Infantile Spasms Pharmacotherapy — ACTH, Vigabatrin, and Combination Strategies: What the Evidence Shows

Synthesising data from 10 key trials and prospective cohorts — including ICISS, UKISS, NISC, and a 2025 combination RCT — comparing ACTH, prednisolone, vigabatrin, and emerging combination strategies for infantile epileptic spasms syndrome. Evidence through 2025.

This is an original evidence synthesis. See References for source studies.

April 10, 2025·17 min read

One-Minute Takeaway

One-Minute Takeaway

Infantile spasms pharmacotherapy with hormonal treatment (ACTH or high-dose prednisolone) combined with vigabatrin produces the highest spasm cessation rates: 72–77% sustained remission at day 14–42 across the ICISS RCT (n=377) and the 2025 Thai combination RCT, compared with 54–56% for hormonal monotherapy and 28–33% for vigabatrin monotherapy.
Hormonal therapy (ACTH or prednisolone) is associated with higher spasm cessation rates than vigabatrin for non-TSC aetiologies in both the UKISS and NISC data, with ACTH producing the highest early response rates (55–65% by day 14) in the prospective NISC cohort of 423 infants.
Despite superior short-term spasm cessation with combination therapy, the ICISS 18-month follow-up showed no statistically significant difference in developmental outcomes (VABS composite scores) or seizure-free rates between combination and hormonal monotherapy groups — though early spasm cessation itself was a strong independent predictor of better developmental outcomes.
Vigabatrin remains the preferred first-line treatment specifically for infantile spasms due to tuberous sclerosis complex (TSC), where it demonstrates superior efficacy compared with hormonal therapies, and should be considered first-line regardless of combination strategies.
Treatment urgency is consistently supported: longer lead-time from spasm onset to treatment initiation is associated with worse developmental and epilepsy outcomes across studies, reinforcing the critical importance of early recognition and rapid treatment initiation.

Why This Topic Matters

Infantile epileptic spasms syndrome (IESS), formerly West syndrome, is the most common epileptic encephalopathy of infancy, typically presenting between 3 and 12 months of age with clustered epileptic spasms and a characteristic hypsarrhythmic EEG pattern. Without effective treatment, IESS carries devastating developmental consequences: approximately 70–90% of affected children develop intellectual disability, and the majority progress to other seizure types including Lennox-Gastaut syndrome.

Infantile spasms pharmacotherapy comparing ACTH vigabatrin and combination treatment strategies — Treatment of infantile epileptic spasms syndrome requires urgent initiation of standard therapy — ACTH, prednisolone, or vigabatrin — with emerging evidence supporting upfront combination approaches.

ACTH, oral corticosteroids (prednisolone/prednisone), and vigabatrin have been the three standard therapies for decades. Yet fundamental questions have remained contentious: which hormonal agent is superior, whether vigabatrin or hormonal therapy should be used first for non-TSC cases, and whether combining agents from the outset yields better outcomes than sequential monotherapy.

A series of landmark international trials — UKISS, ICISS, NISC, and a 2025 Thai combination RCT — have progressively clarified these questions, though important uncertainties remain. This synthesis examines the evidence base for each therapeutic approach and the emerging combination paradigm.

What Evidence Was Reviewed

This synthesis draws on the four largest prospective studies of infantile spasms treatment, their long-term follow-up analyses, the 2025 combination RCT, Cochrane reviews, and international guidelines. Studies were selected for their direct relevance to the comparative effectiveness of standard therapies and emerging combination strategies.

Study	Design	n	Population	Key Finding	Quality
ICISS (O’Callaghan et al. 2017, Lancet Neurol)	Multicentre RCT	377	IESS with hypsarrhythmia, 5 countries	Hormone + vigabatrin: 72% spasm cessation vs 56% hormone alone (day 14–42); p=0.002	High
ICISS 18-month follow-up (2018, Lancet Child)	RCT follow-up	362	ICISS cohort at 18 months	No significant difference in VABS developmental scores or epilepsy outcomes; early response predicted better outcomes	High
UKISS (Lux et al. 2004/2005, Lancet Neurol)	Multicentre RCT	107	IESS without TSC, UK	Hormonal therapy (prednisolone/ACTH) superior to vigabatrin for spasm cessation at 14 days; developmental advantage at 14 months in unknown-aetiology subgroup	High
NISC (Shellhaas et al. 2017; Knupp et al. 2021)	Prospective cohort	423	23 US centres, new-onset IESS	ACTH: highest early response; freedom from treatment failure rates: ACTH > oral steroids > vigabatrin > nonstandard	Moderate
Boonkrongsak et al. 2025 (Ann Clin Transl Neurol)	Single-blind RCT	60	Non-TSC IESS, Thailand	Vigabatrin + prednisolone: 77% sustained remission vs 33% vigabatrin alone (day 14–42); p<0.001	High
Knupp et al. 2016 (Epilepsia)	Prospective cohort (NISC)	118	Children failing first IS treatment	Second standard treatment with different mechanism yielded better response than repeating same class	Moderate
Hancock et al. 2013 (Cochrane)	Systematic review	NR	All IS treatment RCTs	Hormonal therapy results in spasm cessation more often than vigabatrin; ACTH may be more effective than oral steroids but data limited	High
Nolan et al. 2023 (Dev Med Child Neurol)	Retrospective cohort	151	Sequential UKISS protocol, Australia	Prednisolone 40 mg: 63% remission; dose escalation + vigabatrin sequencing produced cumulative 80% response	Moderate
German-Speaking Guideline 2022 (Neuropediatrics)	Evidence-based guideline	NR	All published IS treatment evidence	Recommends hormone monotherapy or hormone + vigabatrin combination as first-line; vigabatrin first for TSC	High
Mytinger et al. 2022/2025 (Neurology)	QI initiative/cohort	NR	Single-centre, non-TSC IESS	Algorithm change prioritising hormones first + rapid second-line escalation improved 3-month remission rates	Moderate

Key Findings: Infantile Spasms Pharmacotherapy

Hormonal Therapy vs Vigabatrin for Non-TSC Aetiologies

The foundational evidence for hormonal superiority comes from the UKISS trial, which randomised 107 infants with IESS (excluding TSC) to either hormonal therapy (prednisolone or tetracosactide/ACTH) or vigabatrin. Hormonal therapy produced significantly higher spasm cessation rates at 14 days. At the 14-month follow-up, infants with unknown aetiology who received hormonal therapy showed better developmental scores than those treated with vigabatrin — a finding that has shaped treatment recommendations globally.

The NISC prospective cohort (423 infants across 23 US centres) confirmed this pattern in a larger, more diverse population. Freedom from treatment failure at 60 days was highest with ACTH, followed by oral steroids, vigabatrin, and nonstandard therapies. However, the NISC data are observational and subject to selection bias — clinicians may have preferentially prescribed ACTH for patients they expected to respond best. Propensity score weighting was used to adjust for this, but residual confounding cannot be excluded.

72–77%Sustained spasm remission with combination therapy (ICISS + 2025 Thai RCT)

54–65%Spasm cessation with hormonal monotherapy (ACTH or prednisolone)

28–33%Spasm cessation with vigabatrin monotherapy (non-TSC)

377Infants enrolled in ICISS — the largest IS treatment RCT

The Combination Paradigm: Hormones Plus Vigabatrin

The ICISS trial (2017) represented a paradigm shift by demonstrating that upfront combination of hormonal therapy with vigabatrin was superior to hormonal monotherapy. Among 377 randomised infants, 72% achieved sustained spasm cessation between days 14 and 42 with combination therapy, compared with 56% with hormonal therapy alone (OR 2.04; 95% CI 1.30–3.22). The electroclinical response rate (spasm cessation plus EEG improvement) at day 14 was 66% for the combination group.

A 2025 single-blind RCT from Thailand (Boonkrongsak et al.) provided further supportive evidence from a different clinical context. This trial compared vigabatrin plus prednisolone to vigabatrin alone in 60 infants with non-TSC IESS. Combination therapy achieved 77% sustained spasm remission between days 14 and 42, compared with 33% for vigabatrin alone — a striking difference consistent with the ICISS findings. Notably, this trial demonstrates the combination advantage specifically when prednisolone (rather than ACTH) serves as the hormonal component, an important finding given the widespread preference for oral steroids over injectable ACTH in many healthcare settings.

Clinical Pearl

The combination advantage appears most pronounced in infants with a low risk of developmental delay at baseline. In the ICISS data, the treatment effect of combination therapy was most clearly demonstrated in this subgroup — suggesting that infants with less severe underlying brain pathology may benefit most from aggressive initial combination treatment. This raises the question of whether aetiology-stratified treatment algorithms could further optimise outcomes.

ACTH vs Oral Prednisolone: Is One Superior?

Whether ACTH (adrenocorticotropic hormone, also known as tetracosactide depot) is superior to high-dose oral prednisolone remains one of the most debated questions in IESS management. North American practice has traditionally favoured ACTH, while UK and Australian guidelines have supported prednisolone as equally effective and more practical.

Neither UKISS nor ICISS was powered to definitively compare the two hormonal agents — in both trials, the choice was left to clinician or parental preference. Meta-analyses suggest that ACTH and high-dose prednisolone (≥40 mg/day) produce comparable spasm cessation rates. The Cochrane review noted a trend favouring ACTH but concluded the evidence was insufficient to establish superiority. The 2022 German guideline states that ACTH is “probably not superior to oral glucocorticoids” when adequate prednisolone doses are used, noting that historical findings of ACTH superiority may reflect the use of subtherapeutic prednisone doses in older trials.

Practically, prednisolone offers significant advantages: oral administration, lower cost, wider availability, and no requirement for intramuscular injection training. However, ACTH may have steroid-independent effects via melanocortin receptor activation and CRH modulation that could theoretically provide additional benefit. Until a definitive head-to-head RCT addresses this question, both agents are considered acceptable first-line hormonal options.

Tuberous Sclerosis Complex: Vigabatrin as First-Line

Vigabatrin remains the preferred first-line agent specifically for IESS due to tuberous sclerosis complex (TSC), where it demonstrates consistently high response rates (65–95% spasm cessation in published series). This TSC-specific advantage is well established and is reflected in all current international guidelines, including the 2021 TSC Diagnostic Criteria and Surveillance Recommendations.

The mechanism underlying vigabatrin’s particular effectiveness in TSC-related spasms likely involves the mTOR pathway dysregulation that characterises TSC. Vigabatrin’s GABAergic mechanism and potential mTOR-independent effects may be particularly well suited to this pathophysiology. Importantly, preventive treatment with vigabatrin in TSC infants identified presymptomatically (before spasm onset) has shown promise in reducing epilepsy severity, though this remains an active area of investigation.

Developmental Outcomes: The 18-Month ICISS Paradox

The ICISS 18-month follow-up (2018) produced a finding that has generated significant discussion: despite the superior short-term spasm cessation with combination therapy, no statistically significant difference in developmental outcomes (VABS composite scores) or epilepsy outcomes at 18 months was observed between the combination and hormonal monotherapy groups.

Several explanations have been proposed. First, infants in the hormonal monotherapy group who did not respond were quickly escalated to vigabatrin (per protocol), potentially narrowing the gap between groups over time. Second, the underlying aetiology — which is the strongest determinant of developmental outcome — was balanced between groups through randomisation but remained the dominant prognostic factor regardless of treatment. Third, 18 months may be too early to detect developmental differences that emerge later in childhood.

Importantly, the same analysis confirmed that early spasm cessation itself — regardless of which treatment achieved it — was strongly and independently associated with better developmental and epilepsy outcomes at 18 months. This finding reinforces the rationale for using whichever strategy most rapidly controls spasms, which the short-term data identify as combination therapy.

Second-Line Treatment After Initial Failure

Approximately 30–45% of infants do not achieve sustained spasm cessation with first-line therapy, necessitating second-line treatment. The NISC data on second-line treatment (Knupp et al. 2016) provide the best available evidence for this scenario. Among 118 infants who failed first-line therapy, switching to a standard medication with a different mechanism of action — for example, from hormonal therapy to vigabatrin, or vice versa — produced better outcomes than nonstandard second-line choices.

An Australian retrospective study using sequential UKISS-protocol dosing (Nolan et al. 2023) showed that the cumulative response rate could reach approximately 80% when prednisolone dose escalation was followed by vigabatrin for non-responders. This sequential approach provides an alternative to upfront combination therapy, though direct comparisons between the two strategies are lacking.

For infants refractory to both standard medications, options include ketogenic dietary therapies, sulthiame, topiramate, valproate, and zonisamide — though the evidence base for these agents is substantially weaker (limited to case series and retrospective cohorts). Early evaluation for epilepsy surgery should be considered in refractory cases, particularly when focal brain lesions are present.

Treatment Urgency: Lead-Time Matters

Across studies, a consistent finding emerges: shorter lead-time from spasm onset to treatment initiation is associated with better outcomes. In the ICISS data, treatment delayed by more than 2 months was linked to lower response rates. The UKISS follow-up demonstrated that longer delays to treatment were associated with worse developmental scores at 4 years. These findings underscore the critical importance of early recognition of infantile spasms by parents and primary care clinicians and rapid referral for treatment — yet the median lead-time to treatment in some cohorts remains disturbingly long (50 days in the 2025 Thai study).

Quality & Consistency of Evidence

Combination therapy (hormones + vigabatrin) produces higher short-term spasm cessation than hormonal monotherapy: Consistent across the ICISS RCT (n=377) and the 2025 Thai RCT (n=60). Concordant results from two independent randomised trials in different populations strengthen this conclusion.

Hormonal therapy is superior to vigabatrin monotherapy for non-TSC IESS: Supported by UKISS (RCT), NISC (prospective cohort with propensity weighting), and multiple Cochrane review syntheses. Consistent but with moderate evidence quality due to open-label designs and observational data contributions.

ACTH vs prednisolone comparative efficacy: Limited and conflicting evidence. No adequately powered head-to-head RCT exists. Meta-analyses suggest equivalence at adequate doses but cannot exclude a modest ACTH advantage. Practice variation between North America (ACTH-preferring) and UK/Australia (prednisolone-preferring) reflects this uncertainty.

Developmental benefit of combination vs monotherapy at 18 months: Not demonstrated in the ICISS follow-up. However, early spasm cessation — which combination therapy achieves more frequently — is itself a strong predictor of better developmental outcomes. The absence of a developmental difference may reflect study design limitations rather than genuine therapeutic equivalence.

Vigabatrin is first-line for TSC-related IESS: Consistent evidence from multiple studies and universally endorsed by international guidelines. Not contested in the literature.

What the Evidence Does Not Show

Important Gaps

Despite being one of the most studied epileptic encephalopathies, several critical treatment questions remain unresolved.

Definitive ACTH vs prednisolone comparison: No adequately powered, randomised, head-to-head trial has compared ACTH to high-dose prednisolone using modern outcome measures. This remains the single most important unanswered question in IESS pharmacotherapy.

Whether upfront combination therapy improves long-term developmental outcomes: The ICISS 18-month data did not show a developmental advantage. Longer follow-up (beyond 4–5 years) and larger studies powered specifically for developmental outcomes are needed to determine whether the short-term cessation advantage translates to meaningful neurodevelopmental benefits.

Optimal dosing and duration of hormonal therapy: There is no consensus on whether ACTH dosing should be “high-dose” (150 IU/m²/day as used in the US) versus “low-dose” (0.5 mg alternate days as used in ICISS), or whether longer treatment courses improve relapse rates. Similarly, whether prednisolone 40 mg/day is sufficient or whether 60 mg/day should be used from the outset remains debated.

Vigabatrin retinal toxicity risk with early, limited exposure: Vigabatrin carries a risk of irreversible peripheral visual field loss that is dose- and duration-dependent. The risk with short-term use (weeks to months) in infancy is less well characterised than with prolonged use, and monitoring visual fields in pre-verbal infants remains challenging. Electroretinography provides partial monitoring, but optimal surveillance protocols for this age group remain undefined.

Practical Implications

Based on the current evidence, the following considerations may inform first-line treatment decisions for infantile epileptic spasms syndrome.

Evidence Supports Upfront Combination of Hormones Plus Vigabatrin for Non-TSC IESS

Two concordant RCTs demonstrate that combining hormonal therapy (ACTH or prednisolone) with vigabatrin from the outset produces the highest short-term spasm cessation rates (72–77%). Both the German-speaking guideline and growing international practice support this approach as a first-line option. Where combination therapy is used, the hormonal component can be either ACTH or high-dose prednisolone based on local availability and clinician preference.

Vigabatrin Should Be First-Line for TSC-Related Spasms

Vigabatrin’s specific efficacy in TSC-related IESS is well established and uncontested. For infants with confirmed or suspected TSC, vigabatrin should be initiated promptly as first-line therapy, with hormonal treatment reserved for non-responders. This recommendation is consistent across all international guidelines.

Rapid Assessment and Early Treatment Initiation Are Critical

Treatment lead-time is a consistently modifiable predictor of outcomes. When infantile spasms are suspected, EEG should be obtained within days and treatment initiated immediately upon confirmation. The 2022 German guideline and AAN quality measures both emphasise that treatment should not be delayed while awaiting aetiological workup results.

Response Assessment at Day 14 Should Guide Escalation

Clinical and electrographic response should be evaluated by day 14 of treatment. Non-responders to initial therapy should be rapidly escalated to a second-line agent with a different mechanism of action. The NISC second-line data support switching between classes (hormonal to vigabatrin or vice versa) rather than adding nonstandard therapies. Refractory cases should be evaluated early for epilepsy surgery candidacy, particularly when focal lesions are present.

Evidence Grade & Bottom Line

Evidence Grade: Moderate

The evidence that combination therapy (hormones + vigabatrin) produces higher short-term spasm cessation rates than either agent alone is strong and consistent across two RCTs. The evidence that hormonal therapy is superior to vigabatrin alone for non-TSC IESS is supported by one RCT and a large prospective cohort. The grade is capped at moderate because (1) key trials are open-label, (2) the comparative efficacy of ACTH versus prednisolone lacks definitive RCT evidence, and (3) long-term developmental benefits of combination therapy over sequential treatment remain undemonstrated.

What This Grade Means

A moderate evidence grade indicates that the short-term efficacy hierarchy is reasonably well established (combination > hormonal monotherapy > vigabatrin alone for non-TSC IESS), but important questions about optimal agent selection within the hormonal class, dosing, and long-term developmental outcomes remain. Treatment decisions should prioritise the most rapid spasm cessation achievable, using the best-supported strategies available.

Bottom Line

Combination therapy (ACTH or prednisolone plus vigabatrin) yields the highest spasm cessation rates at 72–77%, compared with 54–65% for hormonal monotherapy and 28–33% for vigabatrin alone in non-TSC IESS.
The ICISS 18-month follow-up showed no significant developmental advantage of combination over hormonal monotherapy — but early spasm cessation, which combination therapy achieves more often, independently predicts better developmental outcomes.
Vigabatrin is the preferred first-line treatment specifically for TSC-related IESS, with consistently high response rates (65–95%).
A definitive ACTH vs high-dose prednisolone head-to-head RCT, and studies demonstrating long-term developmental benefit from combination therapy, remain the most important evidence gaps.
Treatment urgency is paramount: shorter lead-time from spasm onset to treatment initiation is consistently associated with better developmental and epilepsy outcomes across all studies.

Article Information

For Educational Purposes Only. This is an original evidence synthesis informed by the studies listed below. It does not replace clinical judgement. Drug dosages should be verified against current prescribing information.

References

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