Myron Genel

Pharmacologic Management of Insomnia in Children and Adolescents: Consensus Statement

OBJECTIVE. The purpose of this work was to develop a consensus statement on the current status and future role for pharmacologic management of insomnia in children and adolescents. METHOD. The National Sleep Foundation, in collaboration with Best Practice Project Management, Inc, convened expert representatives involved in the study and treatment of pediatric insomnia and conducted a 2-day conference to examine the role of pharmacologic management of pediatric insomnia and to make recommendations regarding the development of clinical trials in this area. After a series of presentations providing background on the current knowledge of pediatric insomnia and its treatment alternatives, workgroups provided recommendations for the evaluation of pharmacologic treatment of insomnia in specific populations of children and adolescents and developed guidelines for the core methodologic issues relevant to the design of clinical trials. The group developed consensus recommendations for clinical trials in this area encompassing: (1) high-priority patient populations for research, (2) inclusion/exclusion criteria, (3) outcome measures, (4) ethical considerations unique to clinical trials involving children and adolescents, and (5) priorities for future research that will enhance the understanding of pediatric insomnia. RESULTS. Conference participants unanimously agreed that there is a need for pharmacologic management of pediatric insomnia. Furthermore, the widespread use of “hypnotic” and psychotropic medications for children in the absence of safety and efficacy data indicates a knowledge gap about the best pharmacologic practices for management of pediatric insomnia. Attendees reached consensus on methodologic issues in the study of pharmacologic treatment of pediatric insomnia including agreeing on a definition of pediatric insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.” It was agreed that priority should be given to insomnia studies in children with attention-deficit/hyperactivity disorder and those with pervasive developmental disorders/autism spectrum disorder. There was also agreement on the need for pharmacokinetic and pharmacodynamic studies to determine appropriate dose levels and to evaluate safety with a wide range of doses. CONCLUSIONS. The treatment of pediatric insomnia is an unmet medical need. Before appropriate pharmacologic management guidelines can be developed, rigorous, large-scale clinical trials of pediatric insomnia treatment are vitally needed to provide information to the clinician on the safety and efficacy of prescription and over-the-counter agents for the management of pediatric insomnia.

RESTORATION OF NORMAL LIPID AND AMINOACID METABOLISM IN DIABETIC PATIENTS TREATED WITH A PORTABLE INSULIN-INFUSION PUMP

To determine whether abnormalities of lipid and aminoacid metabolism observed in diabetes are corrected when plasma-glucose levels are restored to normal, eight insulin-dependent diabetics were treated for 7-14 days with a portable infusion pump which delivers insulin subcutaneously in basal (between-meal) doses with pulse-dose increments before meals. Mean plasma-glucose (206 +/- 24 mg/dl during conventional insulin treatment) fell to 89 +/- 3 mg/dl at day 7 and 84 +/- 2 mg/dl at day 14 of pump treatment; glycosuria was eliminated. Plasma cholesterol, triglycerides, and free fatty acids were elevated during conventional insulin treatment but fell to normal after 7 days of pump treatment. Plasma-levels of branched-chain aminoacids were 50-60% above control levels during conventional treatment but fell to normal after 7 days of pump therapy. Aminoacids were reduced from their high postprandial levels to normal values after insulin-pump treatment. In addition to restoring plasma-glucose to normal, treatment of diabetes with a portable insulin-infusion system results in restoration of normal lipid and aminoacid metabolism. Long-term use of this system may determine whether metabolic changes resulting from insulin lack cause the complications of diabetes.

Insulin-Infusion-Pump Treatment of Diabetes: Influence of Improved Metabolic Control on Plasma Somatomedin Levels

We examined whether changes in somatomedin accompany those seen in glucose and growth hormone during treatment with the insulin-infusion pump. somatomedin levels in eight insulin-dependent diabetics (13 to 29 years of age) were measured before and after 16 weeks of outpatient insulin-pump treatment, which lowered mean glucose from 245 +/- 21 to 100 +/- 5 mg per deciliter and total glycosylated hemoglobin from 16.2 +/- 1.2 to 9.7 +/- 0.3 per cent (mean +/- S.E.M.). During conventional insulin therapy, both total somatomedin and somatomedin C were within the normal range, despite elevations in growth hormone. Pump treatment resulted in a 70 to 75 per cent increase in both total somatomedin and somatomedin C (P less than 0.05) and a fall in growth-hormone concentrations. In the two growing adolescents, growth velocity doubled during 13 to 15 months of pump treatment. Our data suggest that the improved insulin delivery or metabolic control increases somatomedin levels despite a decrease in growth hormone. Thus, insulin-pump treatment may be useful in optimizing growth in diabetic children.

Normalization of the Growth Hormone and Catecholamine Response to Exercise in Juvenile-Onset Diabetic Subjects Treated with a Portable Insulin Infusion Pump

The plasma growth hormone, epinephrine, and norephinephrine responses to cycle ergometer exercise (15 min at 1 W/kg) were examined in 10 juvenile-onset, insulin-dependent diabetics (ages 10–32 yr) during conventional insulin treatment and after 7 and 14 days of treatment with a portable subcutaneous insulin infusion system that normalizes plasma glucose. During conventional insulin treatment (mean plasma glucose, 205 ± 22 mg/dl), the growth hormone response to exercise was sevenfold greater than in normal controls (P < 0.01). After 1 wk of insulin pump treatment (mean plasma glucose, 89 ± 3), the growth hormone response fell 62% (P < 0.001); by 2 wk the growth hormone response had fallen 83% (P < 0.001) to values comparable to those of controls. Exercise resulted in a two- to threefold rise in plasma epinephrine in diabetics (P < 0.001) during conventional treatment but failed to elicit a consistent increment in epinephrine in normal control subjects or in the diabetic patients after 14 days of pump treatment. The rise in plasma norepiriephrine after exercise in conventionally treated diabetic patients was 12-fold greater than in healthy control subjects (P < 0.025) but fell 82% (P < 0.001) after 7 days and 88% (P < 0.001) after 14 days of pump treatment to values similar to those of controls. These data indicate that treatment of insulin-dependent diabetics with a subcutaneous portable insulin infusion system that normalizes plasma glucose results in normalization of the growth hormone and catecholamine response to exercise within 7 to 14 days of institution of treatment.

Outpatient treatment of juvenile-onset diabetes with a preprogrammed portable subcutaneous insulin infusion system

Seven patients with juvenile-onset, insulin-dependent diabetes (aged 13 to 32 years) were continuously treated for 12 to 32 weeks while out of the hospital in their usual environment with a portable, battery-powered infusion pump which delivers insulin subcutaneously in basal (between-meal) doses with pulse dose increments before meals. Mean blood glucose levels (237 +/- 28 mg/dl during conventional insulin therapy) fell to 105 +/- 5 mg/dl after four weeks of pump treatment (p less than 0.01) and were maintained at 80 to 104 mg/dl as pump treatment was continued beyond eight weeks. Glycosylated hemoglobin levels (16.0 +/- 1.5 per cent before pump therapy) also fell within two weeks (p less than 0.01) reaching normal values (9.9 +/- 0.3) after eight weeks of pump therapy. Mean plasma cholesterol and triglyceride levels were elevated during conventional therapy and fell to normal after pump treatment. After the first month of pump treatment, only minor adjustments in insulin dose (less than 5 per cent of total daily dose) were made. No episode of mechanical pump failure occurred during the 1,110 patient-days of treatment. Overinsulinization and underinsulinization due to human error were relatively rare (four and six episodes, respectively) and failed to result in symptoms of hypo- or hyperglycemia. All patients performed their usual home, work or school activities during pump treatment. We conclude that normalization or near normalization of blood glucose levels can be achieved with a portable subcutaneous insulin infusion system when continuously used to treat patients with juvenile-onset, insulin-dependent diabetes outside the hospital for three to eight months.

Evidence for defective immunoregulation in the syndrome of familial candidiasis endocrinopathy.

We studied three children with candidiasis endocrinopathy syndrome, together with their parents and five siblings, to explore the possibility that defective immunoregulation allows autoimmune phenomena to be involved in the pathogenesis of this syndrome. Inheritance of the syndrome appeared to be autosomal recessive. Immunologic abnormalities in this family included hypergammaglobulinemia, selective IgA deficiency, anergy, autoimmune endocrinopathies and active chronic hepatitis. Defective suppressor T-cell function was noted in the two surviving children with clinically apparent disease and in a clinically normal sibling. Analysis of the immunologic abnormalities in the family suggests that defective immunoregulation rather than disordered effector mechanisms may explain the large number of immunologic defects noted. These defects, in turn, may result in the clinical manifestation of the syndrome.

Ethylmalonic-adipic aciduria. In vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases.

The mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-(14)C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-(14)C]lysine and [2-(14)C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation of these three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the case of glutaric aciduria type II. Because activities of multiple acyl-CoA dehydrogenases are reduced, a deficiency of electron-transferring flavoprotein, which serves as a hydrogen-acceptor for these dehydrogenases, is postulated as the underlying mechanisms of these two diseases, but a genetic heterogeneity was indicated by significant differences in the residual activities in these two types of cells. The hypothesis of more than one mutant allele of an autosomal recessive gene was also suggested by the study on cells from asymptomatic members of the family.

DAX1 Mutations Map to Putative Structural Domains in a Deduced Three-Dimensional Model

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.

Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, type IIA : Implications for therapy

A girl 5 years 11 months of age, belonging to an extensive kindred with multiple endocrine neoplasia, type IIA (MEN IIA), was found to have multifocal medullary thyroid carcinoma with metastasis in one paraglandular lymph node after positive findings on a calcium-pentagastrin stimulation test. Her sister, 3 years 8 months of age, also had an elevated calcitonin level, and thyroidectomy revealed C-cell hyperplasia and a focus of medullary thyroid carcinoma. These two cases underscore the need for prophylactic thyroidectomies in MEN IIA patients as young as 5 years of age and strict yearly provocative screening beginning at age 1 year.

Effect of intensive insulin treatment on linear growth in the young diabetic patient

Although impaired growth is a well-recognized complication of uncontrolled diabetes, it has not been established whether less severe metabolic derangements commonly seen with conventional treatment adversely affected growth potential. To examine this question, growth velocity was measured in nine type 1 diabetic patients (age 14 +/- 3 years) before and after six months of intensive insulin treatment either with the insulin pump or with multiple injections, which lowered mean plasma glucose concentration from 270 +/- 96 to 105 +/- 55 mg/dl and total glycosylated hemoglobin from 12.4 +/- 3.0 to 8.4 +/- 1.5% (mean +/- SD). During conventional treatment, growth velocity (5.3 +/- 2.2 cm/year) was within the range of normal despite elevations in plasma glucose concentrations. However, growth velocity increased sharply during intensive treatment (to 9.4 +/- 3.9 cm/year, P less than 0.005), reaching values in excess of normal in seven patients. The increase in growth velocity observed during intensive treatment was associated with a twofold rise in plasma somatomedin-C values. Skeletal maturation, previously normal or slightly delayed, did not advance excessively. These data indicate that the metabolic changes accompanying intensive treatment may enhance growth in diabetic children, even in those with apparently normal growth velocity during conventional therapy.