A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Adverse events associated with the use of insect repellents containing N,N-diethyl-m-toluamide (DEET).

DEET is the major component of most topically applied insect repellents used in the US. The DEET Registry is a post-marketing surveillance system to provide systematic and detailed information about medical events temporally associated with DEET use. From 1995 to 2001, 296 moderate and major severity cases were included in the DEET Registry. Of these, 36 (14.5%) cases were deemed to be probably and 157 (65%) cases possibly related to DEET exposure. Insufficient data prevented determination of causality in the remaining 49 (20.2%) cases. Forty-one percent of the cases were in children 19 or younger. Forty-two percent of children experienced a seizure of moderate or major severity. The widely variable spectrum of other neurological symptoms reported in the Registry makes it unlikely they were due to one agent. People with an underlying neurological disorder were not disproportionately represented in the DEET Registry. Data showed no clear relationship between case severity and DEET concentration or concurrent use of common medicines. Recognizing the extensive use of DEET in the US and considering the information about the more serious adverse events described in the Registry, the risk of serious neurological events following the use of DEET repellents is quite low.

GM2 ganglioside lysosomal storage disease in cats with beta-hexosaminidase deficiency.

Two kitteens with progressive neurologic disease had increased concentrations of GM2 ganglioside in their cerebral cortex. Examination under the light microscope revealed cytoplasmic vacuolation of neurons and hepatocytes. Transmission and scanning electron microscopy demosntrated cytoplasmic inclusions encompassed by membranes in various central nervous system cell types and in hepatocytes. Beta-D-N-acetyl-hexosaminidase activity was reduced to about 1.0 percent of normal in brain, liver, and cultured skin fibroblasts of the diseased kittens; both major electrophoretic forms, A and B, of the enzyme were deficient. In fibroblasts from the parents of the diseased kittens, this enzyme activity was intermediate between that of affected and normal cats, suggesting an autosomal recessive mode of inheritance of the enzyme defect. Histopahtological and ultrastructural lesions, glycolipid storage, enzyme defect, and pattern of inheritance are similar to those of human GM2 gangliosidosis type 2.

Asymptomatic hyperammonemia in patients receiving valproic acid.

To determine the frequency of hyperammonemia in asymptomatic patients receiving valproic acid, plasma ammonia concentrations were measured in 55 patients receiving this drug and in 12 patients receiving other anticonvulsants. Twenty-nine of the 55 patients receiving valproic acid and none of the control patients had plasma NH3 levels above the normal range. Ten of the 11 patients receiving both valproic acid and phenytoin sodium in combination had elevated NH3 levels, as did five of six patients receiving both valproic acid and phenobarbital sodium. Elevations in plasma NH3 levels, as high as 140 mumole/L, were well tolerated, and valproic acid dose reductions were not necessary. Based on our findings, hyperammonemia is not an indication for reducing or eliminating valproic acid therapy.

Left vagal nerve stimulation in children with refractory epilepsy. Preliminary observations.

OBJECTIVE: To observe the tolerance and efficacy of periodic left vagal nerve stimulation in a group of children with medically intractable epilepsies. DESIGN: A vagal nerve stimulator (Cyberonics Inc, Webster, Tex) was implanted in 12 children with medically and surgically refractory epilepsies. These children were followed up for 2 to 14 months. OUTCOME MEASUREMENTS: (1) The number of seizures recorded during the final month of observation was compared with the number recorded during the month before the implantation of the vagal nerve stimulator. (2) Parents were asked to compare overall status of their child, relative to the period prior to using the vagal nerve stimulator, on a global rating scale. (3) The number of antiepileptic drugs at the last visit was compared with the number before the use of this device. (4) Adverse events were recorded. RESULTS: Five of the 12 patients had a greater than 90% reduction in the number of monthly seizures. Global evaluation scores indicated that there were no deteriorations from baseline and that there was a considerable number with improved status. Four patients were able to reduce the number of antiepileptic drugs used. No significant adversities were noted. CONCLUSIONS: The vagal nerve stimulator is well tolerated in children with intractable epilepsies, and it may have a role in their medical management. We were unable to determine specific epilepsies or seizures that were sensitive to this intervention.

Comparison of valproic acid and phenytoin in newly diagnosed tonic-clonic seizures.

Sixty-one newly diagnosed epileptic patients with generalized tonic-clonic, clonic, or tonic seizures were randomly allocated to treatment with valproate (VPA) and phenytoin (PHT). After 6 months, both drugs had been effective in preventing recurrence of seizures. Seventy-three percent of patients receiving VPA and 47% of patients receiving PHT had no recurrences. Side effects of either drug were mild. Laboratory abnormalities were similar for both drugs. Except for one PHT patient with toxic hepatitis, therapy was not discontinued.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Valproate monotherapy in children.

Seizures are more common in children than in adults. Since most pediatric epilepsies can be controlled with a single antiepileptic drug, children with epilepsy should receive monotherapy when possible or switch from polytherapy to monotherapy. More than half of the epileptic patients receiving multiple antiepileptic drugs will have better seizure control as well as fewer side effects with monotherapy. Most of the pediatric epilepsies occur as primary generalized seizures, for which valproate is a preferred drug. Children can begin to receive valproate treatment in a dosage of 20 to 30 mg/kg per day in two or three divided doses. After several days, plasma levels may be useful in adjusting the dosage. The major adverse effect of valproate in children is fatal hepatotoxicity. The risk of this complication is considerably lower with valproate monotherapy (one per 10,000 patients) than with polytherapy. Other advantages of valproate monotherapy, compared with polytherapy, include the avoidance of drug interactions, lower cost, and reduced potential for impaired cognitive function, which is particularly important in children.

Heterozygote detection in Fabry disease utilizing multiple enzyme activities.

In Fabry disease, as in other X-linked traits, identification of all heterozygotes is difficult. Reduced plasma alpha-galactosidase activities will correctly identify 60-70% of the carriers. The identification rate improves when an alpha/beta-galactosidase activity enzyme ratio is used. We measured alpha-galactosidase activity in reference to several other enzyme activities, beta-galactosidase, beta-hexosaminidase, and alpha-fucosidase in plasma and leukocytes from 22 suspected and 9 obligate carriers from 4 kindreds of Fabry disease patients. Utilizing such ratios or various combinations of ratios in plasma we have correctly identified the carrier state in 91% of heterozygotes. Leukocyte alpha/beta-galactosidase identified one more female than leukocyte alpha-galactosidase activities alone. We recommend the use of such multiple biochemical tests to identify carriers of Fabry disease.

Left vagal nerve stimulation in six patients with hypothalamic hamartomas.

Six patients with medically refractory epilepsy secondary to hypothalamic hamartomas were treated with intermittent stimulation of the left vagal nerve. Three of the patients had remarkable improvements in seizure control. Four of these six patients had severe autistic behaviors. Striking improvements in these behaviors were observed in all four during treatment with intermittent stimulation. This finding suggests that vagal nerve stimulation can control seizures and autistic behaviors in patients with hypothalamic hamartomas.

Vagal nerve stimulation in tuberous sclerosis complex patients.

This is an open-label, retrospective, multicenter study to determine the outcome of intermittent stimulation of the left vagal nerve in children with tuberous sclerosis complex and medically refractory epilepsy. The records of all children treated with vagal nerve stimulation were reviewed in five pediatric epilepsy centers to locate those with tuberous sclerosis complex who had been treated with vagal nerve stimulation for at least 6 months. These patients were compared with (1) a series of patients obtained from the literature, (2) 10 similar control patients with epilepsy obtained from a registry of patients receiving vagal nerve stimulation, and (3) four published series of tuberous sclerosis complex patients whose epilepsy was surgically managed. Ten tuberous sclerosis complex patients with medically refractory epilepsy treated with vagal nerve stimulation were found. Nine experienced at least a 50% reduction in seizure frequency, and half had a 90% or greater reduction in seizure frequency. No adverse events were encountered. Comparison with published and registry patients revealed improved seizure control in the tuberous sclerosis complex patients. Comparison with the group undergoing seizure surgery demonstrated improved outcomes after surgery. Vagal nerve stimulation appears to be an effective and well-tolerated adjunctive therapy in patients with tuberous sclerosis complex and seizures refractory to medical therapy. Resective surgery has a better prospect for improved seizure control.

Adverse events in children receiving intermittent left vagal nerve stimulation.

The purpose of this study was to determine the frequency of unexpected events during intermittent vagal nerve stimulation in 24 patients stimulated for a total of 61 patient years. The charts of 24 children undergoing periodic stimulation of the left vagal nerve on research protocols were reviewed to determine the nature and frequency of adverse events and the total length of time they were stimulated. Fifteen adverse events were discovered in 12 patients. Thirteen were likely related to the device, and four other events might have been related. Two of these resulted in voluntary termination of vagal nerve stimulation, and the rest were treatable. Vagal nerve stimulation was tolerated in this series of patients. As opposed to the more standard drug therapies, adverse events during vagal nerve stimulation do not necessitate termination of therapy, but these events frequently lead to unforeseen surgery under general anesthesia.

Leukocyte tubuloreticular inclusions in Reye's syndrome.

Tubuloreticular inclusions (TRI) have been observed in the rough endoplasmic reticulum of blood lymphocytes and monocytes in two cases of Reye's syndrome initiated by influenza infections. Tubuloreticular inclusions are seen in these mononuclear leukocytes during the acute phase of illness, but not during convalescence. Since TRI have been demonstrated in peripheral mononuclear leukocytes in patients with acquired immunodeficiency syndrome, systemic lupus erythematosus, and certain viral infections including T-cell leukemia, it may be that the finding of TRI in Reye's syndrome reflects a viral infection and/or immune dysfunction, if such association is not proved to be fortuitous.

Hunter' syndrome. Ultrastructural features in young children.

Ultrastructural abnormalities in two stepbrothers with Hunter's syndrome, ages 1 and 4 years, were found in cortical neurons, neurons of the myenteric plexus, and skin. Inclusions containing little or no electron-dense material were noted in most tissues, and lamellar figures were restricted to cortical neurons and neurons of the myenteric plexus. These changes correlate with those described in tissues obtained at post mortem.

Neurochemical changes in Leigh's disease.

A series of children with Leigh's disease had normal hepatic pyruvate carboxylase activity, increased cerebral thiamine diphosphate, and decreased cerebral thiamine triphosphate. These thiamine esters were normal in liver. The author suggests that the histologic changes of Leigh's disease, as well as the similar changes of Wernicke's disease, could be due to a deficiency of cerebral thiamine triphosphate.

Gluteal fold flaps for perineal reconstruction.

Defects of the perineum are created during ablative procedures for gynaecological, urological and colorectal malignancies. The gluteal fold flap is a reliable means of reconstructing these defects. We retrospectively reviewed case notes of gluteal fold flaps performed for perineal reconstruction over four years (2007-2010) in our institution. 77 perineal defects were reconstructed using unilateral or bilateral gluteal fold flaps (127 flaps in total). 50% of all patients are discharged before 11 days, and 90% were discharged within one month. Mean time to discharge was 13.2 days. 70% of all patients were completely healed at 2 months, and 85% completely healed at three months. Pre-operative radiotherapy was found to have a prolonging effect on the time to discharge (P<0.05) but did not reach statistical significance when considering the eventual time to healing. The number of co-morbidities that each patient had at the time of surgery had a prolonging effect on both time to discharge and time to healing (P<0.03). The type of resected areas that required reconstruction did not have a statistically significant effect on the time to discharge, but defects where the anus had been resected did eventually take longer to heal than those were the anus was not resected (P<0.01). 124 flaps were successful (97.6%) with total or partial flap loss occurring in three. Complications were seen in 34 of the 77 patients (44%), with simple wound breakdown resulting in delayed healing seen most frequently (30%). The gluteal fold fasciocutaneous flap is a versatile option for reconstructing a wide range of pelvic and perineal defects. Patients with multiple co-morbidities, cases with radiotherapy and instances where the anus has been resected are more likely to experience longer healing times. We present our algorithm for management for perineal defects after tumour resection.