Elsevier

Pediatric Neurology

Volume 28, Issue 2, February 2003, Pages 130-133
Pediatric Neurology

Original article
Topiramate effectiveness in Prader-Willi syndrome

https://doi.org/10.1016/S0887-8994(02)00490-3Get rights and content

Abstract

Prader-Willi syndrome is a neurologic disorder caused by a mutation on chromosome 15. It is characterized by short stature, obesity, mild-to-moderate mental retardation, and multiple behavior problems including mood, self-abusive behavior, and compulsive-eating disorder. These behaviors have detrimental effects on the mental and physical health of patients with Prader-Willi syndrome. This study evaluates the effectiveness of a new antiepileptic medication, topiramate, on behavior, mood, and compulsive-eating disorder associated with Prader-Willi syndrome. Recent studies have indicated that topiramate affects behavior, as well as reducing appetite and weight in some patients. We evaluated seven patients with Prader-Willi syndrome and determined that, in these patients, topiramate appeared to have a positive effect on reducing self-abusive behavior, improving mood, and stabilizing weight.

Introduction

Prader-Willi Syndrome (PWS) is a neurologic disorder that was first described by Prader, Labhart, and Willi in 1956 [1]. The clinical manifestations include, but are not limited to, variable degrees of mental subnormality, infantile hypotonia, and neuroendocrinologic abnormalities. Also associated with PWS are mood and behavioral problems, self-abusive behavior, and a compulsive-eating disorder, often resulting in gross obesity. Patients with PWS typically have small hands and feet, almond-shaped eyes, and fair skin and hair. It has been determined that PWS is caused by a deletion on chromosome 15, in the q11-q13 region, or a uniparental disomy, in which there are two copies of the maternal chromosome 15 [2].

Controlling behavior in children with PWS is a difficult challenge for families, with many children requiring a complex regimen of behavioral modification and medications. The uncontrolled behavior, including obsessive-compulsive behavior, aggression, and self-abuse, are present in most patients, along with an overeating disorder. The compulsive overeating has substantial, long-term implications for patients with PWS, including a greater risk for diabetes, hypertension, and cardiovascular disease, along with the effects on self-esteem and social development. Most patients and families try behavioral modification, caloric restriction, exercise programs, and medication in an attempt to control appetite. These routines are often met with poor compliance and limited success. If diet and weight could be controlled, then the quality of life and health of these patients would be vastly improved.

The mechanism of the compulsive-eating component of PWS is not well understood. It has been suggested that it relates to the obsessive-compulsive behavior associated with PWS [3]. However, recent publications suggest that a dysfunction in hypothalamic pathways may affect the appetite in patients with PWS [4], [5]. It may be that patients with PWS have disrupted chemical pathways in the hypothalamus, affecting its normal influence over hunger and satiety to control eating. If this is the case, then drugs with central nervous system effects may be of benefit in this disorder by acting on the hypothalamus and controlling satiety.

Topiramate is a relatively new antiepileptic drug with many possible mechanisms of action on the central nervous system that has also been shown to have effects on behavior and appetite. Some mechanisms that have been proposed for topiramate are that it modulates voltage-activated sodium channels, enhances gamma-aminobutyrate (GABA)-mediated inhibition by effecting GABA-A receptor sites, and blocks kainate/α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) type glutamate receptors [6].

Recent literature suggests that in addition to its anti-epileptic effect, topiramate may also have positive benefits in controlling binge-eating, bulimia nervosa, and obesity, as well as improving mood [7], [8], [9], [10]. It has been noted that topiramate is associated with weight loss in patients treated with seizure disorders [6]. In preclinical and recently published studies conducted in rats, topiramate has been found to reduce energy gain and fat deposition, decrease food intake, and increase energy expenditure (independent of one another), increase lipoprotein lipase activity in adipose tissue, and reduce circulating levels of leptin and corticosterone. Finally, topiramate effects on the glutamatergic system may also lead to weight loss. Review of the rat studies suggests that topiramate may influence numerous mechanisms in the regulation of energy balance that are potentially attributable to its weight loss effects [11], [12].

The observed action of topiramate on satiety and weight loss is unclear. It could be tolerability and effectiveness of topiramate on mood, behavior, and compulsive eating in patients with Prader-Willi syndrome.

Section snippets

Materials and methods

This investigation was an open-label study in which topiramate was administered to patients with an established diagnosis of PWS. All patients were known to have PWS, confirmed by genetic studies to have either a maternal uniparental disomy or a deletion on the paternal chromosome region 15q11-q13, with one patient having a rare Robinsonian translocation of chromosomes 13 and 15. All patients had undergone an appropriate trial of behavioral management, dietary restrictions, and exercise

Results

Side effects occurred in three patients who experienced increased somnolence. One patient’s symptoms resolved with time without altering the dose. The other patients’ symptoms resolved by changing the dosing schedule and reducing the dose.

All seven patients who continued on the drug were found to have a positive change in mood. Improvement in mood, as reported by the parents, included increased interactions with family, friends, and other children as well as increased self-esteem.

All seven

Discussion

This trial was undertaken to evaluate whether topiramate could benefit PWS patients by weight reduction or stabilization and improve behaviors. These results indicate a benefit to all patients in regards to weight, with treatment resulting in weight loss or a reduction in weight gain. The behavioral benefit for these patients was significant as well, with all patients or parents reporting improved mood, less aggression, less obsessive-compulsive behaviors, and in general, more controlled

Acknowledgements

This work was supported in part by an educational grant from Ortho-McNeil Pharmaceutical, Inc.

References (16)

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