Cardiometabolic outcomes in children and adolescents with West syndrome

The cardiometabolic characteristics of patients with West syndrome from infancy through early childhood to childhood/adolescence have not been addressed. In this observational study, patients with West syndrome exhibited increased rates of obesity, elevated BP, and dyslipidemia (hypertriglyceridemia and elevated TG:HDL-c ratios). Infants with West syndrome who were treated with ACTH were characterized by higher weight and weight-to-length values, albeit within the normal range, and higher TG levels compared to infants with West syndrome who did not receive ACTH. These differences in metabolic characteristics between treatment groups became less evident during early childhood and childhood/adolescence.

Although the proportion of preterm births among our entire cohort was high relative to normal values, most of the pregnancies were uncomplicated and had followed spontaneous conception in healthy mothers, leading to appropriate birth weights and suggesting that the in-utero environment was non-contributory. It would appear, therefore, that the weight gain during infancy and childhood was most likely related to exposure to postnatal factors. One-quarter of our study infants with West syndrome were categorized as being obese. Moreover, infants who received ACTH treatment weighed more and had normal adjusted weight-to-length ratios compared to those who were not treated with ACTH and were underweight. The lower weight status in the non-ACTH treated group could stem from their medical complexity leading to poor oral intake. However, the finding that weight status during early childhood and during childhood and adolescence did not differ between the groups suggests that the ACTH treatment contributed to the weight gain observed in the ACTH-treated group during infancy, which masks their lower weight status. Weight gain in infants with West syndrome during the course of ACTH treatment which resolved following cessation of therapy has been reported in several studies [22, 23]. In contrast, weight gain was observed after the cessation of ACTH treatment in our study cohort. Preterm birth was more frequent in the children who did not receive ACTH treatment, but prematurity is a less plausible explanation for our finding since anthropometric measurements were adjusted for gestational age. Moreover, the differences in weight cannot be attributed to the underlying etiologies since the distribution was similar between treatment groups. Thyroid function was within the normal range, thereby not supporting it having any role in weight gain.

Hypertension (HTN) was observed in the majority of infants with West syndrome. Others have reported a link between preterm birth and elevated BP levels that had been detected as early as infancy [24, 25]. It is plausible that prematurity may contribute to the elevated BP levels observed in the current work, but it could not be the sole explanatory factor since only ~ 30 % of the children were born preterm. Notably, although the vital signs were measured by registered nurses who specialize in pediatrics, it is possible that some of the measurements were spuriously elevated due to suboptimal conditions (crying toddlers, emergency room setting). ACTH therapy for the indication of infantile spasms has been reported to cause HTN [23, 26], but it could not be the sole cause of elevated BP observed in our study since BP levels were similar between the treatment groups. HTN was less evident in childhood and adolescence during which there was a normal distribution of diastolic BP values. BP was not monitored in all of the studied children, which may have led us to underestimate the incidence of HTN among children with West syndrome who had and had not been treated with ACTH. Despite significant concerns about side effects of ACTH therapy, including HTN and cardiomyopathy, there are no evidence-based guidelines to assist in the monitoring and management of these adverse effects.

Many of the patients in the current study had evidence of dyslipidemia; hypertriglyceridemia during infancy, as well as a high TG:HDL-c ratio from infancy through childhood/adolescence, although the dyslipidemia became less prominent over time. There is convincing evidence to suggest that the origins of atherosclerosis begin in childhood and that lipid abnormalities contribute to this process [19, 27]. A high TG:HDL-c ratio is associated with arterial stiffness in children and adolescents [13], and it indicates an atherogenic lipid profile and predicts the risk for development of extensive coronary disease in adults [28, 29]. Patients with epilepsy may exhibit dysregulation of thyroid functions which may impact serum lipid levels [30], however, thyroid functions were within the normal range and were unlikely to cause dyslipidemia among our study patients. Despite the efficacy of therapies, such as ACTH, many children with West syndrome will relapse and can develop other seizure types. As such, neurologists may consider selection of other anti-seizure medications and exploration of dietary interventions. Treatments that may be associated with hypertriglyceridemia include antiepileptic drugs (e.g., valproic acid, carbamazepine), and the ketogenic diet [31‐33], and carbamazepine and other antiepileptic drugs have been associated with high HDL-c levels as well [31, 33]. Treatment of tuberous sclerosis complex with everolimus or sirolimus is a potential cause of dyslipidemia [34], however, none of the patients in the current study were treated with these drugs. Prematurity may also be associated with dyslipidemia later in life, but probably not with changes in triglyceride or HDL-c levels [24]. One study did find high TG levels in adolescent boys who were born preterm [35]. These explanations could account for some of our findings at best. TG levels were higher in infants and children treated with ACTH, compared to those who were not. Taken together, these findings suggest a possible link between ACTH treatment and hypertriglyceridemia.

The major limitations of this study are its retrospective nature and the relatively small sample size. Some of the data extracted from the medical files relied on the parent-reported information, such as perinatal history, and physicians documented, such as dosage and duration of the administered treatment. Yet, access to the patient’s comprehensive HMO medical files contributed to the clinical and laboratory data, medications prescribed, and thus limits information bias. Moreover, growth parameters and cardiometabolic assessment were not available for the entire cohort, introducing ascertainment bias. Notably, more data were missing for the non-resident study participants who comprised the larger proportion of the group that had not received ACTH treatment. In addition, BP measurements were obtained in several different care settings without standardized methods.

Despite these limitations, our tertiary care center serves all sectors of the Israeli population including varied ethnic origins and socio-economic position, therefore this study should be representative of the Israeli population, apart from an under-representation of patients from the Arab sector.

In conclusion, our findings suggest that children with West syndrome have an increased prevalence of acute and subacute cardiometabolic derangements (obesity, HTN, and dyslipidemia), which are more pronounced during infancy and in ACTH-treated patients. An optimistic interpretation of our findings may be the transitory nature of the metabolic derangements. Still, they highlight the need to monitor these children at risk for cardiometabolic derangements, given that the origin of atherosclerosis begins in childhood and adolescence. The health implications in adulthood of cardiometabolic derangements during critical periods of growth and development have yet to be elucidated and warrant further investigation.