Long-term outcome in children with infantile epileptic spasms syndrome: a multicenter retrospective study in Korea

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Clin Exp Pediatr. 2026;.cep.2025.02089

Publication date (electronic) : 2026 February 19

doi : https://doi.org/10.3345/cep.2025.02089

Sun Ah Choi, MD, PhD¹, Minhye Kim, MD², Hye Jin Kim, MD³, Woo Joong Kim, MD⁴, Byung Chan Lim, MD, PhD⁴, Ji Yeon Han, MD⁵, Hunmin Kim, MD, PhD⁶, Min-Jee Kim, MD, PhD⁷, Mi-Sun Yum, MD, PhD⁷, Jiwon Lee, MD, PhD⁸, Jeehun Lee, MD, PhD⁸, Hyewon Woo, MD⁹, Jon Soo Kim, MD, PhD^,9

¹Department of Pediatrics, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea

²Department of Pediatrics, Inje University Haeundae Paik Hospital, Busan, Korea

³Department of Pediatrics, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea

⁴Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea

⁵Department of Pediatrics, Inha University Hospital, Inha University College of Medicine, Incheon, Korea

⁶Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

⁷Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea

⁸Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

⁹Department of Pediatrics, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea

Corresponding author: Jon Soo Kim, MD, PhD. Department of Pediatrics, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 776 Sunhwan-1-ro, Seowon-gu, Cheongju 28644, Korea Email: pedkjs79@gmail.com

Received 2025 September 8; Revised 2025 November 5; Accepted 2025 November 14.

Abstract

Introduction

Infantile epileptic spasms syndrome (IESS) is a severe form of epilepsy syndrome, characterized by clusters of brief spasmodic seizures and a distinct electrographic pattern, often accompanied by developmental regression [1]. IESS is associated with poor long-term outcomes, such as a high risk of persistent epilepsy and neurodevelopmental impairment. About 70% of patients develop other types of epilepsy, and 18%–23% progress to Lennox-Gastaut Syndrome (LGS) [2]. In addition, 80% of patients have combined intellectual disability, and often accompanied by autism spectrum disorder [3]. Several factors such as persistent spasms or tonic seizure after 90 days, developmental delay before onset of spasms, and abnormal brain imaging have been reported as poor prognostic factors [4].

Hormonal therapy and vigabatrin are known as the standard treatment for IESS. Numerous randomized controlled trials have been published exploring various treatments, dosages, and combinations to achieve both electroclinical remission and neurodevelopmental outcomes. For short-term outcome controlling spasms, hormonal therapy is generally more effective than vigabatrin, although vigabatrin shows greater efficacy in tuberous sclerosis complex (TSC)-associated spasms [5]. In hormonal therapy, outcome of adrenocorticotropic hormone (ACTH) was better than that of prednisolone. The difference in long-term neurodevelopmental outcomes according to treatment regimens have not yet been clarified. However, it is certain that early initiation of the first-line treatment regimen and a timely electroencephalography (EEG) assess for resolution of spasms improve neurodevelopmental outcomes [6].

Management of IESS exhibits considerable variation across the countries, reflecting differences in treatment prioritization, diagnostic protocols, and regional resource availability. Several countries made consensus guidelines for diagnosis and treatment of IESS [7-9]. In Korea, the next-generation sequencing (NGS) panel testing and chromosomal microarray (CMA) are actively utilized in clinical practice [10]. However, there is no consensus guidelines for etiologic investigation and treatment of IESS. This study aimed to evaluate long-term outcomes of children with IESS and review the evaluation and treatment in a real-world Korean multicenter clinical practice over the past decades.

Methods

Results

A total of 378 patients with IESS were included in this study. The mean age at spasm onset was 7.3 (standard deviation [SD] 4.4, range 1–24) months (Table 1). The mean follow-up duration was 7.9 (SD, 5.6; range, 2–28) years. The etiology of IESS was identified in 65.1% of the cohort, with acquired structural causes being the most common (29.9%), followed by genetic-structural (12.2%) and congenital structural causes (11.4%) (Fig. 1). Of acquired structural causes, hypoxic-ischemic encephalopathy (42.5 %, 48 of 113) and brain injury secondary to prematurity (37.2%, 42 of 113) were common. There were 75 children with genetic and genetic-structural etiologies including 52 single nuclear gene disorders and 23 chromosomal disorders (Supplementary Table 1). Among the single nuclear gene disorders, 35 cases were TSC accounting for 76.1% of genetic-structural etiology. In chromosomal disorders, there were 8 Down syndrome, 3 Miller-Dieker syndrome, and 3 15q duplication syndrome. The responder rate was 36.4%, and relapse occurred in 8.0% (23 of 286 children with available data).

Table 1.

Demographics of children with infantile epileptic spasms syndrome (N=378)

Fig. 1.

Etiology of infantile epileptic spasms syndrome (IESS).

Results

A total of 378 patients with IESS were included in this study. The mean age at spasm onset was 7.3 (standard deviation [SD] 4.4, range 1–24) months (Table 1). The mean follow-up duration was 7.9 (SD, 5.6; range, 2–28) years. The etiology of IESS was identified in 65.1% of the cohort, with acquired structural causes being the most common (29.9%), followed by genetic-structural (12.2%) and congenital structural causes (11.4%) (Fig. 1). Of acquired structural causes, hypoxic-ischemic encephalopathy (42.5 %, 48 of 113) and brain injury secondary to prematurity (37.2%, 42 of 113) were common. There were 75 children with genetic and genetic-structural etiologies including 52 single nuclear gene disorders and 23 chromosomal disorders (Supplementary Table 1). Among the single nuclear gene disorders, 35 cases were TSC accounting for 76.1% of genetic-structural etiology. In chromosomal disorders, there were 8 Down syndrome, 3 Miller-Dieker syndrome, and 3 15q duplication syndrome. The responder rate was 36.4%, and relapse occurred in 8.0% (23 of 286 children with available data).

At the last follow-up, 77.8% of cohort were considered as having chronic epilepsy taking ASMs while 22.2% had discontinued ASMs (Fig. 2). Among those who take ASMs, 29.1% were considered as having DRE, 25.9% achieved seizure control while on ASMs, and 22.8% continued to have nondisabling seizures while on ASMs. Children with an unknown etiology showed better seizure outcomes than those with structural (acquired or congenital), infectious, or genetic-structural etiologies (Table 2, Supplementary Table 2). Records of neurodevelopmental assessments were available for 350 children at the last follow-up. Of these, 225 were assessed by physicians and 154 underwent standardized neuropsychological evaluations such as the Bayley Scales or Wechsler intelligence tests. Overall, 89.7% (314 of 350) were identified as having some degree of intellectual disability (164 of 225 assessed by physicians and 150 of 154 assessed by standardized neuropsychological evaluations). Among the children who met age criteria for school attendance and had available data, 53.9% (62 of 115 eligible children) received special education in kindergarten and/or elementary school. In addition, 59.6% (28 of 47 eligible children) had special educational support in their junior high school. In a subgroup analysis by treatment period, seizure outcomes after 2012 were significantly improved compared with those treated before 2012 (chi-square= 23.69, P<0.001). The proportion of DRE cases was significantly reduced in children treated after 2012, whereas neurodevelopmental outcomes remained unchanged (Table 3). As natural or synthetic ACTH were not available in Korea, the main treatments used for spasms control were vigabatrin and steroid therapy. In overall cohort, 240 children had vigabatrin monotherapy, 115 had combination of vigabatrin and steroid therapy, 7 children had steroid monotherapy, and 15 had other ASMs (Fig. 3). Two forms of steroids, oral prednisolone (73%, 89 of 122) and intravenous methylprednisolone therapy (37%, 33 of 122) were used. Most children who received intravenous methylprednisolone transitioned to oral prednisolone. In 35 children with TSC, 31 had vigabatrin monotherapy, 3 with combination therapy, and 1 with oral prednisolone. In addition to medical treatment, 22.2% (84 of 378) of the cohort received dietary therapy and 4.0% (15 of 378) had epilepsy surgery. In comparison of outcomes between combination therapy and vigabatrin monotherapy, the proportion of seizure-free children was higher in combination therapy while a higher proportion of children achieving seizure control with ASM in vigabatrin monotherapy (Supplementary Table 3). However, there were no significant differences in other seizure outcomes such as DRE or in neurodevelopmental outcomes.

Fig. 2.

Long-term epilepsy outcomes at the last follow-up. ASM, antiseizure medication.

Table 2.

Epilepsy outcomes by etiology

Table 3.

Epilepsy and neurodevelopmental outcomes by treatment period

Fig. 3.

Treatments used to control epileptic spasms. *Combination with other antiseizure medications of diet therapy are included.

Discussion

This study demonstrates the long-term epilepsy and developmental outcomes based on how children with IESS were treated from the late 1990s to the early 2020s. Overall, three-quarters of the children eventually developed chronic epilepsy, with one-third of the children being considered as DRE. This is in keeping with the literature which describes that, in long-term, two-thirds of the children had seizures and 18-23% evolved into LGS [2,3,13]. In a subgroup analysis, we found out that the proportion of DRE cases was significantly reduced in children treated after 2012. This improvement may be attributed to the broad range of therapeutic options available for DRE and the more aggressive treatment strategies for IESS. Children with an unknown etiology showed better seizure outcomes than those with structural, infectious, or genetic-structural etiologies. This is consistent with the well-established observation that idiopathic etiologies generally have a more favorable prognosis than symptomatic etiologies [4]. In this study, we measured neurodevelopmental outcomes by clinical assessment and found out that 90% of children with IESS experienced some degree of neurodevelopmental delay and half of them had special education. These findings are comparable to the long-term Finnish study which reported 83% (122 of 147 survivals) had mild to severe intellectual disabilities and required educational support [2]. Various prognostic factors of neurodevelopmental outcome have been reported, such as cryptogenic etiology, short latency time to treatment, and normal development before the onset of spasms. It is clear that early recognition and prompt treatment of spasm remains the most crucial factor for better neurodevelopmental outcome [14,15]. Children with IESS are generally at high risk of having poor neurodevelopmental outcomes, therefore they should be referred for early evaluation and intervention if there are any developmental concerns.

Similar to the results from United Kingdom Infantile Spasms Study (UKISS) and National Infantile Spasms Consortium (NISC), 65.1% of children with IESS had a proven etiology [12,16]. Specifically, acquired structural etiologies made up the largest proportion in our cohort (29.6%) which also comprised 22.4% in the NISC [12,17]. Hypoxicischemic encephalopathy and brain insults associated with prematurity were major findings in acquired structural etiology. Brain magnetic resonance imaging demonstrated causal abnormalities in 53.4% of children, and thus necessary as a first-line investigation. If there is structural lesion related to a genetic disorder, relevant specific genetic testing would be recommended. If imaging is uninformative, combination of genetic testing such as CMA or NGS epilepsy gene panels would be considered. When considering genetic and genetic-structural etiology, nuclear gene disorders were more common than chromosomal disorders. The recent Indian study of genetic IESS demonstrated wide heterogeneity of monogenic disorders and reported that monogenic disorders are the common genetic cause of genetic IESS [18]. On contrary, when we focused on 29 children with pure genetic IESS, we found a higher frequency of chromosomal disorders (62%, 18 of 29) than in nuclear gene disorders (38%, 11 of 29). This could be attributed to our inclusion criteria of which include few children who underwent NGS gene panel. Wirrell et al. [12] mentioned the combination of array comparative genomic hybridization and epilepsy gene panel provide a high yield of definitive diagnosis in more than 40% of children without obvious cause, suggesting CMA and gene panel as compatible for the first-tier assessment. Single nuclear gene disorders were the dominant cause of genetic IESS and these involved genes are widely heterogeneous, WES can be considered as a second-tier assessment [19]. Our study suggest that metabolic disorders are a rare cause of IESS, 1.1% of our cohort (Supplementary Table 4).

ACTH, prednisolone, or vigabatrin are commonly used as first-line treatment for IESS. There were various clinical trials comparing natural or synthetic ACTH, high or low doses of ACTH, high or low doses of vigabatrin, and combinations of hormonal therapy with vigabatrin [6]. Vigabatrin either as monotherapy or combination therapy with steroid has been the mainstay treatment for spasms in Korea over the past 20 years. Oral prednisolone or intravenous methylprednisolone was used as hormonal therapy, but these steroid monotherapies were less common than we expected. Hormonal therapy is known as superior to the vigabatrin that responder rate of hormonal therapies ranges from 70%–87%, while that of vigabatrin ranges 35%–54% [20-22]. A recent systematic review which compared the efficacy of vigabatrin and hormonal therapy recommended hormonal monotherapy for non-TSC-associated spasms while vigabatrin as the first-line treatment for TSC-associated IESS [23]. They concluded that there is limited evidence for combination therapy of vigabatrin and steroid. Yet, there is no specific treatment which has advantage on the neurodevelopmental outcome. The UKISS study reported better developmental outcomes in children with cryptogenic etiology who were treated with steroids, but there were no significant differences in epilepsy or developmental outcomes at age 4 between those treated with hormonal therapy and those treated with vigabatrin [14,24]. The ICISS trial also demonstrated that combination therapy (hormonal and vigabatrin) was more effective at controlling spasms but did not show any advantage in developmental outcomes [25,26]. Furthermore, no advantage in developmental outcomes was observed between ACTH and oral prednisolone [27]. The proportion of DRE and intellectual disability did not differ significantly between the combination therapy and vigabatrin monotherapy groups. Although there were differences in specific epilepsy outcomes between the 2 treatment groups, we were unable to determine the underlying reasons for these differences due to the retrospective nature of the study. Confounding factors such as etiology or lead time to treatment may have influenced the epilepsy outcomes rather than a direct effect of the treatment. Given that ACTH is not available in Korea and high dose steroid are as effective as ACTH, high dose prednisolone of 40 to 60 mg/day would be strongly recommended for controlling spasms [5,28]. Vigabatrin could be considered a first-line treatment for children with TSC and those contraindicated to steroid therapy. Combination of high dose prednisolone and vigabatrin could also be another option, however, there are limited data on long-term outcomes and concerns of adverse effects. We found that there was a considerable variation in the dosage and duration of vigabatrin prescription. Thus, consensus guidelines are needed for each treatment approach in detail. In addition, while one-third of cohort were considered as DRE, most of them relied on the medical treatment. Only 4% had epilepsy surgery which can be another beneficial option for DRE. This might be attributed to underutilization of surgical interventions and neuromodulations in Korea which highlighting the importance of considering surgical interventions.

Our study has several limitations. As a retrospective study, there was variability in individual follow-up durations which might have influenced the overall outcomes. In addition, data on the time from diagnosis to treatment initiation and definite date of spasms cessation were not available. We were unable to determine how the treatment latency and early treatment response affected the overall outcomes. We assessed neurodevelopmental status by clinical assessment rather than comprehensive neuropsychiatric evaluations. This may lead to variations in neurodevelopment outcome according to the criteria applied for neurodevelopmental assessment. For the long-term outcomes, we included children who followed up at least 2 years. This could act as a selection bias by excluding children who were recently diagnosed and underwent gene panels or WES. Despite these limitations, our study provides real-world evidence how children with IESS have been managed. Also, this study highlights the needs of diagnostic and treatment consensus guidelines based on the Korean healthcare setting. The nationwide consensus guidelines including diagnostic approach for etiological investigation and a timely stepwise treatment selection would be necessary to improve the overall outcomes.

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