Showing papers by "Josemir W. Sander published in 2006"

Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations

Abstract: Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).

Efficacy assessment of phenobarbital in epilepsy: a large community-based intervention trial in rural China.

Abstract: Summary Background Many people with epilepsy need not experience further seizures if the diagnosis and treatment are correct. Most epilepsy patients have convulsions, which are usually fairly easy to diagnose. This study tested a model for treatment of people with convulsive forms of epilepsy at primary health-care level in rural areas of China. Methods Patients with convulsive epilepsy were identified at primary care level and provided with phenobarbital monotherapy. Local physicians, who were provided with special training, carried out screening, treatment, and follow-up. A local neurologist confirmed the diagnoses. Efficacy was assessed from the percentage reduction in seizure frequency from baseline and the retention of patients on treatment. Findings The study enrolled 2455 patients. In 68% of patients who completed 12 months' treatment, seizure frequency was decreased by at least 50%, and a third of patients were seizure free. 72% of patients who completed 24 months' treatment had reduction of seizure frequency of at least 50% and a quarter of patients remained seizure free. Probability of retention was 0·84 at 1 year, and 0·76 at 2 years. Medication was well tolerated and reported adverse events were mild; only 32 patients (1%) discontinued medication because of side-effects. Interpretation This pragmatic study confirmed that this simple protocol was suitable for the treatment of convulsive forms of epilepsy in rural areas of China. Physicians with basic training could treat epilepsy patients with phenobarbital, with beneficial effects for most patients with convulsive seizures. Few cognitive or behavioural adverse events were noted, but formal psychometric testing was not done.

Premature mortality in people with epilepsy in rural China: a prospective study

Abstract: Summary Background In China, few studies have described annual mortality associated with epilepsy in a general population and these have provided a range of 3·0–7·9 deaths per 100 000 people. We calculated the case fatality rate (CFR), proportional mortality rate (PMR), and standardised mortality ratio (SMR) to assess mortality in people with epilepsy in rural China. Methods The target population was people with epilepsy who participated in an assessment of epilepsy management at primary health level in rural China. Neurologists confirmed the diagnosis using strict criteria in all participants who were then treated with phenobarbital. Demographic data and putative cause of death were recorded for each person whose death was reported. PMRs for each cause of death and SMRs were estimated on the basis of the 2004 Chinese population. Findings Case fatality rate was 1·4% (35 deaths) among 2455 people with epilepsy. The age-adjusted PMRs for injury, stroke, neoplasm, myocardial infarction, and pneumonia were 30%, 30%, 15%, 6%, and 5%, respectively. The SMR was 3·9 (95% CI 3·8–3·9). Patients aged 15–29 years had higher mortality ratios than did those in other age-groups, with SMRs exceeding 23. Interpretation Risk for premature death is three to four times higher in people with epilepsy than in the general Chinese population. Furthermore, the risk in young people with epilepsy in China is much higher than previously reported. Injury, stroke, myocardial infarction, and pneumonia are among the leading putative causes of death in patients with epilepsy in rural China.

Pregabalin: A new antiepileptic drug for refractory epilepsy

Abstract: Pregabalin is a recently licensed and marketed antiepileptic drug for use as adjunctive treatment of partial epilepsy. It acts at presynaptic calcium channels, modulating neurotransmitter release in the CNS, properties it shares with gabapentin. Its clinical development over the past decade has included its use in the treatment of neuropathic pain, and generalized anxiety disorder, in addition to epilepsy. Three multi-centre randomised, double-blind, placebo-controlled trials enrolling patients with refractory partial epilepsy have demonstrated an antiepileptic effect of pregabalin against placebo, as adjunctive therapy, with 31-51% of patients showing a 50% reduction in seizure frequency. Adverse effects were dose related, the commonest being somnolence, dizziness, and ataxia. Weight gain was seen in 14% of patients on the highest dose of 600 mg/day. Around 9000 people have been exposed to pregabalin in its development for all indications. No idiosyncratic reactions have been described to date. Pregabalin may be a useful addition in the treatment of refractory partial epilepsy. As with all new AEDs long-term follow up and post marketing surveillance is required.

Seizures and epilepsy in oncological practice: causes, course, mechanisms and treatment

Abstract: There are few data available on the causes and mechanistic basis, outcome and treatment of seizures and epilepsy in people with systemic cancer. Seizures and epilepsy in people with cancers other than primary brain tumours are reviewed here. Articles published in English, which discussed the neurological manifestations and complications of cancer and its treatment, were searched and information on the frequency, aetiology, and course of seizures and epilepsy was extracted. The frequency, aetiology and outcome of seizure disorders in patients with cancer differ from those in the general population. Intracranial metastasis, cancer drugs and metabolic disturbances are the most common causes. Infections, cerebrovascular complications of systemic cancer and paraneoplastic disorders are among the rarer causes of seizures in patients with neoplasms. Several drugs used in the treatment of cancer, or complications arising from their use, can trigger seizures through varied mechanisms. Most drug-induced seizures are provoked and do not require long-term treatment with antiepileptic drugs.

The long term retention of levetiracetam in a large cohort of patients with epilepsy

Abstract: Levetiracetam (Lev) is a new antiepileptic drug with a distinct mechanism of action, shown in regulatory trials to be effective. These controlled trials do not always predict how useful a drug will be in day to day clinical practice. Retention rates can provide a better indication of efficacy and tolerability in everyday use. Patients attending a tertiary referral centre for epilepsy and who received Lev in the first 2 years of its marketing were assessed (n = 811) to determine continuation rates of treatment with this drug. At the last follow up, 65% of patients were still taking Lev, and the estimated 3 year retention rate was 58%. In total, 11% attained seizure freedom of at least 6 months. Patients taking greater numbers of concurrent antiepileptic drugs (AEDs) were more likely to discontinue Lev, and those reaching higher maximum daily dosages were less likely to discontinue Lev. The retention rate for Lev compares favourably with that of other new AEDs.

In situ metabolism of levetiracetam in blood of patients with epilepsy.

Abstract: Summary: Purpose: Although levetiracetam undergoes minimum metabolism, B-esterases have been identified in whole blood that are capable of metabolising levetiracetam. The present study was designed to ascertain any variability in levetiracetam blood concentrations that could be attributed to in situ metabolism and which could impact on the utility of such concentration measurements in guiding therapeutic management. Methods: Blood samples were collected from 40 patients that were prescribed levetiracetam. Sera (Groups 1 and 2) or whole blood (Groups 3 and 4) were compared. Paraoxan, an inhibitor of B-esterase activity, was added to samples assigned to Groups 2 and 4. Samples within each group were assigned to Time 0 (frozen within 30 min of sample collection), Time 2 days and Time 7 days (samples kept at ambient temperature for 2 and 7 days). Results: For serum samples, mean levetiracetam concentrations at Time 2 days and Time 7 days were indistinguishable from Time 0, regardless of whether B-esterase activity was inhibited on not. In contrast, for whole blood, in the absence of B-esterase inhibition, mean levetiracetam concentrations declined over time (11% and 29%; 2 and 7 days) compared to baseline values. In the presence of B-esterase inhibitor, mean levetiracetam concentrations at 2 days were indistinguishable from baseline values, although at 7 days values declined by 4%. Conclusions: If therapeutic monitoring of levetiracetam is to be undertaken, serum should be the matrix of choice and that whole blood should be separated as soon as possible after patient sampling so as to minimize in situ levetiracetam metabolism which could result in spuriously low concentrations and substantial intrapatient variability.

Assessing the disease burden due to epilepsy by disability adjusted life year in rural China.

Abstract: Summary: Purpose: To demonstrate the application of Disability Adjusted Life Year (DALY) as an aid in health outcome measures to evaluate the epilepsy disease burden in rural China and to provide Chinese data to achieve a better understanding of disease burden due to epilepsy. Methods: The DALY is the sum of the number of years of survival with disability (Years Lived with Disability, YLD) and the number of years lost because of premature mortality (Years of Life Lost, YLL). We calculated the YLD based on the prevalence survey of epilepsy among 66,393 people sampled in Heilongjiang, Henan, Jiangsu, Ningxia, Shanghai, and Shanxi provinces in 2000. The epilepsy mortality data from Chinese literature provided the YLL due to epilepsy. We applied sensitivity analysis to evaluate the influence of uncertainty on the epilepsy mortality value and disability weight in the study. Results: In 2000, epilepsy caused 1.83 and 2.48 DALY lost per 1,000 population in Henan and Ningxia province, which had the lowest and the highest DALY lost among the six study areas. Overall, epilepsy caused 1.41 YLLs and 0.67 YLDs per 1,000 population; thus the DALYs lost because of epilepsy was 2.08 per 1,000 population, representing the epilepsy disease burden in rural China. Conclusions: The DALY measure, which includes the extent of disability from epilepsy, provides a useful tool for the epilepsy disease burden assessment. The disease burden of epilepsy in China is considered higher than previous estimations.

Sudden unexpected death in epilepsy. Risk factors, possible mechanisms and prevention: a reappraisal.

Abstract: People with epilepsy are more likely to die prematurely than those without epilepsy. The most common epilepsy-related category of death is sudden unexpected death in epilepsy (SUDEP), accounting for up to one fifth of epilepsy deaths in some series. SUDEP is more common in populations of people with intractable epilepsy, the annual incidence being as high as one in 200 patient years in these settings. The majority of people dying with SUDEP have a history of generalised tonic clonic seizures, and high seizure frequency and polytherapy also seem to be risk factors. The goal of treatment should therefore be seizure freedom, using the lowest effective number and dosage of AEDs. Evidence for many other risk factors is conflicting. The most commonly suggested mechanisms for SUDEP are cardiac abnormalities and apnoea, but the cause of SUDEP is still unknown. Clarification of risk factors and establishment of the mechanisms of SUDEP are important so that as many people as possible can be saved from SUDEP.

The role of hippocampal sclerosis in antiepileptic drug-related depression in patients with epilepsy: A study on levetiracetam

Abstract: Summary Objective Hippocampal sclerosis (HS) has been described as a relevant factor for the development of topiramate-related depression and cognitive deficits. The aim of our study was to clarify whether patients with temporal lobe epilepsy (TLE) and HS were also at risk during therapy with levetiracetam (LEV). Methods Data of 156 patients was analysed: 78 with TLE and HS and 78 with TLE and normal MRI matched for age, starting dose and titration schedule of LEV. Patients were selected from a population of consecutive patients started on LEV between 2000 and 2002. Results No differences were observed in prevalence of cognitive adverse events and depression between the two groups. Conclusions LEV treatment is not associated with cognitive adverse events and depression in patients with hippocampal sclerosis.

Cost–effectiveness of carbamazepine in epilepsy

Abstract: Carbamazepine is widely recommended as a first-line antiepileptic drug for new-onset partial seizures with or without generalization. Branded carbamazepine remains commonly prescribed. Newer antiepileptic drugs have higher acquisition costs than carbamazepine, but may offer advantages in terms of tolerability and side-effect profile that may offset their additional cost. Furthermore, generic carbamazepine is often cheaper than branded forms, and many argue for a policy of prescribing the cheapest available generic form. This study reviews the scant health economic data concerning the use of carbamazepine to treat epilepsy to establish whether use of this drug is cost effective. Carbamazepine would appear to be a cost-effective treatment for epilepsy in certain contexts, although evidence from a prospective, randomized, controlled trial is awaited and this assertion may not be true for certain patient subgroups, or in developing world health services. Furthermore, at this time there is insufficient evidence to support policies of cheapest generic or brand-only prescribing.

Nurse prescribing and the management of epilepsy.

Abstract: The United Kingdom (U.K.) health system is organized in a hierarchical way with general practitioners (GPs) acting as gatekeepers to the system. Most people are registered with a GP who is contracted to provide free general medical services. Patients in need of specialist intervention are referred by their GP to local hospitals. However, a shortage of specialists in epilepsy exists, and in some socially deprived areas, GPs are scarce. Patients with epilepsy in these areas are at higher risk of SUDEP (sudden unexplained death from epilepsy). GPs treat many patients with refractory epilepsy, although they may be unfamiliar with complex epilepsy and with new treatments. The consequences include inadequate treatment and increased morbidity and mortality (1–4). Up to half of the >1,000 epilepsy-related deaths each year might have been prevented by optimal antiepileptic drug (AED) treatment or epilepsy surgery (1). The National Institute for Clinical Excellence (responsible for clinical governance and the use of evidence-based management within the health system) has issued clinical guidelines for the management of epilepsy. They include recommendations that specialists diagnose epilepsy and review patients with refractory epilepsy and that patients have access to epilepsy nurse specialist (ENS) services (5). A new contract established for GPs offers incentive payments for having a register of patients with epilepsy, recording seizure frequency, and performing medication reviews (6). Calls have been made for nurses to take responsibility for the management of chronic conditions and, in consultation with the multidisciplinary team, to provide health assessments, arrange and interpret investigations, plan and implement treatment, and prescribe medications (7).