|Ahead of print
Pulse methylprednisolone plus low-dose prednisolone versus low-dose prednisolone alone for treatment of children with West syndrome: A single-center, open-label randomized controlled trial
Nisha Kumari1, Sanjiv Nanda1, Jaya Shankar Kaushik1, Kiran Bala2
1 Department of Pediatrics, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India
2 Department of Neurology, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India
|Date of Submission||21-Feb-2021|
|Date of Decision||01-May-2021|
|Date of Acceptance||11-Jan-2022|
|Date of Web Publication||12-Jul-2022|
Jaya Shankar Kaushik,
Department of Pediatrics, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak 124001, Haryana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: There are preliminary reports of the benefit of additional pulse methylprednisolone (MP) to oral prednisolone in the treatment of West syndrome. Aim: To compare the efficacy and safety of intravenous pulse MP followed by low-dose prednisolone versus low-dose prednisolone alone for children with West syndrome. Materials and Methods: This randomized, open-labeled, controlled clinical trial was conducted among children aged two months to 30 months with a diagnosis of West syndrome. They were randomized to either of pulse MP (30 mg/kg for 3 days) followed by low-dose prednisolone (2 mg/kg) [n = 26] or low-dose prednisolone (2 mg/kg) alone [n = 24] for four weeks. Results: The efficacy of pulse MP was comparable with oral prednisolone in terms of spasms cessation (11 [45.8%] vs. 7 [26.9%]; RRR [95% confidence interval [CI]: 0.74 [0.47–1.14]; P = 0.24), more than 50% spasms reduction (16 [66.6%] vs. 11 [42.3%]; RRR [95% CI]: 0.57 [0.31–1.12]; P = 0.09), more than 90% reduction (11 [42.8%] vs. 7 [26.9%]; RRR [95% CI]: 0.74 [0.47–1.14]; P = 0.24), and primary electroclinical remission (5 [20.8%] vs. 2 [7.6%]; RRR [95% CI]: 0.85 [0.68–1.08]; P = 0.21). The adverse effect profile was comparable in the two groups. Conclusion: Pulse MP therapy followed by oral prednisolone in low-dose (2 mg/kg) was as effective as low-dose prednisolone (2 mg/kg) therapy alone in West syndrome. Although pulse MP did not result in any adverse outcome, routine use of the same before initiation of oral prednisolone needs further studies with a larger sample size; longer follow-,up and comparative trial with high dose steroids (4 mg/kg).
Keywords: Epileptic encephalopathy, epileptic spasm, hypsarrhythmia, infantile spasm, steroids
|How to cite this URL:|
Kumari N, Nanda S, Kaushik JS, Bala K. Pulse methylprednisolone plus low-dose prednisolone versus low-dose prednisolone alone for treatment of children with West syndrome: A single-center, open-label randomized controlled trial. J Pediatr Neurosci [Epub ahead of print] [cited 2023 Sep 29]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=350285
| Introduction|| |
West syndrome is an electroclinical syndrome characterized by infantile spasms, electroencephalography (EEG) showing evidence of hypsarrhythmia with or without developmental delay. Infantile spasms are an epilepsy syndrome characterized by a type of seizure called epileptic spasms that begins at the age of 4–8 months but can persist till 3–4 years of age. Epileptic spasms are often confused with myoclonic seizures. The majority of children with West syndrome are secondary to perinatal injury in developing countries. Hormonal therapy and vigabatrin remain the mainstay of treatment of West syndrome.,,, Among the hormonal treatment, there is sufficient evidence to suggest that high-dose oral prednisolone is as effective as an adrenocorticotropic hormone for short-term management of epileptic spasms with low cost and ease of administration.
Recently, high-dose prednisolone (4 mg/kg/day) has shown more efficacy when compared with low-dose prednisolone (2 mg/kg/day). There were few papers on the role of pulse methylprednisolone (MP) in West syndrome.,,, In a study by Singhi et al., among 18 children who received pulse MP followed by oral prednisolone, 10 children had achieved >50% seizure reduction in two weeks, and four children had spasms cessation at six weeks follow-up. In another series from Iran, authors observed that pulse MP followed by oral prednisolone resulted in a reduction of seizure to more than 50% in 12 of the 20 children with infantile spasms. Recently, a randomized controlled trial demonstrated comparable efficacy of spasm freedom (54.8% vs. 68.9%; P = 0.26) with pulse MP and oral prednisolone group. Exploring the evidence further, the present randomized controlled trial was designed to compare the efficacy and safety of intravenous pulse MP followed by low-dose prednisolone versus low-dose prednisolone in the management of children with West syndrome.
| Materials and Methods|| |
This open-label, randomized control trial was conducted in the Department of Pediatrics and Neurology of a tertiary care referral center of India. The data were collected from February 2018 to March 2019. Ethical approval from the Institutional Ethics Committee was obtained. Written informed consent was obtained from the parents. All children aged two months to 30 months, diagnosed with West syndrome, were consecutively enrolled in the study. Children with new-onset epileptic spasms with electroencephalographic evidence of hypsarrhythmia or its variants were considered were included in the study. Children with recognized progressive neurological illness, children with renal, pulmonary, cardiac, or hepatic dysfunction, and severe malnutrition (weight for length and height for less than 3 SD for mean as per WHO growth charts) were excluded from the study. The trial was registered in the Clinical Trial Registry of India (CTRI) (CTRI/2017/12/010877 [dated: Dec. 17, 2017))
All eligible children were subjected to detailed clinical history and examination. Type of the spasms, frequency, age at onset, age at diagnosis, frequency of spasms, perinatal details, family history, developmental status, and treatment history were recorded. A baseline electroencephalogram (video-EEG whenever possible) was performed in all children at the time of enrollment for a minimum of 1 h, including at least one sleep-wake cycle. All children were subjected to Mantoux test and chest X-ray to screen for latent tuberculosis. All treatment naive children were commenced on oral sodium valproate or levetiracetam (among those where the etiology is not clear) and clonazepam till the workup for tuberculosis is completed. Children with negative Mantoux test and normal chest X-ray were enrolled consecutively in the study. They were randomized by block randomization using a variable block size of 2, 4, and 6 using computer-generated random number tables in two groups: Intravenous MP (30 mg/kg/day for 3 days) followed by oral prednisolone (2 mg/kg/day for next 25 days) and oral prednisolone (2 mg/kg/day for 28 days). Sealed opaque envelopes containing group codes were prepared. Envelopes were sequentially numbered and kept in order according to their serial numbers. The envelope was opened at the time of randomization, and the patient was allocated to their respective group. The investigator (SN) generated the random allocation sequence, investigator NK enrolled the participants, and investigator (JSK) assigned participants to intervention.
Percentage reduction in seizure frequency as compared with the baseline was assessed per daily seizure log maintained by parents. Parents had recorded the total number of spasms in their diary. At the end of the four-week study period, the proportion of patients who achieve spasms freedom, >90% and >50% reduction in spasms frequency in both the groups were recorded. Time to cessation of spasms and the proportion of children with treatment failure was also recorded. A repeat EEG was performed to look for the resolution of hypsarrhythmia.
The primary outcome of the study was spasms cessation. The absence of spasms for consecutive 28 days within 14 days of commencement of treatment was considered as “cessation of spasms.” The secondary outcomes were the proportion of children with >50% reduction, >90% reduction, and primary electroclinical remission. Percentage reduction in the frequency of spasms as estimated by mean frequency of spasms in preceding week when compared with the baseline spasms frequency was considered to estimate the proportion of children with more than 50% and more than 90% seizure reduction. The resolution of EEG findings of hypsarrhythmia when performed at four weeks following the commencement of treatment or within one week of cessation of spasms, whichever was earlier, was considered as the resolution of hypsarrhythmia. Primary electroclinical remission was considered when there was a cessation of spasms along with the resolution of hypsarrhythmia.
This trial was planned to test the hypothesis that administration of additional MP may be more efficacious than low-dose steroids alone. By use of a null hypothesis that the two groups would not have a significant difference in spasms control outcome, and by defining 25% as minimum outcome difference of clinical importance, the authors estimated that a sample size of 56 patients per group (1:1 allocation ratio) would enable the detection of difference that will be significant at 5% with a power of 80% assuming 40% spasm freedom with oral steroid group based on the previous study.
All data collected was entered in Microsoft Excel (MS Excel). Data were analyzed using SPSS 21.0 version. All categorical variables were expressed in numbers (percentage); all continuous variables were expressed as mean (SD) or median (interquartile range [IQR]). Categorical variables were compared using χ2 test or the Fischer exact test. Continuous variables were compared between cases and controls using the Student's t-test or Wilcoxon Rank-Sum test. A P value of <0.05 was considered significant.
| Results|| |
Among the 57 eligible participants, 50 children were enrolled in the study and were randomized to receive pulse MP followed by oral prednisolone (n = 24) or oral prednisolone alone (n = 26) [Figure 1]. All the demographic and clinical characteristics were comparable between the two groups [Table 1]. The majority of participants had developed West syndrome secondary to hypoxic ischemic encephalopathy in both groups. The efficacy of pulse MP was comparable with oral prednisolone in terms of spasms cessation (11 [45.8%] vs. 7 [26.9%]; P = 0.24). However, the chances of not achieving spasm freedom were reduced by 74% in the pulse MP group when compared with the low-dose prednisolone group (RRR [95% CI]: 0.74 (0.47–1.14). Similarly, efficacy in terms of more than 50% spasms reduction (16 [66.6%] vs. 11 [42.3%]; RRR [95% CI]: 0.57 [0.31–1.12]; P = 0.09) and primary electroclinical remission (5 [20.8%] vs. 2 [7.6%]; RRR [95% CI]: 0.85 [0.68–1.08]; P = 0.21) was comparable [Table 2]. Similarly, time to cessation of spasms (8 [6.3%] vs. 5.8 [2.5%]; P = 0.41) was comparable. The adverse effect profile was comparable in the two groups.
|Table 1: Baseline demographic and clinical characteristics of enrolled participants (n = 50)|
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| Discussion|| |
The present randomized controlled trial revealed comparable efficacy of additional pulse MP over low-dose prednisolone alone. The present study provides preliminary evidence to discourage the use of additional pulse MP to low-dose oral steroids in the management of children with West syndrome. The findings also mitigate the need for hospitalization, securing intravenous cannulation, and the associated risk of hospital-acquired infections associated with intravenous pulse MP.
Pulse MP followed by high-dose prednisolone (4 mg/kg/day) would have been an ideal choice, but for the lack of safety data on such a high dose of cumulative steroid, authors decided to use low-dose prednisolone in the present study. The institutional practice of using 2 mg/kg prednisolone forced authors to use that as a comparative arm instead of 4 mg/kg as the comparator. Looking back at the study design, we feel that we could have very well used 4 mg/kg as the comparator arm. A recently published trial had rather demonstrated the safety of 4 mg/kg following pulse MP. Hence, the results of the present study with a limited sample size need to be interpreted in the context of the use of low-dose steroids.
Findings in the present study are in contrast with experience from other authors ,, [Table 3]. The comparable results in the MP group and the low-dose prednisolone group need to be interpreted along with the effect size. Although the proportion of children achieving spasm freedom did not reach statistical significance, looking at the effect size, the chances of not achieving spasm freedom were reduced by almost 75% with the pulse MP group compared with the low-dose group. Hence, the comparable results in both groups in terms of hypothesis testing could be attributable to the small sample size, large time gap in seeking medical attention, and predominant structural etiology in both the groups. Moreover, there is a wide variation in the inclusion criteria, the definition of spasms freedom, a dose of oral prednisolone, and the dose of MP among these studies, which could probably explain this discrepancy. The present study had recruited patients with a mean age of 15.2 months, which often results from a delay in seeking medical attention or an inability to recognize epileptic spasms. Time lag to diagnosis is one of the biggest predictors of treatment response. Considering that many of our patients were daily wage workers who tend to migrate from one place to another, such unusual time lag is often inevitable. A time lag of 6–9 months in both groups could also contribute to lower clinical response in the present study.
|Table 3: Table comparing the studies on methylprednisolone (MP) in the management of children with West syndrome|
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In a Korean observational study by Yeh et al., 14 patients with West syndrome received pulse MP (30 mg/kg/day for three days) followed by a low dose (1 mg/kg two doses) of oral prednisolone. The outcome measure included spasms freedom, which was defined as a cessation of spasms within 14 days of administering pulse MP for more than seven days. The authors found that 9 out of 14 patients (64.3%) had achieved spasms freedom. Transient spasms cessation for 5–7 days has been observed by previous authors as well. The present study adopted the definitions according to the Delphi consensus statement with the cessation of spasms for the next consecutive 28 days. This could explain comparatively lower success rates in the present study with pulse MP. Moreover, the study had used low-dose steroids in contrast to recommend high-dose steroids, which could also contribute to lower success rates in the comparator arm. Hence, neither therapy resulted in more than 20% resolution of hypsarrhythmia, which is an exceptionally low-response rate.
In a study by Mytinger et al., pulse MP (30 mg/kg/day for three days) was followed by oral prednisolone in a tapering dose starting from 4 mg/kg/day for the first two weeks followed by 3 mg/kg/day and 2 mg/kg/day for subsequent two weeks. This was tapered gradually over a total duration of 60 days. This treatment protocol was used for 10 patients with West syndrome. The authors found that 5 out of 10 patients had achieved the cessation of spasms within 2–6 days of starting the treatment. Similarly, remission of hypsarrhythmia was evident in 5 out of 10 patients. Among those five children, four had a recurrence of spasms but eventually achieved the cessation of spasms at the end of two months.
In a recently published study, Kapoor et al., had demonstrated comparable efficacy of pulse MP and oral prednisolone (4 mg/kg/day) at two weeks in terms of spasm cessation and electroclinical remission. Authors had observed higher weight gain with the oral prednisolone group and higher rates of irritability, sleep disturbances, and hypertension among the pulse MP group. However, the authors observed comparable rates of adverse effects in both the groups probably owing to the use of low-dose steroids in both the groups in the present study.
The present study had excluded children with severe malnutrition for fear of immunocompromised state among them and a flare-up of latent tuberculosis and other infection with the administration of steroids. Moreover, all children were subjected to the Mantoux test and chest X-ray to screen for latent tuberculosis before the administration of steroids. A total of 10 children were excluded from the positive Mantoux test in the present study. There are no clear guidelines on screening and utility of screening for latent tuberculosis before planning a short course of steroids. Hence, it is difficult to say if those 10 children could have also benefitted from steroid therapy. Considering the latency of a few days for completion of tubercular workup, all children were commenced on antiseizure medications. This could be an additional factor that needs to be kept in mind while interpreting the study results.
The present study provides additional evidence to discourage the use of additional pulse MP to oral steroids in the treatment of children with West syndrome. Low-sample size appears to be an obvious limitation. Despite this concern, we had recruited 24 patients in one and 26 patients in another group, which is reasonably a good sample size with minimal follow-up loss when compared with previous studies where 10–15 patients have been recruited with no parallel arm.,,, The short-term outcome has been assessed at one month instead of two weeks, which could probably take care of recurrence immediately following the achievement of spasms freedom.
One of the major limitations of the present study is the use of low-dose steroids. In view of limited safety data in children on the use of pulse MP followed by high-dose steroids, authors could not use the recommended high dose steroids in both groups till they encountered encouraging results of another Indian study. High-dose steroids have been a convention in the treatment of children with West syndrome since UKISS trial has been published, and some authors from the west have used it.,,, In light of limitations in the present study and safety of pulse MP, future studies are recommended on comparison of pulse MP followed by high-dose steroids versus high-dose steroids. Although the present study provides the outcome of a single course of pulse steroids, further studies could probably address the role of intermittent pulse steroids in the treatment of West syndrome as in Lennox Gestaut syndrome and electrical status epilepticus of sleep. Randomized controlled trials with adequate sample size and long-term follow-up to assess the developmental outcome and its impact on cognition, behavior, and quality of life are suggested.
To conclude, this single institution, open-label randomized controlled trial demonstrated that pulse MP therapy followed by oral prednisolone in low dose (2 mg/kg) was as effective as oral prednisolone (2 mg/kg) therapy alone in achieving a cessation of spasms among children with new-onset West syndrome. Although pulse MP did not result in any adverse outcome, routine use of the same before initiation of oral prednisolone needs further studies with a larger sample size; longer follow-up, and comparative trial with high dose steroids. Hence in practice, it will be difficult to implement the routine use of pulse MP for the treatment of children with West syndrome. The safety data of pulse MP among children with West syndrome in the present study provide courage to pursue further studies with high-dose prednisolone.
Financial support and sponsorship
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
Conflicts of interest
No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article
JSK: Concept and design of the study; NK, SN, KB, JSK: data collection, analysis, and interpretation of data, JSK, NK: drafting the manuscript and review of literature; JSK, SN, KB: Critical review of the manuscript for intellectual content and final approval of the version to be published; JSK: Clinician-in-charge, critical review of the manuscript for intellectual content, final approval of the version to be published and will act as guarantor for the paper. All authors approve of the final version.
An institutional ethical approval was obtained before the commencement of the study
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[Table 1], [Table 2], [Table 3]