Søren A. Pedersen

Long-term study of gamma-vinyl GABA in the treatment of epilepsy

ABSTRACT – The purpose of this study was to investigate the long‐term efficacy and tolerability of gamma‐vinyl GABA (GVG) in the treatment of epilepsy. 36 patients with severe therapy resistant epilepsies participated, the majority exhibiting complex partial seizures. The mean follow‐up period was 9.3 months. GVG was administered as add‐on therapy, to keep serum levels of concomitant treatment constant. The mean dose of GVG was 2.6 gs per day.

Effects of Growth Hormone Replacement Therapy on IGF-Related Parameters and on the Pituitary-Gonadal Axis in GH-Deficient Males

It has been suggested that growth hormone (GH) may play a regulatory role in male reproductive function. To express full anabolic effect in immature boys testosterone apparently requires the presence of GH. In GH-deficient adults, GH replacement therapy exerts a variety of anabolic actions, some of which are similar to the effects of gonadal steroids. However, little is known about the potential effects of GH on gonadal steroids and on dynamic tests of pituitary-gonadal function in adults with GH deficiency. We evaluated the pituitary-gonadal axis in a 4-month double-blind, placebo-controlled GH study in 13 young males with childhood-onset GH deficiency of which 6 had isolated GH deficiency. GH treatment significantly increased serum levels of total IGF-I from 98 (68) to 323 (126) µg/l, free IGF-I from 0.48 (0.47) to 2.24 (1.66) µg/l, IGFBP-3 from 1,874 (1,178) to 3,520 (778) µg/l and ALS levels from 9,182 (5,524) to 16,872 (6,278) µg/l (all p < 0.0001). We found no differences in basal testosterone levels in the 13 patients between the GH and placebo treatment periods (21.9 (5.1) vs. 24.5 (8.1) nmol/l, nonsignificant). Furthermore, no effect of GH on the testicular response to hCG after 72 h was seen compared to placebo (36.2 (6.4) vs. 38.8 (10.3) nmol/l). In addition, no differences existed in basal SHBG, DHT, free testosterone, Δ4-adion and DHEA-S levels. There were no statistically significant differences in maximal FSH and LH response to a GnRH challenge between the GH and the placebo periods (15.7 (5.3) vs. 18.0 (8.8) U/l and 47.0 (26.4) vs. 40.4 (26.5) U/l, respectively). Furthermore, there was no effect on cortisol responses after ACTH between the GH and the placebo periods. However, significantly higher estradiol levels were seen after GH treatment (110 (50) pmol/l) compared to after placebo (89 (34) pmol/l, p = 0.03). Prostate-specific antigen levels decreased after GH treatment compared to after placebo (0.42 (0.54) vs. 0.47 (0.48) µg/l) and this difference almost reached statistical significance (p = 0.059). Inhibin-B levels were significantly lower in hypogonadal patients substituted with androgens, but GH had no effect on inhibin-B levels. In conclusion, GH replacement therapy in 13 GH-deficient young adult males resulted in significant increases in total and free IGF-I as well as in ALS levels in all patients, but had no significant effect on: (1) the pituitary FSH and LH response to GnRH; (2) basal and hCG-stimulated levels of androgens and SHBG; (3) basal inhibin-B levels; (4) ACTH-stimulated cortisol secretion. By contrast, GH administration had subtle anti-androgenic effects in terms of elevated elevated estradiol levels and decreased prostate-specific antigen levels, although both parameters remained within the normal range. Thus, at the level of blood chemistry the effects of GH administration do not appear to involve major alterations in the pituitary-gonadal axis.

Threshold electrical stimulation (TES) in ambulant children with CP: a randomized double-blind placebo-controlled clinical trial

A randomized double‐blind placebo‐controlled clinical trial was carried out to determine whether a group of stable children with cerebral palsy (36 males, 21 females; mean age 10 years 11 months, range 5 to 18 years) would improve their motor skills after 12 months of threshold electrical stimulation (TES). Two thirds received active and one third received inactive stimulators. For the primary outcome we constructed a set of plausible motor function tests and studied the change in summary indices of the performance measurements. Tests were videotaped and assessed blindly to record qualitative changes that might not be reflected in performance measurements. We also judged range of motion, degree of spasticity, and muscle growth measured by CT. Fifty seven of 82 outpatients who were able to walk at least with a walker, completed all 12 months of treatment (hemiplegia n=25, diplegia n=32). There was no significant difference between active and placebo treatment in any of the tested groups, nor combined. Visual and subjective assessments favoured TES (ns), whereas objective indices showed the opposite trend. We conclude that TES in these patients did not have any significant clinical effect during the test period.

The insulin–like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

Serum concentrations of growth hormone–dependent insulin–like growth factor I (IGF–I) and insulinlike growth factor binding protein–3 (IGFBP–3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross–linked telopeptide of type I collagen (ICTP) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double–blind treatment periods (200 and 800 μg) and one open, non–randomized treatment period (400 μg). All periods were 18 days’duration. Budesonide treatment was associated with a dose–related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included (p < 0.01; z =–2.7) and when it was excluded from the calculations (p < 0.01; z =–2.6), indicating reduced synthesis of type III collagen. A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations (p= 0.05; z =–1.9). No other statistically significant variations were seen.

GH-Replacement Therapy in Adults

Growth hormone (GH) deficiency in adults, whether GH deficient since childhood or patients rendered GH deficient in adult life, is associated with psychosocial maladjustment, reduced muscle strength and reduced exercise capacity. Body composition is significantly altered with increased fat and decreased muscle volume as compared to healthy subjects. Kidney function is subnormal, and so is sweat secretion. Epidemiological data suggest premature mortality due to cardiovascular disease in hypopituitary patients. Short-term GH treatment trials have shown improved psychosocial performance, normalization of body composition, increased muscle strength, improved exercise capacity, increased cardiac performance and increase in bone mineral mass as well as in serum markers of bone turnover, and normalization of kidney function. Thus GH replacement therapy in GH-deficient adults exhibits potential long-term beneficial effects. A number of important questions has to be addressed before long-term GH replacement therapy in GH-deficient adults can be considered on a routine basis.

Impact of protein energy malnutrition on Trichuris suis infection in pigs concomitantly infected with Ascaris suum.

The objective of this experiment was to investigate a possible interaction between protein and energy malnutrition (PEM) and intestinal nematode infections. We report on a 3 x 2 factorial study in which pigs were fed either a low protein energy (LPE), low protein (LP) or a normal protein energy (NPE) diet, and 6 weeks later inoculated with Trichuris suis (4000 infective eggs). Secondarily, in order to obtain a polyparasitic status, pigs were concomitantly inoculated with Ascaris suum (600 infective eggs). The number of T. suis-infected pigs was higher in LP pigs compared with NPE pigs (100 versus 58%; P = 0.037), although the differences in median T. suis worm burdens between groups at necropsy 10 weeks post-infection (p.i.) (LPE: 795; LP: 835; NPE: 48 worms; P = 0.33) were not significant. Interestingly, only T. suis in NPE were highly aggregated (k = 0.44), in contrast to a more uniform distribution among pigs in LPE (k = 1.43) and LP (k = 1.55) i.e. the majority of pigs harboured moderate worm burdens in LPE and LP, while most pigs had few or no worms in NPE. Further, T. suis worms in the LPE and LP groups were decreased in length (mean: LPE: 23.5 mm; LP: 24.3 mm; NPE: 29.4 mm; P = 0.004). The pre-patency period of T. suis was also extended in the LPE and LP groups, as reflected by lower faecal egg output at week 6 (P = 0.048) and/or 7 p.i. (P = 0.007). More A. suum worms were recovered from LP compared with the NPE group (mean: 5.4 versus 0.6; P = 0.040); this was accompanied by a higher faecal egg output in the former (P = 0.004). The low protein diets resulted in lower pig body weight gains, serum albumin, haemoglobin and packed cell volume (PCV) levels as well as diminished peripheral eosinophil counts. Infection significantly altered these parameters in the low protein groups, i.e. the pathophysiological consequences of infection were more severe in the PEM pigs. These results demonstrate that reduced protein in the diet leads to malnourishment of both the host pigs and T. suis, and compromises the pigs ability to resist infection by T. suis and A. suum.

Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study

Tiagabine, a specific gamma-aminobutyric acid-uptake inhibitor, has been shown to be reasonably well tolerated and efficacious as adjunctive treatment for partial seizures in adults and is now being investigated in children. This 4-month, single-blind study evaluated the tolerability, safety and preliminary efficacy of ascending doses (0.25-1.5 mg/kg/day) of tiagabine add-on therapy in 52 children over the age of 2 years with different syndromes of refractory epilepsy. Adverse events, mostly mild to moderate, were reported by 39% of children during the single-blind placebo period and by 83% of children during tiagabine treatment. The events predominantly affected the nervous system with asthenia (19%), nervousness (19%), dizziness (17%) and somnolence (17%) being the most common. Only three children (6%) withdrew because of adverse events. Tiagabine appeared to reduce seizures more in localisation-related epilepsy syndromes than in generalised epilepsy syndromes. Twenty-three patients with localisation-related epilepsy syndromes were included and 17 of these patients entered the fourth dosing period. The 17 patients had a median reduction of seizure rate in the fourth month of treatment of 33% compared with baseline. In comparison, 13 of 22 children with seven different generalised epilepsy syndromes entered the fourth dosing period with a median change of seizure rate of 0%. Two patients experienced single episodes of status epilepticus during treatment; both cases resolved. Tiagabine showed efficacy mainly in localisation-related syndromes and was well tolerated by most children in a group of very refractory patients and warrants further study in children with epilepsy.

Effect of iron deficiency on Trichuris suis and Ascaris suum infections in pigs

The objective of this experiment was to detect a possible interaction between iron deficiency and intestinal nematode infections. We report on a 2 x 2 study where thirty-one 10-week-old pigs fed a low or a normal iron diet were infected with both Trichuris suis (4500 eggs) and Ascaris suum (1200 eggs). No significant difference was detected between diet groups with respect to parasitological parameters for A. suum or the total number of adult T. suis recovered at necropsy 10 weeks p.i. However, in the low iron group T. suis were located more proximally and the worms were increased in length. A higher proportion of pigs with initial faecal egg excretion at 6 weeks p.i. was observed in the low iron group, indicating a shortened pre-patency period. Worm fecundity and total faecal egg excretion were also highest in the low iron group. A significant correlation was found between female worm length and fecundity. The peripheral eosinophil counts were diminished in the low iron host groups. The infected low iron group experienced more severe pathophysiological changes in terms of hypoalbuminaemia and decreases in erythrocyte volumes. A significant inverse correlation existed between iron content in the bone-marrow and liver (body) store. In conclusion, iron deficiency increased the severity of T. suis infection in pigs.

Marginal vitamin A deficiency in pigs experimentally infected with Trichuris suis: a model for vitamin A inadequacy in children

The development of an experimental model for marginal vitamin A deficiency in humans is of major interest, enabling the elucidation of possible interactions with helminth infections. We established a useful experimental model for human vitamin A deficiency in young pigs; deficiency was induced through a depletion method encompassing both sow and offspring. We report on a 2 x 2 study in which 18-week-old vitamin A deficient pigs and vitamin A sufficient littermates were infected with both of the intestinal nematodes Trichuris suis and Ascaris suum and followed for 14 weeks through 32 weeks of age. Forty-nine pigs were followed with respect to bodyweight, liver biopsies and blood samples for retinol concentration and faecal samples for parasite eggs and worms. Liver and serum concentrations of vitamin A were significantly diminished in the vitamin A deficient (VAD) group as compared to the vitamin A sufficient (VAS) group both before (P < 0.001) and after inoculation with T. suis and A. suum (P < 0.02). A significant correlation between retinol content in micro-biopsy needle samples and gross liver content was found (r = 0.457, n = 48, P = 0.001). The adult T. suis worms in the VAD group were marginally smaller (36.7 vs 40.2 mm; P = 0.08), more orally located (section 2.9 vs 3.9; P = 0.08) and had a higher proportion of males (0.58 vs 0.50; P = 0.08) whereas there were no effects of diet treatment on fecundity. The proportion of pigs with faecal T. suis egg excretion 12 weeks post inoculation (p.i.) was significantly lower in the VAD group compared with the VAS infected group (21 vs 78%; P = 0.036). In addition, faecal T. suis egg excretion was significantly lower in the VAD group at both week 11 (P = 0.040) and week 12 p.i. (P = 0.021). Vitamin A deficiency may have altered the functional integrity of the mucosal intestinal epithelium, disrupting the normally delicate attachment of T. suis and leading to the premature termination of infection. However, a possible antagonistic interaction, if verified, should not preclude interventions to improve vitamin A status, i.e., treatment should accompany anthelmintic treatment.

The Challenges of Epilepsy in Children

Summary: Among the most distinct and challenging characteristics of childhood epilepsy are the high incidence, the risk of cognitive function deterioration, the age relationship of various types of epilepsy, and the existence of particular clinical and EEG patterns that characterize epilepsy syndromes. With regard to antiepileptic drug (AED) treatment, one must take into account age‐dependent pharmacokinetics, response to treatment according to the type of epilepsy, and ethical constraints in the development of controlled trials that often prevent the early introduction of new AEDs to the pediatric market.