High-dose oral prednisolone for infantile spasms: An effective and less expensive alternative to ACTH

doi:10.1016/j.yebeh.2009.01.023

Epilepsy & Behavior

Volume 14, Issue 4, April 2009, Pages 674-676

https://doi.org/10.1016/j.yebeh.2009.01.023 Get rights and content

Abstract

The ideal treatment of infantile spasms is unclear, but many studies advocate hormonal treatment. In the United States, intramuscular ACTH is most widely used, despite the problematic financial cost and side effect profile. Since September 2007, we have replaced ACTH with high-dose oral prednisolone (40–60 mg/day) according to the 2004 United Kingdom Infantile Spasms Study (UKISS). Ten of 15 (67%) infants with new-onset and previously treated infantile spasms became spasm free within 2 weeks; 4 later recurred. More children with an idiopathic etiology for infantile spasms were spasm free than were symptomatic cases (88% vs 43%, P = 0.10). Spasm freedom was equivalent to our most recent 15 infants receiving ACTH, with 13 (87%) responding, P = 0.16. Oral prednisolone had fewer adverse effects (53% vs 80%, P = 0.10) and was less expensive ($200 vs approximately $70,000) than ACTH. We now routinely recommend oral prednisolone to all families of children with infantile spasms.

Introduction

Infantile spasms (IS) is an epileptic encephalopathy with poor developmental outcomes. Unfortunately, since its original description in 1841 [1], there are limited well-studied therapies other than hormonal therapy and vigabatrin. In the United States, many physicians perceive ACTH as first-line therapy, as this was the only treatment in the 2004 American Academy of Neurology practice parameter classified as “probably” effective, with vigabatrin deemed only “possibly” effective [2]. At this time, vigabatrin is not currently licensed in the United States.

Vigabatrin is, however, available in many other countries, but in the UKISS study [3], hormonal therapy was successful in 73% of infants after 2 weeks compared with vigabatrin in 54%. These results were similar to another prospective comparison of these therapies from 1997 (74% vs 48%) [4]. Based on these and other studies, a recent Cochrane review [5] suggested hormonal treatment was better than vigabatrin in the short term.

The treatment of IS became even more problematic in the United States in August 2007 when the cost of H.P. ACTHar Gel (Questcor Pharmaceuticals, Union City, CA, USA) was increased from $1650 to $23,000 for a vial, with typically three vials required for a 1-month treatment course. Oral corticosteroids are a logical, less expensive alternative, but results for IS are conflicting. Two previous studies [6], [7] reported that oral corticosteroids were less effective (29–33% spasm-free incidence) and they therefore have not been recommended [2]. However, in the hormonal treatment arm of the UKISS study, oral prednisolone was equivalent to synthetic ACTH (70% vs 76% spasm freedom after 14 days, respectively) [3]. A higher dose of oral steroids was used in the UKISS study [3], nearly double the dose in the previous reports [6], [7]. We expected that oral prednisolone would be equivalent to published efficacy rates for ACTH and our center’s previous experience as well.

Section snippets

Methods

We have consistently used high-dose oral prednisolone in 15 consecutive infants with IS since September 2007. Families were counseled about all choices including topiramate [8], [9] and the ketogenic diet [10], but were informed they would need to obtain ACTH and vigabatrin at another institution if either of these therapies was chosen. In some cases, they were prescribed ACTH or vigabatrin at another institution. Those treatments were deferred and they were seen for a second opinion by our

Results

The median age of the 15 children treated with oral prednisolone was 6 months (range: 3–19 months). Patient demographics are provided in Table 1. Eight had new-onset IS, with the other 7 having failed therapies including topiramate, levetiracetam, and the ketogenic diet. Those with idiopathic etiology for IS were slightly more likely to become spasm free (7/8, 88%) compared with 3 of 7 (43%) with symptomatic etiologies (P = 0.10). There was no influence of age, gender, or duration of spasms prior

Discussion

Despite the unfortunate financial impetus for finding steroid alternatives, our center’s experience over the past 18 months using oral prednisolone showed equivalence to our ACTH experience and supported results from the UKISS study [3]. There are distinct advantages to using oral prednisolone over ACTH. An insurance preapproval potentially requiring days to complete is not typically necessary with prednisolone, which is widely available in most pharmacies. Painful intramuscular injections are

Conflict of interest

None of the authors have any conflicts of interest to disclose.

Acknowledgments

Dr. Adam Hartman was supported by a Neurological Sciences Academic Development Award (K12NS001696). The authors gratefully acknowledge the email correspondence of Dr. John Osborne in helping guide our use of oral prednisolone.

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Cited by (78)

Clinical profile, treatment modalities, and outcomes in patients with infantile spasms: A retrospective study from the United Arab of Emirates (UAE)
2022, Epilepsy and Behavior
Citation Excerpt :
None of our patients have received ACTH, probably due to a combination of factors such as lack of its availability, limited insurance coverage, and/or the absence of a well-trained epilepsy nurse to provide proper parental training for injections. In agreement with our results, several prospective studies have shown the efficacy of high-dose Prednisolone UKISS protocol as a feasible and less expensive alternative to ACTH [16,17,38,40]. Vigabatrin is considered the preferred 1st line treatment for patients with newly diagnosed IS in many institutes [30,41,42].
Infantile spasms (IS) are an epileptic encephalopathy where the prognosis is generally poor, with most patients exhibiting psychomotor retardation or intractable epilepsy. However, it is claimed that early and aggressive treatment is related to better response rate and outcome, especially in patients with idiopathic IS.
To investigate different treatment modalities and outcomes in patients with IS attending a pediatric neurology clinic at a specialized neurology center in Abu Dhabi, United Arab Emirates.
Retrospective chart review was done for detailed history, demographic data, etiology, neuro-diagnostic workup, treatment modalities, and the outcomes for all patients diagnosed with IS from September 2014 to September 2019.
Three treatment modalities were identified as 1st line- Prednisolone United Kingdom Infantile Spasms Study (UKISS) (N = 15, 46.8%), Anti-Seizure Medications (ASMs) (N = 12, 37.5%), and Vigabatrin (N = 5, 15.6%). The complete response rate to Vigabatrin as a 1st line treatment showed the highest statistical significance (X² = 7.34, p = 0.007). Patients with idiopathic IS showed a comparable response to treatment to those with symptomatic IS. Additional response to 2nd line treatment with Prednisolone UKISS protocol (25%) and Vigabatrin (15%) was noted in patients who showed partial or no response to the 1st line treatment. None of our patients received Adrenocorticotropic Hormone as treatment. All patients with desirable final outcomes were with idiopathic IS and none were symptomatic.
More than a third of our patients showed poor treatment response whenever they were not offered treatment according to the current available protocols. This indicates an urgent need for having a unified treatment protocol that takes into consideration the availability of medications, professional expertise as well as diagnostic workup outside major tertiary care centers in our region.
Medication selection, health services outcomes, and cost trajectories for Medicaid beneficiaries with infantile spasms
2021, Epilepsy Research
There are three recommended first-line treatments for infantile spasms, adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin, though non-standard treatments such as topiramate are sometimes selected. Is it uncertain how treatment selection influences health services outcomes.
We conducted a retrospective cohort study of Medicaid beneficiaries newly diagnosed with infantile spasms from 2009–2010. We included infants with a new diagnosis of infantile spasms between age 2–9 months who filled ACTH (reference), prednisolone, vigabatrin, or topiramate prescriptions. Multivariable Cox proportional hazards regression compared time to first emergency department (ED) visit or hospitalization across treatment groups during 2 years of follow-up. Monthly costs for each treatment were examined in 6-month intervals and compared in a multivariable generalized linear model.
Among 256 children with infantile spasms, 116 received ACTH, 62 prednisolone, 15 vigabatrin, and 63 topiramate. The rate of ED visit or hospitalization per person-year did not differ significantly for prednisolone (0.9 [95 % CI 0.7–1.2]; adjusted hazard ratio [aHR] 0.84, 95 % CI 0.57–1.24), vigabatrin (0.8 [95 % CI 0.4–1.5]; aHR 0.91, 95% CI 0.45–1.84), or topiramate (1.7 [95 % CI 1.3–2.3]; aHR 1.15, 95 % CI 0.80–1.65), when compared to ACTH (1.1 [95 % CI 0.9–1.3]). The median payment for ACTH was $96,406 (interquartile range 70,742–138,476) during the first 6 months. The adjusted mean total payment in the first 6 months was 73% lower for prednisolone (95% CI −82, −61), 69% lower for vigabatrin (95% CI −84, −40), and 73% lower for topiramate (95% CI −82, −59). However, in subsequent 6-month intervals, costs associated with ACTH were not significantly different compared to other treatments.
Compared to other treatments for infantile spasms, use of ACTH was associated with greater cost in the first 6 months of treatment, but not with reduced ED visits or hospitalizations. The cost effectiveness of ACTH depends on its relative clinical efficacy, and merits additional research.
Acthar® Gel (repository corticotropin injection) dose–response relationships in an animal model of epileptic spasms
2021, Epilepsy and Behavior
Studies were undertaken to evaluate the effectiveness of Acthar® Gel (repository corticotropin injection [RCI]) in the tetrodotoxin (TTX) model of early-life-induced epileptic spasms. Repository corticotropin injection (RCI) is widely used in the United States to treat infantile spasms. A major component of RCI is N25 deamidated ACTH. Additionally, we hoped to provide some insight into the possible role circulating corticosteroids play in spasm cessation by comparing the RCI dose–response relationships for spasm suppression to RCI-induced corticosterone release from the adrenal gland. Spasms were induced by chronic TTX infusion into the neocortex beginning on postnatal day 11. Repository corticotropin injection (RCI) dosages were between 8 and 32 IU/kg/day. Drug titration protocols were used, and comparisons were made to injections of a vehicle gel. Video/EEG recordings (24/7) monitored the drug’s effects continuously for up to 2 months. Tetrodotoxin (TTX)-infused control rats were monitored for the same period of time. In separate experiments, the same dosages of RCI were given to rats and 1 h later plasma was collected and assayed for corticosterone. A parallel study compared the effects of 1-day and 10-day RCI treatments on circulating corticosterone. Results showed that RCI was ineffective at dosages of 8, 12, and 16 IU/kg/day but eliminated spasms in 66% of animals treated with 24 or 32 IU/kg/day. Treating animals with 32 IU/kg/day alone produced the same degree of spasms suppression as observed during the titration protocols. In rats that had hypsarrhythmia-like activity, RCI eliminated this abnormal interictal EEG pattern in all rats that became seizure-free. In terms of plasma corticosterone, 1- and 10-day treatments with RCI produced similar increases in this hormone and the levels increased linearly with increasing dosages of RCI. This stood in sharp contrast to the sigmoid-like dose–response curve for decreases in spasm counts. Our results further validate the TTX model as relevant for the study of infantile spasms. The model should be useful for investigating how RCI acts to eliminate seizures and hypsarrhythmia. Dose–response results suggest that either very high concentrations of circulating corticosteroids are required to abolish spasms or RCI acts through a different mechanism.
West syndrome: A study of 26 patients receiving short-term therapy
2021, Epilepsy and Behavior
We describe the electroclinical characteristics of a series of 26 patients with idiopathic West syndrome (WS), who had an excellent response to treatment with vigabatrin (VGB) and corticosteroids alone or in combination.
Evaluating the records of 178 patients with WS studied at Garrahan Hospital, Niño Jesús Hospital, and Clínica San Lucas between January 2005 and June 2017, we selected 26 patients that met the inclusion criteria of idiopathic WS.
The inclusion criteria for idiopathic WS were (1) no personal history of disease, (2) normal neurological examination and neurodevelopment, (3) symmetric spasms in clusters not preceded by any other type of seizure, (d) symmetric hypsarrhythmia, (e) normal electroencephalogram (EEG) background, e.g., normal sleep EEG pattern, (f) normal magnetic resonance imaging (MRI) recording, (g) normal neurometabolic and genetic studies, and (h) at least 2 years of follow-up.
Fifteen boys and 11 girls met the inclusion criteria of idiopathic WS. The current age of the children ranges between 2 years 10 months and 12 years 10 months. Age at first epileptic spasms (ES) ranged from 4 to 11 months, with a mean age of 7 and a median of 7.5 months, respectively; ES were in clusters, bilateral and symmetrical in all cases. Spasms were flexor in nine (34.7%), mixed flexor-extensor in 15 (57.7%), and extensor in three (7.6%). In all patients the EEG showed typical pattern of hypsarrhythmia.
These patients with idiopathic WS who have an excellent response to initial treatment should be treated for a short period of time with adrenocorticotropic hormone (ACTH) and VGB alone or in combination.
Modeling epileptic spasms during infancy: Are we heading for the treatment yet?
2020, Pharmacology and Therapeutics
Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by definition (occurring in 1 per 3200–3400 live births), IS represent a major social and treatment burden. The etiology of IS varies - there are many (>200) different known pathologies resulting in IS and still in about one third of cases there is no obvious reason. With the advancement of genetic analysis, role of certain genes (such as ARX or CDKL5 and others) in IS appears to be important. Current treatment strategies with incomplete efficacy and serious potential adverse effects include adrenocorticotropin (ACTH), corticosteroids (prednisone, prednisolone) and vigabatrin, more recently also a combination of hormones and vigabatrin. Second line treatments include pyridoxine (vitamin B6) and ketogenic diet. Additional treatment approaches use rapamycin, cannabidiol, valproic acid and other anti-seizure medications. Efficacy of these second line medications is variable but usually inferior to hormonal treatments and vigabatrin. Thus, new and effective models of this devastating condition are required for the search of additional treatment options as well as for better understanding the mechanisms of IS. Currently, eight models of IS are reviewed along with the ideas and mechanisms behind these models, drugs tested using the models and their efficacy and usefulness. Etiological variety of IS is somewhat reflected in the variety of the models. However, it seems that for finding precise personalized approaches, this variety is necessary as there is no “one-size-fits-all” approach possible for both IS in particular and epilepsy in general.
A Serendipitous Case for Shorter Steroid Course in Infantile Spasms
2019, Pediatric Neurology

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Brief CommunicationHigh-dose oral prednisolone for infantile spasms: An effective and less expensive alternative to ACTH

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Conflict of interest

Acknowledgments

Lancet

Lancet

J Pediatr

Practice parameter: medical treatment of infantile spasms. Report of the American Academy of Neurology and the Child Neurology Society

Neurology

Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study

Epilepsia

Brief Communication
High-dose oral prednisolone for infantile spasms: An effective and less expensive alternative to ACTH