Epilepsy as a systemic condition: Link with somatic comorbidities.

BACKGROUND: People with epilepsy have more concomitant medical conditions than the general population; these comorbidities play an important role in premature mortality. We sought to generate explanatory hypotheses about the co-occurrence of somatic comorbidities and epilepsy, avoiding causal and treatment-resultant biases. METHODS: We collected clinical, demographic and somatic comorbidity data for 2016 consecutive adults with epilepsy undergoing assessment at a tertiary centre and in 1278 people with epilepsy in the community. Underlying causes of epilepsy were not classed as comorbidities. RESULTS: Somatic comorbidities were more frequent in the referral centre (49%) where people more frequently had active epilepsy than in the community (36%). Consistent risk factors for comorbidities were found in both cohorts. Using multivariable ordinal regression adjusted for age, longer epilepsy duration and an underlying brain lesion were independently associated with a smaller burden of somatic conditions. The treatment burden, measured by the number of drugs to which people were exposed, was not an independent predictor. Shorter epilepsy duration was a predictor for conditions that conceivably harbour significant mortality risks. CONCLUSIONS: Somatic comorbidities do not occur randomly in relation to epilepsy; having more severe epilepsy seems to be a risk factor. Independently from age, the early period after epilepsy onset appears to be at particular risk, although it is not clear whether this relates to an early mortality or to a later decrease in the burden of comorbidities. These results suggest that, for some people, epilepsy should be considered a systemic condition not limited to the CNS.

Long-term risk of developing epilepsy after febrile seizures: a prospective cohort study.

OBJECTIVE: We report the prospective follow-up of a cohort of people from the onset of febrile seizures for a median of 24 years to estimate the long-term risk of developing epilepsy. METHODS: The National General Practice Study of Epilepsy is a large prospective community study of 1,195 people with a first suspected seizure followed from the 1980s, of whom 220 (18%) had febrile seizures. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for subsequent epilepsy were calculated in 5-year age bands. RESULTS: Follow-up information was obtained for 181 (83%) people with a mean follow-up for the whole cohort of 21.6 (SD 6.0) years. Of these, 175 (97%) were seizure-free in the preceding 5 years, whereas 171 (94%) were seizure-free and off antiepileptic drugs. Six percent developed epilepsy, but the risk of developing epilepsy in the cohort over the whole follow-up period was almost 10 times that of the general population (SIR 9.7, 95% CI 5.7-16.4). The SIR was significantly elevated in the 0- to 14-year age groups but not in the 15- to 19-year age group (SIR 4.5, 95% CI 0.6-32.1). CONCLUSION: The risk of developing epilepsy in people who had febrile seizures seems to decrease with time. Further long-term studies are needed to confirm this.

Cancer risk in people with epilepsy using valproate-sodium.

OBJECTIVES: Based on reports of antitumour properties of sodium-valproate, we hypothesised that valproate has a cancer-protective effect in people with epilepsy. We aimed to determine cancer risk in people with epilepsy using sodium-valproate. MATERIALS AND METHODS: Continuous data for 2997 people with epilepsy who had been prescribed valproate for at least two years, and for 11,988 unexposed people were provided by the UK General Practice Research Database. Hazard ratios (HRs) for all cancers and individual cancers between the exposed and unexposed groups, with smoking and alcohol consumption and age as covariates, were calculated using the Cox proportional hazards method. RESULTS: Exposure to valproate had no influence on the incidence of the composite of all cancers [HR: 1.19, 95% CI: 0.97-1.47, P = 0.10]; there was, however, a significant excess of colon cancers [HR: 3.95, 95% CI: 1.97-7.92, P = 0.001] and a trend towards an excess of prostate neoplasms [HR: 2.15, 95% CI: 0.92-5.02, P = 0.08] and in addition, a trend towards reduced incidence of breast cancer [HR: 0.40, 95% CI: 0.14-1.30, P = 0.08] in the exposed group. CONCLUSIONS: The lack of an inverse association between valproate use and hazard ratios for all cancers and several individual cancer sites does not lend support for a cancer-protective role for valproate.

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

BACKGROUND: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. METHODS: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). RESULTS: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). CONCLUSION: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.

Drowning in people with epilepsy: how great is the risk?

BACKGROUND: People with epilepsy are known to be at increased risk of death by drowning but there are few data available regarding the size of the risk. We aimed to quantify the risk using meta-analysis. METHODS: A literature search identified 51 cohorts of people with epilepsy in whom the number of deaths by drowning in people with epilepsy and the number of person-years at risk could be estimated. Population data were taken from the WHO Statistical Information Service or from the UK Office for National Statistics where available. Standardized mortality ratios (SMRs) with 95% CIs were calculated for each cohort, for groups of cohorts, and for the total population. Additionally, an SMR for drowning in people with epilepsy in England and Wales (1999-2000) was calculated using National Registries. RESULTS: Eighty-eight drowning deaths were observed compared with 4.70 expected, giving an SMR of 18.7 (95% CI 15.0 to 23.1). Compared with community-based incident studies (SMR 5.4), the SMR was significantly raised in prevalent epilepsy (SMR 18.0), in people with epilepsy and learning disability (SMR 25.7), in those in institutional care (SMR 96.9), and in those who had a temporal lobe excision (SMR 41.1). The SMR for people with epilepsy in England and Wales was 15.3. CONCLUSION: The risk of drowning in people with epilepsy is raised 15- to 19-fold compared with people in the general population. It is important that people with epilepsy and their carers be informed of these risks so that deaths can be prevented.

Gross and histopathological observations of long-term catheterized vessels in experimental sheep.

Chronic indwelling central vessel catheters provide vascular access for compartmental infusion or sampling. However, complications with catheter patency during the postoperative and/or experimental period often arise. In order to identify physiological occurrences common with such complications, 10 multicatheterized sheep (61.8 +/- 7.8 kg BW), obtained from a previous nutrient flux study were used for gross and histopathological investigation. Catheters had been surgically placed in a hepatic portal vein (PVC), a hepatic vein (HVC), a distal mesenteric vein (MVC) and a mesenteric artery (MAC). In the previous study, catheters (PVC, HVC and MAC) were used to collect blood samples or infuse (MVC) p-aminohippurate. Catheters were maintained for a total of 58 days prior to necropsy. Histopathological findings indicated that catheter failures were associated with the following tissue responses: (i) thromboses with frequent focal vasculitis; (ii) euplastic tissues associated with extensive fibrosis; (iii) granulomas; (iv) neo-vascularization of the media; (v) calcification processes; and (vi) micro-abscesses. Additional studies are needed that address and incorporate improvement of catheter design and placement to minimize irritation of endothelium, improvement of catheter treatments and therapeutic regimes, and development and use of alternative anti-coagulants. A greater understanding of the mechanisms leading to failure will help researchers improve catheter performance and patency.

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

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.

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

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.

Predictive value of death certification in the case ascertainment of epilepsy.

OBJECTIVES: Death certificates are an unreliable source of information on cause of death, and mortality due to epilepsy can thus be underestimated. METHODS: We investigated people with epilepsy who had died, and attempted to identify factors that influence inclusion of epilepsy on the death certificate; eight factors were hypothesised and entered into a univariate logistic regression model. RESULTS: Epilepsy was on the death certificate of 16/243 (7%) people who had had epilepsy. Factors that influenced whether or not epilepsy appeared on the certificate were seizure frequency, antiepileptic drug treatment, cause of death, and certifying physician. Factors that did not seem to influence the inclusion of epilepsy were presence of convulsive seizures, occurrence of seizures during follow up, and age at death. CONCLUSIONS: We have estimated the degree of unreliability of death certificates (as currently used in the UK) as a source of information on cause of death in epilepsy. We have found that epilepsy may not appear on death certificates even if people had active epilepsy.

A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis.

Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs (<35, 35-54, >54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the >54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35-54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.

Information recalled by women taking anti-epileptic drugs for epilepsy: a questionnaire study.

Women with epilepsy have different needs from men, particularly associated with childbearing. Despite clinical guidelines, the care of women with epilepsy remains suboptimal. The aim of this study was to establish whether women with epilepsy recall being given information on topics relating to childbearing. Design of study and methods included a postal questionnaire study of 795 women with epilepsy and of childbearing age. The respondents were identified through both general practices and hospital clinics as part of the Clinical Standards Advisory Group study into Epilepsy Services. Of those women who considered the questions personally relevant, 38-48% recalled receiving information about contraception, pre-pregnancy planning, folic acid and teratogenicity, with lower overall proportions among adolescent women. The proportions that recalled receiving information about vitamin K, safety in child-care and breast-feeding were lower at 12, 24 and 24%, respectively. While it is recognised that information provided may not be recalled, our results suggest that further measures are required to improve the effectiveness of information provision in the UK in relation to women of childbearing age with epilepsy.

The epidemiology of epilepsy: the size of the problem.

The prevalence of epilepsy is generally taken as between 5 and 10 cases per 1000 persons, and the overall incidence as about 50 cases per 100,000 persons. The rates are dependent on case ascertainment and on definitions used. The prognosis depends on many factors, including the number of seizures at presentation, the seizure type and the use of anti-epileptic drugs. Epilepsy carries an excess mortality; the cause of death can be unrelated to epilepsy, related to the underlying disease causing epilepsy, or related to epilepsy itself.

A longitudinal quantitative MRI study of community-based patients with chronic epilepsy and newly diagnosed seizures: methodology and preliminary findings.

Experimental and human data suggest that progressive cerebral damage may result from the cumulative effect of brief recurrent seizures. Longitudinal studies addressing this fundamental question, however, are lacking. We have addressed this need with a large prospective community-based observational study, which aims to rescan 154 patients with chronic active epilepsy and 90 patients with newly diagnosed seizures, after an interval of 3.5 years. Here, we describe the quantitative magnetic resonance methods used to identify subtle volume changes in hippocampal, cerebellar, and neocortical structures over time and report preliminary findings. Using this methodology, we have previously shown that we can reliably detect individual hippocampal volume (HV) and cerebellar volume (CBV) changes greater than 3.1 and 3.0%, respectively (Lemieux et al, 2000). Analysis of the first 53 subjects (24 patients with chronic active epilepsy, 9 patients with newly diagnosed seizures, and 20 controls) has demonstrated significant HV losses in 4 individuals. Automated and semiautomated calculation has detected significant reductions in CBV, total brain volume, and gray matter volume in 2, 3, and 1 subject, respectively. There were no significant white matter volume losses detected. Data collected from rescanning the entire cohorts will help to provide further information on the relationship between recurrent seizures and secondary brain damage.

The epidemiology of epilepsy: the size of the problem.

The prevalence of epilepsy is generally taken as between 5 and 10 cases per 1000 persons, and the overall incidence as about 50 cases per 100 000 persons. The rates are dependent on case ascertainment and on definitions used. The prognosis depends on many factors, including the number of seizures at presentation, the seizure type and the use of anti-epileptic drugs. Epilepsy carries an excess mortality; the cause of death can be unrelated to epilepsy, related to the underlying disease causing epilepsy, or related to epilepsy itself.

Tiny TIM: a small, tetrameric, hyperthermostable triosephosphate isomerase.

Comparative structural studies on proteins derived from organisms with growth optima ranging from 15 to 100 degrees C are beginning to shed light on the mechanisms of protein thermoadaptation. One means of sustaining hyperthermostability is for proteins to exist in higher oligomeric forms than their mesophilic homologues. Triosephosphate isomerase (TIM) is one of the most studied enzymes, whose fold represents one of nature's most common protein architectures. Most TIMs are dimers of approximately 250 amino acid residues per monomer. Here, we report the 2.7 A resolution crystal structure of the extremely thermostable TIM from Pyrococcus woesei, a hyperthermophilic archaeon growing optimally at 100 degrees C, representing the first archaeal TIM structure. P. woesei TIM exists as a tetramer comprising monomers of only 228 amino acid residues. Structural comparisons with other less thermostable TIMs show that although the central beta-barrel is largely conserved, severe pruning of several helices and truncation of some loops give rise to a much more compact monomer in the small hyperthermophilic TIM. The classical TIM dimer formation is conserved in P. woesei TIM. The extreme thermostability of PwTIM appears to be achieved by the creation of a compact tetramer where two classical TIM dimers interact via an extensive hydrophobic interface. The tetramer is formed through largely hydrophobic interactions between some of the pruned helical regions. The equivalent helical regions in less thermostable dimeric TIMs represent regions of high average temperature factor. The PwTIM seems to have removed these regions of potential instability in the formation of the tetramer. This study of PwTIM provides further support for the role of higher oligomerisation states in extreme thermal stabilisation.

Preliminary crystallographic studies of triosephosphate isomerase (TIM) from the hyperthermophilic Archaeon Pyrococcus woesei.

Recombinant triosephosphate isomerase (TIM) from a hyperthermophilic Archaeon, Pyrococcus woesei, has been crystallized. Three crystal forms have been obtained: monoclinic, orthorhombic and hexagonal. The monoclinic crystals belong to space group P21 with cell dimensions a = 79.1, b = 89.2, c = 145.4 A and beta = 92.8 degrees, and diffract to at least 2.6 A. The orthorhombic crystals belong to space group P21212 with a = 89.4, b = 155.9, c = 79.5 A, and diffract to 2.9 A. Diffraction from the hexagonal form showed extensive disorder. The monoclinic form contains two tetramers in the asymmetric unit, which are in the same orientation but related by a pseudo-centering. The orthorhombic form contains one tetramer in the asymmetric unit which is in approximately the same orientation as in the monoclinic form. Knowledge of the structure of this hyperthermostable TIM, which is tetrameric in contrast to dimeric forms previously observed, will add to our understanding of protein thermostability.

The effect of aspirin desensitization on urinary leukotriene E4 concentrations in aspirin-sensitive asthma.

Patients with aspirin sensitive asthma (ASA) can be desensitized to aspirin but the mechanisms by which this happens are unknown. To test the hypothesis that there may be a reduction in aspirin-induced leukotriene release following aspirin desensitization, we studied nine patients with ASA, 37 +/- 2.3 yr of age (mean +/- SEM) with a baseline FEV1 of 94 +/- 3.5%. Urinary leukotriene E4 (LTE4) and FEV1 were measured before and after ingestion of a threshold dose of aspirin leading to a 15% decrease in FEV1, and then at intervals following desensitization, when a maintenance dose of 600 mg aspirin was ingested. Prior to desensitization, the maximum decrease in FEV1 following ingestion of a threshold dose of aspirin was 15.3 +/- 3.9%, and urinary LTE4 rose from a baseline value of 235 +/- 79.4 pg/mg creatinine to 1,714 +/- 783 pg/mg creatinine at 3 h. Immediately after acute desensitization, which was performed over several days, 600 mg aspirin provoked a maximum decrease in FEV1 of only 3.3 +/- 2.4%, and urinary LTE4 increased from a baseline of 645 +/- 223 pg/mg creatinine to 1,256 +/- 456 pg/mg creatinine. Following ingestion of 600 mg aspirin for 9 +/- 3.2 mo (n = 5; chronic desensitization), urinary LTE4 rose from a basal level of 432 +/- 127 pg/mg creatinine to 749 +/- 257 pg/mg creatinine at 3 h after 600 mg aspirin, and this was accompanied by a maximum decrease in FEV1 of 7.4 +/- 4.5%. Although there was significantly less aspirin-induced LTE4 excretion after acute desensitization, substantial amounts of LTE4 were still produced without any significant change in lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the 5-lipoxygenase inhibitor ZD2138 on allergen-induced early and late asthmatic responses.

BACKGROUND: Leukotrienes are lipid mediators generated from arachidonic acid by the 5-lipoxygenase pathway which may play an important part in the pathophysiology of asthma. Previous studies have demonstrated attenuation of the allergen-induced early and late asthmatic responses by leukotriene receptor antagonists. The effect of the 5-lipoxygenase inhibitor ZD2138, a non-redox lipoxygenase inhibitor which inhibits leukotriene synthesis for 24 hours after single doses of 350 mg, on allergen-induced early and late asthmatic responses has been assessed. METHODS: Eight asthmatic subjects with baseline FEV1 > 70% were studied. On screening, all subjects developed an allergen-induced biphasic asthmatic response to grass pollen, cat dander, or house dust mite. ZD2138 (350 mg) or placebo was given on two occasions separated by two weeks in a randomised double blind fashion. Allergen inhalation challenge was performed four hours after dosing and FEV1 was measured for eight hours. The inhibitory activity of ZD2138 on the 5-lipoxygenase pathway was assessed by measurements of calcium ionophore-stimulated generation of LTB4 in whole blood ex vivo and by analysis of urinary LTE4 levels before administration of drug or placebo and at regular intervals after oral drug dosing and allergen challenge. RESULTS: ZD2138 produced no significant bronchodilatation or attenuation of the early or late asthmatic response, although there was 82% inhibition of whole blood generation of LTB4 in response to calcium ionophore stimulation and 52% reduction in urinary excretion of LTE4. CONCLUSIONS: In asthmatic subjects the 5-lipoxygenase inhibitor ZD2138 did not protect against allergen-induced asthmatic responses, despite substantial inhibition of 5-lipoxygenase.

Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma.

BACKGROUND: The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor. METHODS: Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration. RESULTS: ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion. CONCLUSIONS: In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase.