Non-interventional surveillance study of adverse events in patients with epilepsy.

OBJECTIVES: Compare adverse events (AEs) in patients with epilepsy taking different antiepileptic drugs (AEDs) using standardized physician-completed questionnaires. MATERIALS AND METHODS: Multicenter, observational, cross-sectional study in epilepsy patients aged ≥4 , stable on 1-2 AED(s) for ≥3 months. RESULTS: One thousand and nineteen patients were evaluated: 28.7% took newer, 71.3% older (or older + newer) AED(s); 56.9% monotherapy; 43.1% polytherapy. Overall, 68.3% reported ≥1 AE (61.3% newer; 71.1% older AEDs), most commonly: cognitive function disturbances, sedation, psychological problems. Patients taking newer AEDs were significantly less likely to report ≥1 AE (OR [95% CI]: 0.64 [0.46-0.89], P = 0.008). Treatment/dose changed at study visit: 22.8% (17.5% newer; 24.9% older AEDs) because of (newer/older); lack of efficacy (6.2%/7.8%); AEs (4.1/8.4%); absence of seizures (3.8/4.0%). Patients receiving levetiracetam or lamotrigine were significantly less likely to report AEs/modify treatment. CONCLUSION: Patients taking newer AEDs were significantly less likely to report AEs, although the non-randomized study design does not allow the lower rate of AEs to be attributed with certainty to the use of newer AEDs. A standardized AE questionnaire appeared useful for monitoring AEs/optimizing AED therapy.

Assessment of a dose-response relationship of levetiracetam.

The aim of this study was to assess the relationship between levetiracetam dose and both efficacy and safety in adult patients with refractory partial epilepsy. Dose-response relationships for levetiracetam efficacy were evaluated using pooled data from three trials including adults with refractory partial epilepsy. Two were randomized, double-blind, placebo-controlled, parallel-group trials in which doses of 1000-3000 mg/day of levetiracetam were administered as adjunctive therapy. The third consisted of the two parts of a crossover randomized, double-blind study in which levetiracetam (1000 or 2000 mg/day) or placebo was added to ongoing therapy. Data from each part of the crossover trial were included as if it was an independent parallel-group study. A fourth randomized double-blind trial was added for the safety evaluation. It included data from adults receiving placebo or 2000 mg/day of levetiracetam as adjunctive therapy for refractory partial seizures. The combined analysis showed an increasing effect with increasing dose. The responder rates (> or = 50% reduction in seizures) for placebo and levetiracetam 1000, 2000, and 3000 mg/day were 13.1%, 28.5%, 34.3%, and 41.3%, respectively. The respective values for seizure freedom were 0.8%, 4.7%, 6.3%, and 8.6%. There was no evidence of a dose-response relationship with regard to adverse events, including those (asthenia, dizziness, somnolence) most commonly associated with this antiepileptic drug. Patients who do not become seizure-free at the lowest recommended levetiracetam dose (1000 mg/day) should be titrated to 2000 or 3000 mg/day to provide the greatest opportunity for efficacy with little or no increased risk for adverse events.

Hereditary otovestibular dysfunction and Ménière's disease in a large Belgian family is caused by a missense mutation in the COCH gene.

OBJECTIVE: To report the clinical, auditory, and vestibular characteristics of a nonsyndromic otovestibular dysfunction in a large Belgian family caused by a missense mutation of the DFNA9 gene: COCH. STUDY DESIGN: Retrospective study of the clinical, audiologic, and vestibular data of 60 genetically affected cases. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carry the genetic (P51S) defect linked to the inherited hearing and vestibular impairment. INTERVENTIONS: Diagnostic otologic, audiometric, and vestibular analysis and imaging. MAIN OUTCOME MEASURES: Pure tone audiometry, supraliminary audiometry. and vestibular investigation. RESULTS: The autosomal dominant inherited impairment was characterized by peripheral degeneration of the inner ear, leading to total deafness and bilateral vestibular areflexia. CONCLUSIONS: The genetically affected persons of a Belgian family shared a progressive sensorineural hearing loss starting between the third and sixth decade. Vestibular symptoms started at about the same age as the hearing loss. The vestibular symptoms consisted of instability in darkness, a tendency to fall sideways, light-headiness, a drunken feeling, and attacks of vertigo. Most of the patients reported tinnitus, and half of them reported pressure in the ears. Clinically, 9 of the 60 patients met the criteria for definite Ménière's disease, and another 13 and 17 patients met the criteria for probable or possible Ménière's disease, respectively. All 9 were older than the age of 35, but only 1 was older than 55 years, so more than 30% of the patients were between 35 and 55 years old. A specific pattern could be recognized in the evolution of the otovestibular impairment. Under the age of 35 years, almost all the affected family members had normal hearing, whereas above the age of 55 years, the hearing loss was at least moderate, and vestibular hypofunction occurred. In between, there was a transition period of two to three decades, when deterioration of the cochleovestibular function occurred, with a temporary audiometric and vestibular asymmetry.

Optimal parameters for transurethral intravesical electrostimulation determined in an experiment in the rat.

OBJECTIVE: Parameters of current for transurethral intravesical electrostimulation (IVES) are studied in the rat to determine the settings which elicit optimal detrusor contractions. Action mechanisms related to the induction of detrusor contractions upon ives are also investigated. METHODS: In 24 female Wistar rats transurethral IVES was performed using 95 combinations of different pulse durations and frequencies. The reference electrode was positioned in the bladder, in the urethra, or on the abdominal wall. RESULTS AND CONCLUSIONS: The optimal detrusor contractions are induced in the rat with a current of 10 Hz frequency and 20 ms pulse duration. A mathematical correlation is found between frequency and pulse duration which permits to determine the best combination. Evidence for the existence of local factors inducing detrusor contractions by IVES is given. The detrusor contractions proved independent of the position of the reference electrode.

Elastic properties of human aortas in relation to age and atherosclerosis: a structural model.

A new structural model is described for the tension-radius relationship of blood vessels, taking into account their mechanically important constituents: collagen, elastin and smooth muscle. The model has four characteristic parameters: EC, the Young's modulus of the collagen fibres; ESE, the Young's modulus of the combined smooth-muscle/elastin network; epsilon mu, the amount of strain at which the high stiffness region on the tension-radius curve is reached, and eta an indicator for the degree of collagen fibre stretching. The structural stiffness of the wall constituents is reflected by EC and ESE whereas the global stiffness of the entire blood vessel is described by epsilon mu and eta. All these elasticity parameters are pressure independent, in contrast to generally quoted values for the incremental modulus or vascular compliance which are strongly pressure dependent. Hence, an objective comparison of the mechanical properties for various types of blood vessel, based on the present model parameters, has been made possible. The model was successfully fitted to tension-radius data of 65 human aortas, age range 30-88 years, with moderate or severe atherosclerosis. The structural as well as the global stiffness changes with age, e.g. collagen stiffness shows a ninefold increase over 60 years. Global stiffness depends on atherosclerosis.

Founder effect in a Belgian-Dutch fragile X population.

For many years, the high prevalence of the fragile X syndrome was thought to be caused by a high mutation frequency. The recent isolation of the FMR1 gene and identification of the most prevalent mutation enable a more precise study of the fragile X mutation. As the vast majority of fragile X patients show amplification of an unstable trinucleotide repeat, DNA studies can now trace back the origin of the fragile X mutation. To date, de novo mutations leading to amplification of the CGG repeat have not yet been detected. Recently, linkage disequilibrium was found in the Australian and US populations between the fragile X mutation and adjacent polymorphic markers, suggesting a founder effect of the fragile X mutation. We present here a molecular study of Belgian and Dutch fragile X families. No de novo mutations could be found in 54 of these families. Moreover, we found significant (P < 0.0001) linkage disequilibrium in 68 unrelated fragile X patients between the fragile X mutation and an adjacent polymorphic microsatellite at DXS548. This suggests that a founder effect of the fragile X mutation also exists in the Belgian and Dutch populations. Both the absence of new mutations and the presence of linkage disequilibrium suggest that a few ancestral mutations are responsible for most of the patients with fragile X syndrome.