|Ahead of print
Magnitude, determinants, and impact of treatment lag in West syndrome: A prospective observational study
Abinaya Anbarasu, Jitendra Kumar Sahu, Naveen Sankhyan, Pratibha Singhi
Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
|Date of Submission||01-May-2021|
|Date of Decision||13-Nov-2021|
|Date of Acceptance||03-Dec-2021|
|Date of Web Publication||12-Jul-2022|
Jitendra Kumar Sahu,
Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: Early recognition and initiation of standard therapy are crucial for the management of West syndrome. The study aimed to assess the magnitude, potential determinants, and impact of treatment lag impact on short-term therapeutic outcomes. Materials and Methods: The study design was prospective, observational, and data were ascertained through personal interviews with caregivers and reviewing medical records according to a pre-structured questionnaire. We defined short-term therapeutic response as the cessation of epileptic spasms commencing within 14 days of initiation of hormonal therapy and sustained for ≥28 days. Results: Of 82 consecutively enrolled children with West syndrome, the median treatment lag was 90 days (95% confidence interval [CI]: 110–198 days). The significant determinants of treatment lag in our study were as follows: the preexisting developmental delay, educational status of the parents, and qualification of the first practitioner visited. Our study showed that a shorter treatment lag (<1 month) was associated with a favorable cessation of epileptic spasms (85% vs. 15%; P = 0.011). Conclusion: We observed a significant treatment lag in children with West syndrome. The lead time to treatment emerged as a potentially modifiable risk factor for short-term therapeutic response with hormonal therapy.
Keywords: Hypsarrhythmia, India, infantile spasms, misdiagnosis
| Introduction|| |
West syndrome, also known as infantile spasms syndrome, is the most common epileptic encephalopathy encountered worldwide and is associated with a poor outcome. It is characterized by infantile-onset epileptic spasms and mostly hypsarrhythmia in electroencephalogram (EEG). The high-quality evidence for first-line therapeutic options belongs to hormonal therapy (adrenocorticotropic hormone or oral steroids) and vigabatrin., The initial therapeutic success as a cessation of epileptic spasms is a predictor of favorable outcomes.
Globally, it has been observed that diagnosis of West syndrome is commonly delayed.,, The magnitude of diagnostic and treatment lag varies due to knowledge, attitude, and practices of treating pediatricians and caregivers. It has been shown that treatment lag is an important predictor of therapeutic response and outcomes in West syndrome.,,, However, there is scarce quality data on treatment lag and its determinants from developing countries, and most data are from retrospective observations.,, It is important because the landscape of West syndrome is peculiar in developing countries due to the high proportion of structural etiology.,,, Furthermore, it has been shown that a significant number of pediatricians lack precise knowledge on evidence-based management of West syndrome. Therefore, this study was planned with a primary objective to elucidate the magnitude and underlying determinants of treatment lag in children with West syndrome. The secondary objective was to evaluate the effect of treatment lag on short-term therapeutic response with the initial hormonal therapy.
| Materials and Methods|| |
This study was an observational study, and data were prospectively collected through personal interviews with parents or caregivers and review of medical records according to a prestructured questionnaire. The Institute Ethics Committee approved the study design.
All consecutive diagnosed children with West syndrome attending the outpatient services of Pediatric Neurology Unit, Advanced Pediatric Center, Postgraduate Institute of Medical Education and Research, Chandigarh over 1-year period (January 2014–December 2014) were screened for eligibility. Eligible children were included in the study after obtaining informed consent from caregivers. The diagnosis of West syndrome was by a pediatric neurologist based on the clinical and compatible EEG. The magnitude and determinants of treatment lag which is the primary outcome of the study were evaluated in all these children. For further exploration of the effect of treatment lag on hormonal (adrenocorticotrophic hormone/oral steroid) therapy, the following children were excluded: (1) children who had received hormonal therapy for less than a period of 2 weeks or (2) children who had a diagnosis of tuberous sclerosis complex, inborn errors of metabolism, or who had received vigabatrin as a first-line therapy. The standard practice for hormonal therapy was to hospitalize these children for 3–5 days and initiate synthetic adrenocorticotropin hormone 40–60 IU therapy as once-daily dose via intramuscular route for 2 weeks and then tapering over 4–6 weeks. Alternative, oral steroids therapy dosing was oral prednisolone at 2–3 mg/kg/day for 2 weeks and subsequent tapering over 4–6 weeks on an outpatient basis.
The exact dates of the first practitioner visit, diagnosis of West syndrome, and initiation of therapy were recorded, and the treatment lag was calculated in days. The treatment lag was estimated as the time (days) between the onset of epileptic spasms to the initiation of hormonal therapy. This period includes the time taken to make the definitive diagnosis which was considered as the diagnostic lag in our study. The exact age of onset of spasms, if not precisely known, was rounded off to the nearest week. The treatment lag was also categorized into the following five categories: 0–30 days, 31–60 days, 61–90 days, 91–120 days, and beyond 120 days interval.
In our study, short-term response to treatment was taken as the cessation of epileptic spasms commencing within 14 days of initiation of hormonal therapy and sustained for ≥28 days from the last witnessed spasms. We have ascertained short-term response to hormonal therapy, which is a first-line therapy at our center. All cases were classified as per the International League Against Epilepsy classification into structural, genetic, or unknown. Etiological classification was attempted with help of history, review of record, available investigations, and analysis of neuroimaging data by a pediatric neurologist. We have grouped genetic and unknown cases into one group “nonstructural” for ease of analysis.
Data were analyzed by the Statistical Package for Social Sciences (SPSS) software program, version 22.0 (IBM Corporation, Armonk, NY, USA). We presented the continuous data as mean, median, standard deviation (SD) and 95% confidence interval (CI), and categorical data as proportions (percentages). For statistical analysis, Fisher’s exact test, chi-square test, and Mann–Whitney U test were used whenever appropriate. All the reported P values were two-sided, and a value of P < 0.05 was considered significant.
| Results|| |
Flow of the study
During the study period, 82 consecutive children with West syndrome were assessed. The magnitude and determinants of treatment lag were ascertained in all. To determine the effect of treatment lag on short-term response to hormonal therapy, we excluded 15 children. The reasons for exclusion were the following: received <2 weeks of hormonal therapy (n = 9), received vigabatrin as initial therapy (n = 4), and did not receive hormonal therapy (n = 2) [Figure 1].
|Figure 1: Schema of enrollment of children with West syndrome in the study|
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There was a male preponderance of 81% (n = 66) in our study. The age of the children at the time of enrolment in our study ranged from 5 to 37 months (median 12, 95% CI 12–15.7 months). The mean age at onset of epileptic spasms was 29 weeks (median 24, 95% CI 25–33 weeks). Developmental delay before the onset of epileptic spasms was present in 81% (n = 66) of children. In our study, 67 (82%) had underlying structural pathology, and 15 (18%) had non-structural (probable genetic/ unknown) etiology. Hypoxic-ischemic brain injury (n = 40, 60%), hypoglycemic brain injury (n = 10, 15%), cerebral malformations (n = 10, 15%), neonatal sepsis/meningitis (n = 15, 7%), and perinatal stroke (n = 2, 3%) formed the structural etiology. EEG findings were hypsarrhythmia in 23 children, modified hypsarrhythmia in 52 children, and other than hypsarrhythmia in 7 children.
Magnitude of treatment lag
Of 82 children, 2 had extremely long treatment lag (1060 and 1116 days) and considered outliers. Of the remaining 80 children, the median diagnostic lag was 37 days (95% CI: 56–121 days). The median duration between the diagnosis and initiation of therapy was 30 days (95% CI: 38–97 days). The median treatment lag was 90 days (95% CI: 110–198 days). The distribution of children among five categories of treatment lag were as following: 0–30 days (n = 14), 31- 60 days (n = 15), 61- 90 days (n = 11), 91- 120 days, (n = 8), and >120 days (n = 34) [Figure 2].
|Figure 2: Distribution of children with West syndrome according to treatment lag|
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Determinants of treatment lag
Misconceptions about the nature of spasms were observed among the parents of the study population [[Table 1]]. Only 29% (n = 24) of them considered initial epileptic spasms as a seizure. The median time duration between the onset of spasms to the first practitioner visit noticed in our study was 22 days (95% CI: 23–90 days). Lack of achievement of graduate education by any parent was significantly associated with an extended treatment lag (P = 0.018). Children with preexisting development delay had a considerably longer treatment lag (43 vs. 133 days; P = 0.006).
|Table 1: Characterization of treatment lag in children with West syndrome|
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Among our cohort, 56% (n = 46) of cases had a diagnosis of West syndrome mentioned on records by the first practitioner visited. Approximately 15% (n = 12) of cases had a diagnosis of cerebral palsy, and 24% (n = 20) cases had a diagnosis of nonepileptic events. Gastroesophageal reflux disease was the most common misdiagnosis as nonepileptic events in 13 (65%) of cases [Figure 3]. Other misdiagnoses were startle reaction in three children, urinary tract infection, and tremors in two children each. No specific diagnosis was mentioned in 5% (n = 5) of cases. Treatment lag also differed depending upon the qualification of the initial health-care provider. Diagnosis of West syndrome was made by 100% (n = 7) of the child neurologists seen, 67% (n = 31) of the pediatricians, and 28% (n = 7) of the general practitioners.
|Figure 3: Pie diagrams showing various diagnoses given by practitioners at first visit among the study population|
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Treatment with the antiepileptic drug was initiated in 73% of children (n = 60), with valproate being the most commonly prescribed drug in 55% (33) children. Hormonal therapy was started in nine (15%) cases as first-line therapy followed by phenobarbitone and phenytoin in seven (12%) children each, and vigabatrin was initiated in four (6%) children.
Factors affecting treatment response
Of 67 children treated with hormonal therapy (65 ACTH and 2 oral steroids), clinical cessation of spasms occurred in 47.5% (n = 39: ACTH 38 and oral steroids 1) children. Of two children who received oral steroid therapy, one child had cessation of epileptic spasms. We analyzed four factors: age of onset of spasms, etiology, treatment lag, and gender for their association with the therapeutic response [Table 2]. Our study showed that a shorter treatment lag was associated with a better cessation of epileptic spasms (P = 0.011).
|Table 2: Association of potential risk factors with short-term treatment response of hormonal therapy|
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| Discussion|| |
We observed a long treatment lag in children with West syndrome. Contributing factors were preexisting developmental delay of the children, educational status of the parents, and the qualification of initial practitioner visited. Among the multiple risk factors studied for the therapeutic response, a shorter treatment lag (<4 weeks) was associated with a favorable outcome. The majority of children were male and had underlying structural etiology.
Most of the western studies reported a treatment lag of 3–8 weeks (18). However, the median treatment lag in our study was high 90 days (95% CI: 110–198 days). Similarly, Kaushik et al. from India reported a significantly longer mean treatment lag of 7.9 (SD 7.4) months. Preexisting development delay, recognized as a patient factor attributing a long treatment lag, is explained by a preponderance of structural etiology (82%) in our cohort. Other studies from North India also reported a majority of structural etiology in their cohorts.,, A short treatment lag (<4 weeks) was observed as a favorable predictor of short-term therapeutic response. Widjaja et al., in their systematic review, reported a risk ratio of 1.52 (95% CI: 1.06–2.17) treatment lag <4 weeks vs. >4 weeks for the good neurodevelopmental outcome of eight studies.
Our study showed that pediatricians are initial contact. A knowledge, attitude, and practices survey on West syndrome among pediatricians by Vaddi et al. observed that a substantial gap is prevalent. It highlights the need to empower the pediatricians on management aspects of West syndrome who are the primary caregiver in developing countries. The recognition was more delayed in children with preexisting delay. This suggests the need of clinical surveillance of this high-risk cohort during visits for pediatricians for developmental delay and immunizations. Similarly, families of high-risk neonates may be empowered to recognize epileptic spasms by sharing teaching videos of epileptic spasms.
The strength of the study was a prospective study design. However, the limitation was a short follow-up. Our study highlights that there is a long-treatment lag for the management of West syndrome. Treatment lag emerged as a potentially modifiable predictor and need to be addressed. Further studies with a more extended follow-up period are necessary to observe the long-term impact of the treatment lag in developing countries.
Ethical policy and institutional review board statement
The study was approved by the Institute Ethics Committee.
We acknowledge all families of children with West syndrome who participated in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]