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Biomedical subjects

Martin J Brodie

Publications and source records attributed to Martin J Brodie.

At least 19 recordsLinked to original sources
PubMed2006

Sudden unexpected death in epilepsy: a search for risk factors.

Sudden unexpected death in epilepsy (SUDEP) is the commonest cause of seizure-related mortality in people with refractory epilepsy. Of the 6140 patients registered with the Epilepsy Unit at the Western Infirmary in Glasgow between 1982 and 2005, 529 had died, 62 (11.7%) of whom succumbed to SUDEP. All but 2 deaths occurred at home; 3 were witnessed. Two living controls were matched with each SUDEP case for year of birth, gender, and syndromic classification. Mean duration of epilepsy was significantly longer in cases compared with controls (P=0.001). More people succumbing to SUDEP had had a seizure within the previous year (P=0.007). There were no significant associations between SUDEP and a history of generalized tonic-clonic seizures, drug polytherapy, and current use of carbamazepine. There is an urgent need for a large-scale, prospective, international, community-based study of SUDEP to explore more closely the risk factors to plan preventive strategies.

Adolescent↗
PubMed2006

Outcomes research: clinical trials in the elderly.

Very few clinical trials have been done in the elderly. This report reviews results of two completed studies and describes one in progress. The largest published study was a United States Veterans Affairs Administration study in newly diagnosed patients with epilepsy. It compared carbamazepine to gabapentin and lamotrigine, and found that, although equivalent in efficacy, the newer antiepileptic drugs (AEDs) were better tolerated. This study also highlighted many of the difficulties in recruiting and retaining elderly patients in studies, the large number of comorbidities, and the problems of distinguishing seizures in the elderly from other symptoms. Another study of new-onset epilepsy suggested that a large percentage of elderly patients respond to initial AED therapy, but side effect profiles differ. More studies are needed to better define the risk/benefit relationships in elderly patients.

Aged↗
PubMed2006

Pharmacological outcomes in older people with newly diagnosed epilepsy.

BACKGROUND: Old age is the most common time in life to develop epilepsy. Despite this, there are few published data exploring pharmacological outcomes in this population. METHODS: We analyzed outcomes in 117 older patients (median age, 73; range, 65-92) for whom localization-related epilepsy was newly diagnosed and treatment begun at a single center over a 20-year period. RESULTS: Seventy-three (62%) patients became seizure-free for at least 12 months on their first AED, with 30 (26%) failing to respond and 14 (12%) not tolerating the treatment. Following pharmacological manipulation, 93 (79%) patients attained remission, 87 (93%) on monotherapy and 6 (7%) on duotherapy. No individual AED was more likely to confer seizure freedom than any other. Patients attaining remission were more likely to have had fewer pretreatment seizures (P=0.0078) than those who did not obtain full seizure control. CONCLUSION: The prognosis in epilepsy may be better in older than younger people, perhaps reflecting lower lesional epileptogenicity and genetic predisposition.

Age Factors↗
PubMed2006

Active control comparisons: the ideal trial design.

This report describes the concept for a clinical trial that uses carbamazepine as the gold-standard active control for a study of newly diagnosed patients. The authors describe an endpoint including efficacy and tolerability, and a stopping rule that uses a series of interim analyses in order to reach a conclusion as efficiently as possible without sacrificing reliability.

Anticonvulsants↗
PubMed2006

Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study.

BACKGROUND: People with epilepsy are at increased risk of premature death compared with the general population. Many clinicians are unsure whether and when this issue should be broached with their patients. We analysed mortality in patients with newly diagnosed and chronic epilepsy over a 20-year period. METHODS: Patients who attended the epilepsy service at the Western Infirmary in Glasgow, UK between 1981 and 2001, with newly diagnosed epilepsy (n=890) or referred after receiving unsuccessful treatment elsewhere (n=2689) were included in the study. Mortality data were obtained from the General Registrar Office for Scotland. Causes of death were ascertained from death certificates and primary care and health authority records. The two patient cohorts were compared with age-matched and sex-matched Scottish comparison groups. Standardised mortality ratios (SMR) were calculated for each epilepsy type, 10-year age band, and cause of death category. FINDINGS: Newly diagnosed patients had a 42% increase in mortality (SMR 1.42, 95% CI 1.16-1.72) compared with the comparison group. Increased mortality was recorded in those who had not responded to treatment, with no increase in risk observed in patients who were seizure free. In the chronic epilepsy cohort, there was more than double the expected number of deaths (2.05, 1.83-2.26). The incidence of sudden unexpected death in epilepsy was 1.08 and 2.46 per 1000 patient-years in patients with newly diagnosed and chronic epilepsy, respectively. The greatest excess in mortality was reported in patients younger than 30 years. INTERPRETATION: Mortality risks and preventive strategies should be discussed with patients with epilepsy when treatment fails or is refused despite recurrent seizures.

Adult↗
PubMed2006

Modern antiepileptic drugs: guidelines and beyond.

PURPOSE OF REVIEW: Ten antiepileptic drugs have been licensed since 1990. Their usage will be briefly reviewed focusing on new data and inclusion in guidelines. The hypotheses exploring the underlying basis of pharmacoresistance will be presented. RECENT FINDINGS: Lamotrigine, gabapentin, topiramate, and oxcarbazepine are available for use as monotherapy in many countries following comparative studies with older antiepileptic drugs. Zonisamide and pregabalin have recently obtained licences as adjuvant therapy in the US and Europe for partial epilepsy with or without secondary generalization. The UK National Institute for Clinical Excellence guideline has advised, largely based on cost, against the routine use of modern antiepileptic drugs, except when older drugs have failed or are contraindicated. This contrasts with the US guidelines which are less conservative. Surgically resected specimens from patients with refractory epilepsy have led to the development of two hypotheses to explain pharmacoresistant epilepsy. SUMMARY: The introduction of 10 new antiepileptic drugs has provided greater choice for patients and doctors, although evidence in support of their superiority over the older drugs is sparse. This has led to conflicting advice in guidelines. Recent developments in the understanding of pharmacoresistance may explain the relatively high incidence of refractory epilepsy.

Anticonvulsants↗
PubMed2006

Refractory epilepsy: mechanisms and solutions.

Pharmacoresistance remains a major challenge in epilepsy management. The availability of ten new antiepileptic drugs since the late 1980s has not dramatically improved the outcome of refractory epilepsy. This article provides an overview of the contemporary understanding of epilepsy and the limitation of current treatment modalities, discusses putative biological mechanisms of medical intractability and reviews some of the novel strategies under investigation to overcome the challenge of pharmacoresistance.

Anticonvulsants↗
PubMed2006

Combination therapy in epilepsy: when and what to use.

After being regarded as a last resort for over two decades, the role of combination therapy as a treatment strategy for epilepsy is undergoing re-evaluation. This is a result of the growing appreciation that all seizures cannot be controlled by monotherapy in a substantial proportion of patients, and of the development of a range of modern antiepileptic drugs (AEDs), some of which are better tolerated and less prone to complex pharmacokinetic drug interactions than their older counterparts.Robust evidence to guide clinicians on when and how to combine AEDs is lacking, and current practice recommendations are largely empirical. Monotherapy should remain the treatment of choice for newly diagnosed epilepsy. A combination of two AEDs can be considered after failure, resulting from lack of efficacy, of one or two different monotherapy regimens. A few patients will become seizure-free with a combination of three AEDs, but treatment with a combination of four or more is unlikely to be successful. There is some evidence to support a pharmacomechanistic approach to AED combination. Care should be taken to avoid excessive drug load, which is associated with increased toxicity. Bigger and better randomised, controlled studies are needed to determine the optimal time and way to combine AEDs.

Anticonvulsants↗
PubMed2005

Zonisamide as adjunctive therapy for refractory partial seizures.

Zonisamide (Zonegran) has been used extensively worldwide (>2 million patient-years experience) for the effective treatment of a broad range of epilepsy indications. Four randomised, placebo-controlled trials (duration or=300 mg/day to be efficacious in treating refractory partial seizures in adults. In a pivotal European study, zonisamide 500 mg/day was significantly superior to placebo in reducing the frequency of complex partial seizures (-51% versus -16%), all partial seizures and all seizures, with dose-dependent benefit provided over a 100-500 mg/day dose range. Supporting trials have confirmed significant increases in reduction in median seizure frequency (up to 41%) and responder rates (35-42%) compared with placebo following zonisamide 400-600 mg/day, enabling 20-27% of patients to attain >or=75% reduction in seizure frequency. Pooled data from all four placebo-controlled trials demonstrate an excellent tolerability and safety profile; adverse events are generally of mild-moderate severity with few leading to discontinuation, and incidence of serious adverse events is comparable to placebo. These data support the use of zonisamide in combination with commonly used antiepileptic drugs to provide efficacious and well-tolerated treatment for patients with refractory partial seizures.

Adolescent↗
PubMed2005

A randomized, double-blind, placebo-controlled trial of topiramate in adults with epilepsy and intellectual disability: impact on seizures, severity, and quality of life.

This randomized, double-blind, placebo-controlled UK trial evaluated the effect of topiramate as add-on therapy on seizure frequency, seizure severity, and quality of life in patients with epilepsy and intellectual disability. There were three phases: 4 weeks baseline, 18 weeks titration to 200-400 mg topiramate/day (adults) or 5-9 mg/kg/day (children), 12 weeks maintenance. Recruitment was low (88/120); analyses were underpowered. Seizure frequency varied enormously (median 17.7, maximum 1706.2). There was no significant difference in reduction in mean total seizure frequency or number of responders between the groups. Topiramate reduced seizure frequency by >30% from baseline (placebo 1%); post hoc analyses showed a trend toward significance (R ratio, P=0.052). There were no significant differences between the groups with respect to mean seizure severity or other outcome measures. Topiramate was generally well tolerated; body weight (P=0.015) and systolic blood pressure (P=0.043) were reduced. The study suggests that topiramate reduces seizure frequency in patients with epilepsy and intellectual disability without the added burden of behavior effects, and was potentially advantageous to physical well-being.

Adaptation, Psychological↗
PubMed2005

Medical therapy of epilepsy: when to initiate treatment and when to combine?

Most patients reporting more than one well-documented or witnessed seizure require prophylactic antiepileptic (AED) therapy. Those with an underlying brain disorder and/or an abnormal electroencephalogram should probably be treated after their first event. The goal should be maintenance of a normal lifestyle by complete seizure control with no or minimal side-effects. Failure of the first AED due to lack of efficacy implies refractoriness. A policy of consecutive substitutions is unlikely to be an effective strategy. Thus, if the first or second monotherapy improves control but does not produce seizure freedom, an AED with different and perhaps multiple mechanisms of action should be added. Strategies for combining drugs should involve individual assessment of patient-related factors, including seizure type and epilepsy syndrome classifications coupled with an understanding of the pharmacology, side-effects and interaction profile of the AEDs. Reducing the dose of one or more AEDs may help accommodate the introduction of a second or third drug. An orderly approach to the pharmacological management and, when appropriate, surgical investigations for each epilepsy syndrome will optimise the chance of perfect seizure control and help more people achieve safer and more fulfilled lives.

Anticonvulsants↗
PubMed2005

Levetiracetam in refractory epilepsy: a prospective observational study.

This prospective open-label study used flexible dosing schedules of levetiracetam (LEV) in patients with refractory epilepsy attending a single centre to explore its effectiveness in everyday clinical practice. One hundred and fifty-six patients with uncontrolled localisation-related or idiopathic-generalised epilepsy were prescribed adjunctive LEV following a 3-month baseline. The primary end points were seizure freedom for at least 6 months, > or = 50% reduction (responder) or <50% reduction for 6 months, or discontinuation of LEV due to lack of efficacy, adverse effects or both. Overall, 40 (26%) patients became seizure free on adjunctive LEV, including 8 (40%) with idiopathic-generalised epilepsy. Twenty-five (63%) of the seizure-free patients took 1000 mg LEV per day or less. A further 33 (21%) patients were classified as responders. LEV was withdrawn in 46 (29%) patients (27 adverse effects, 8 lack of efficacy, 11 both). Intolerable sedation, reported by 20 (13%) patients, was the commonest complaint leading to treatment failure. Behavioural side effects led to LEV withdrawal in 7 (5%) patients. LEV is an effective adjunctive treatment for refractory idiopathic and localisation-related epilepsies. Many patients who responded optimally to LEV did so at 1000 mg per day or less.

Adolescent↗
PubMed2005

Outcomes in newly diagnosed localization-related epilepsies.

A total of 558 patients with a range of localization-related epilepsy syndromes starting treatment in a single centre were followed over a period of up to 20 years. Overall, 343 (62%) patients became seizure free for 12 months or more (responders), 92% of whom (57% of total population) remained in remission until the end of follow-up. Only 27 (5%) responders relapsed and subsequently developed refractory epilepsy. The remaining 215 (38%) patients never became seizure free for any 12-month period. There were no significant differences in outcome between cryptogenic (56% remission) and symptomatic (57% remission) epilepsies. Patients with underlying cortical atrophy (71% remission; p<0.05) or cerebrovascular disease (70% remission; p<0.01) did better, while those with traumatic brain injury (35% remission; p<0.001) did worse than the remainder of the symptomatic group. Remission rates in patients with cortical dysplasias (60%), hippocampal atrophy (50%) and primary brain tumors (52%) appeared no different from those with other symptomatic epilepsies. Overall, 20-40% patients with each epilepsy syndrome reported no further seizures after starting AED treatment including 21% with hippocampal atrophy and 33% with cortical dysplasia. More than 50% of patients developing localization-related epilepsy during adolescence or in adulthood had a good outcome. Prognosis in those with underlying hippocampal atrophy or cortical dysplasia was not always bad.

Adolescent↗
PubMed2005

Pharmacological outcomes in newly diagnosed epilepsy.

The response to antiepileptic drugs (AEDs) has been examined in 780 adult and adolescent patients with newly diagnosed epilepsy presenting with a range of seizure types and epilepsy syndromes over a 20-year period. Carbamazepine (CBZ, n=312), sodium valproate (VPA, n=315), and lamotrigine (LTG, n=249) were the most common AEDs prescribed as monotherapy. More patients with localization-related epilepsies became seizure free with LTG (63%) than with CBZ (45%, P=0.006) or VPA (42%, P=0.006). For idiopathic generalized epilepsies a greater proportion of patients achieved control with VPA (68%) than with CBZ (31%) or LTG (45%). In particular, more patients with juvenile myoclonic epilepsy responded to VPA (75%) compared with LTG (39%, P=0.014). Seizure freedom was achieved with modest or moderate daily doses (median CBZ 400mg, VPA 1000 mg, (LTG) 150 mg) of all three AEDs in the majority of patients achieving remission. Time to first seizure did not differ among these three drugs when given as first treatment. Adverse effects leading to withdrawal were more frequent with CBZ (16%) than with VPA (7%, P=0.03) or LTG (7%, P=0.018). In patients failing initial monotherapy, response to a combination of two AEDs (27%) was not different from that with alternative monotherapy (32%). The majority of patients with newly diagnosed epilepsy responding to treatment did so rapidly and completely with moderate doses of AEDs, with no differences in time to first seizure.

Adolescent↗
PubMed2005

Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy.

The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.

Adult↗
PubMed2005

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures.

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001). The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.

Adolescent↗