Ennio Del Giudice

Gastrointestinal manifestations in children with cerebral palsy

We describe the prevalence and nature of gastrointestinal (GI) symptoms in 58 children affected by cerebral palsy (range: from 6 months to 12 years of age) referred to a pediatric neurology outpatient clinic. In each patient we assessed (GI) symptoms and defined the associated GI functional or structural abnormalities. Furthermore, we tried to correlate the type of GI dysfunction with findings on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. Our results showed that 92% of children with cerebral palsy had clinically significant gastrointestinal symptoms. Swallowing disorders were present in 60% of patients, regurgitation and/or vomiting in 32%, abdominal pain in 32%, episodes of chronic pulmonary aspiration in 41% and chronic constipation in 74%. Dysfunction of the oral and/or pharyngeal phase of swallowing was found in 28 of 30 (93%) patients with swallowing disorders. Of the 45 patients with symptoms suggesting gastroesophageal reflux, 41 (91%) had an abnormal pH-monitoring and/or esophagitis. Furthermore, a significant delay in the scintigraphic gastric emptying of liquids was found in 12 of 18 patients (67%) and an abnormal esophageal motility in 11 of the 18 (61%) investigated patients. In 25 patients with chronic constipation evaluation of colonic transit showed a delay at level of the proximal segments of the colon in 13 (52%), at level of the left colon and rectum in 9 (36%) and in 3 (12%) at level of the rectum only. Computed tomography and/or magnetic resonance imaging were normal in 5 (9%) and abnormal in 53 (91%) of the 58 children with cerebral palsy. No GI symptom was significantly associated with any kind of abnormal neuroimaging. In conclusion, children with cerebral palsy exhibited diffuse GI clinical manifestations, mostly due to disorders of GI motility. The GI symptoms seemed not to be related to any specific finding on CT or MRI of the brain.

Effect of the dietary fiber glucomannan on chronic constipation in neurologically impaired children

OBJECTIVE Inadequate dietary fiber intake is a widely accepted explanation for chronic constipation in children with severe brain damage. The aim of our study was to evaluate the efficacy of glucomannan, a soluble fiber, as a treatment for chronic constipation in these children. STUDY DESIGN Twenty children with severe brain damage and chronic constipation were randomly assigned to double-blind treatment with either glucomannan (n = 10) or placebo (n = 10) for 12 weeks. Stool habits, total and segmental gastrointestinal transit times, and anorectal motility were evaluated in all children before and after the treatment period. RESULTS Glucomannan significantly increased (P <.01) stool frequency, whereas the effect of placebo was not significant. Laxative or suppository use was significantly reduced (P <.01) by glucomannan but was not affected by placebo. Clinical scores of stool consistency were significantly improved and episodes of painful defecation per week were significantly reduced by glucomannan (P <.01) but not by placebo. However, neither glucomannan nor placebo had a measurable effect on total and segmental transit times. CONCLUSIONS In neurologically impaired children, glucomannan improves stool frequency but has no effect on colonic motility.

Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome

Mutations in PNPO are a known cause of neonatal onset seizures that are resistant to pyridoxine but responsive to pyridoxal phosphate (PLP). Mills et al. show that PNPO mutations can also cause neonatal onset seizures that respond to pyridoxine but worsen with PLP, as well as PLP-responsive infantile spasms.

Long-Term Enzyme Replacement Therapy for Pompe Disease With Recombinant Human Alpha-glucosidase Derived From Chinese Hamster Ovary Cells

Pompe disease is a rare autosomal recessive myopathy due to the deficiency of lysosomal acid alpha-glucosidase. Clinical phenotypes range from the severe classic infantile form (hypotonia and hypertrophic cardiomyopathy), to milder late onset forms (skeletal myopathy and absence of significant heart involvement). Enzyme replacement therapy with recombinant human alpha-glucosidase derived from either rabbit milk or Chinese hamster ovary cells has been introduced and is undergoing clinical trials. Reported is a long-term follow-up of 3 Pompe patients presenting without cardiomyopathy, treated with recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. This study suggests that enzyme replacement therapy can lead to significant motor and respiratory improvement in the subgroup of patients who start the therapy before extensive muscle damage has occurred. The recombinant enzyme derived from Chinese hamster ovary cells, administered at doses significantly higher than previously reported, appears to have the same safety as the drug derived from rabbit milk.

Spatial cognition in children. I. Development of drawing-related (visuospatial and constructional) abilities in preschool and early school years

The present study aimed to investigate the acquisition of visuospatial and graphomotor capacities during the pre-school and early schooling years in order to follow the normal development of drawing-related abilities and spatial cognition. Eighty children aged 3-5 years, divided in four subgroups each different for a 6-month period, and 80 children aged 8-9 years were administered a neuropsychological battery for visuospatial and visuoconstructional analysis. The battery explored five cognitive domains: visual scanning, visuospatial perceptual and representational abilities, visuomotor control and graphomotor skills. Results showed that the total scores significantly improved in each group of children with respect to the previous one, but the pattern of skill acquisition was not homogeneous. We observed a gradient from explorative and visuomotor to perceptive, representational and graphomotor abilities. Explorative and visuomotor abilities were almost mature at a time when visuoperceptual capacities began to develop. On the contrary, at that time we found very low performances at representational and constructional tasks. Our findings could suggest that constructional abilities need both perceptual and representational competences to develop properly.

Upper gastrointestinal tract motility in children with progressive muscular dystrophy

Gastric emptying was evaluated in 15 children (mean age, 8.0 years) with progressive muscular dystrophy to detect early gastrointestinal smooth muscle involvement; 10 of the children also underwent esophageal manometry. Clinical evidence of skeletal muscle dysfunction was minimal in 14 of the 15 patients; 10 of them had no gastrointestinal symptoms. Gastric emptying studies were performed by using 500 muCi of technetium 99m-sulfur colloid bound to a scrambled egg, and scintigraphic measurements were made continuously for 60 to 90 minutes. Gastric emptying studies and manometric tracings were compared with those from 11 children (mean age, 8.4 years) without gastrointestinal or muscular disorders. Mean (+/- SD) percentage retention of gastric isotope was significantly greater in patients with muscular dystrophy than in control subjects. No differences were found between the two groups in distal esophageal motility or in upper and lower esophageal sphincter pressures or relaxation. Contraction amplitudes in the upper portion of the esophagus, however, were significantly lower in patients with myopathy than in control subjects. These data suggest that dysfunction of smooth muscle of the upper gastrointestinal tract is detectable in children with muscular dystrophy early in the course of the disease, even when gastrointestinal symptoms are absent and skeletal muscle symptoms are minimal.

Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

Sanfilippo B syndrome (MPS III B): mild and severe forms within the same sibship.

Clinical heterogeneity for Sanfilippo B syndrome (MPS III B) in the same family has never been reported previously. We describe two clinically severe cases and one clinically mild case of MPS III B in a Neapolitan sibship. We could not detect N‐acetyl‐α‐D‐glucosaminidase activity in the sera of either the severe or mild cases. Mucopolysac‐chariduria mainly due to heparan sulfate excretion was consistently high in the severely affected patients and extremely variable in the mildly affected one.

Atypical expression of ß-galactosidase deficiency in a child with Hurler-like features but without neurological abnormalities

A 28‐month‐old child was found to have several clinical features of lysosomal storage diseases, including: coarse facies, hepatosplenomegaly, lumbar kyphosis due to hypoplastic beaked L1 and L2 vertebral bodies, vacuolated lymphocytes in blood smears and rare foamy hystiocytes in bone marrow. However, no signs of neurological or ocular abnormalities were detected. A β‐galactosidase deficiency was demonstrated in leukocytes and cultured skin fibroblasts, with a residual activity toward 4‐methylumbelliferyl‐β‐galactopyranoside ranging between 5 and 15% of the normal mean. Normal activities were found for several other lysosomal acid hydrolases. β‐galactosidase activities in leukocytes and cultured skin fibroblasts from both parents were within the normal ranges. The patient seems to represent an atypical expression of acid β‐galactosidase deficiency, since his clinical picture does not exactly correspond to that of either the two classical types of GM1‐gangliosidosis or other atypical patients reported in the literature having β‐galactosidase deficiency.

Cisapride in neurologically impaired children with chronic constipation

The efficacy of cisapride as a treatment for chronic constipation in children with severe brain damage was studied in 20 children. Each subject was randomly assigned to double-blind treatment with either cisapride (N=10) or placebo (N=10) for 12 weeks. Stool habits, total gastrointestinal transit time, colonic segmental transit times, and anorectal motility were evaluated in all children before and at the end of the treatment period. Although cisapride significantly (P<0.05) increased stool frequency from baseline to week 12 and no significant change was documented in the placebo group, the mean change in stool frequency per week from baseline to 12 week was not significantly different between the two treatment groups. The use of laxatives or suppositories was significantly (P<0.05) decreased by cisapride, but remained unchanged in the placebo group. Furthermore, cisapride significantly (P<0.05) reduced rectal compliance but had no effect on total gastrointestinal transit time and colonic segmental transit times. In summary, in neurologically impaired children with chronic constipation, cisapride increased bowel frequency but did not alter the delay in total and segmental gastrointestinal transit times.