[Substitutive and dietetic approaches in childhood autistic disorder: interests and limits]. / Approches substitutive et diététique du trouble autistique de l'enfant : intérêts ou limites ?

INTRODUCTION: Autism is a developmental disorder that requires specialized therapeutic approaches. Influenced by various theoretical hypotheses, therapeutic programs are typically structured on a psychodynamic, biological or educative basis. Presently, educational strategies are recommended in the treatment of autism, without excluding other approaches when they are necessary. Some authors recommend dietetic or complementary approaches to the treatment of autism, which often stimulates great interest in the parents but also provokes controversy for professionals. Nevertheless, professionals must be informed about this approach because parents are actively in demand of it. LITERATURE FINDINGS: First of all, enzymatic disorders and metabolic errors are those most frequently evoked in the literature. The well-known phenylalanine hydroxylase deficit responsible for phenylketonuria has been described as being associated with autism. In this case, adapted diet prevents mental retardation and autistic symptoms. Some enzymatic errors are also corrected by supplementation with uridine or ribose for example, but these supplementations are the responsibility of specialized medical teams in the domain of neurology and cannot be applied by parents alone. Secondly, increased opoid activity due to an excess of peptides is also supposed to be at the origin of some autistic symptoms. Gluten-free or casein-free diets have thus been tested in controlled studies, with contradictory results. With such diets, some studies show symptom regression but others report negative side effects, essentially protein malnutrition. Methodological bias, small sample sizes, the use of various diagnostic criteria or heterogeneity of evaluation interfere with data analysis and interpretation, which prompted professionals to be cautious with such diets. The third hypothesis emphasized in the literature is the amino acid domain. Some autistic children lack some amino acids such as glutamic or aspartic acids for example and this deficiency would create autistic symptoms. However, for some authors, these deficits are attributed to nutritional deficits caused by the food selectivity of children. A fourth hypothesis concerning metabolic implication in autism is the suspicion that a food allergy phenomenon could interfere with development, and it has been observed that Ig levels are higher in autistic children than in control children. Autistic children with a positive reaction to food Ig would have a more favourable outcome with diet excluding some kinds of food; but most of those diets are drastic and ethically debatable. Fifth, glucidic catabolism could be deleterious with an excess of ketonic products that will initiate comitial seizures. Few studies with ketogenic diet have been conducted but, as it has been described with epileptic subjects, those diets would diminish autistic symptoms. Not enough studies have been conducted that would allow one to draw any firm conclusions. The sixth hypothesis is linked with vitamin deficiencies that are a notably important area of research in the treatment of autism. Vitamin B12 or B6 deficiencies have been studied in several articles, and many of them were controlled studies. French teams also emphasize an interest in supplementation with B12 or B6. The two last hypotheses concern auto-immune patterns and the toxic effects of heavy metals like mercury. There is a paucity of methodologically satisfying studies that support these two hypotheses and diet recommendations. Following these assumptions, some dietetic approaches have been recommended, even though the methodological aspects of supporting studies are poor. The most famous diet is the gluten-free and/or casein-free diet. Only two controlled studies attracted our attention. Even if for some autistic children such a diet was positive, for others, gluten-free or casein-free diets were poorly tolerated and, for some authors, not without considerable side effects, the more prejudicial of which was the Kwashiorkor risk. Ketogenic diets have been studied in one non controlled study, but even if positive results have been noted by the authors, the ketogenic diet is very restricting and the long term effects have not been evaluated. Vitamin supplementation is the one and only diet domain where there have been many repeated and placebo-controlled studies. Side effects are rare and mild even if high doses of vitamin B6 are advocated in these studies. In total, as evoked by Rimland, 11 controlled placebo-blind studies have been conducted and 50% of autistic children with this supplementation had improved autistic signs. However, these results still remain debated. Finally, more rarely, enzymatic abnormalities need specific diets which have some positive consequences, but such diets could not be applied by parents alone and are the responsibility of specialized teams. For discussion purposes we can emphasize that, in spite of the amount of studies concerning the effects of specialized diets, few are methodologically satisfying. We can not ignore that some side effects are possible with such approaches and parents need to be informed of them. Some are even potentially serious, such as diets with metal chelators. In spite of those results, vitamin supplementation seems to be the only one that some specialized teams in autism could apply, always with parent agreement. In conclusion, within this scientific field, studies on eating habits of autistic children should be conducted because of their food selectivity or avoidance.

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of carmustine (BCNU) in combination with temozolomide as first-line chemotherapy before and after radiotherapy (RT) in patients with inoperable, newly diagnosed glioblastoma multiforme (GBM). PATIENTS AND METHODS: Forty patients were treated with BCNU (150 mg/m2) on day 1 and temozolomide (110 mg/m2/day) on days 1 through 5 of each 42-day cycle for up to four cycles prior to conventional RT (2 Gy fractions to a total of 60 Gy). After RT, BCNU + temozolomide was administered for four additional cycles or until progression. The primary end point was response rate; secondary end points included progression-free survival (PFS); overall survival (OS) and safety. RESULTS: Sixty per cent of patients completed four cycles of neo-adjuvant BCNU + temozolomide. Objective response rate (intention-to-treat) was 42.5% (95% confidence interval 27% to 58%), including two (5%) complete and 15 (37.5%) partial responses. In the eligible population (n=37) the objective response rate was 46%. Nine (24%) patients had stable disease and 14 (35%) had progressive disease. Median PFS and OS were 7.4 and 12.7 months, respectively. Age was the only significant prognostic factor and tumor location (lobar versus multifocal versus corpus callosum) showed a trend. Grade 3-4 toxicities included thrombocytopenia (n=11) and neutropenia (n=7) for both pre- and post-RT chemotherapy. Four patients required platelet transfusions. No patient discontinued treatment because of toxicity. CONCLUSIONS: The combination of BCNU plus temozolomide as neo-adjuvant therapy in inoperable GBM exhibited promising activity with a good safety profile and warrants further evaluation.

[Bioequivalence and therapeutic equivalence in psychiatry]. / Bioéquivalence et équivalence thérapeutique en psychiatrie.

Many psychotropics on the market are generic forms and essentially similar products. Bioequivalence is the method used in order to demonstrate the therapeutic equi-valence between the reference drug and the new product. The principles, methods and limits of these studies are presented and illustrated by some examples for CNS drugs.

[Cytomegalovirus pneumopathies in pediatric intensive care units]. / Pneumopathies à cytomégalovirus en réanimation pédiatrique.

BACKGROUND: Cytomegalovirus (CMV) infection can result in major complications in immunocompromised infants and children. CMV pneumonia may be difficult to diagnose and the true pathogenic role of the virus in the disease is not always clear. This report describes a cohort of 20 children who suffered from CMV pneumonia. POPULATIONS AND METHODS: Twenty children aged 1 month to 11 years 10 months were admitted to our intensive care unit between 1981 and 1990 because of pneumonia with evidence of CMV infection. They were classified into three groups: group I (cases 1-10) with hemopathy or cancer, group II (cases 11-14) with AIDS, and group III (cases 15-20): non immunodeficient or immunosuppressed children. CMV infection was diagnosed after isolation of CMV from bronchoalveolar lavage (BAL) fluid (15 patients), lung biopsy revealing intranuclear inclusions or CMV antigens, or CMV-positive cultures (four patients), CMV-positive urine cultures (one patient). RESULTS: Clinical manifestations and X-rays findings were unspecific; interstitial pneumonia was found only in immunodeficient patients. CMV pneumonia was diagnosed only in two patients on post mortem examination. Concomitant pneumocystis carinii was found on BAL in two patients (group I) and two others (group II). Thirteen patients required ventilation. Eleven patients were given ganciclovir for 2 or 3 weeks; one of them was given a single dose. This treatment was well tolerated. Mortality was 90% in group I, 100% in group II and 33% in group III. CONCLUSION: Ganciclovir did not appear to benefit the immunocompromised patients with CMV pneumonia. Future treatment should include hyperimmune CMV immunoglobulins plus ganciclovir. Careful hand washing is important for all those caring for these patients to prevent contamination as is the use of CMV-negative blood products.

Venovenous single lumen cannula extracorporeal lung support in neonates. A five year experience.

The authors have developed a venovenous extracorporeal lung support technique with an original single lumen cannula to avoid the carotid ligation of venoarterial extracorporeal membrane oxygenation (ECMO). During a 5 year period, the authors have used the technique in 107 neonates (weight: 3.045 +/- 0.6 1 kg; gestational age: 38.1 +/- 2.2 weeks). All of the neonates had severe respiratory failure despite maximal conventional treatment and the same indications as those for ECMO. The venovenous technique associates extracorporeal CO2 removal and apneic oxygenation. The system includes a single lumen cannula, an alternating clamp that generates a tidal flow, and an original non-occlusive roller pump that avoids the use of a venous bladder. The PaCO2 was normal (34.6 +/- 3.9 mmHg) with a blood flow of 40-50% of the total cardiac output. Under apneic oxygenation, PaO2 improved rapidly, allowing a decrease in FiO2 and mean airway pressure, minimizing barotrauma. The mean duration of bypass was 117.8 +/- 83.9 hr, and 91 of the 107 (85%) neonates were weaned from AREC. The technical complications were less important than those associated with venoarterial ECMO. The authors conclude that AREC is as effective as venoarterial ECMO and is easier to use.

[Treatment of precocious puberty with an LH-RH agonist (D-TRP6-LH-RH)]. / Traitement des pubertés précoces par un agoniste du LH-RH (D-TRP6-LH-RH).

Chronic administration of luteinizing hormone-releasing hormone (LH-RH) is currently considered as the most appropriate therapy of precocious puberty. A delayed release preparation of D-Trp-6-LH-RH (Décapeptyl in microcapsules) designed to release the agonist for 28 days after intramuscular injection of 60 micrograms/kg body wt was given to 12 boys and 26 girls with precocious puberty. Plasma levels of gonadotropins and sex steroids were suppressed to prepubertal levels within 3 weeks, whilst pituitary responses to LH-RH test were almost abolished within 7 weeks. A significant improvement of secondary sex characteristics, as well as gonadal size, was observed within 6 months. Growth velocity (cm/yr, mean +/- SD) was reduced in boys and girls from 9.9 +/- 3.4 and 9.6 +/- 3.3 respectively before treatment to 5.2 +/- 1.0 and 5.3 +/- 1.3 respectively during the third year of treatment. The mean ratio height age/bone age was just before treatment 0.91 in boys and 0.88 in girls and increased to 1 after 3 yr of treatment. This study shows that Décapeptyl in microcapsules induced a prolonged suppression of gonadal function and a relative blockade of bone maturation. A significant improvement of adult height relative to the effect of conventional treatments should be expected.

The effects of treatment combining an agonist of gonadotropin-releasing hormone with growth hormone in pubertal patients with isolated growth hormone deficiency.

The final height of patients treated with growth hormone for isolated growth hormone deficiency has, up to now, been subnormal, with a mean below -2 SD in the series reported, an insufficient height at the onset of puberty and a more or less accelerated bone maturation during puberty being two important factors of the poor results. A long-acting analogue of gonadoliberin, Trp6-GnRH, has been given to GH-treated patients with isolated growth hormone deficiency at the time they reached pubertal stage 2, in combination with unchanged doses of GH, for one year in 11 and for two years in 7 of them. It resulted in an increase in the height age/bone age ratio and a reduction of the height insufficiency for bone age. The increase was slight but significant after one year, and fair after two years, in spite of reduced annual growth rate. Post-analogue follow-up in 5 patients with continued GH treatment showed a good development of growth and of puberty. It is concluded that combination of the long-acting Trp6-GnRH analogue and GH for 1-2 years in patients with isolated growth hormone deficiency whose puberty starts with a very insufficient height may be an appropriate way to improve their growth parameters. Studies with increased doses of GH or increased frequency of injections could help to optimize the results. Several years of follow-up are needed for demonstrating the results on final height.

Growth and precocious puberty.

Treatment of precocious puberty of central origin is aimed at controlling the development of sexual characteristics and improving final height. Increased growth rate is one of the major clinical symptoms, accompanied by an even more marked advance in bone age. Medroxyprogesterone acetate and cyproterone acetate have provided almost satisfactory control of pubertal characteristics, but with accompanying adrenal insufficiency. The data with regard to growth and bone maturation are contradictory. LHRH analogues have recently become available, and provide good control of gonadotrophin secretion. In a series of 21 cases (13 girls, 8 boys), a significant decrease in growth rate was achieved in both sexes with an LHRH analogue, with a significant increase in the height age/bone age ratio; control of gonadal secretions was also obtained. These results are only preliminary, but provide hope that the final height of these children will be improved.

[Comparison of 2 modes of treatment of diabetic ketoacidosis in children]. / Comparaison de deux modes de traitement de l'acidocétose diabétique de l'enfant.

In two groups of children with diabetic ketoacidosis, the effects of intramuscular insulin injections associated with intensive rehydration and alkalisation were compared with low-dose continuous intravenous infusion associated with well-controlled fluid and electrolyte therapy. Although correction of ketoacidosis was as effective with both methods, the second appeared to offer several advantages: 1. More progressive normalization of metabolic parameters; 2. Reduced risks of hypoglycemia and hypokaliemia; 3. Easier control of the decrease in plasma glucose levels; 4. Better correction of hyponatremia; 5. More gradual increase in pH values. These results confirmed that low-dose continuous insulin infusion with proper monitoring of fluid and electrolyte replacement was a safe, simple and effective treatment of diabetic ketoacidosis in children.

[Treatment of diabetes in children under 3 years of age. Indications, methods and results]. / Traitement du diabète de l'enfant de moins de 3 ans. Indications, méthodes et résultats.

Before modern methods of diabetes management were available, the achievement of strict glycemic control was considered almost impossible in most children with early onset of the disease. The present results obtained over 2 years in 31 children aged 21 +/- 2 (SEM) months at the onset of the disease indicate the efficiency of intensive conventional therapy in 21 of them: glycosylated hemoglobin averaged 7.0 +/- 0.3% (N = 4.7 +/- 0.7%) during the observed 26 +/- 7 months, with only 0.02 +/- 0.01 hypoglycemic attack per patient-month and no diabetic ketoacidosis. In the remaining 10 children, who resisted intensive conventional therapy, we used insulin pumps to improve blood glucose control, with the following results over 21 +/- 4 months: Glycosylated hemoglobin decreased from 9.3 +/- 0.3% (before pump) to 8.0 +/- 0.4% (p less than 0.05). The frequency of hypoglycemia decreased dramatically from 1.7 +/- 0.7 to 0.03 +/- 0.01 episode per patient-month. The frequency of ketonuria and ketoacidosis was unchanged. We concluded that intensification of therapy through conventional means, or pump treatment if necessary, allows a long term efficient control of blood glucose in preschool children.

Treatment of precocious puberty with a long-acting preparation of D-Trp6-LHRH.

D-Trp6-LHRH was tested in 6 girls 1-8 years old and 7 boys 2-10 years old with precocious puberty. All children had advanced bone age, breast or testis enlargement and a pubertal LH response to LHRH. 60 micrograms LHRH-A/kg body weight was given intramuscularly on days 1 and 21 and thereafter every 4 weeks for 6-21 months. In girls, breast enlargement disappeared and mean uterus size decreased within 6 months. Mean ovary length decreased from 25.0 +/- 1.9 to 16.0 +/- 2.7 (p less than 0.02). In boys, mean testis volume decreased from 8.0 +/- 1.1 to 6.7 +/- 1.4 ml (p less than 0.05) within 6 months. In both sexes, growth velocity decreased significantly and bone maturation was reduced. Plasma levels of estradiol or testosterone and FSH levels decreased significantly within 3 weeks. The LH response to LHRH was reduced to normal prepubertal values after 7 weeks. No secondary clinical or biochemical escape occurred. No side effects occurred except for transient vaginal bleeding in one girl after the first and second injection. No antibodies to LHRH-A were detected in the patients' sera. This study demonstrates the ability of a delayed release formulation of D-Trp6-LHRH to suppress pituitary and gonadal secretion and pituitary response to LHRH for as long as 2 years of therapy. This treatment appears to be more efficient in treating both clinical and biochemical abnormalities than does treatment with inhibitory steroids. Additionally the method of administration is more practical and ensures better patient compliance.