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Epileptic spasms: Evidence for oral corticosteroids and implications for low and middle income countries

Open ArchivePublished:May 15, 2018DOI:https://doi.org/10.1016/j.seizure.2018.05.008

      Highlights

      • Treatment of epileptic spasms, is challenging in Low and Middle Income Countries.
      • Class III evidence supports the efficacy of oral corticosteroids for epileptic spasms.
      • Long-term development for infants managed with oral corticosteroids is not defined.
      • RCTs are needed to compare oral corticosteroids with ACTH.

      Abstract

      Implementation of international guidelines for the treatment of epileptic spasms, is challenging when access to adrenocorticotrophic hormone (ACTH) and vigabatrin is restricted, especially in Low and Middle Income Countries (LMIC). Oral corticosteroids are alternative interventions but evidence for the optimal agent, dose, duration, efficacy and long-term effects is lacking.
      A systematic review of the literature was performed to assess the quality of evidence of prednisone and prednisolone (oral corticosteroids) for the management of epileptic spasms.
      There is level C recommendation based on class III evidence to support the efficacy of oral corticosteroids for the acute clinical control of epileptic spasms and EEG resolution. Efficacy of oral corticosteroids in comparison to the internationally recommended intervention of ACTH has class IV evidence supporting level U recommendation. Similarly, there is no data on the risk of relapse with oral corticosteroids (class IV, level U), compared to ACTH. There is class IV evidence supporting level U recommendation for the safety of oral corticosteroids and class II evidence for level B recommendation for ACTH. In terms of oral corticosteroids and effects on long-term development there is class IV evidence leading to level U recommendation, compared to class III evidence supporting level C recommendation for ACTH.
      Randomized controlled studies are needed to compare oral corticosteroids with ACTH, the optimal dosage and regimen as well as the long-term neurodevelopmental outcomes. Based on the limited existing studies a treatment guideline for LMIC is proposed which could be used to standardize interventions permitting clarification of these unmet questions.

      Keywords

      1. Introduction

      Access to hormonal and synthetic adrenocorticotrophic hormone (ACTH) is limited in many regions of the world [
      • Talan J.
      Debate: ACTH or prednisolone for infantile spasms?.
      ]. This report explores the evidence to support use of oral corticosteroids, namely prednisolone or prednisone, in comparison to ACTH and other agents in the management of children with epileptic spasms.
      The incidence of childhood epilepsy is highest in the infantile period and epileptic spasms are the most common seizure type in this age period [
      • Wilmshurst J.M.
      • Gaillard W.D.
      • Vinayan K.P.
      • Tsuchida T.N.
      • Plouin P.
      • Van Bogaert P.
      • et al.
      Summary of recommendations for the management of infantile seizures: task Force Report for the ILAE Commission of Pediatrics.
      ].
      Epileptic spasms are characterized by a brief contraction followed by a sustained tonic contraction of the neck, trunk, upper and lower legs and may be flexor, extensor or mixed [
      • Pavone P.
      • Striano P.
      • Falsaperla R.
      • Pavone L.
      • Ruggieri M.
      Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013.
      ]. They tend to occur in clusters, usually while awakening or just before sleep [
      • Wilmshurst J.M.
      • Ibekwe R.C.
      • O'Callaghan F.J.
      Epileptic spasms – 175 years on: trying to teach an old dog new tricks.
      ]. Spasms are frequently misdiagnosed with conditions such as colic, gastrooesophageal reflux and constipation, which results in delayed intervention [
      • Germain B.
      • Maria B.L.
      Epileptic encephalopathies.
      ]. The diagnosis of epileptic spasms is based on the semiology of the seizure and the interictal pattern of hypsarrhythmia on the EEG [
      • Traitruengsakul S.
      • Seltzer L.E.
      • Paciorkowski A.R.
      • Ghoraani B.
      Developing a novel epileptic discharge localization algorithm for electroencephalogram infantile spasms during hypsarrhythmia.
      ]. Hypsarrhythmia is defined as random high voltage slow waves accompanied by focal, multifocal or generalized spikes [
      • Gibbs E.L.
      • Fleming M.M.
      • Gibbs F.A.
      Diagnosis and prognosis of hypsarhythmia and infantile spasms.
      ]. Variations from classic hypsarrhythmia are called modified hypsarrhythmia and may include focality, burst suppression, slow waves without spikes and partial preservation of the background [
      • Germain B.
      • Maria B.L.
      Epileptic encephalopathies.
      ].
      The incidence of epileptic spasms in high income countries range between 0.25 and 0.42 per 1000 live births per year, peak onset is between 4 and 6 months, with a slight male preponderance [
      • Cowan L.D.
      • Hudson L.S.
      The epidemiology and natural history of infantile spasms.
      ]. The term “epileptic spasms” replaced “infantile spasms”, as the seizure type may persist or have the potential to develop beyond the infantile period [
      • Berg A.T.
      • Berkovic S.F.
      • Brodie M.J.
      • Buchhalter J.
      • Cross J.H.
      • van Emde Boas W.
      • et al.
      Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009.
      ].
      The United Kingdom Infantile Spasms Study (UKISS) found that the most common aetiologies for ES were hypoxic ischaemic encephalopathy (10%), chromosomal (8%), cerebral malformations (8%), cerebrovascular disease (8%), Tuberous Sclerosis Complex (TSC) (7%), periventricular leukomalacia or haemorrhage (5%) but in 33% no cause could be identified [
      • Osborne J.P.
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • et al.
      The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification.
      ]. Data was collected from a high income resource equipped setting. Data is limited on epilepsy in Africa in general, especially from sub-Saharan Africa, and even less so for this specific seizure type. A study based in rural Uganda in 1997, found that 7 out of 440 children with epilepsy, had a history suggestive of “infantile spasms”[
      • Duggan M.B.
      Epilepsy and its effects on children and families in rural Uganda.
      ]. However, this may be an underestimation, since lack of resources, such as EEG, made it challenging to make a syndromic diagnosis [
      • Duggan M.B.
      Epilepsy and its effects on children and families in rural Uganda.
      ].
      Additional challenges facing Low and Middle Income Countries (LMIC) include greater numbers of aetiologies, such as perinatal asphyxia, which is associated with worse long term outcome [
      • Wanigasinghe J.
      • Arambepola C.
      • Sri Ranganathan S.
      • Sumanasena S.
      • Muhandiram E.C.
      The efficacy of moderate-to-high dose oral prednisolone versus low-to-moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial.
      ].
      Epileptic spasms are difficult to treat and associated with a high morbidity, with up to 90% of patients having intellectual disability [
      • Germain B.
      • Maria B.L.
      Epileptic encephalopathies.
      ,
      • Knupp K.G.
      • Coryell J.
      • Nickels K.C.
      • Ryan N.
      • Leister E.
      • Loddenkemper T.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      ]. The persistence of hypsarrhythmia appears to be associated with ongoing epileptic encephalopathy, as such it is important to treat this finding until there is resolution on the EEG [
      • Germain B.
      • Maria B.L.
      Epileptic encephalopathies.
      ]. This differs from standard approaches in the management of epilepsy, where treatment of clinical events is promoted. For infants with epileptic spasms “normalization” of the EEG plays a critical role with regards to long-term developmental outcome. International evidence based recommendations support use of ACTH graded at level B and vigabatrin at level C, as graded according to the American Academy of Neurology Practice Parameters following systematic review [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ,
      • GGaJ French
      Invited Article: practice parameters and technology assessments: what they are, what they are not, and why you should care.
      ]. According to the Cochrane review by Hancock et al hormonal treatment resolves spasms in more infants than vigabatrin, and if prednisolone or vigabatrin are used, high dose is recommended [
      • Hancock E.C.
      • Osborne J.P.
      • Edwards S.W.
      Treatment of infantile spasms.
      ].
      The lag time refers to the time taken between ES onset and intervention with treatment. Early cessation of spasms and a shorter lag time to treatment result in a reduced total duration of epileptic encephalopathy and resultant developmental delay [
      • O'Callaghan F.J.
      • Lux A.L.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • et al.
      The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.
      ]. Prolonged lag time and acquired aetiologies (e.g. HIE, post-infectious) in LMICs result in lower rates of spasm freedom compared to high income countries. This is further compounded by lack of health-seeking behaviour of parents, lack of awareness among health care professionals and inappropriate antiepileptic drug use [
      • Chellamuthu P.
      • Sharma S.
      • Jain P.
      • Kaushik J.S.
      • Seth A.
      • Aneja S.
      High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial.
      ].
      A systematic review of the literature was undertaken to establish the quality of evidence relating to the use of oral prednisolone and prednisone in the management of children with epileptic spasms. This review was driven by the need to develop a recommendation to standardize a safe and effective regimen using this product over other agents, such as ACTH and vigabatrin in LMICs, where access to these internationally recommended agents is lacking.

      1.1 Systematic review

      Using the MeSH terms “infantile spasms” and “prednisolone” and keywords “epileptic spasms”, “treatment”, “management”, “prednisone” and “oral corticosteroids” in Pubmed, Web of Science, Scopus incl. Embase, Medline,
      Africa-Wide, Cinahl, Cochrane reviews and clinical trials.com a total of 114 studies were found between 1990 and 2017, n = 96 were excluded as they did not address the study question. There were n = 18 studies in total, n = 14 addressing the intervention and immediate outcome and n = 4 the long-term outcome [
      • O'Callaghan F.J.
      • Lux A.L.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • et al.
      The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.
      ,
      • Wanigasinghe J.
      • Arambepola C.
      • Ranganathan S.S.
      • Sumanasena S.
      Randomized, single-Blind, parallel clinical trial on efficacy of oral prednisolone versus intramuscular corticotropin: a 12-month assessment of spasm control in west syndrome.
      ,
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Newton R.W.
      • et al.
      The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial.
      ,
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Lux A.L.
      • et al.
      Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial.
      ]. Search terms were broad to encompass any studies which utilised oral corticosteroids in the management of ES. Studies were critiqued for directness to the study question of “efficacy in the management of ES” and consistency in study methodology across studies to permit comparison of outcome data. Clinical human studies were included, as well as articles in English. Review articles were checked for additional papers not captured by the search. Quality of data was graded according to the American Academy of Neurology (AAN) practice parameters [
      • GGaJ French
      Invited Article: practice parameters and technology assessments: what they are, what they are not, and why you should care.
      ]. In accordance with AAN practice parameters, level A evidence recommendations are established as effective, ineffective or harmful, level B probably effective, ineffective or harmful, level C possibly effective, ineffective or harmful and level U data is inadequate or conflicting [
      • GGaJ French
      Invited Article: practice parameters and technology assessments: what they are, what they are not, and why you should care.
      ,

      American Academy of N. American Academy of Neurology Classification of Evidence. 2010.

      ]. Findings from the included studies are summarised in Table 1.
      Table 1Overview of the studies which included oral corticosteroids in the management of epileptic spasms.
      Author, year Add country/regionStudy DesignClassSample SizeTreatmentDirectness to study questionConsistency across studiesEfficacyOutcomes Short Term Long Term
      Demarest et al

      2017

      USA
      • Demarest S.T.
      • Shellhaas R.A.
      • Gaillard W.D.
      • Keator C.
      • Nickels K.C.
      • Hussain S.A.
      • et al.
      The impact of hypsarrhythmia on infantile spasms treatment response: observational cohort study from the National Infantile Spasms Consortium.
      Prospective, observational study,

      multicenter
      Class II447 total;

      366 with hypsarrhythmia, 81 without hypsarrhythmia
      196 ACTH 75IU/m2 twice/day for 2 weeks followed by gradual tapering over 2 weeks, 85 prednisolone 10 mg 4 times daily for 2 weeks followed by weaning by 10 mg/day every week, 66 vigabatrin 50–150 mg/kg/day divided into 2 dosesYesYesPrednisolone more effective than vigabatrin but less effective than ACTH in the treatment of epileptic spasms. Actual percentage response rate not givenVigabatrin odds ratio (OR) 5.2, prednisolone OR 8, ACTH OR 10.2 cessation of spasms and resolution of hypsarrhythmia and no relapse within 3 months
      Yeh et al

      2017

      Korea
      • Yeh H.R.
      • Kim M.J.
      • Ko T.S.
      • Yum M.S.
      • You S.J.
      Short-term outcome of intravenous methylprednisolone pulse therapy in patients with infantile spasms.
      Prospective open-label, uncontrolled, multicenter (2 tertiary hospitals)Class III14Methylprednisone 30 mg/kg/day for 3 days followed by tapering doses of prednisolone 1 mg/kg 2 doses, rapidly reduced each week for 2–4 weeksYesConsistent with doses compared to UKISS and Hussain et al, only sleep EEG’s performed, follow up till 3 monthsYes, based on electroclinical response after 3 weeks.

      Overall response to steroids comparable to other studies
      64.3% responded after 3 weeks with resolution of hypsarrythmia on EEG. Relapse rate for spasms 45.5%55.5% remained seizure free after discontinuing steroids at 3 months. Developmental outcomes not assessed
      Tang-Wai et al

      2017

      Canada
      • Tang-Wai R.
      • Mailo J.
      • Rosenblatt B.
      Breaking the cycle: a comparison between intravenous immunoglobulins and high dosage prednisone in the treatment of medically intractable epilepsy in children.
      Retrospective observational study, single centerClass III26 IVIG vs 25 prednisoneIVIG 1 g/kg every 3 weeks and prednisone 2 mg/kg/day (max 60 mg/day) for 2 weeks followed by 6–8 week taper OR prednisone 1–2 mg/kg/day (max 60 mg/day) for 2–4 weeks followed by 4–6 week taperYesOnly study comparing IVIG with prednisone. Only 1 other study (Bara, et al) with same dose of Prednisone. Follow up EEG’s not consistent in IVIG group.84.6% responded to IVIG, mean seizure reduction 77.3% after mean 9.8 weeks, 24% responded to prednisone with mean seizure reduction of 95%, 2.7 weeks mean time to max responsePercentage of seizure reduction higher for IVIG compared to prednisone (p = 0.001)Long term and cognitive outcomes not assessed
      O’Callaghan et al

      2017

      (ICISS)

      Australlia, Germany, New Zealand, Switzerland, UK
      • O'Callaghan F.J.
      • Edwards S.W.
      • Alber F.D.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • et al.
      Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial.
      Randomised, multi center, open labelClass I186 vigabatrin and hormonal therapy vs. 191 on hormonal therapyVigabatrin (50–150 mg/kg/day) and hormonal treatment, 51 ACTH (40IU alternate days for 2 weeks), 134 prednisolone (10 mg 4 times/day) for 2 weeks, tapered by 10 mg every 5 days vs. hormonal treatment (60 ACTH, 131 prednisolone)YesConsistent with doses of prednisolone in Wanigasinghe et al, Ware et al, Mohamed et al and follow up. Parents allowed to choose type of hormonal therapyYes, hormonal treatment with vigabatrin significantly more effective at stopping spasms than hormonal therapy alone, similar to primary clinical response in UKISS BUT different definitions for “cessation of spasms”.Cessation of spasms in 89% on combination therapy vs. 69% on hormonal therapy (p < 0.001) on days 13 & 14, 19% relapsed by day 42 (33 on combination and 24 on hormonal treatment).Day 14–42, no spasms in 72% combination therapy vs. 57% on hormonal therapy (p = 0.002). Electroclinical response 66% combination therapy vs. 55% hormonal therapy (p = 0.023).
      Knupp et al

      2016

      USA
      • Knupp K.G.
      • Coryell J.
      • Nickels K.C.
      • Ryan N.
      • Leister E.
      • Loddenkemper T.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      Prospective, observational, multi centerClass II230 total − ACTH 97, 54 prednisolone, 47 vigabatrin, 32 non-standard therapyACTH 75IU/m2 twice/day for 2 weeks followed by gradual weaning over 2 weeks, prednisolone 10 mg 4 times daily for 2 weeks followed by weaning by 10 mg/day every week, vigabatrin 50–150 mg/kg/day divided into 2 dosesYesConsistent with doses in ICISS, Ware et al, Mohammed et al and follow up in the short and long term. All patients received EEG’s. Treatment not randomized, providers allowed to choose medication therefore biased based on aetiology and development status.ACTH associated with higher response rate than vigabatrin (p = 0.038) and oral corticosteroids (p-0.06)After 2 weeks, 55% responded to ACTH, 39% to prednisolone, 36% to vigabatrin electroclinically. Relapse rate highest for oral corticosteroids, 24%.After 3 months, sustained response to ACTH significantly higher than vigabatrin and marginally higher than oral corticosteroids. Long term developmental outcomes not assessed.
      Wanigasinghe et al

      2015

      Sri Lanka
      • Wanigasinghe J.
      • Arambepola C.
      • Sri Ranganathan S.
      • Sumanasena S.
      • Muhandiram E.C.
      The efficacy of moderate-to-high dose oral prednisolone versus low-to-moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial.
      ,
      • Wanigasinghe J.
      • Arambepola C.
      • Sri Ranganathan S.
      • Sumanasena S.
      • Attanapola G.
      Randomized, single-blind, parallel clinical trial on efficacy of oral prednisolone versus intramuscular corticotropin on immediate and continued spasm control in west syndrome.
      Randomised control trial, single center, single blindedClass II48 prednisolone vs. 49 ACTHPrednisolone 10 mg 4 times/day for 2 weeks followed by tapering by 10 mg/day per week over 3 weeks or ACTH 40IU alt days for 2 weeks

      followed by taper over the next 3 weeks
      YesConsistent with doses in ICISS, Ware et al, Mohammed et al and follow up in the short and long term. EEG recording limited to 30 mins and not done at every visit due to resource constraints. Spasm-free periods determined by parental reports from preceding week at each testing periodCessation of spasms at 14 days 58.3% prednisolone vs. 36.7% ACTH (p = 0.03). Electroclinical remission on day 14 in 43.75% prednisolone and 18.4% on ACTH (p = 0.007). On day 42 cessation of spasms in 66.7% on prednisolone vs. 38.7% on ACTH (p = 0.079).

      After 28 days electroclinical response 31.2% prednisolone and 12.22% ACTH (p = 0.008).
      Significantly better control of spasms with prednisolone at 14 days and 28 days. 6 relapsed in prednisolone group and 8 from ACTH group.Follow up study at 3 months showed significantly better spasm control if treated with prednisolone 64.6% than ACTH 38.8% p = 0.01. Spasm control at 6 months, 58.3% prednisolone and 44.9% ACTH p = 0.19. At 12 months spasm cessation 56.2% prednisolone and 40.8% ACTH p = 0.13. After 12 months no difference in relapse between groups.

      Cognitive outcomes not assessed
      Jones et al

      2015

      Canada
      • Jones K.
      • Snead 3rd, O.C.
      • Boyd J.
      • Go C.
      Adrenocorticotropic hormone versus prednisolone in the treatment of infantile spasms post vigabatrin failure.
      Retrospective observational study, single centerClass III15 ACTH vs 5 PrednisoloneACTH 1.9 mg/m2 alt days followed by a tapering schedule from week 2–12 vs Prednisolone 4-4.5 mg/kg/day for 1–2 weeks, followed by 3 mg/kg/day for 1 week, then 1.5 mg/kg/day for 1 weekYesSecond line treatment after failed course of vigabatrinNo, prednisolone not effective, hormonal treatment used a second line agents if no response to vigabatrin80% electroclinical response to ACTH vs. 20% response to prednisolone (p = 0.03) after 2 weeks58% relapsed on ACTH, 100% relapse, follow up between 6–38 months from spasm onset (p = 0.26). Cognitive outcomes not assessed
      Yi et al

      2015

      China
      • Z-s Z.-S.
      • W H.-P.
      • Yu X.-Y.
      • Chen Y.
      • Zhong J.-M.
      Efficacy and tolerability of high-dose prednisone in Chinese children with infantile spasms.
      Observational study, single centerClass III20 prednisolonePrednisolone 10 mg 4 times/day for 2 weeks reduced weekly to complete a 7 weeks courseYesConsistent with doses of prednisolone with Wanigasinghe et al, Ware et al, Mohamed et al, UKISS consistent with EEG’sYes, higher response rate to prednisolone after 2 weeks compared to Wanigasinghe et al, Ware et al, Mohamed et al, UKISS studies80% cessation of spasms after 2 weeks prednisoloneMedian follow up time 10.5 months, 47.1% relapse. Neuroodevelopmental outcome, lower developmental quotient after treatment but not significant (p = 0.098)
      Chellamuthu et al

      2014

      India
      • Chellamuthu P.
      • Sharma S.
      • Jain P.
      • Kaushik J.S.
      • Seth A.
      • Aneja S.
      High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial.
      Randomised control trial, single center, not blindedClass II32 low dose prednisolone vs. 31 high dose prednisolonePrednisolone

      2 mg/kg/day vs.

      4 mg/kg/day in 3 divided doses for 2 weeks followed by tapering over 2 weeks
      YesDose consistent with Kossoff et al, follow up only for 6 months, EEG recorded for 1 h.

      Relying on parental reporting of spasm frequency
      High dose prednisolone (51.6%) significantly more effective than

      low dose prednisolone (25%) for spasm resolution after 14 days (p = 0.03). Electroclinical response high dose prednisolone 38.7% vs. 21.9% low dose prednisolone, not significant (p = 0.15).
      Response rate lower than HMIC (UKISS, Kossoff et al), comparable to ACTH in LMICAt 6 months, 4 children relapsed in the usual dose group and 5 in the high dose group.

      Cognitive outcomes not measured
      Hussain et al

      2014

      USA
      • Hussain S.A.
      • Shinnar S.
      • Kwong G.
      • Lerner J.T.
      • Matsumoto J.H.
      • Wu J.Y.
      • et al.
      Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone.
      Retrospective observational study, single centerClass III27Response to prednisolone at 8 mg/kg/day (max 60 mg/day) divided in 3 doses for 2 weeks followed by tapering over 2 weeksYesOnly study that used prednisolone at this dose, video EEG response to treatment, limited follow up timeVery high dose prednisolone significantly higher efficacy than lower doses from prior studies (Baram et al)63% responded completely (video-EEG response) to prednisolone after 2 weeks2 patients relapsed at 2 and 5 months respectively. Cognitive outcomes not measured
      Ware et al 2012

      Australia
      • Ware T.L.
      • Mackay M.T.
      • Harvey A.S.
      • Freeman J.L.
      Epileptic spasms: experience with a high-dose oral corticosteroid protocol.
      Retrospective observational study, single centerClass III17 Prednisolone vs. 6 vigabatrin, 5 not treated as per protocolPrednisolone 10 mg 4 times/day for 2 weeks followed by tapering by 10 mg every 5 days and vigabatrin 50–150 mg/kg/dayYesConsistent with doses in ICISS, Wanigasinghe et al and Mohamed et al, TSC patients not excluded in this study. Follow up EEG findings not documentedYes, response to prednisolone higher than UKISS, Wanigasinghe et al and Mohammed et al, TSC patients not excludedInitial response to spasm cessation on day 14 76% prednisolone and 17% vigabatrinFollow up 21 months, none who received prednisolone with cryptogenic aetiology relapsed and 10 with symptomatic aetiology relapsed (not specified how many received prednisolone or not treated with protocol), 4 of the 6 with TSC who received vigabatrin relapsed. Cognitive outcomes not measured
      Mohamed et al

      2011

      (UK)
      • Mohamed B.P.
      • Scott R.C.
      • Desai N.
      • Gutta P.
      • Patil S.
      Seizure outcome in infantile spasms – a retrospective study.
      Retrospective observational study, single centerClass III54 Vigabatrin vs. Steroids in 18 (17 Prednisolone, 1 ACTH)Prednisolone 2–4 mg/kg/day prior to UKISS, after UKISS 40 mg daily for 2 weeks followed by tapering by 10 mg every 5 days,

      Vigabatrin 25–50 mg/kg/day increased up to 150 mg/kg/day
      YesInconsistent with prednisolone doses − different doses used before and after UKISS, after UKISS doses consistent with UKISS, consistent with EEG’s, inconsistent with follow upPrednisolone and vigabatrin similar efficacy, responsiveness to steroids less than UKISS, vigabatrin comparable other studies (Elterman et al, Appelton et al, Aicardi et al).

      Steroids more effective in children with cryptogenic aetiology. Faster response to steroid therapy
      61.1% response to steroids, 3 relapsed. 42.5% response to vigabatrin, 7 relapsed1 relapsed on steroids after 11 months and 1 relapsed on vigabatrin. Neurodevelopmental outcomes not specified
      Mytinger et al

      2010

      (USA)
      • Mytinger J.R.
      • Quigg M.
      • Taft W.C.
      • Buck M.L.
      • Rust R.S.
      Outcomes in treatment of infantile spasms with pulse methylprednisolone.
      Prospective, not randomised, single centerClass III10Methylprednisone 20 mg/kg for 3 days followed by prednisolone 4 mg/kg/day for 2 weeks, followed by tapering over 6 weeksYesLower dose pulse Methypred compared to Yeh et al. Relied on parent reporting of spasms at 2 weeks.

      Follow up not consistent
      Lower response rate than high dose prednisolone used by Yeh et al. Results complicated by use of ineffective antiseizure drugs prior to starting treatment50% remission confirmed on video EEG between 2–6 days. 80% of primary responders relapsed60% had relapse or continuation of spasms at follow up. Cognitive outcomes not measured
      Noureen et al

      2010

      Pakistan
      • Noureen N.
      • Rana M.T.
      Clinical profile and response to oral prednisolone in infantile spasm.
      Retrospective, observational study, single centerClass III50Response to prednisolone 2 mg/kg/day in 3 divided doses for 4 weeks followed by tapering over 2 weeksYesLower dose of prednisolone given compared to ICISS, Wanigasinghe et al, Cochrane reviewLower response to steroids compared to ICISS and Wanigasinghe et al BUT lower dose of prednisolone used. Also lower response to Azam et al (low dose prednisone)Cessation of spasms or >50% reduction in spasms noted in 54% after 2 weeks. Relapse in 8%.Long term data and cognitive outcomes not measured
      Kossoff et al

      2009

      USA
      • Kossoff E.H.
      • Hartman A.L.
      • Rubenstein J.E.
      • Vining E.P.
      High-dose oral prednisolone for infantile spasms: an effective and less expensive alternative to ACTH.
      Retrospective observational study, single centerClass III15Response to prednisolone at 40–45 mg/kg/day in 3 divided doses for 2 weeks followed by tapering over 2 weeksYesConsistent with dose in 2008 Cochrane reviewYes, prednisolone response rate similar to UKISS, 10/15 (67%) responded to prednisolone vs. 13/15 (87%) to ACTH at same center p = 0.16 Results not statistically significant but comparison to ACTH from previous data.67% spasm free within 2 weeks, 40% relapse after initial responseNo long term data available
      Azam et al

      2005

      Pakistan

      • Azam M.
      • Bhatti N.
      • Krishin J.
      Use of ACTH and prednisolone in infantile spasms: experience from a developing country.
      Retrospective comparative study, single centerClass III23 ACTH, 72 prednisoloneACTH 20–40IU/day for 4 weeks and tapered over 2 weeks vs. Prednisolone 2–3 mg/kg/day in 2 divided doses total duration incl. tapering 6–8 weeksYesLower dose of prednisolone compared to ICISS, UKISS, Wanigasinghe et al, no 24 h EEG monitoring or follow up EEG’s, parents chose ACTH or prednisoloneResponse to treatment defined as spasm cessation OR >50% reduction in spasms. Response to prednisolone comparable to studies mentioned but different definitions used82% responded to ACTH and 71% to prednisolone, difference not significant (p = 0.41)Follow up variable 6–10 months. 33% ACTH remained spasm free, 24% prednisolone spasm free. No long term data re: relapse rate or cognitive outcomes
      Lux et al

      2005

      (UKISS)

      UK
      • O'Callaghan F.J.
      • Lux A.L.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • et al.
      The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.
      ,
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Newton R.W.
      • et al.
      The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial.
      ,
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Lux A.L.
      • et al.
      Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial.
      Randomised control trial, multicenter, not blindedClass II30 prednisolone, 25 ACTHPrednisolone 10 mg 4 times/day for 2 weeks followed by tapering by 10 mg every 5 days vs. ACTH 40–60IU alt days for 2 weeks followed by tapering every 5 daysYesPrednisolone dose not consistent-lower than ICISS, Wanigasinghe et al, Ware et al. Consistent with follow up.Cessation of spasms at 14 days-hormonal treatment more effective than vigabatrin, no difference at 12–14 months of age. No significant difference prednisolone and ACTH.70% responded to prednisolone and 76% to ACTH – no significant difference (p = 0.61)No difference in spasm control at 12–14 months. No identified aetiology led to better developmental outcomes at 14 months and 4 years of age
      Baram et al

      1996

      USA
      • Baram T.Z.
      • Mitchell W.G.
      • Tournay A.
      • Snead O.C.
      • Hanson R.A.
      • Horton E.J.
      High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study.
      Randomised, prospective, single blinded, single centerClass II15 ACTH vs 14 prednisoneACTH 150IU/m2/day for 2 weeks followed by tapering over 2 weeks vs. Prednisone 2 mg/kg/day in 2 divided doses for 2 weeks followed by tapering over 2 weeksYesPrednisone given instead of prednisolone, low dose prednisone only consistent with Azam et al consistent with EEG’sACTH significantly more effective than prednisone86.6% responded clinically and EEG to ACTH, 28.6% to prednisone (p = 0.002) after 2 weeks. Relapse rate not reportedLong term data not available

      1.2 Management of epileptic spasms

      Standardized management protocols for infants with epileptic spasms have resulted in an increase of affected patients receiving recommended first-line treatment, with improved remission rates three months after diagnosis [
      • Fedak E.M.
      • Patel A.D.
      • Heyer G.L.
      • Wood E.G.
      • Mytinger J.R.
      Optimizing care with a standardized management protocol for patients with infantile spasms.
      ]. For children whose spasms result from aetiologies, excluding TSC, ACTH is the preferred first line intervention (level B recommendation), at either low or high dose (level B recommendation) [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ]. Evidence supports a level A recommendation that vigabatrin should be the first line treatment for epileptic spasms in children with TSC [
      • Hancock E.
      • Osborne J.P.
      Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review.
      ]. According to the meta-analysis in 2012, there is insufficient evidence to recommend the use of oral corticosteroids for the short-term treatment of epileptic spasms (level U recommendation). There is weak evidence that the use of ACTH or prednisolone, in children with previously called cryptogenic aetiology may lead to an improved developmental outcome (level C recommendation) [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ], but no data specifically addressing prednisone.
      Oral corticosteroids are increasingly being used off-label for the treatment of epileptic spasms [
      • Talan J.
      Debate: ACTH or prednisolone for infantile spasms?.
      ,
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ,
      • Arya R.
      • Shinnar S.
      • Glauser T.A.
      Corticosteroids for the treatment of infantile spasms: a systematic review.
      ]. The product is less expensive, easy to administer and readily available worldwide [
      • Mytinger J.R.
      • Camfield P.R.
      Synthetic ACTH is not superior to prednisolone for infantile spasms: randomized clinical trials and tribulations.
      ]. Prednisolone is the active form of prednisone and should not be considered as equivalent treatments for infants, who have a reduced capacity to metabolise prednisone in the first 6 months of life [
      • Hancock E.
      • Osborne J.
      • Milner P.
      Treatment of infantile spasms.
      ]. Prednisone is not as effective as its active form [
      • Hancock E.
      • Osborne J.
      • Milner P.
      Treatment of infantile spasms.
      ]. In Africa, most institutions will have access to prednisone rather than prednisolone.
      Access to ACTH is limited, especially in resource-poor settings, by high cost, discomfort from injections and duration of hospitalization [
      • Chellamuthu P.
      • Sharma S.
      • Jain P.
      • Kaushik J.S.
      • Seth A.
      • Aneja S.
      High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial.
      ]. In the US, after Questcor acquired the rights to ACTH the price increased dramatically and since then the company has maintained the monopoly. ACTH (natural gel) costs approximately US$150 000 per treatment course compared to US$200 for prednisolone [
      • Talan J.
      Debate: ACTH or prednisolone for infantile spasms?.
      ]. In South Africa, a 10 day course of ACTH (synthetic) costs approximately ZAR200 000 (US$17 250) and 14 day course of prednisone ZAR17 (US$1,5). Based on issues of cost and access to care in 2016 the South African Essential Drug committee removed ACTH and vigabatrin from the national code list [
      ]. In a setting where previously there was capacity for treatment of ES in line with international recommendations, this policy returned the country to the situation evident in most other sub-Saharan Africa settings, where the only viable agent is likely to be prednisone. As a result an urgent national and regional need arose to establish an alternate evidence based guideline for the management of ES using available agents.
      Whilst there is a significant body of data for the management of ES with ACTH which supported its inclusion in guidelines and Cochrane review [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ,
      • Hancock E.C.
      • Osborne J.P.
      • Edwards S.W.
      Treatment of infantile spasms.
      ], based on the systematic review (Table 1) the same cannot be said for oral prednisone or prednisolone. Table 1 illustrates this in the summaries of the existing studies. Of the identified studies assessing the use of prednisolone, prednisone or methylprednisone there was marked variation evident in study methodologies, limiting comparison across studies. There was 1 class I study, 6 class II studies and 11 retrospective observational or uncontrolled comparative studies (class III). Six studies were based in LMICs.

      1.3 Optimal cessation of spasms

      Of the studies, the UKISS study was not powered enough to compare hormonal subgroups, however, prednisolone given at 40–60 mg/day resulted in a remission rate of 70% and ACTH 76% at the final clinical assessment at 14 months [
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Newton R.W.
      • et al.
      The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial.
      ]. The difference was not significant and neither was the risk of relapse between the groups [
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Newton R.W.
      • et al.
      The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial.
      ]. A retrospective observational class III study, by Kossoff et al (n = 15), found no statistical difference between ACTH and oral prednisolone in the resolution of spasms after 2 weeks [
      • Kossoff E.H.
      • Hartman A.L.
      • Rubenstein J.E.
      • Vining E.P.
      High-dose oral prednisolone for infantile spasms: an effective and less expensive alternative to ACTH.
      ]. According to Arya et al. 2 mg/kg of prednisolone was less effective compared to ACTH [
      • Arya R.
      • Shinnar S.
      • Glauser T.A.
      Corticosteroids for the treatment of infantile spasms: a systematic review.
      ] and Chellamuthu et al concluded that a significantly higher proportion of children had spasm cessation on day 14 who had received high dose prednisolone (4 mg/kg/day) compared to those who received half the dose [
      • Chellamuthu P.
      • Sharma S.
      • Jain P.
      • Kaushik J.S.
      • Seth A.
      • Aneja S.
      High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial.
      ]. In the same year, Hussain et al demonstrated that very high dose prednisolone, 8 mg/kg/day, had a significantly greater efficacy than lower doses reported from previous studies [
      • Hussain S.A.
      • Shinnar S.
      • Kwong G.
      • Lerner J.T.
      • Matsumoto J.H.
      • Wu J.Y.
      • et al.
      Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone.
      ]. O’Callaghan et al. in their 2017 report concluded that the combination of hormonal therapy and vigabatrin, was statistically more effective at stopping epileptic spasms than hormonal therapy alone. However, due to the lack of randomization of the hormonal group, it could not be determined if ACTH or prednisolone was more effective [
      • O'Callaghan F.J.
      • Edwards S.W.
      • Alber F.D.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • et al.
      Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial.
      ].
      The lack of consistency in study methodologies, directness in study questions and class I studies across reports limits forming a consensus on the evidence to support the use of prednisolone, especially as a replacement to ACTH. There was marked variation in the inclusion criteria, drop-outs, treatment lag, definition of response, proportion of low-risk/high risk, symptomatic patients, dose and duration of therapy and length of follow-up limiting comparison across studies. In addition, the optimal dose of prednisone and prednisolone still needs to be determined. For optimal care, combination therapy may be needed, as evidenced by ICISS study [
      • O'Callaghan F.J.
      • Edwards S.W.
      • Alber F.D.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • et al.
      Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial.
      ].
      In terms of other steroid formulations, 57% of patients responded to dexamethasone in a retrospective observational study by Haberlandt et al, class III study, compared to 64% to ACTH. They concluded that pulsed dexamethasone is a suitable alternative to ACTH, however, relapse rate was not stated and long term outcomes not measured [
      • Haberlandt E.
      • Weger C.
      • Sigl S.B.
      • Rauchenzauner M.
      • Scholl-Burgi S.
      • Rostasy K.
      • et al.
      Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes.
      ]. More recently, a small study by Yeh et al, n = 14 class III study, concluded that short-term methylprednisolone pulsed therapy resulted in rapid resolution of epileptic spasms and hypsarrythmia without serious adverse effects [
      • Yeh H.R.
      • Kim M.J.
      • Ko T.S.
      • Yum M.S.
      • You S.J.
      Short-term outcome of intravenous methylprednisolone pulse therapy in patients with infantile spasms.
      ]. There is insufficient evidence to recommend other therapies in the treatment of epileptic spasms such as valproic acid, nitrazepam, pyridoxine, zonisamide, thyrotropin-releasing hormone, topiramate, levetiracetam and ketogenic diet [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ,
      • Song J.M.
      • Hahn J.
      • Kim S.H.
      • Chang M.J.
      Efficacy of treatments for infantile spasms: a systematic review.
      ].
      Adverse effects of steroids are a concern, particularly the increased risk of infections, such as tuberculosis, in LMICs, and the complications from immunodeficiency in HIV-infected infants. Other side effects include increased appetite, weight gain, hypertension, cushingoid facies, irritability, glycosuria and cerebral atrophy [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ,
      • Chellamuthu P.
      • Sharma S.
      • Jain P.
      • Kaushik J.S.
      • Seth A.
      • Aneja S.
      High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial.
      ]. It is advisable that prior to starting treatment, for HIV status, chest x-ray, tuberculin skin test, baseline weight and blood pressure to be recorded [
      • Chellamuthu P.
      • Sharma S.
      • Jain P.
      • Kaushik J.S.
      • Seth A.
      • Aneja S.
      High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial.
      ].

      1.4 Developmental outcome

      According to UKISS, there was no difference in the neurodevelopmental outcome in overall data on children with ES who received hormonal treatment or vigabatrin at 14 months and 4 years of age. However, there was significant improvement in developmental scores in those who received hormonal treatment without an identifiable aetiology. [
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Newton R.W.
      • et al.
      The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial.
      ,
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • Kennedy C.R.
      • Lux A.L.
      • et al.
      Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial.
      ] In the same study, an increase in lag time to treatment was significantly associated with a lower developmental score at 4 years after adjusting for age of onset, aetiology and treatment [
      • O'Callaghan F.J.
      • Lux A.L.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • Johnson A.L.
      • et al.
      The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.
      ].
      Factors that result in a more favourable long term cognitive outcome include a shorter lag time to treatment with hormonal treatment or vigabatrin (level C) [
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • Stephens D.
      • Adams-Webber T.
      • Ashwal S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ], shorter duration of hypsarrhythmia [
      • Rener-Primec Z.
      • Lozar-Krivec J.
      • Krivec U.
      • Neubauer D.
      Head growth in infants with infantile spasms may be temporarily reduced.
      ] and “cryptogenic” cause of epileptic spasms [
      • Riikonen R.
      Long-term outcome of patients with West syndrome.
      ]. There are currently no studies assessing the long-term outcomes of children treated with prednisolone (level U recommendation).

      2. In conclusion

      Further randomised studies are needed to compare oral corticosteroids to ACTH and to determine the optimal dose, comparison efficacy, as well as long-term studies looking at the neurodevelopmental outcomes of these groups. High dose oral prednisolone appears to be evolving as a strong alternate candidate for infants with epileptic spasms, especially in settings where access to ACTH is not viable. In children with epileptic spasms and TSC vigabatrin remains the first line recommended agent. In settings where oral corticosteroids are used, standardized protocols should be in place and outcomes audited. Based on the accumulated data a recommendation has been compiled (Fig. 1) for settings without reliable access to ACTH and vigabatrin.
      Fig. 1
      Fig. 1Recommended Low and Middle Income Country treatment guideline based on existing evidence.
      Whilst there appears to be efficacy using oral corticosteroids for children with ES (level C recommendation), the optimal dose has not been defined beyond limited case series promoting higher doses. Of concern it remains unclear whether these children have a disadvantage for their relapse rate, subsequent epilepsy syndrome development and neurodevelopmental outcome.
      In summary, there is class III evidence supporting a level C recommendation for the efficacy of oral corticosteroids for the acute clinical control of epileptic spasms and EEG resolution. Use of oral corticosteroids in comparison to the internationally recommended intervention of ACTH has class IV evidence resulting in a level U recommendation. Similarly, the risk of relapse with oral corticosteroids has class IV evidence and level U recommendation, and compared to ACTH, class IV evidence with level U recommendation. There is class IV evidence resulting in level U recommendation for the safety of oral corticosteroids and class II evidence supporting level B recommendation for ACTH. In terms of oral corticosteroids and effects on long-term development evidence is class IV evidence leading to level U recommendation, compared to ACTH which has class III evidence supporting level C recommendation.

      Conflict of interest

      None.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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