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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

      Abstract

      Background

      The role of therapy on improvement of hypsarrhythmia has not been systematically assessed. This study was performed to assess the efficacy of oral prednisolone and intramuscular adrenocorticotrophin hormone in improving hypsarrhythmia in West syndrome.

      Method

      Children (2 months-2 years), with previously untreated West syndrome, were randomized to receive 40-60 IU every other day of intramuscular adrenocorticotrophin hormone or 40-60 mg/day of oral prednisolone for 14 days. Children with tuberous sclerosis were excluded. Improvement of hypsarrhythmia was assessed blindly using a hypsarrhythmia severity scale before and after completion of therapy. Adverse effects were assessed on day 14 using symptom diary. (Clinical trial registry identifier: SLCTR/2010/010.)

      Results

      From 92 newly diagnosed West syndrome infants, 48 were randomized to receive prednisolone and 44 to receive adrenocorticotrophin hormone. Eighty infants completed the posttreatment evaluation according to specifications. The hypsarrhythmia severity score, significantly improved with hormonal therapy for 2 weeks (10.45 ± 2.65 vs 3.45 ± 2.67); P < 0.01. When individual treatment arms were compared using mean differences in the improvement of scores, improvement in prednisolone arm (7.95 ± 2.76) was significantly greater than that in the adrenocorticotrophin hormone arm (6.00 ± 2.61); P < 0.01. Both forms of therapy were tolerated well. Frequent crying, irritability, weight gain, increased appetite, and abdominal distension were more common (but not statistically significant) with prednisolone.

      Conclusions

      Hypsarrhythmia severity score improved significantly with both hormonal therapies, but this improvement was significantly better with oral prednisolone than intramuscular adrenocorticotrophin hormone. This is the first ever documentation of a superior therapeutic role of oral steroids in West syndrome.

      Keywords

      See related article on page 13.

      Introduction

      West syndrome is an epileptic encephalopathy of infancy characterized by epileptic spasms accompanied by the electroencephalographic (EEG) appearance of hypsarrhythmia. Hypsarrhythmia includes high voltage (generally >200 μV) slow waves with variable amplitude; spike and waves from many foci; and lack of synchrony, all of which contribute to the described “chaotic” appearance.
      • Gibbs F.A.
      • Gibbs E.L.
      Infantile Spasms. Atlas of Electroencephalography.
      Seizure control in West syndrome is often difficult, and the resulting developmental regression may be catastrophic. The cause of this acute regression is suggested to be the combined effect of frequent spasms and hypsarrhythmia.
      • Lux A.L.
      Is hypsarrhythmia a form of non-convulsive status epilepticus in infants?.
      However, even in the absence of clinical spasms (i.e. during prespasm stage), hypsarrhythmia may be associated with an encephalopathic state with reduced alertness to objects, noises, and caregivers; absent or severely reduced social smiling; negative opticofacial reflex; and visual inattention.
      • Philippi H.
      • Wohlrab G.
      • Bettendorf U.
      • et al.
      Electroencephalographic evolution of hypsarrhythmia: toward an early treatment option.
      • Jambaque I.
      • Chiron C.
      • Dulac O.
      • Raynaud C.
      • Syrota P.
      Visual inattention in West syndrome: a neuropsychological and neurofunctional imaging study.
      In the past, the persistence of hypsarrhythmia, irrespective of the spasm control (clinical response), has been debated as an indication for continuation of treatment. In evaluation of therapeutic interventions for West syndrome, improvement of hypsarrhythmia (electrical response), has been considered an important primary outcome measure by the West Delphi group.
      • Lux A.L.
      • Osborne J.P.
      A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group.
      Treatment of West syndrome to date remains largely empirical. This is often attributed to the poor understanding of its underlying pathophysiology. Vigabatrin, an inhibitor of γ-amino butyric acid transaminase, is favored for tuberous sclerosis. Hormonal therapies, mainly adrenocorticotrophin hormone (ACTH) and prednisolone are recommended for all other etiologies.
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • et al.
      Child Neurology SAmerican Academy of N
      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.
      • Mackay M.
      • Weiss S.
      • Snead 3rd, O.C.
      Treatment of infantile spasms: an evidence-based approach.
      • Hancock E.C.
      • Osborne J.P.
      • Edwards S.W.
      Treatment of infantile spasms.
      The mode of action of ACTH and glucocorticoids is postulated to be based on their effect on immune, inflammatory, and other derangements observed in West syndrome.
      • Riikonen R.S.
      Steroids or vigabatrin in the treatment of infantile spasms?.
      The response to these therapies is primarily described as clinical response, EEG response, or as electroclinical response, which is a composite incorporating seizure and EEG resolution. Most prospective clinical trials and retrospective case studies in West syndrome have described only cessation of spasms (clinical outcome) as the primary outcome measure.
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • et al.
      The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial.
      • Azam M.
      • Bhatti N.
      • Krishin J.
      Use of ACTH and prednisolone in infantile spasms: experience from a developing country.
      • Snead 3rd, O.C.
      • Benton J.W.
      • Myers G.J.
      ACTH and prednisone in childhood seizure disorders.
      Some others have described the electroclinical outcome.
      • Hrachovy R.A.
      • Frost Jr., J.D.
      • Kellaway P.
      • Zion T.E.
      Double-blind study of ACTH vs prednisone therapy in infantile spasms.
      • 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.
      • Vigevano F.
      • Cilio M.R.
      Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study.
      No randomized clinical trial has specifically addressed the effect of therapy, especially hormonal treatments, on the resolution of hypsarrhythmia (EEG response).
      We report the comparison of the efficacy of moderate-to-high dose oral prednisolone and moderate-to-low dose intramuscular ACTH administered for 2 weeks on the improvement of hypsarrhythmia (electrical response) in previously untreated West syndrome.

      Methods

      Selection of the sample

      A single-blind, parallel, randomized controlled clinical trial was conducted at the Lady Ridgeway Children's Hospital in Sri Lanka from 2010 to 2013. This is the premier tertiary care children's hospital in the country and is said to be the world's largest children's hospital.

      http://www.lrh-hospital.health.gov.lk/: Lady Ridgeway Hospital for Children.

      It provides specialist neurology care for inpatients and outpatients referred from all parts of the country.
      Infants who were either directly admitted to the hospital or referred from other hospitals by pediatricians, with newly diagnosed infantile spasms occurring in clusters, were eligible for the study. The diagnosis of infantile spasms was confirmed based on spasms directly observed by the lead author or in videos provided by parents or clinical spasms observed on video telemetry. Of them, only those with hypsarrhythmia were included. This was identified in a 30-minute sleep EEG performed using digital EEG software (Compumedics) with concurrent video recording. To perform the records during a uniform sleep state (NREM sleep), the recordings were performed within first 30 minutes of falling asleep. This was ensured by administering sedation to the babies using chloral hydrate and observing them in the laboratory till fall asleep. At the end of 30 minutes, the babies were aroused to record 5 minutes of wakefulness. Within 24 hours of admission, EEG assessments were performed and interpreted by the lead author who was blinded to the treatment arm.
      Of the infants diagnosed with West syndrome, we excluded the ones aged <2 or >30 months or with a diagnosis of tuberous sclerosis, previous treatment for West syndrome, and contraindications for use of hormonal therapies. Patients were also excluded if their parents did not provide proxy consent or seemed incapable of monitoring the response to therapy as judged by the investigator who did the recruitment. Previous prescription of other anticonvulsants for any other seizure type was permitted.
      Parents of the eligible infants were explained the study in detail and invited to participate in the study by a medical officer not affiliated to the hospital (E.M.). If willing, informed written consent was obtained before recruiting their children to the study. Before treatment allocation, baseline developmental assessments were performed, using the Bayley-III infant and toddler developmental scales by one of the investigators (S.S.).

      Method of randomization

      All consenting and eligible infants were randomized to the two treatment groups: prednisolone and ACTH groups. The minimum sample size required to achieve an expected effect size of 25% in the improvement of electrical response in West syndrome with ACTH against prednisolone was 90 (45 in each treatment arm), based on 86.6% of infants revealing clinical and EEG improvement on day 14 of the ACTH treatment,
      • 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.
      alpha error of 0.05, and power of 80%. Considering decline or subsequent ineligibility of 25%, it was decided to invite 112 infants to participate in the study. Randomization was performed independently using computer-generated random numbers by one coinvestigator (C.A.) who took no part in the recruitment or outcome assessment. Assignment to treatment arm was sequentially allocated and kept in sealed envelopes.

      Allocation and monitoring of treatment

      Treatment followed the guidelines of the United Kingdom Infantile Spasms Study protocol.
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • et al.
      The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial.
      The ACTH group received synthetic depot ACTH of 40-60 IU (0.5-0.75 mg) intramuscularly every other day for 14 days. The prednisolone group received daily oral prednisolone of 40-60 mg divided into four doses per day for 14 days.
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • et al.
      The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial.
      Patients were reassessed at 7 days, and if there was even a single spasm on that day, the dose was increased to prednisolone of 15 mg four times a day or ACTH of 60 IU every other day. At 14 days, the EEG was repeated. Thereafter, a gradual step down of medication was achieved for both groups over the next 3 weeks using prednisolone as follows: 10 mg three times daily; 10 mg twice daily; and 10 mg daily reducing every week. (If the higher dose was used, 10 mg four times a day, 10 mg twice daily, and 10 mg daily, reducing weekly.) The same generic preparations were used throughout the clinical trial.
      Prednisolone was crushed and packeted in sachets and administered dissolved in breast milk. This was carried out by mothers under the supervision of nursing offices during the first 2 days of hospital stay. ACTH was administered by the nursing staff. Daily oral antacid therapy was provided to both groups during the total 5 weeks of hormonal treatment. Any other anticonvulsant commenced before the onset of spasms was continued. No alterations to the treatment protocol was made during the 14 days unless at the request of parents. Crossover of treatment arm or to another therapeutic agent was performed only at the end of taper, unless requested by the parent or decided by the lead author based on the spasm load. Protocol violations of dose were defined as deviations from the correct schedule by >24 hours or >10% of the expected dose.
      The ACTH group was given the option of inpatient therapy or every other day review for administration of injections as outpatients. Those in the prednisolone group were discharged after 48 hours of treatment. Both groups of mothers were monitored via telephone conversations to ensure the treatment continuation and monitoring of adverse outcomes. The mothers were also instructed to note any adverse events using a symptom diary. The process of enrollment, treatment allocation, and evaluation is depicted in Figure.
      Figure thumbnail gr1
      FigureThe process of enrollment, treatment allocation, evaluation, and data analysis.

      Outcome assessment

      The primary outcome was improvement in the severity of hypsarrhythmia (electrical response). The secondary outcome was the development of adverse effects to treatment. The adverse effects were further evaluated by one investigator (E.M.) on day 14, using a preidentified comprehensive list of adverse effects reported for prednisolone and ACTH.
      Hypsarrhythmia severity was quantified using a hypsarrhythmia severity scale described by Kramer et al.
      • Kramer U.
      • Sue W.C.
      • Mikati M.A.
      Hypsarrhythmia: frequency of variant patterns and correlation with etiology and outcome.
      (Table 1). Components of this scale included the EEG background organization, slow wave activity, amplitude of the spikes, and frequency of spikes. Each of these components was given a score ranging from 0 to 3. These components were evaluated by selecting a 10-second epoch of EEG in NREM sleep that was considered most severe and most representative of hypsarrhythmia. Three other features were given a score of one if present in most of the sleep record: burst suppression, electrodecremental responses, and the absence of sleep transients. Relative normalization of background and epileptic discharges in wakefulness lasting for a minimum duration of 10 seconds was scored as one and was the fourth feature. This was performed by evaluating 5 minutes of record after arousal. Altogether, they accounted for a maximum score of 16, a greater score indicating higher severity. Improvement in the severity of hypsarrhythmia was measured as a reduction in the hypsarrhythmia score, based on the pretreatment (D0) and posttreatment (D14) EEG assessments. Uniformity of the assessment of hypsarrhythmia was ensured by performing the posttreatment EEG under similar conditions as described previously to capture the same state of sleep. The EEG evaluations and hypsarrhythmia severity scoring were performed by the lead author who remained blinded to the treatment arm.
      Table 1Hypsarrhythmia Scoring System: A Single Relatively Uniform 10-Second Segment That Contains the Most Representative and Severe Hypsarrhythmic Part of the Tracing Was Chosen for Scoring
      Adapted from Kramer et al.,
      • Kramer U.
      • Sue W.C.
      • Mikati M.A.
      Hypsarrhythmia: frequency of variant patterns and correlation with etiology and outcome.
       1997.
      ComponentScore
      Disorganization
       Good gradient and synchrony (normal for age)0
       Partially formed gradient with some synchrony1
       No gradient, some synchrony of background2
       Chaos, no synchrony, and no gradient3
      Diffuse delta activity (%)
       <500
       ≥50 but <751
       ≥75 but <1002
       1003
      Voltage (μV)
       <1200
       120-2001
       200-5002
       >5003
      Spikes and sharp waves
       No spikes or sharp waves0
       Spikes at a frequency of ≤1/5 seconds1
       Spikes at a frequency of 1/5 seconds-1 per second2
       Spikes at a frequency of ≥1 per second3
      Other items
       Electrodecremental discharges1
       Burst suppression in sleep1
       Absence of normal sleep pattern1
       Relative normalization in wakefulness1
      The maximum total score is 16 for the most severe hypsarrhythmia; minimum total score is 0 for a normal electroencephalography.
      To assess the intraobserver reliability of hypsarrhythmia scores, randomly selected 40 EEGs (20 pretreatment and 20 posttreatment) were rescored by the same investigator after 2 weeks. When the level of agreement between the scores and repeat-scores was assessed using spearman correlation coefficient, all components and the total scores revealed a significantly high correlation (>0.75). In addition, the total and individual component scores did not reveal a significant difference between the first and repeat measurements (P > 0.05), implying high reliability.
      The study was approved by the ethics review committees of the Lady Ridgeway Children's Hospital and the Faculty of Medicine, University of Colombo. It was registered in the Sri Lanka clinical trials registry before commencement (SLCTR/2010/010).

      Data analysis

      Data were analyzed using SPSS version 20. Descriptive statistics included mean, S.D. for quantitative data, and proportions for categorical data. Significance of the differences between the two treatment arms were assessed using chi-square test in relation to categorical baseline characteristics and posttreatment side effects and using independent t test in relation to quantitative baseline characteristics.
      Improvement in the severity of hypsarrhythmia was assessed for each individual by calculating (pre-post) treatment scores. The significance of this improvement among all infants treated with hormonal therapy and separately in infants on prednisolone or ACTH was assessed by testing the significance of their mean (pre-post) treatment scores using paired t test. The same analysis was performed in the entire sample and also within each individual component of the hypsarrhythmia assessment tool. Finally, significance of the improvement in the severity of hypsarrhythmia between the two treatment groups was assessed by comparing the mean (pre-post) treatment scores between the two groups, using independent t test.

      Results

      Of the 121 eligible infants with confirmed West syndrome, 113 (93%) gave consent. Only 105 underwent EEG evaluation and of them, 12 were excluded because of the absence of hypsarrhythmia and one because of spontaneous resolution of spasms, leaving 92 who were randomized to receive prednisolone (n = 48) and ACTH (n = 44) (Figure). The majority (71%) had an identified cause (symptomatic) for the West syndrome, although 18% had no cause evident after detailed history and examination, imaging (computed tomography or magnetic resonance imaging of brain), and metabolic screening (cryptogenic), 11% did not complete the investigations. The underlying symptomatic causes included hypoxic-ischemic injury (moderate-to-severe) in 23, neonatal seizures related to perinatal complications (excluding infection) in 10, central nervous system infection in six, congenital ischemic stroke in six, prematurity related in five, agenesis and/or dysgenesis of corpus callosum in four, trisomy 21 in two, neurofibromatosis in one, and poststatus epilepticus in one. Average age of the infants in the prednisolone group was 7.5 months (S.D. = 5.2) and 10.8 months (S.D. = 9.5) in the ACTH group, with no significant difference between the two groups (P = 0.06). There was also no significant difference between the two groups in demographic characteristics, baseline seizure duration, and severity (P > 0.05) (Table 2). No significant differences were noted in those lost for follow-up and those who continued with the study (P > 0.05).
      Table 2Baseline Characteristics of the Children Treated With Prednisolone and ACTH
      Baseline CharacteristicTreatment ArmLevel of Significance
      P values obtained for assessing significant differences between the two treatment arms in relation to baseline characteristics (chi-square test used for categorical data; independent t test used for quantitative data).
      Prednisolone, n = 48ACTH, n = 44
      n%n%
      Sex
       Male1947.52565.80.1
       Female2152.51334.2
      Ethnicity
       Sinhala3485.03386.80.9
       Tamil12.5012.6
       Muslim512.50410.5
      Gestation
       Preterm410.312.60.2
       Term3589.73797.4
      Birth weight (kg)
       <2.51334.21231.60.8
       >2.52565.82668.4
      Age of onset of spasms (mo)
       <123897.43386.80.08
       >1212.6513.2
      Preceding and/or concurrent seizures
       Present1333.31231.60.8
       Absent2666.72668.4
      Duration of treatment lag (days)
       ≤282155.31643.20.3
       >281744.72156.8
      Previous treatment with AED
       Yes923.11026.30.7
       No3079.92873.7
      Age of onset of spasms (mo)
       <123897.43386.80.08
       >1212.6513.2
      MeanS.D.MeanS.D.Level of Significance
      Birth weight (kg)2.610.52.670.50.6
      Baseline developmental scores
       Cognitive60.610.358.28.00.2
       Language58.612.855.911.70.3
       Motor53.513.450.99.10.3
      Spasm load (clusters per day)4.913.25.062.40.8
      P values obtained for assessing significant differences between the two treatment arms in relation to baseline characteristics (chi-square test used for categorical data; independent t test used for quantitative data).
      Of the 92 randomized infants, only 40 from each treatment group had posttreatment EEGs on day 14. This was because of deviation from protocol by one (prednisolone group), failure to return for the posttreatment EEG by eight (five in prednisolone and three in ACTH groups), and inability to obtain a sleep record in three (one in prednisolone group and two in ACTH group).
      When the improvement in the severity of hypsarrhythmia of the entire sample treated with either form of hormonal therapy was considered, it revealed an average pretreatment score of 10.45 (S.D. = 2.65), improving with treatment to an average posttreatment score of 3.45 (S.D. = 2.67). The mean of (pre-post) treatment scores was 7.0 (S.D. = 2.84), which was statistically significant (paired t = 21.72; degrees of freedom = 78; P < 0.01).
      When the improvement in the severity of hypsarrhythmia was assessed within each treatment arm, the mean of (pre-post) treatment scores was significant for each treatment (P < 0.01) (Table 3). Furthermore, when the improvement of severity of each individual component of the hypsarrhythmia was considered, a significant improvement in all the components was revealed whether treated with either prednisolone or ACTH (Table 3). The improvement was maximal in background organization (mean = 1.74; S.D. = 1.11) followed by improvement in background slowing (mean = 1.50; S.D. = 1.04).
      Table 3Improvement in the Severity of Hypsarrhythmia With Hormonal Therapies (n = 80)
      Components in the Hypsarrhythmia Assessment ToolImprovement in Hypsarrhythmia Scores
      Improvement in the severity of hypsarrhythmia was assessed by the mean (pre-post) treatment scores.
      Level of Significance
      P values obtained for assessing the significance of the mean of (pre-post) treatment scores using paired t test.
      MeanS.D.
      Background organization1.741.11<0.001
      Background slowing1.501.04<0.001
      Amplitude1.120.82<0.001
      Spike index1.190.98<0.001
      Burst suppression0.420.54<0.001
      Electrodecremental pattern0.120.490.02
      Normalization in wakefulness0.430.62<0.001
      Absence of sleep transients0.430.59<0.001
      Overall score7.002.84<0.001
      Improvement in the severity of hypsarrhythmia was assessed by the mean (pre-post) treatment scores.
      P values obtained for assessing the significance of the mean of (pre-post) treatment scores using paired t test.
      When the improvement in the severity of hypsarrhythmia was assessed within each treatment arm, the mean pretreatment score for prednisolone and ACTH were 10.55 (S.D.=2.51) and 10.33 (S.D.=2.82) respectively. This improved to 2.61 (S.D.= 2.31) in the prednisolone group and to 4.33 (S.D.=2.76) in the ACTH group. When the mean (pre-post) treatment scores were compared between the two groups, the prednisolone group revealed a significantly greater improvement in severity than that of the ACTH group (7.95 ± 2.76 vs 6.00 ± 2.61; P < 0.01) (Table 4). When the mean (pre-post) treatment score of each individual component was assessed, all components improved better with prednisolone than with ACTH. However, only in the spike index, there was a statistically significant improvement. The electrodecremental pattern was equally improved in the two groups.
      Table 4Comparison of the Improvement of Hypsarrhythmia Severity Between the Prednisolone (PNL) and Adrenocorticotrophin Hormone (ACTH) Groups
      Components in the Hypsarrhythmia ScoresImprovement in the Hypsarrhythmia Severity
      Improvement in the hypsarrhythmia severity was assessed by the mean of (pre-post) treatment scores.
      Level of Significance
      P values obtained for assessing the significant difference of the mean (pre-post) treatment scores between the two treatment groups using paired t test.
      PNL GroupACTH Group
      MeanS.D.MeanS.D.
      Organization1.900.901.571.280.2
      Background slowing1.571.081.421.000.51
      Amplitude1.300.790.940.830.05
      Spike index1.500.900.860.960.004
      Burst suppression0.520.590.310.470.09
      Electrodecremental pattern0.122.760.130.570.95
      Normalization in wakefulness0.480.670.380.650.48
      Absence of sleep transients0.500.550.360.630.33
      Overall score7.952.766.002.610.002
      Because of multiple comparisons, the level of significance was adjusted to P < 0.05 by Bonferroni correction: αadjusted = α/c (where α is the overall experimentwise alpha [0.05] and c is the number of comparisons made [9]).
      Improvement in the hypsarrhythmia severity was assessed by the mean of (pre-post) treatment scores.
      P values obtained for assessing the significant difference of the mean (pre-post) treatment scores between the two treatment groups using paired t test.
      Both forms of therapies were reasonably well tolerated, but weight gain, increased appetite, irritability, frequent crying spells, and abdominal distension were experienced more frequently in those treated with prednisolone (Table 5). None of these symptoms was severe enough to cause withdrawal from the study, but one child in the prednisolone group withdrew because of hypertension. During the trial period of 5 weeks, which included the treatment regimen and taper period, no deaths occurred.
      Table 5Comparison of Side Effects Experienced With Prednisolone and Adrenocorticotrophin Hormone (ACTH) (n = 80)
      Side EffectPrednisoloneACTHLevel of Significance
      Because of multiple comparisons, the level of significance was adjusted to P < 0.00294 by Bonferroni correction: αadjusted = α/c (where α is the overall experimentwise alpha [0.05] and c is the number of comparisons made [17]).
      n%n%
      Increased appetite2578.51542.90.006
      Weight gain1751.51028.60.05
      Frequent crying spells1545.5822.90.04
      Drowsiness39.1617.10.32
      Cushinoid features824.2514.30.29
      Insomnelence39.112.90.27
      Lethargy26.112.90.52
      Reduction in social behavior26.112.90.52
      Abdominal distension721.2000.004
      Hypertension13.012.90.99
      Increased susceptibility to infection0012.90.32
      Irritability824.225.70.03
      Nausea13.0000.29
      Vomiting13.0000.29
      Diarrhea26.112.90.52
      Dyspepsia13.012.90.96
      Electrolyte imbalances26.1000.32
      Because of multiple comparisons, the level of significance was adjusted to P < 0.00294 by Bonferroni correction: αadjusted = α/c (where α is the overall experimentwise alpha [0.05] and c is the number of comparisons made [17]).

      Discussion

      Our study is the first randomized clinical trial to reveal superiority of prednisolone over ACTH for the treatment of West syndrome from the perspective of improvement of hypsarrhythmia (EEG response). Both treatment arms were well tolerated, although frequent crying spells, weight gain, irritability, increased appetite, and abdominal distension were more common in those provided prednisolone. Contrary to expectations, this high-dose prednisolone therapy did not result in a significant risk of infective complications in our setting with a high risk of communicable diseases. The clinical outcome (sustained spasms control) is not described in the present article because assessment is still ongoing. These findings will be described in a future article after study completion.
      The choice of improvement of hypsarrhythmia as our primary outcome measure is justified in part by a German study from 2008. In this study, 16 infants with an early onset cerebral insult had sequential EEGs and eventually developed West syndrome. Over a 3- to 6-week interval, there was a gradual build-up of hypsarrhythmia before the onset of spasms.
      • Philippi H.
      • Wohlrab G.
      • Bettendorf U.
      • et al.
      Electroencephalographic evolution of hypsarrhythmia: toward an early treatment option.
      A gradual worsening of the EEG discharges was evident even before the onset of spasms. During this progressive, prespasm stage, the infants revealed progressive encephalopathic behavior. This indicated that in West syndrome, the chaotic EEG is also responsible for the developmental regression. Further, many have stressed that adequate therapy must abolish hypsarrhythmia early and effectively.
      • Lux A.L.
      Is hypsarrhythmia a form of non-convulsive status epilepticus in infants?.
      • Eisermann M.M.
      • DeLaRaillere A.
      • Dellatolas G.
      • et al.
      Infantile spasms in Down syndrome–effects of delayed anticonvulsive treatment.
      Other studies and guidelines have stressed the importance of early treatment to allow the possibility of better developmental outcome; however, this proposal has not been definitively proven.
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • et al.
      Child Neurology SAmerican Academy of N
      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.
      • Eisermann M.M.
      • DeLaRaillere A.
      • Dellatolas G.
      • et al.
      Infantile spasms in Down syndrome–effects of delayed anticonvulsive treatment.
      • Lombroso C.T.
      A prospective study of infantile spasms: clinical and therapeutic correlations.
      Based on current information, it appears that a therapeutic agent that reverses hypsarrhythmia promptly has some chance of improving the developmental outcome. Underlying etiology also may play a role in the improved developmental outcome. However, comparison of results separately for symptomatic and cryptogenic etiologies could not be performed adequately in this group because 11% of the infants did not complete the investigations for etiology.
      Historically, the accepted therapeutic options for West syndrome have been mainly vigabatrin and hormonal therapies. Although both forms of hormonal therapies (ACTH and corticosteroids) have been used as first-line hormonal therapy for over 40 years, unlike ACTH, corticosteroids have not often been recommended as a first-line choice for short-term therapy. The reason appears to be the lack of “adequate” evidence as outlined in several evidence-based meta-analyses.
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • et al.
      Child Neurology SAmerican Academy of N
      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.
      • Arya R.
      • Shinnar S.
      • Glauser T.A.
      Corticosteroids for the treatment of infantile spasms: a systematic review.
      There are many case series and retrospective reports of successful treatment of West syndrome with oral prednisolone,
      • Azam M.
      • Bhatti N.
      • Krishin J.
      Use of ACTH and prednisolone in infantile spasms: experience from a developing country.
      • 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.
      • Mohamed B.P.
      • Scott R.C.
      • Desai N.
      • Gutta P.
      • Patil S.
      Seizure outcome in infantile spasms–a retrospective study.
      prednisone,
      • Hrachovy R.A.
      • Frost Jr., J.D.
      • Kellaway P.
      • Zion T.E.
      Double-blind study of ACTH vs prednisone therapy in infantile spasms.
      IV pulsatile dexamethasone,
      • Haberlandt E.
      • Weger C.
      • Sigl S.B.
      • et al.
      Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes.
      and IV methyl prednisolone.
      • Mytinger J.R.
      • Quigg M.
      • Taft W.C.
      • Buck M.L.
      • Rust R.S.
      Outcomes in treatment of infantile spasms with pulse methylprednisolone.
      However, because of lack of class I or II evidence, there has been a reluctance to accept oral corticosteroids as effective.
      • Go C.Y.
      • Mackay M.T.
      • Weiss S.K.
      • et al.
      Child Neurology SAmerican Academy of N
      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.
      • Mackay M.
      • Weiss S.
      • Snead 3rd, O.C.
      Treatment of infantile spasms: an evidence-based approach.
      • Hancock E.C.
      • Osborne J.P.
      • Edwards S.W.
      Treatment of infantile spasms.
      • Mackay M.T.
      • Weiss S.K.
      • Adams-Webber T.
      • et al.
      Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society.
      Of the studies, which favored ACTH, a class II (n = 29) randomized clinical trial revealed marked superiority of high-dose ACTH (86.6%) over low-dose prednisone (28.6%); however, the doses of ACTH and prednisone were not comparable.
      • 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.
      A class IV retrospective case series (n = 116) reported 100% response to ACTH vs 51% response to prednisone.
      • Snead 3rd, O.C.
      • Benton J.W.
      • Myers G.J.
      ACTH and prednisone in childhood seizure disorders.
      Other studies have reported no significant difference between ACTH and oral corticosteroids. These include a class III (n = 24) trial published in 1983
      • Hrachovy R.A.
      • Frost Jr., J.D.
      • Kellaway P.
      • Zion T.E.
      Double-blind study of ACTH vs prednisone therapy in infantile spasms.
      and a large class III (n = 55) trial in 2004 revealing equal spasm response rates of 76% (ACTH) and 70% (prednisolone).
      • Lux A.L.
      • Edwards S.W.
      • Hancock E.
      • et al.
      The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial.
      This last trial was underpowered to prove a superiority of one form of hormone over the other. Lately, in a retrospective analysis of outcome with prednisolone (n = 15), which was used because of the high cost of ACTH, spasm freedom within 2 weeks was reported in 67%.
      • 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.
      The systematic review by Arya et al.
      • Arya R.
      • Shinnar S.
      • Glauser T.A.
      Corticosteroids for the treatment of infantile spasms: a systematic review.
      on corticosteroids for treatment of West syndrome concluded that, based on available evidence, the effects of high-dose corticosteroids (3-4 mg/kg/day) are similar to low-dose ACTH (40-60 mg/day).
      One of the crucial issues related to these trials is the absence of comparative doses of ACTH and prednisolone. A well-known study that is referenced in most meta-analyses on therapeutic outcomes used very high dose of ACTH (150 U/m2/day) compared with a small dose of prednisone (2 mg/kg/day).
      • 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.
      Although this referenced randomized clinical trial fulfills criteria for meticulous study design, the imbalance in the doses may have biased the study outcome. It is likely that such a high dose of ACTH would have a higher rate of adverse effects. The best equivalent dose for ACTH and oral corticosteroids is still unknown. It is also possible that the mechanism of action of these two treatments on altering the neurobiology in West syndrome is different.
      • Snead 3rd, O.C.
      How does ACTH work against infantile spasms? Bedside to bench.
      • Tsao C.Y.
      Current trends in the treatment of infantile spasms.
      Further, two different compounds of ACTH (natural or synthetic) have been used in trials.
      • Watemberg N.
      Infantile spasms: treatment challenges.
      Apart from issues of efficacy, the greatest advantage associated with prednisolone therapy is its low cost. Completion of the treatment course in the United States with oral prednisolone typically costs less than $100 versus $70,000 for natural ACTH and $7000 for synthetic ACTH preparations.
      • 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.
      • Mytinger J.R.
      • Quigg M.
      • Taft W.C.
      • Buck M.L.
      • Rust R.S.
      Outcomes in treatment of infantile spasms with pulse methylprednisolone.
      Recent increase in the cost has worsened this situation even further. Another major advantage of oral corticosteroids is the ease of administration, which may indirectly increase the quality of holistic care to the infant.
      We conclude that moderate-to-high doses of oral prednisolone appear to be more effective than low-to-moderate doses of ACTH for the initial treatment of West syndrome to reverse the hypsarrhythmia. It is hoped that this would establish recognition of oral prednisolone as a form of primary treatment option for West syndrome. Our findings should be particularly important to parts of the world where ACTH is simply not affordable or not available. On the other hand, it may also be welcomed by countries with recently escalated cost of ACTH therapy.
      This clinical trial was funded by the Sri Lanka Medical Association , which is the oldest medical professionals' organization in the country. The authors also specially thank Profs. Carol and Peter Camfield, Professors of Paediatrics at the Dalhousie University (Canada), who took a keen interest in the preparation of the manuscript and made useful suggestions. They also acknowledge the Australia–Compumedics Limited for donating the digital electroencephalography recording equipment. The authors appreciate Subadhra Liyanage and Chamila Liyanage, the electroencephalographic technicians, for their technical support. None of the authors have any conflicts of interest to disclose. No part of the trial was industry sponsored. The authors confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The author C.A. is responsible for biostatistics.

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