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D Chadwick

Publications and source records attributed to D Chadwick.

At least 55 records · Page 3Linked to original sources
PubMed1997

Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies.

The focus in assessing new antiepileptic drugs (AEDs) varies with the needs of the assessor. Patients and doctors seek evidence-based clinical information, regulatory agencies look for efficacy and safety, and the health-care industry demands data on the risk-benefit ratio attached to a product. The pharmaceutical companies attempt to satisfy the interests of all parties involved. Most new AEDs obtain a first license based on placebo-controlled, randomized clinical trials as add-on therapy in patients with chronic refractory partial epilepsy, a method which, in fact, explores the efficacy of different drug combinations rather than measuring the efficacy of the new drug itself. Although that methodology satisfies the requirements of the licensing authorities, it fails to provide the clinical community with the information necessary to make rational treatment decisions, as would be derived from monotherapy studies. This article reviews controversies surrounding monotherapy studies and the design of comparative monotherapy clinical trials. A persuasive argument can be made that the goal of clinical trial design should be ethically acceptable, clinically meaningful studies in which new AEDs are compared with optimal doses of standard AEDs to inform clinical practice, meet licensing requirements, guide reasonable marketing efforts, and allow appropriate reimbursement.

Acetates↗
PubMed1996

FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes.

We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered.

Angelman Syndrome↗
PubMed1996

Gabapentin in generalized seizures.

The efficacy of gabapentin (Neurontin), in generalized seizures was evaluated in this 14 week, double-blind, placebo-controlled, parallel-group, add-on, multicenter study. A total of 129 patients with refractory generalized seizures were randomized to receive either placebo or 1200 mg/day gabapentin as add-on therapy. Patients received their standard regimens of antiepileptic drugs (AEDs) during a 12 week baseline period, and gabapentin or placebo was added-on in the subsequent 14 week evaluation period. Results of both an intent-to-treat (ITT) and evaluable-patient analyses showed that gabapentin provided greater reduction in the frequency of generalized tonic-clonic seizures than did placebo; however, the differences between treatments were not statistically significant. Gabapentin did not affect the frequency of absence or myoclonic seizures. Adverse events were reported by 67% of gabapentin-treated patients and by 56% of placebo-treated patients. The most frequently occurring adverse events among patients receiving gabapentin were somnolence, fatigue, and dizziness. Gabapentin is well tolerated by patients with generalized seizures. The results of this study show a trend toward an effect of gabapentin in reducing the frequency of generalized tonic-clonic seizures and suggest that further exploration of high dose gabapentin in generalized epilepsy is warranted.

Acetates↗
PubMed1996

A survey comparing lamotrigine and vigabatrin in everyday clinical practice.

The objective of this study was to compare the efficacy and tolerability of two new antiepileptic drugs, lamotrigine (LTG) and vigabatrin (GVG) in everyday clinical practice. A comprehensive retrospective survey of a computerized data base and hospital case notes was carried out at the Mersey Regional Epilepsy Clinic (MREC), Liverpool, which services a population of 3 million in the North West of England. The study comprised 333 out-patients with refractory epilepsy exposed to LTG and GVG forming a subset in a total population of 2250 patients with epilepsy held on a comprehensive database. The main outcome measures were duration of treatment with each drug described by a Kaplan-Meier survival curve, seizure control determined by a 50% decrease in seizure frequency and freedom from seizures, and incidence of adverse drug effects leading to discontinuation. The Kaplan-Meier curve indicated a 57% probability of patients continuing to take LTG and 43% GVG after 40 months. A 50% improvement in seizure control followed the addition of LTG in 45% of patients, with 10% seizure free, compared with 32% and 6%, respectively after the addition of GVG. LTG was discontinued because of adverse events (most frequently skin rash) in 15% of patients compared to GVG in 25% (particularly because of personality disturbance and psychiatric disorder). Both LTG and GVG are effective new AEDs in patients with refractory epilepsy, treated in a tertiary referral out-patient setting. LTG has a broader spectrum of antiepileptic efficacy for patients with both partial and idiopathic generalized seizures, whereas GVG should be reserved for patients with partial seizures at low risk of psychiatric disorder.

Anticonvulsants↗
PubMed1996

Tiagabine and non-convulsive status epilepticus.

Three patients who developed clinical evidence of non-convulsive status epilepticus while on high doses of the investigational antiepileptic drug, tiagabine are reported. This apparently paradoxical phenomenon developed when the tiagabine dose was increased to 48 mg/day in one patient, and to 60 mg/day in two other patients, in combination with other antiepileptic drugs. Seizure control improved following reduction in tiagabine dose in one patient and discontinuation of tiagabine in the two others. The observation raises the possibility of a clinically relevant paradoxical epileptogenic effect of GABA-ergic drugs such as tiagabine.

Adult↗
PubMed1996

Quality of life measurements in epilepsy.

In the treatment of the patient with epilepsy not only seizure control but quality of life issues are important aspects of management. Aspects that have an impact on the quality of life include seizure frequency and severity, social functioning, psychological well-being, disease specific measures, and general health status.

Anticonvulsants↗
PubMed1996

Comparing antiepileptic drugs.

The physician's choice of antiepileptic drug for a particular patient should be based on firm evidence. The current body of evidence generated from randomized, controlled monotherapy trials is discussed. Attention is focused on four recently published randomized trials in which monotherapy with one drug is compared with monotherapy with another. The limitations of our current knowledge are discussed and some suggestions for future research are made.

Anticonvulsants↗
PubMed1996

Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group.

PURPOSE: To determine the risk of further seizures and probability of further remission after a first seizure recurrence in patients in remission of their epilepsy, and to examine the prognostic factors influencing this risk. METHODS: Continued follow-up of a cohort of 409 patients with a recurrence of seizures after randomization to the Medical Research Council (MRC) Antiepileptic Drug Withdrawal Study. RESULTS: By 3 years after a seizure, 95% of patients have experienced a further 1-year remission of their epilepsy and by 5 years 90% of patients have experienced a further 2-year remission. The most important factors contributing to the risk of further seizures after a first seizure after randomization were the previous seizure-free interval, having partial seizures at recurrence, and having previously experienced seizures while receiving treatment. There was no evidence that the group of patients who had discontinued or reduced treatment before the occurrence of their first seizure after randomization had a different outcome from those patients who continued treatment. CONCLUSION: Our results provide no evidence that discontinuation of antiepileptic drugs (AEDs) modifies the long-term prognosis of a person's epilepsy, although it does increase the risk of seizures in the 1- to 2-year period after discontinuation.

Adolescent↗
PubMed1996

Risk of accidents in drivers with epilepsy.

OBJECTIVE: To estimate the risks of road traffic accidents over a period of three years in drivers with a history of single seizures or epilepsy, and to compare them with a cohort of drivers followed up by the Transport Research Laboratory (TRL). DESIGN: A retrospective survey of driving and accident experience by self-completion questionnaire. SUBJECTS: 16,958 drivers with a previous history of epilepsy responding to the survey and 8888 non-epileptic drivers responding to a TRL survey. MAIN OUTCOME MEASURES: The risk of any accident, any accident producing an injury, and any accident producing a serious injury, over a three year period. RESULTS: After adjustment for differences in age, sex, driving experience, and mileage between the two populations there was no evidence of any overall increase in risk of accidents in the population of drivers with a history of epilepsy. However, there was evidence of an increased risk of more severe accidents in the population with epilepsy. The risk was increased by about 40% for serious injuries and there was evidence of a twofold risk of increase in non-driver fatalities. These increases seem largely explicable by the occurrence of seizures in this population during the three years of driving that the survey covered. CONCLUSIONS: The acceptability of driving for people with a history of epilepsy should be determined by an acceptable risk of accidents resulting in injury or serious injury rather than overall accident rates. As people with epilepsy can now drive after a 12 month seizure free period rather than the required two year period when this survey was undertaken, it is important to ascertain whether there is any increased risk of injury associated accidents with this policy.

Accidents, Traffic↗
PubMed1996

Linkage analysis of juvenile myoclonic epilepsy and microsatellite loci spanning 61 cM of human chromosome 6p in 19 nuclear pedigrees provides no evidence for a susceptibility locus in this region.

Linkage analysis in separately ascertained families of probands with juvenile myoclonic epilepsy (JME) has previously provided evidence both for and against the existence of a locus (designated "EJM1"), on chromosome 6p, predisposing to a trait defined as either clinical JME, its associated electroencephalographic abnormality, or idiopathic generalized epilepsy. Linkage analysis was performed in 19 families in which a proband and at least one first- or two second-degree relatives have clinical JME. Family members were typed for seven highly polymorphic microsatellite markers on chromosome 6p: D6S260, D6S276, D6S291, D6S271, D6S465, D6S257, and D6S254. Pairwise and multipoint linkage analysis was carried out under the assumptions of autosomal dominant inheritance at 70% and 50% penetrance and autosomal recessive inheritance at 70% and 50% penetrance. No significant evidence in favor of linkage to the clinical trait of JME was obtained for any locus. The region formally excluded (LOD score < -2) by using multipoint analysis varies depending on the assumptions made concerning inheritance parameters and the proportion of linked families, alpha-that is, the degree of locus heterogeneity. Further analysis either classifying all unaffected individuals as unknown or excluding a subset of four families in which pyknoleptic absence seizures were present in one or more individuals did not alter these conclusions.

Adolescent↗
PubMed1996

A general practice records audit of the process of care for people with epilepsy.

BACKGROUND: The appropriateness of epilepsy as a topic for general practice audit activity has been emphasized, but few audits have been undertaken to data and those that have are small scale. Historically, management of epilepsy has been a neglected area, and services for people with epilepsy remain generally poor. AIM: The study was designed to examine the process of care for people with epilepsy through a region-wide audit of general practitioner records. METHOD: General practitioners in 31 randomly selected general practices in one UK health region undertook a notes audit for all patients identified as having active epilepsy (patients who had had seizures in the last 2 years, or were currently seizure-free but on antiepileptic medication). A standard pro forma was used to collect information relating to diagnosis, drug treatment, and primary and secondary care contacts. RESULTS: Recording of information in the notes was generally good, but poor for some key items essential to the effective management of the condition; results suggest that a number of recommendations about provision of care for epilepsy are not being met: in particular, EEG and CT investigations often appear poorly directed; prescribed antiepileptic therapy is not always optimal; significant numbers of patients are being treated in hospital by non-neurologists; there is little evidence of any regular review being undertaken by general practitioners of their patients with epilepsy; and counselling about the non-clinical aspects of epilepsy often appears inadequate. CONCLUSIONS: Despite recommendations in a number of recent reports, gaps and inconsistencies in epilepsy care persist, both at the primary and secondary level. The means by which such shortcomings can be reduced (e.g. by specialist epilepsy nurses working across the primary-secondary care interface) should now be systematically examined. The study has highlighted a need for evidence-based guidelines which span the primary-secondary care interface and clarify the contribution of the various practitioners involved in the provision of care for people with epilepsy.

Adolescent↗
PubMed1995

Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.

Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.

Adolescent↗
PubMed1994

[Value of sodium valproate in the treatment of partial epilepsy].

There seems no doubt, in reviewing the literature from controlled randomized studies, that valproate is effective in the treatment of partial epilepsy. There is unanimity amongst a number of large comparative studies that valproate seems as effective as carbamazepine in suppressing secondarily generalized seizures. Controlled studies that have used minimum doses of carbamazepine or valproate in previously untreated patients with partial epilepsy have not suggested that the outcomes with the two drugs are significantly different; however, a Veterans Administrations Study which included over 200 patients who had been previously treated with other antiepileptic drugs suggested the possibility that carbamazepine might be somewhat more effective in suppressing complex partial seizures than valproate. In practice the choice between the two current first-line antiepileptic drugs (carbamazepine and valproate) would seem to be determined by their different adverse effect profiles. Valproate is better tolerated in the shorter term because of the absence of idiosyncratic skin reactions, whilst those patients who tolerate carbamazepine initially may have fewer long-ferm problems and seem less prone to develop weight gain than patients treated with sodium valproate. For patients presenting with seizures that cannot easily be classified, valproate would seem to be the drug of choice because of its broader spectrum of antiepileptic drug activity.

Adolescent↗
PubMed1994

Gabapentin.

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Acetates↗