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Biomedical subjects

Josemir W Sander

Publications and source records attributed to Josemir W Sander.

At least 19 recordsLinked to original sources
PubMed2006

Mortality and morbidity rates are increased in people with epilepsy: is stress part of the equation?

People with epilepsy (PWE), particularly those with more severe seizures, are at risk of premature death. The contribution of deaths unrelated to epilepsy to this risk is likely to be significant. Recent studies indicate that comorbid conditions are similarly increased in PWE. The reason for these increases in unrelated deaths and comorbid conditions is unclear. In this article, we argue that having seizures is psychologically stressful, and that this stress can lead to a whole range of pathophysiological changes that may trigger various physical illnesses. Hence, psychological stress may be a significant factor contributing to the increase in mortality and comorbidity rates in PWE. This speculation is unlikely to be proven at this stage because of the complexity of the trials required. In PWE who continue to have seizures, more needs to be done to help them cope with the stress. Additionally, attention needs to be paid to improve nutritional status and physical fitness. These steps are likely to enhance the overall health of PWE and may reduce premature mortality and comorbidity rates.

Epilepsy↗
PubMed2006

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

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.

Adult↗
PubMed2006

Adult epilepsy.

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possible presentations and causes. Although incidence in childhood has fallen over the past three decades in developed countries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. A clinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene can lead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits with environmental effects acting on inherited susceptibility, mediated by common variation in particular genes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome. Brain imaging is making great progress in identifying the structural and functional causes and consequences of the epilepsies. Current antiepileptic drugs suppress seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Pharmacogenetic studies hold the promise of being able to better individualise treatment for each patient, with maximum possibility of benefit and minimum risk of adverse effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changing cure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neural stimulation, and biological grafts.

Adult↗
PubMed2006

The impact of levetiracetam on challenging behavior.

An observational longitudinal design was employed to evaluate whether treatment with the antiepileptic drug levetiracetam (LEV) adversely impacts behavior in people with intellectual disabilities and/or acquired brain damage. Thirty-five adults were assessed once off the drug and once when on LEV therapy, with a 2-month interval between assessments. Behaviors were rated using an adaptation of the Yale-Brown Obsessive Compulsive Scale and the Challenging Behaviour Scale. Challenging behaviors were rated as more frequent and severe when individuals were taking LEV. Behavioral worsening was not related to better seizure control or increased levels of engagement in activities. Families and professionals need to be aware of the potential reversible adverse effects of this drug.

Adult↗
PubMed2006

Pregabalin: a new antiepileptic drug for refractory epilepsy.

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.

Adolescent↗
PubMed2006

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

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.

Adolescent↗
PubMed2006

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

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.

Adolescent↗
PubMed2006

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

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.

Adult↗
PubMed2006

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

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.

Adult↗
PubMed2005

Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Adolescent↗
PubMed2005

Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial.

Animal studies and a preliminary clinical observation suggest that nutritional supplementation with long chain omega-3 fatty acids (omega-3 FAs) may be useful in the nonpharmacological treatment of patients with epilepsy. Omega-3 FAs increase seizure thresholds, and lower inflammatory mediators, which are increased in patients with epilepsy. In this first randomized, placebo-controlled parallel group trial of omega-3 FA supplementation with 1 g eicosapentaenoic acid (EPA) and 0.7 g docosahexaenoic acid (DHA) daily, 57 patients completed a 12-week double-blind phase. Seizure frequency was reduced over the first 6 weeks of treatment in the supplement group, but this effect was not sustained. The supplementation produced a significant increase in EPA and DHA concentrations and a reciprocal fall in arachidonic and linoleic acid concentrations. No change in serum AED concentrations was detected. Further studies are required to examine different omega-3 FA preparations, different doses, longer treatment duration, and larger sample sizes.

Adult↗
PubMed2005

Periodic lateralized epileptiform discharges (PLEDs) as the sole electrographic correlate of a complex partial seizure.

We describe a patient in whom the only electrographic manifestation of a complex partial seizure recorded by video-EEG telemetry was periodic lateralized epileptiform discharges (PLEDs) with a left anterior temporal emphasis. The abnormality, which persisted throughout the whole recorded seizure, lends support to the claim that PLEDs can be an ictal phenomenon.

Adolescent↗
PubMed2004

Cancer risk in people with epilepsy: the role of antiepileptic drugs.

There has been considerable debate about the relationship between epilepsy and cancer, in particular whether the incidence of cancer is increased in people with epilepsy and whether antiepileptic drugs promote or protect against cancer. We review available evidence from animal experiments, genotoxicity studies and clinico-epidemiological observations, and discuss proposed mechanisms underlying the association between epilepsy and cancer. A carcinoma-promoting effect has been seen unequivocally in rodent models for phenobarbital and phenytoin; phenobarbital promoted liver tumours and phenytoin caused lymphoid cell and liver tumours in rats. Early human epidemiological studies found an association between phenobarbital and hepatocellular carcinoma, and several subsequent studies suggested an association with lung cancer. An association with brain tumours has also been demonstrated. Phenytoin has been causally implicated in three human cancers: lymphoma, myeloma and neuroblastoma, the latter specifically in the setting of foetal hydantoin syndrome. However, despite considerable long-term pharmaco-epidemiological data being available for both antiepileptic drugs, evidence for human carcinogenicity is not consistent and both are considered only possibly carcinogenic to humans. Valproate, however, has been found to exert an antiproliferative effect on certain cancer cell lines both in vitro and in vivo. A corresponding cancer-suppressive effect has not been studied in human epidemiological studies, though there are now preliminary reports of the use of valproate in human haematological and solid tumours. The anticancer activity of valproate appears to be driven by histone deacetylase inhibition and to be independent of hormone or multidrug protein resistance dependent mechanisms. The newer antiepileptic drugs appear to be safe, as no carcinogenicity has been demonstrated either during regulatory testing or in post-marketing surveillance. Nevertheless, the subject of cancers and epilepsy constitutes a promising agenda for clinical and experimental research in the future.

Animals↗
PubMed2004

Life expectancy in people with newly diagnosed epilepsy.

Epilepsy carries a risk of premature mortality, but little is known about life expectancy in people with the condition. The UK National General Practice Study of Epilepsy is a prospective, population-based study of people with newly diagnosed epilepsy. A cohort of 564 patients with definite epilepsy has been followed for nearly 15 years and there have been 177 deaths. These data have been used to estimate life expectancy of people in this cohort by employing a parametric survival model based on the Weibull distribution. Life expectancy in people with epilepsy was estimated as a function of age at, and time from, diagnosis according to two broad aetiological groups. These estimates were then compared with life expectancy in people of the same age and sex in the general population. Reduction in life expectancy can be up to 2 years for people with a diagnosis of idiopathic/cryptogenic epilepsy, and the reduction can be up to 10 years in people with symptomatic epilepsy. Reductions in life expectancy are highest at the time of diagnosis and diminish with time. Our model provides broad estimates, but it appears that the higher mortality rates in people with newly diagnosed epilepsy translate into decreased life expectancy.

Adolescent↗
PubMed2004

Is omega-3 fatty acid deficiency a factor contributing to refractory seizures and SUDEP? A hypothesis.

Epilepsy, the commonest serious neurological condition, is associated with an increased risk in premature deaths, including an estimated 500 sudden unexpected deaths (SUDEP) per year in the UK. In some patients seizures are associated with cardiac arrhythmias, which are thought to be a major factor in SUDEP. Omega-3 fatty acids have been shown to reduce cardiac arrhythmias in animal studies and to reduce sudden cardiac deaths, thought to be due to cardiac arrhythmias, in both healthy subjects and in those who have had one myocardial infarction. Additionally, omega-3 fatty acids in animal studies and in a small clinical observation study have shown anti-seizure effects. Omega-3 fatty acid supplementation in patients with refractory seizures may reduce seizures and seizure associated cardiac arrhythmias and hence SUDEP.

Arrhythmias, Cardiac↗
PubMed2004

The epidemiology of the comorbidity of epilepsy in the general population.

PURPOSE: To describe the epidemiology of somatic and psychiatric conditions in adults with epilepsy in the community and compare it to that of people without epilepsy. METHODS: A cross-sectional population-based study extracting data from the UK General Practice Research Database for the period 1995-1998. Age- and sex-standardized prevalence rates were estimated for selected conditions and groups of conditions (categorized by ICD-9 chapters) in adults with epilepsy registered with primary care physicians. Results were compared with those in adults without epilepsy in the cohort, and prevalence ratios were calculated according to two broad age groups (16-64 and older than 64 years). RESULTS: Conditions common in the general population also were common in adults with epilepsy. Psychiatric disorders occurred twice as often, and the risk of somatic disorders was increased in people with epilepsy, with the exception of musculoskeletal and connective tissue disorders in older adults. The prevalence ratio of neoplasia, excluding intracranial tumors, was not increased in epilepsy. The prevalence ratio of brain tumors was particularly increased in young adults [prevalence ratio (PR), 70.7] and of meningiomas in older adults (PR, 91.9). Neurodegenerative conditions, particularly dementias and Alzheimer' disease (PR, 6.3 and 8, respectively) and Parkinson' disease (PR, 3.2), appeared more frequently in people with epilepsy. Upper gastrointestinal bleed occurred more frequently in epilepsy (PR, 4.3), as did cardio- and cerebrovascular disorders, fractures, pneumonia and chronic lung diseases, and diabetes. Eczema, osteoarthritis, and rheumatoid arthritis did not occur more frequently in epilepsy. CONCLUSIONS: The prevalence ratio of many common psychiatric and somatic conditions is increased in adults with epilepsy who consult a primary care physician in the U.K. These findings may have implications in the diagnosis and management of epilepsy and coexisting conditions, as well as in health care provision.

Adolescent↗