Mortality from second tumour among long-term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry.

Survivors of retinoblastoma (Rb) are at high risk of dying from second malignant tumour. The occurrence of second malignant neoplasm (SMN) and related mortality in a cohort of 1111 cases from the Italian Retinoblastoma Registry was analysed, considering the possible role of both genetic and iatrogenic causes. Rb patients had a greater than 10-fold excess in overall mortality compared with the general population (standardized mortality ratio (SMR) 10.73, 95% CI 9.00-12.80). Their excess risk attributable to cancers other than Rb was 14.93 95% CI 10.38-21.49). Survivors of hereditary Rb had an SMR for all causes of 16.25 (95% CI 13.20-20.00), whereas their SMR for all cancers was 25.72 (95% CI 17.38-38.07). Survivors of unilateral sporadic Rb had an SMR of 4.12 from all cancers (95% CI 1.55-10.98) and a much higher excess for overall mortality (SMR 13.34, 95% CI 10.74-16.56). As expected, survivors of hereditary Rb had higher mortality from cancers of the bone (SMR 391.90, 95% CI 203.90-753.20) and soft tissue (SMR 453.00, 95% CI 203.50-1008.40), small intestine (SMR 1375.50, 95% CI 344.00-5499.70), nasal cavity (SMR 13.71, 95% CI 1.93-97.35) and cancers of the brain and central nervous system (SMR 41.14, 95% CI 13.2-127.55).

Aicardi syndrome with favorable outcome: case report and review.

Aicardi syndrome is a congenital disorder characterized by severe psychomotor retardation, corpus callosum agenesis, chorioretinal lacunae, and early-onset infantile spasms. The prognosis is generally poor for children with the classical form. We report a peculiar case of Aicardi syndrome characterized by corpus callosum hypoplasia, brain malformations with subependymal heterotopias, extensive chorioretinal lacunae, seizures, and normal cognitive functions. Therefore, the clinical picture of the syndrome is broader than originally described. Cognitive disorders should not be considered inevitable and the prognosis not ineludibly poor.

Intractable reflex audiogenic seizures in Aicardi syndrome.

Aicardi syndrome (AS) is a rare disorder which includes the triad of total or partial agenesis of the corpus callosum, infantile spasms, and chorioretinal anomalies. Seizures and electroencephalogram findings observed in AS are polymorphic with both focal and generalized seizures. We first report on a patient affected by AS who presented with reflex audiogenic seizures specifically triggered by the starting tune of a popular television news. No other type of stimuli, either simple or complex, were able to precipitate the seizures in the patient. The severe cortical-subcortical lesions commonly observed in AS are associated with hyperexcitability of the cortices and may well account for the broad electroclinical patterns noted in this group of patients. From our report, the context of these patterns should be extended to include reflex audiogenic seizures.

Seizures and electroencephalographic findings in CDKL5 mutations: case report and review.

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been detected in patients presenting with seizures in the first few months of life and Rett syndrome features. Twenty-seven cases have been detected to date. Generalized intractable seizures, as infantile spasms, and generalized tonic-clonic seizures and myoclonic seizures characterize the clinical picture of CDKL5 mutations. Here we report on a patient who presented with sleep-related hyperkinetic seizures. Our observation and review of the literature suggest that a broader polymorphic electroclinical pattern with both generalized and focal seizures may occur in patients with CDKL5 mutations. A screen for CDKL5 mutations is useful in patients, mainly females, with a history of early onset intractable seizures and becomes mandatory when idiopathic infantile spasms and/or atypical Rett syndrome features are also present.

Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy.

The aim of this multicentric, retrospective, and uncontrolled study was to evaluate the efficacy and safety of levetiracetam (LEV) in 81 children younger than 4 years with refractory epilepsy. At an average follow-up period of 9 months, LEV administration was found to be effective in 30% of patients (responders showing more than a 50% decrease in seizure frequency) of whom 10 (12%) became seizure free. This efficacy was observed for focal (46%) as well as for generalized seizures (42%). In addition, in a group of 48 patients, we compared the initial efficacy (evaluated at an average of 3 months of follow-up) and the retention at a mean of 12 months of LEV, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Twenty-two patients (46%) were initial responders. After a minimum of 12 months of follow-up, 9 of 48 patients (19%) maintained the improvement, 4 (8%) of whom remained seizure free. A loss of efficacy was observed in 13 of the initial responders (59%). Maintained LEV efficacy was noted in patients with focal epilepsy and West syndrome. LEV was well tolerated. Adverse events were seen in 18 (34%) patients. The main side effects were drowsiness and nervousness. Adverse events were either tolerable or resolved in time with dosage reduction or discontinuation of the drug. We conclude that LEV is safe and effective for a wide range of epileptic seizures and epilepsy syndromes and, therefore, represents a valid therapeutic option in infants and young children affected by epilepsy.

Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy.

The aim of this multicentric, prospective and uncontrolled study was to evaluate the efficacy and safety of levetiracetam in 110 children with refractory epilepsy, of whom 21 were less than 4 years old. After a median follow-up period of 7 months, levetiracetam administration was effective (responders with >50% decrease in seizure frequency) in 39% of children, of whom 10 (9%) became seizure-free. The efficacy was higher in patients with localization-related epilepsy (58% of responders) than in those with generalized epilepsy (37% of responders). Levetiracetam was well tolerated. The main side effects of somnolence and irritability occurred in 14% of patients. In one patient acute choreoathetosis occurred after few doses of levetiracetam. Overall, the adverse effects were not severe. Children younger than 4 years were particularly tolerant. In conclusion, the present study confirms that levetiracetam is effective and well tolerated as an add-on treatment in children with refractory epilepsy. Our preliminary data also indicate that levetiracetam may be a valid therapeutic option for epilepsy in infants and young children.

Efficacy and safety of topiramate in infants according to epilepsy syndromes.

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravet's syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravet's syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Controlled study in diabetic children comparing insulin-dosage adjustment by manual and computer algorithms.

A controlled trial of a new microprocessor device for insulin-dosage adjustment was undertaken in two matched groups of a priori well-controlled diabetic children. A prospective study design with three equal 8-wk periods was used. In the first period, both groups used manual methods for insulin-dosage adjustment after manual criteria. In the second period, one group of children adjusted insulin dosage by computer algorithms, whereas the other continued to use manual methods. In the third period, both groups again adjusted insulin by traditional methods. Mean premeal glycemia and glycosylated hemoglobin levels did not change in either group throughout the study. During the second period, episodes of hypoglycemia were more frequent in children without the computer than in those who used the device. In keeping with the latter outcome, the group that used the microprocessor device was given less insulin in the second period than the first (0.88 +/- 0.02 vs. 0.94 +/- 0.02 U.kg-1.day-1, P less than 0.0001) and in comparison to the control group of patients who concurrently were given an increased insulin dose in the second period compared with the first. This study showed that insulin treatment through specific computer-mediated dosage-adjusting algorithms was safe and minimized hypoglycemia by effectively accommodating seasonally changing insulin requirements. We recommend the device to help diabetic children and their families in the care of insulin-dependent diabetes.

Blue-on-yellow and achromatic perimetry in diabetic children without retinopathy.

OBJECTIVE: We compared blue-on-yellow perimetry with achromatic perimetry to determine whether the first was more sensitive in detecting visual field defects. RESEARCH DESIGN AND METHODS: We studied 50 children and adolescents (22 male, 28 female) with IDDM, ranging in age from 10.1 to 16.3 years (mean 13.3+/-2.1 years), with a disease duration of 5.2-10.0 years (mean 7.1+/-1.9 years). Patients were divided into subgroups according to the presence of persistent microalbuminuria. No one had signs of diabetic retinopathy when studied with fluorescein angiography. RESULTS: By achromatic perimetry, the analysis of subareas of the central 30 degrees of the visual field (0-9 degrees; 10-18 degrees; out of 18 degrees) showed no differences between diabetic subgroups in the central 18 degrees of the visual field, while a significant difference between the same subgroups was found outside the 18 degrees of the 24-2 program of the Humphrey perimeter (P = 0.027). By blue-on-yellow perimetry, in all three of the perimetric subareas evaluated, the sensitivity was lower in microalbuminuric patients than in normoalbuminuric ones. The differential sensitivity between the perimetric tests performed with blue-on-yellow and with achromatic stimuli showed statistically significant data, with a higher level of significance in the central 18 degrees (P < 0.0001) than outside the 18 degrees (P = 0.033). CONCLUSIONS: Our study suggests that blue-on-yellow perimetry is more useful and more sensitive than achromatic perimetry in the detection of preclinical visual field defects in diabetic children with microalbuminuria but without clinically detectable retinopathy.

Discontinuation of anticonvulsant therapy in children with partial epilepsy.

To evaluate when it is possible to discontinue anticonvulsant treatment in children with cryptogenic partial epilepsy, the authors studied 89 epileptic children divided into two groups: Group A, 45 children whose therapy was discontinued after 1 year from the last seizure; and Group B, 44 children whose therapy was stopped after 2 years from the last seizure. After 5 years of follow-up, the recurrence rate was similar in the two groups of patients (Group A, 28.8%; Group B, 25%). It is safe to discontinue the anticonvulsant therapy in children with cryptogenic partial epilepsy who were seizure free for only 1 year.

Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid.

Weight gain has been recognized as an adverse effect of valproic acid therapy, but there are are no data about serum leptin levels in patients receiving this drug. To evaluate if valproic acid treatment in epileptic patients in whom obesity develops modifies serum levels of insulin and leptin, 40 female patients with epilepsy were evaluated before therapy and after 1 year of therapy. At the end of follow-up, 15 patients were obese and showed higher serum leptin and insulin levels than patients who did not gain weight. As in other types of obesity, elevation of serum leptin concentrations is related to the increase in body mass index.

Familial Axenfeld-Rieger anomaly, cardiac malformations, and sensorineural hearing loss: a provisionally unique genetic syndrome?

Axenfeld-Rieger anomaly (ARA) is an autosomal dominant disorder of the anterior chamber of the eye that includes a prominent and anteriorly displaced Schwalbe line and an iridocorneal synechiae, and is associated with iris hypoplasia, corectopia, and hole formation. Extraocular developmental abnormalities, especially of the teeth, facial bones, and periumbilical skin, have also been reported with ARA, in the context of the so-called Axenfeld-Rieger syndrome (ARS). Genetic heterogeneity exists, as ARA maps to chromosome 6p25, whereas ARS can be linked to both chromosome 4q25 and chromosome 13q14. Here we describe a new family in which ARA is associated with cardiac malformations and sensorineural hearing loss. No abnormalities of the teeth, facial bone, or periumbilical skin, which are considered of paramount importance in the diagnosis of ARS, were observed in our patients. Genetic studies will clarify if these patients represent a unique phenotypic expression of ARS or constitute the clinical presentation of a new genetic syndrome.

Char syndrome: an additional family with polythelia, a new finding.

This report describes a father and daughter with Char syndrome, a rare autosomal dominant disorder. Both affected individuals had typical face, strabismus, and foot anomalies. The girl also had a patent ductus arteriosus. In addition, both patients had polythelia (supernumerary nipples), a finding not described before in the Char syndrome.

Corpus callosum agenesis, multiple cysts, skin defects, and subtle ocular abnormalities with a de novo mutation [45,XX,der(5), t(5;;14) (pter;q11.2)].

We report on a 2-year-old girl with a de novo mutation [45,XX,der(5),t(5;14) (pter;q11.2)] with corpus callosum agenesis, multiple cysts (cerebral and cardiac), subtle eye abnormalities, and at least two different skin defects, strongly indicating neuroectodermal involvement, as a neuromuscular choristoma (hamartoma) and an eccrine hamartoma. Fluorescent in situ hybridization with different single-locus probes showed that chromosome 5 has a very small deletion, confined to a region composed of repetitive sequences. By contrast, the long (q) arm of chromosome 14 seems to be much more involved in the rearrangement, with partial monosomy spanning from the centromere to the D14S72 and D14S261 loci. The extent of the deleted region of chromosome 14 is approximately 16 cM. To our knowledge, this is the smallest reported deletion involving the chromosome 14q11.2 region to be associated with a developmental disorder resulting in variable eye, skin, and brain anomalies. We suggest that a new syndrome, mimicking in some ways the MLS phenotype, is caused by a deletion in the chromosome 14q11.2 region.

Leptin levels in non-obese and obese children and young adults with type 1 diabetes mellitus.

OBJECTIVE: To evaluate serum leptin levels in children and young adults with type 1 (insulin-dependent) diabetes mellitus and to investigate whether they are different in prepuberty, puberty and young adulthood. DESIGN: Three groups of diabetics (prepubertal, pubertal and young adults) subdivided into obese and non-obese were studied. Three groups of healthy subjects matched for sex, age and body mass index served as controls. RESULTS: Diabetic patients had serum leptin concentrations similar to those of controls in all three groups. A small non-significant increase in leptin from the prepubertal to the young adult age group for both diabetics and controls was found. A significant association of serum leptin level with body mass index (P < 0.001), female sex (P < 0.001) and age (P < 0.01) in both the diabetic and control group was present. Insulin-dependent diabetes was not associated with higher leptin concentration. CONCLUSIONS: Serum leptin concentrations are similar in diabetic patients and healthy controls. The association between obesity and leptin concentration was similar in the diabetic and non-diabetic subjects. Type 1 diabetes mellitus does not modify serum leptin concentration.

Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study.

Vacuolating megalencephalic leukoencephalopathy (VML) with subcortical cysts is a neurodegenerative disorder clinically characterized by megalencephaly with onset in the first year of life, progressive ataxia, spasticity and relatively spared cognitive function. Conventional MRI findings consist of diffusely abnormal cerebral white matter with subcortical cysts. Recent single-voxel proton MR spectroscopy studies have shown mild metabolic abnormalities in the white matter. We report here a combined proton MR imaging and MR spectroscopic imaging (1H-MRSI) study on 2 new, unrelated patients with this rare disorder. 1H-MRSI examinations, which can provide simultaneously metabolic information from many different brain regions, showed inhomogeneous decreases in all normally detected metabolites with significant widespread decreases in the ratio of N-acetylaspartate to creatine+phosphocreatine and concomitant small increases in lactate in the white matter of both hemispheres. Metabolic abnormalities were milder in the frontal white matter and more severe in the posterior white matter. The 1H-MRSI pattern of the gray matter was normal in both patients. In one patient, a subsequent 1H-MRSI examination (performed 3 years after the first) confirmed the presence of widespread decreases in the ratio of N-acetylaspartate to creatine+phosphocreatine in the white matter. We conclude that severe metabolic abnormalities can be found in the white matter of VML patients. This suggests that, despite the apparently mild clinical course, a severe neurodegenerative process may occur in the white matter of these patients.

Association of Chiari I malformation, mental retardation, speech delay, and epilepsy: a specific disorder?

OBJECTIVE: The Chiari I malformation is defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum. Although Chiari I malformation is considered to derive from a mesodermal disorder resulting in underdevelopment of the posterior fossa relative to its content, evidence for a possible heterogeneous etiology also has been reported. The aim of the present study is to elucidate the relationship between Chiari I malformation and mental retardation, speech delay, and epilepsy to consider a possible specific pathogenetic background. METHODS: Thirty-five patients with Chiari I malformations were identified by use of magnetic resonance imaging during a period between 1993 and 1999. The study consisted of nine patients (four boys and five girls) who were affected by mental retardation, speech delay, and epilepsy. All patients underwent electroencephalography and brain and cervical spine magnetic resonance imaging. RESULTS: All patients were mentally retarded with a mean intelligence quotient of 50. Seven patients had a positive history for speech delay, and five were epileptic. Electroencephalograms demonstrated abnormalities in seven patients. The mean tonsillar displacement was 10.1 mm. A thin corpus callosum and a wide cavum septum pellucidum were present in three patients. Neither hydromyelia nor scoliosis was observed. No correlation between the degree of the ectopia and clinical manifestation was noted. CONCLUSION: The association of Chiari I malformation with epilepsy, speech delay, and mental retardation may not be a mere incidental finding but may be a marker for a different pathogenetic background.

Serum copper, zinc, selenium, glutathione peroxidase and superoxide dismutase levels in epileptic children before and after 1 year of sodium valproate and carbamazepine therapy.

To assess whether epileptic children have abnormal values of serum copper (Cu), zinc (Zn), selenium (Se), glutathione peroxidase (GSH-PX) and superoxide dismutase (CuZn-SOD), and to evaluate the effect of long-term therapy with sodium valproate (VPA) and carbamazepine (CBZ) on these parameters, we studied 36 epileptic patients before the beginning of therapy and after 1 year of therapy with VPA or CBZ. Before the beginning of therapy, there were no differences in levels of all parameters studied between controls and epileptics. After 1 year of therapy, patients treated with VPA and CBZ continued to show normal values. In conclusion our study demonstrates that epilepsy per se and treatment with VPA and CBZ do not affect levels of Cu, Zn, Se, GSH-PX and CuZn-SOD concentrations.

Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine.

OBJECTIVE: To evaluate plasma homocysteine (Hcy) concentrations in children receiving sodium valproate (VPA) and carbamazepine (CBZ), monotherapy, in comparison with healthy control subjects and to determine the possible relationship between Hcy levels and dosage and plasma concentrations of the antiepileptic drugs. METHODS: We measured levels of fasting and post-methionine Hcy, plasma pyridoxal 5'-phosphate (PLP, active vitamin B6), serum folate, erythrocyte folate and serum vitamin B12 in 60 epileptic patients (29 females, 31 males), aged from 14.2 to 17.9 years, subdivided into two groups according to their therapy. Sixty-three healthy sex- and age-matched children served as controls. These measurements have been performed before the beginning of therapy and after 1 year of therapy with VPA or CBZ. RESULTS: Before the beginning of therapy, there were no significant differences in fasting and post-methionine Hcy, plasma PLP, serum folate, erythrocyte folate and serum vitamin B12 values between the control group and the two groups of epileptic children. After 1 year of therapy, patients treated with VPA and CBZ showed a significant increase of the plasma concentrations of Hcy when compared to baseline data and controls values. Moreover, was observed a significant decrease of serum folate and plasma PLP. On the contrary, serum vitamin B12 and erythrocyte folate levels remained in the normal range. CONCLUSIONS: Our study demonstrates that prolonged treatment with VPA and CBZ increases plasma concentrations of Hcy.