Daniela Trotta

Valproate-induced hyperammonemic encephalopathy

Valproic acid (VPA) is an effective anticonvulsant useful in many types of epilepsy and, although it is usually well tolerated, it has been associated with many neurological and systemic side effects. Among these, one of the most important is VPA-induced hyperammonemic encephalopathy (VHE): its typical signs are acute onset of impaired consciousness, focal neurologic symptoms, and increased seizure frequency. The pathogenesis of VHE is still unclear, but it has been suggested that hyperammonemia can produce encephalopathy via inhibition of glutamate uptake by astrocytes which may lead to potential neuronal injury and perhaps cerebral edema. Glutamine production is increased, whereas its release is inhibited in astrocytes exposed to ammonia. The elevated glutamine increases intracellular osmolarity, promoting an influx of water with resultant astrocytic swelling. This swelling could compromise astrocyte energy metabolism and result in cerebral edema with increased intracranial pressure. Moreover, VHE seems to be more frequently in patients with carnitine deficiency or with congenital urea cycle enzymatic defects.

Microvascular and macrovascular complications associated with diabetes in children and adolescents

Department of Pediatrics, Ulleval University˚Hospital, and Faculty of Medicine, University of Oslo, NorwayCorresponding author:Assoc. Prof. Kim DonaghueThe Children’s Hospital at Westmead, Locked Bag 4001,Westmead, NSW 2145, Australia.Tel: C61 2 9845 3172;fax: C61 2 9845 3170;e-mail: kimd@chw.edu.auAcknowledgments: Esko Wiltshire, Gisela Dahlquist, KennethLee Jones, Edna Roche, Amina Balafrej and Riccardo Bonfanti.Conflicts of interest: The authors have declared no conflictsof interest.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

Microvascular and macrovascular complications

Clinically evident diabetes-related vascular complications should be rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. There has been a declining incidence of complications reported in many areas with specialized clinics (1–3). This has occurred over a period of time during which there have been major changes in diabetes management, identification of putative risk factors, and the advent of regular screening for complications. There is no evidence that this is a worldwide occurrence: in areas where health care is not optimal, a greater risk of complications will remain. Interventional studies of intensive glycemic control

Insulin Resistance in Epileptic Girls Who Gain Weight After Therapy With Valproic Acid

Valproic acid is effective for treatment of many types of epilepsy, but its use in epileptic patients can be associated with an increase in body weight that could interfere with treatment compliance. The weight gain may result from different mechanisms, but the exact pathogenesis is still unknown. To evaluate insulin sensitivity in adolescents who gained weight during treatment with valproic acid, we studied 20 girls with different types of epilepsy: 15 patients had primary generalized seizures, including absence seizures (3 cases), and 5 patients had partial seizures. After 1 year of valproic acid treatment, the obese patients had serum insulin levels significantly higher than patients who did not gain weight (51.4 ± 25.3 versus 28.2 ± 12.9). Moreover, we observed that epileptic patients who gained weight were also insulin resistant in comparison with nonobese epileptic subjects. At the end of treatment, all patients showed normal levels of serum testosterone, androstenedione, dehydroepiandrosterone sulfate, follicle-stimulating hormone (FSH), and luteinizing hormone. We found no significant correlation between insulinemia and serum valproic acid concentrations in obese and nonobese patients treated with valproic acid. Our study demonstrates that basal hyperinsulinemia and insulin resistance can be present in patients who develop obesity during valproic acid treatment. Therefore, these obese patients could be exposed to the risks related to these metabolic abnormalities; if these data are confirmed in longer studies, these side effects may raise some concerns about the safety of valproic acid. (J Child Neurol 2002;17:265-268).

Valproate-induced insulin resistance and obesity in children.

Background: Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial. Methods: In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically. Results: Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic β-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects. Conclusions: The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research.

Diabetic neuropathy in children and adolescents

Abstract:  Diabetic neuropathy (DN) represents a major complication of type 1 diabetes mellitus (T1DM) but there is considerable uncertainty as to its incidence, prevalence, diagnosis and prognosis in pediatric population.

Typical and atypical rolandic epilepsy in childhood: a follow-up study.

Atypical features of rolandic epilepsy are not uncommon, although the long-term prognosis of this condition is not known. Eighty-five children (50 male and 35 female) attending the Department of Pediatrics of the University of Chieti, the Department of Pediatrics of Brindisi Hospital, and the Department of Neurology of San Valentino Hospital were selected for the study; these patients were subdivided into two groups according to their clinical presentation. Group A consisted of children who suffered from typical rolandic epilepsy and Group B consisted of children with atypical features of rolandic epilepsy. All patients of both groups were re-evaluated after at least 8 years from the first evaluation, and the frequency of seizures and the response to treatment were similar in the two groups of children. In spite of this fact, in patients who suffered from atypical rolandic epilepsy, we found a significantly higher percentage of learning and behavioral disabilities than in children affected by the classical form of rolandic epilepsy (45.5% vs 7.8%; P < 0.0001). In conclusion, atypical rolandic epilepsy seems to be associated with a high percentage of learning and behavioral disorders.

Ictal cardiorespiratory arrest in Panayiotopoulos syndrome

Panayiotopoulos syndrome (PS) is a syndrome of childhood susceptibility to benign autonomic seizures and affects approximately 6% of children with nonfebrile seizures.1–4 The clinical features are infrequent, often single, focal seizures comprising autonomic symptoms; behavioral changes; and other ictal clinical manifestations. Half of the seizures progress to become generalized; two thirds occur during sleep. The seizures can last 5 to 15 minutes, but some are prolonged, lasting hours, constituting autonomic status epilepticus (ASE).5 Even after severe seizures, the patient recovers within a few hours. Prognosis is excellent. Remission usually occurs within 1 to 2 years from onset. EEG is characterized by multifocal spikes that predominate in the posterior regions.4,6 Ictal EEG shows frontal or posterior onset.4,5,7 Ictus emeticus (nausea, …

Effects of antiepileptic drugs on evoked potentials in epileptic children.

To evaluate the visual and auditory function in children and adolescents who are undergoing monotherapy with sodium valproate, carbamazepine, and phenobarbital visual-evoked potentials and brainstem auditory-evoked potentials were measured in 58 epileptic patients (30 males and 28 females), ages 13.7 +/- 6.9 years. Fifty healthy sex- and age-matched children served as controls. The measurements were performed before the beginning of therapy and after 12 months. Before the beginning of therapy, there were no significant differences in visual- and auditory-evoked potentials between the control group and the three groups of epileptic children. After 12 months of therapy, patients treated with carbamazepine demonstrated a significant (P < 0.001) increase of P100 latencies when compared with baseline data and control values; moreover, these patients exhibited a significant increase of peak latencies of waves I-III-V and interpeak interval I-V at auditory second evaluation. The patients treated with sodium valproate manifested a significant (P < 0.05) increase in VEP P100 latencies. On the contrary, children receiving phenobarbital did not manifest any significant abnormality at visual- and auditory-evoked potentials measurements. Our study demonstrates that for patients treated with carbamazepine and sodium valproate, an electrophysiologic dysfunction of visual and auditory sensory pathways can be present after 12 months of treatment.

Visual evoked potentials in young persons with newly diagnosed diabetes: a long‐term follow‐up

To evaluate the presence of electrophysiological abnormalities in the visual function of young persons with diabetes, visual evoked potentials were recorded, in basal conditions and after photostress, in 30 patients with newly diagnosed insulin‐dependent diabetes mellitus. Their mean age was 17.6 years (3.6 SD), and their glycosated haemoglobin (HbA1c) was 9.4% (1.6 SD). Thirty healthy age‐ and sex‐matched individuals were evaluated as the control group. This study showed that the P100 latency was significantly delayed in patients with diabetes compared with the control group (p<0.01), while the N75 to P100 amplitude was similar in both groups. These measurements were repeated after 6 months, when all participants with diabetes had achieved good metabolic control (HbA1c 7.2% [1.5 SD]). At this second evaluation a complete normalisation of all parameters was observed. These findings suggest that early functional abnormalities of the optic nerve can be detected at onset of diabetes, and that glycaemic control reverses these abnormalities.