Adrenocorticotropic Hormone versus Prednisolone for Infantile Epileptic Spasms Syndrome: A Systematic Review and Economic Evaluation

Abstract

Background Infantile epileptic spasms syndrome (IESS) is the most common epileptic encephalopathy in infancy and early childhood. At present, adrenocorticotropic hormone (ACTH) and prednisolone are commonly used as drug treatment regimens for IESS. However, evidence of efficacy and economics remains controversial. This study aimed to evaluate the effectiveness, safety, and economy of ACTH and prednisolone of IESS.

Methods Seven literature databases and two clinical trial registration platforms were searched, and a meta-analysis was conducted. From the perspective of the health care system, a 14-day economic evaluation was conducted. The rate of spasm cessation on the 14th day was used as the effect index. The univariate sensitivity analysis was used to verify the robustness of the results.

Results Nine randomized controlled trials (RCTs) were included. Current clinical evidence is not sufficient to prove the difference in the rate of spasm cessation on the 14th day (risk ratio [RR] = 1.05, 95% CI 0.86–1.27, p = 0.64) and total adverse event rate (RR = 0.87, 95% CI 0.53–1.42, p = 0.57). ACTH had an advantage in improving electroclinical response on the 14th day (RR = 1.46, 95% CI 1.09–1.96, p = 0.01) and reducing the number of months taken for relapse (mean difference = 1.65, 95% CI 1.01–2.29, p < 0.01). The cost of ACTH and prednisolone was 5,629.19 yuan and 5.56 yuan, respectively. Univariate sensitivity analysis showed the most influential factor was the cost of ACTH.

Conclusions There is insufficient evidence to determine whether ACTH or prednisolone is better in the short-term regimen of IESS. ACTH may have more advantages in improving the long-term outcome of IESS. In China, a prednisolone regimen of IESS has a lower cost within 14 days.

Keywords

infantile epileptic spasms syndrome - adrenocorticotropic hormone - prednisolone - meta-analysis - cost-minimization analysis

Infantile epileptic spasms syndrome (IESS) is one of the rare diseases in pediatrics that includes both West syndrome and epileptic spasms in infants who do not meet all the criteria for West syndrome.[1] Epidemiological investigation showed that the incidence of IESS was between 1.6 and 4.5 cases per 10,000 live births.[2] [3] [4] [5] Although rare, IESS can be a great burden on families and society. This is due to its high mortality rate, the high likelihood of developmental delay or regression, the difficulty of controlling them with traditional antiseizure medications, and the damage to cognitive and psychosocial functioning.[6]

Adrenocorticotropin (ACTH) is the preferred treatment for children with IESS without tuberous sclerosis.[7] [8] However, ACTH must be administered by injection and the drug cost is high. In China, the price of 25 units of ACTH for injection is 398 yuan, which makes the use of ACTH regimen, bring an economic burden to the family. Prednisolone, as an alternative therapy, has the advantages of being orally available, easy to use, high compliance, and less costly than ACTH. The efficacy of prednisolone has been reported, but clinical evidence is insufficient. The International League Against Epilepsy (ILAE) stated in the 2015 consensus document that glucocorticoids are likely to be effective in the short-term control of spasms but the optimal formulation, dose, and course of regimen have not been determined.[9] It is also important to consider the potential for adverse effects during hormone therapy, including hypertension, immunosuppression, infections, and electrolyte disturbances.[10] [11] [12] [13] [14] [15]

Several randomized controlled trials (RCTs) have compared the effects of ACTH and prednisolone in the regimen of IESS, but the conclusions of each study on the regimen effect and the incidence of adverse reactions are inconsistent. Therefore, the purpose of this study was to systematically evaluate the short-term efficacy, safety, and long-term prognosis of ACTH and prednisolone in the regimen of IESS. Based on the results of a meta-analysis of effect indicators, the pharmacoeconomic evaluation of ACTH and prednisolone was carried out to provide a basis for clinical medical and health decision-making.

Methods

The study followed the guidelines provided by the Preferred Reporting Project for Systematic Reviews and Meta-analyses (PRISMA) 2020. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42024602085.

Meta-analysis

Eligibility Criteria

The type of study included in this study was parallel RCTs. All participants were diagnosed with IESS by evaluating clinical manifestations and/or electroencephalogram (EEG) findings; the intervention groups were treated with prednisolone or ACTH. Children who were diagnosed with tuberous sclerosis or had received hormone therapy for IESS were excluded, as vigabatrin is the first-line treatment for children with concurrent tuberous sclerosis. Records that cannot obtain full text, full-text data are obviously missing, or repeatedly published were also excluded.

Search Strategy

The following English and Chinese databases were retrieved: The Cochrane Library, Medline, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database, Chinese BioMedical Literature Database (CBM); and Clinical Trial Registration Platform: U.S. National Institutes of Health Ongoing Trials Register (http://www.clinicaltrials.gov), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/). The list of references was manually searched. The search subject words were “Infantile Spasm,” “Adrenocorticotropic Hormone,” “Cosyntropin,” “Glucocorticoids,” and “Prednisolone,” the method of combining keywords and free words was used for retrieval. The search period was from the inception of the database to June 11, 2024. Detailed search strategies are provided in [Supplementary Appendix S1] (available in the online version only).

Outcomes

1. Short-term outcomes: Spasm cessation on the 14th day (proportion of children with spasms that was not observed or documented by a physician or parent within 14 days), disappearance of EEG hypsarrhythmia on the 14th day, number of days taken for control of spasms, electroclinical response on 14th day (cessation of spasm and disappearance of EEG hypsarrhythmia).

2. Long-term outcomes: Spasms relapse rate, number of months taken for relapse.

3. Adverse events: Total adverse events rate, hypertension rate, infection rate, electrolyte disturbance rate, irritability rate.

Data Collection and Analysis

After excluding duplicates, the two researchers (R.N.G. and X.C.) followed the inclusion and exclusion criteria by reading the titles and abstracts for initial screening, and then by reading the full text to determine the final included literature. Microsoft Excel was used to extract the basic information of the studies, subject characteristics, interventions, outcome indicators and other information, and the data in the extraction table were entered into Review Manager 5.4. The risk of bias in each included study was assessed according to ROB2.0, a tool for evaluating the risk of bias in RCTs recommended by the Cochrane Handbook of Systematic Evaluation.

Statistical analysis was performed using Review Manager 5.4 software. For the analysis of dichotomous variable data, risk ratio (RR) was selected as the effect size; for the analysis of numerical variable data, mean difference (MD) or standardized mean difference was selected as the effect size, depending on whether the same scale or unit of measurement was used for the results. Heterogeneity between studies was assessed using the p-value of the heterogeneity test and the I ² value of the Q-test as statistical measures, and studies were not statistically heterogeneous when p > 0.1 and I ² < 50%. Meta-analysis was performed using the random-effects model. For outcomes that included more than 10 studies, publication bias was evaluated using funnel plots.

Sensitivity analyses were conducted by using different statistical models (fixed-effects models) and exploring sources of heterogeneity using a literature-by-exclusion approach.

Subgroup analyses were performed according to the type and dose of ACTH and prednisolone used depending on (1) ACTH and Tetracosactide, and (2) high-dose prednisolone (higher than 2 mg/kg/d) and low-dose prednisolone (lower than 2 mg/kg/d).

Pharmacoeconomic Evaluation

Perspective and Model

From a health care system perspective, the evaluation period was 14 days, and the rate of spasm cessation on the 14th day was used as the effect indicator. If there was no statistically significant difference in the effect indicators, analysis was conducted using the cost-minimization analysis and vice versa using the cost-effectiveness analysis.

Model Parameter

The scope of cost recognition was consistent with the model simulation time, and direct medical costs with differences between the two regimen groups within 14 days were included. Drug unit prices were derived from the China Drug Linkage Reference Prices, the median drug price was taken as the cost parameter, and the highest and lowest values of drug prices were taken as the fluctuation ranges for the sensitivity analysis; other direct health care costs were derived from China's Provincial Administrative Region Medical and Healthcare Service Charges Standards. Discounting was not considered due to the short simulation time of the model. The effect data come from the results of the meta-analysis.

Sensitivity Analysis

If the cost-minimization analysis was used, univariate sensitivity analysis was performed. If the cost-effectiveness analysis was used, univariate sensitivity analysis and probabilistic sensitivity analysis were performed.

Results

Search Results

A total of 1,315 records were retrieved from all databases, and 9 RCTs (12 records) were finally included. The screening flowchart is shown in [Fig. 1].

Fig. 1 Flow diagram for study selection.

Characteristics of Studies

The included literature was published from 1996 to 2022, eight single-center clinical trials and one multinational, multicenter clinical trial, with no significant differences in the baseline characteristics of the children in the two regimen groups. For interventions in the ACTH group, O'Callaghan et al 2017 and Lux et al 2004 used Tetracosactide extended-release formulation,[16] [17] Wanigasinghe et al 2014[18] used long-acting synthetic ACTH formulation, and the rest of the studies used natural ACTH formulation; for interventions in prednisolone, Ai et al 2020 and Jiang et al 2019 used prednisolone intravenous drip; the remaining studies used oral administration.[19] [20] Specific characteristics are detailed in [Table 1].

Table 1 Characteristics of studies included in systematic review and meta-analysis

Study	Year	Country	Number of centers	Diagnostic criteria	Follow-up time	Number of participants		Age (months; mean ± SD)		Intervention
						ACTH/Male	Prednisolone/Male	ACTH	Prednisolone	ACTH	Prednisolone
Chen and Liu[32]	2022	China	Single	ILAE diagnostic criteria	2 years	41/Unclear	41/Unclear	5.87 ± 2.69	5.41 ± 2.63	ACTH 2 U/(kg·d) intravenously	Prednisolone 2.0 mg/(kg·d) orally
Ai et al[20]	2020	China	Single	Chinese Antiepileptic Association diagnostic criteria	1 year	34/Unclear	34/Unclear	Unclear	Unclear	ACTH 20 U/d intravenously	Prednisolone 2.0 mg/kg intravenously, q12h[b]
Imannezha et al[35]	2020	Iran	Single	Unclear	2 weeks	25/18	26/14	8.2 ± 3.8	8.1 ± 2.8	ACTH 2–3 U/(kg·d) intramuscularly	Prednisolone 8.0 mg/(kg·d) orally
Jiang et al[19]	2019	China	Single	ILAE diagnostic criteria	3 years	48/Unclear	43/Unclear	1.4 ± 0.8	1.5 ± 0.6	ACTH 20 U/d intravenously	Prednisolone 2.0 mg/kg intravenously, q12h[b]
Gowda et al[36]	2019	India	Single	Delphi consensus	6 months	18/12	16/9	9.4 ± 5.32	13.9 ± 9.2	ACTH 100 U/(m2·d) intramuscularly	Prednisolone 4.0 mg/(kg·d) orally
O'Callaghan et al[16]	2017	Multinational	Multiple	Unclear	Unclear	60/33	131/78	2–11[a]	3–12[a]	Tetracosactide 40 IU intramuscularly, qod[c]	Prednisolone 40 mg/d orally
Wanigasinghe et al[18] [37] [38]	2014	Ceylon	Single	Clinician's assessment	1 year	49/31	48/25	9.93 ± 8.67	8.31 ± 6.19	Synthetic depot ACTH 40 U intramuscularly, qod[c]	Prednisolone 40 mg/d orally
Lux et al[17] [39]	2004	United Kingdom	Multiple	Clinician's assessment	2 weeks	25/14	30/18	2–11[a]	3–12[a]	Tetracosactide 40 IU intramuscularly, qod[c]	Prednisolone 40 mg/d orally
Baram et al[40]	1996	United States	Single	Definition in Jeavons' article	2 weeks	15/4	14/8	5.1 ± 2.1	7.5 ± 4.3	ACTH 150 U/(m2·d) intramuscularly	Prednisolone 2.0 mg/(kg·d) orally

Abbreviations: ACTH, adrenocorticotropic hormone; ILAE, International League Against Epilepsy.

^a Lux et al (2004)[17] and O'Callaghan et al (2017)[16] studies did not report the mean age of children participating in the trials, only the age range was reported.

^b q12h, every 12 hours.

^c qod, every other day.

Risk of Bias

The overall risk of bias for the included studies is shown in [Fig. 2]. Specific risk of bias item scores and reasons were provided in [Supplementary Appendix S2] (available in the online version only).

Fig. 2 Overall risk-of-bias for included studies.

Short-term Outcomes

A meta-analysis was performed on studies reporting short-term outcomes. There is insufficient clinical evidence to support differences in spasm cessation on 14th day (63.33% vs. 60.47%, RR = 1.05, 95% CI 0.86–1.27, p = 0.64, [Fig. 3]), disappearance rate of EEG hypsarrhythmia on 14th day (53.64% vs. 50.69%, RR = 1.09, 95% CI 0.76–1.57, p = 0.63), and number of days taken for control of spasms (7.70 vs. 6.15, MD = 1.04, 95% CI −3.96 to 6.04, p = 0.68) between ACTH and prednisolone regimen groups, but ACTH is superior to prednisolone in improving electroclinical response on 14th day (80.69% vs. 56.31%, RR = 1.46, 95% CI 1.09–1.96, p = 0.01).

Fig. 3 Risk ratio for spasm cessation on the 14th day for ACTH and prednisolone. ACTH, adrenocorticotropic hormone.

Long-term Outcomes

A meta-analysis was performed on studies reporting long-term outcomes. There is insufficient clinical evidence to support a difference in spasms relapse rate between the ACTH and prednisolone regimen groups (12.57% vs. 21.43%, RR = 0.61, 95% CI 0.37–0.99, p = 0.05), but number of months taken for relapse is longer in ACTH (7.19 vs. 5.72, MD = 1.65, 95% CI 1.01–2.29, p < 0.01).

Adverse Events

A meta-analysis was performed on studies reporting adverse events. There was insufficient clinical evidence to support differences in the rates of total adverse events (25.00% vs. 30.23%, RR = 0.87, 95% CI 0.53–1.42, p = 0.57), hypertension (6.76% vs. 10.26%, RR = 0.72, 95% CI 0.26–2.01, p = 0.53), infection (6.29% vs. 5.98%, RR = 1.45, 95% CI 0.68–3.09, p = 0.33), electrolyte disturbance (9.33% vs. 8.18%, RR = 1.44, 95% CI 0.75–2.79, p = 0.28), and irritability (20.57% vs. 30.40%, RR = 0.81, 95% CI 0.58–1.13, p = 0.21) between the ACTH and prednisolone regimen groups.

Forest plots for meta-analyses of other outcomes are shown in [Supplementary Appendix S3], [Supplementary Figs. S1–S10] (available in the online version only).

Sensitivity Analysis

Analysis using fixed-effects models resulted in no change from previous outcomes, except for spasm relapse rate (RR = 0.58, 95% CI 0.37–0.93, p = 0.02). Sensitivity analysis of outcomes with significant heterogeneity using the literature-by-exclusion method revealed that Wanigasinghe et al's study had a greater impact on heterogeneity.[18]

Subgroup Analysis

Subgroup analyses of spasm cessation on the 14th day showed no significant heterogeneity between ACTH (RR = 1.18, 95% CI 0.89–1.57, p = 0.24) and Tetracosactide (RR = 0.98, 95% CI 0.73–1.31, p = 0.89), I ² = 0%, p = 0.36. There was also no significant heterogeneity between high-dose prednisolone (RR = 1.03, 95% CI 0.84–1.28, p = 0.76) and low-dose prednisolone (RR = 1.36, 95% CI 0.71–2.60, p = 0.35), I ² = 0%, p = 0.42. Results of subgroup analyses for other outcomes are shown in [Supplementary Appendix S4], [Supplementary Figs. S1–S17] (available in the online version only).

Pharmacoeconomic Evaluation Results

Meta-analysis showed that the difference in spasm cessation on the 14th day between the two groups was not statistically significant (p = 0.64), therefore, the cost-minimization analysis was used. The costs of the ACTH and prednisolone regimens are shown in [Table 2].

Table 2 Costs of the adrenocorticotropic hormone and prednisolone regimens

Regimen	Name of cost item	Total cost (yuan)	Minimum total cost (yuan)	Maximum total cost (yuan)
ACTH	Corticotrophin for injection	5,572.00	5,014.80	6,129.20
	Sterilized water for injection	6.79	1.40	110.18
	Intramuscular injection	50.40	28.00	127.40
Prednisolone	Prednisolone acetate tablet	5.56	3.70	18.54

Abbreviation: ACTH, adrenocorticotropic hormone.

The results of the cost-minimization analysis showed that the total cost of the ACTH regimen over 14 days of dosing was 5,629.19 yuan and the total cost of the prednisolone regimen over 14 days of dosing was 5.56 yuan. Compared to the ACTH regimen, the prednisolone regimen has lower costs and economic advantages.

The tornado diagram of the one-way sensitivity analysis is shown in [Fig. 4]. The parameter that had the greatest impact on the outcome was the cost of corticotropin for injection, followed by the cost of sterilized water for injection, intramuscular injection, respectively, and the cost of prednisolone acetate tablets had the least impact on the outcome. The above cost parameters do not affect the robustness of the outcome when fluctuating within the range of variation.

Fig. 4 Tornado diagram of one-way sensitivity analysis of the cost parameters of the ACTH and prednisolone regimen. ACTH, adrenocorticotropic hormone.

Discussion

A total of nine RCTs were included in this meta-analysis, and the current clinical evidence is insufficient to demonstrate a difference between ACTH and prednisolone in improving IESS short-term outcomes (except for the improvement in electroclinical response on the 14th day). The overall risk of bias in the included studies was high because ACTH was administered by injection and prednisolone by oral administration, making blinding difficult. Children with IESS may have dysfunctional regulation of the hypothalamic–pituitary–adrenal axis.[21] ACTH can produce endogenous cortisol by stimulating the adrenal cortex, whereas prednisolone has a similar physiological effect and both can indirectly inhibit pro-adrenal cortisol through a negative feedback effect. Negative feedback indirectly inhibits the release of corticotropin-releasing hormone (CRH). The inhibition of CRH by glucocorticoids is a long feedback, and the negative feedback inhibition is weaker; while the inhibition of CRH by ACTH is a short feedback, and the negative feedback inhibition is stronger.[22] In addition, it has been suggested that ACTH can also treat IESS by directly reducing the release of endogenous CRH.[23] However, the results of most studies have shown no difference between the two in terms of improving short-term outcomes, a finding that may suggest that prednisolone, in addition to its negative feedback effects, may also act through mechanisms such as improving immune disorders in children with IESS.[24]

The available evidence supports the superiority of ACTH over prednisolone in terms of improvement in electroclinical response on the 14th day. Most of the included RCTs assessed the outcome measures of treatment effect as the rate of spasm cessation and disappearance of EEG hypsarrhythmia, while some of the RCTs used the “overall effectiveness,” that is, the electroclinical response, as the outcome measure. However, as there are some differences in the definition of “electroclinical response” in these studies, which may lead to bias, a more standardized definition of this indicator is needed for future evaluations. In terms of long-term outcomes, the available clinical evidence supports that ACTH is more effective in controlling spasms relapse, but the disease regression of IESS is more complex,[6] [25] [26] [27] [28] and there are many factors affecting the prognosis of children with IESS,[29] so factors such as the basic condition of the children in the clinical studies and the follow-up regimen during the follow-up time may have an impact on the results. From the results of the included studies, hormone therapy was generally well-tolerated. Studies have shown that the most significant effects on children are immunosuppression, which can lead to a significant increase in the risk of infection, and hypertension, which can lead to the development of congestive heart failure.[30] Therefore, during hormonal therapy, it is important to avoid infections and monitor blood pressure, and prophylactic antibiotics can be used when necessary to avoid the development of Pneumocystis carinii pneumonia.[31]

In addition to controlling the infantile spasms per se, possible developmental delays in children with IESS can be a great burden to the family and society. Chen and Liu used the Griffiths Mental Development Scales-Chinese (GDS-C) to evaluate the developmental level of children, and the results suggested that the GDS-C scores of the ACTH group were higher than those of the prednisolone group after the regimen (p < 0.05).[32] Jiang et al compared the children's Developmental Quotient and Mental Index scores before and after the drug regimen in the two groups, and the results suggested that the scores of the children in the ACTH group were significantly higher after the regimen compared with those of the children in the prednisolone group (p < 0.05).[19] There are fewer studies evaluating the intellectual and motor prognosis of children with IESS, and there is no evidence to suggest which hormonal regimen is superior. However, hormone therapy (ACTH or prednisolone) may result in better neurodevelopmental outcomes in children with cryptogenic IESS relative to Vigabatrin therapy, and shorter regimen delays may improve long-term cognitive outcomes.[8]

Sensitivity analysis using the literature-by-exclusion method revealed that the most significant source of heterogeneity was Wanigasinghe et al's study. The reasons for this may be (1) the diagnosis of IESS in Wanigasinghe et al's study was determined based on spasticity directly observed by the lead author, videos provided by parents, or clinical spasticity observed through video monitoring. The low level of precision in the description of diagnostic criteria compared to other literature may have influenced the inclusion of children. (2) The children included were predominantly Sinhalese, and although no study has yet shown a clear relationship between regimen outcome and race in IESS, the difference in race may account for its heterogeneity. (3) The genetic etiology of IESS plays an important role in its pathogenesis, and different causative gene mutations, genetic structure, and inherited metabolic abnormalities can cause differences in the sensitivity of children to drugs.[33] Currently, genetic testing is not routinely performed in the diagnosis of IESS, so the genetic etiology of the children was not reported in the included studies, and differences in etiology may also account for heterogeneity.

Considering that differences in the type of ACTH preparation and differences in the dose of prednisolone may have an impact on the results, we performed separate subgroup analyses. The results of the subgroup analyses showed that ACTH was superior to Tetracosactide in terms of electroclinical response on the 14th day ([Supplementary Appendix S4], [Supplementary Fig. S4] [available in the online version only]) and spasms relapse rate ([Supplementary Appendix S4], [Supplementary Fig. S5] [available in the online version only]), and that the ACTH subgroup improved better than prednisolone in both outcome measures. For the analyses of high- and low-dose prednisolone, the results were consistent with the main analysis and may indicate that the dose of prednisolone has little effect on efficacy and safety, but only one study was in the low-dose prednisolone group for each of the outcome metrics, thus more evidence is needed to investigate the effect of prednisolone dose in the future.

In the United States, ACTH is an “orphan drug,” produced by a single manufacturer, and its price increased nearly 14-fold in 2007, with the expensive price of the regimen causing a delay in the start of the regimen, which in turn has an impact on regimen efficacy.[34] Similarly, only one pharmaceutical company produces ACTH in China. In 2015, the price of ACTH was reported to be $7.8 per unit, but low production margins and low demand led to a severe shortage of the drug at that time. Currently, the price of ACTH in China has stabilized at 358.2 yuan, which is not economically advantageous compared to prednisolone. In IESS, long-term disease control, growth and development, and quality of life are important for children and families, but there are no clinical studies that use quality-adjusted life years (QALY) as an outcome indicator. Investigating QALY in children with IESS using scales and other measures will not only provide an understanding of the disease burden of IESS but also provide a utility indicator for economic research.

Our study has the following limitations: (1) only Chinese and English literature were included; (2) the dosage and sequential regimen of ACTH and prednisolone used varied among studies; and (3) due to the limitation of data acquisition, only the direct medical costs were included for economic evaluation. RCTs with large sample sizes should be conducted in the future to evaluate the effects of ACTH and prednisolone in the regimen of IESS with long-term follow-up. Although there is still no international consensus on the standardized dosage of hormonal drugs, clinical studies could try to use uniform dosages and courses of hormonal drugs, and if available, the genetic etiology of the subject children can be examined and reported. In addition, we also hope that the price of ACTH will decrease in the future, thus reducing the financial burden on the families of affected children.

Conclusion

In conclusion, ACTH is superior to prednisolone in improving electroclinical response on the 14th day, but there is insufficient evidence to determine whether ACTH or prednisolone is better in other short-term outcomes. There is also insufficient clinical evidence to demonstrate a difference between ACTH and prednisolone in the occurrence of adverse events. ACTH may have advantages in improving long-term outcomes in IESS. In China, a prednisolone regimen of IESS has a lower cost within 14 days.

Conflict of Interest

None declared.

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Publication History

Received: 27 October 2024

Accepted: 15 January 2025

Article published online:
03 February 2025