognitive impairment in PWE, there are controversial views on some risk factors. The early detection and intervention of the risk factors of cognitive impairment are of great therapeutic significance for PWE. However, no systematic review and meta-analysis have been conducted to evaluate the risk factors of cognitive impairment in PWE.

By fully exploring the risk factors that contribute to cognitive impairment in PWE, this study can afford valuable information for clinical management. Note, however, our study has some potential limitations. First, the published literature addressing objectively assessed cognition in epilepsy is extensive, so it appears to be a monumental task. But we have enough members to complete this work. Additionally, the details of study design, such as patient characteristics and the quality of literature, may lead to significant heterogeneity. Therefore, we hope that there will be more rigorous and high-quality studies for the evaluation of risk factors of cognitive impairment in PWE in the future.

This is the first systematic review and meta-analysis to study the risk factors of cognitive impairment in PWE. A broad search range will provide us available evidence to evaluate the outcome indicators. The rigorous inclusion and exclusion criteria will guarantee the quality of included literature. However, the heterogeneity between studies may affect the reliability of the result of our study.

Ethics approval and consent to participate

Our study does not directly involve patients or their personal information, so there is no need for formal ethical approval. The results of our study will be published in a peer-reviewed journal or conference. Important protocol amendments will be reported and updated on PROSPERO.

Consent for publication Not applicable.

Availability of data and materials Not applicable.

Competing interests None declared.

Funding This work was supported by the Fundamental Research Funds for the Central Universities grant number (No.2020-JYB-ZDGG-133).

Author Contributions WX conceived the framework of this systematic review and registered the protocol. LZ participated in the design of this systematic review and made the literature search strategy. YW will serve as a consultant for methodology and conduct data analysis. SW will participate in the dispute resolution as a third reviewer. LL and KW will involve in the literature selection and data extraction. MZ and SY will evaluate the evidence quality by the GRADE pro. JL will supervise the conduct of this systematic review. All authors agreed with the publication of the final manuscript.

Acknowledgements Not applicable.

Provenance and peer review Not commissioned; externally peer-reviewed.

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Editorial decision: Major revision
21 Apr, 2024
Reviewers agreed at journal
16 Feb, 2024
Reviewers invited by journal
31 Jan, 2024
Editor assigned by journal
01 Aug, 2023
First submitted to journal
23 Feb, 2023

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Risk factors for cognitive impairment in patients with epilepsy: a systematic review and meta-analysis protocol

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