Antiepileptic drugs - treating populations

Epilepsy affects 50 million people world-wide. Since 1982, the Western Infirmary Epilepsy Unit has provided a specialist service for over 6900 people with suspected and established seizure disorders. The twelve studies detailed in this thesis discuss the management of epilepsy in different patient populations, and explore beneficial and adverse effects of antiepileptic drugs (AEDs). AED development has allowed advances in pharmacological treatment of localisation-related epilepsies. Thus, outcomes were investigated in 550 such patients followed-up at the epilepsy clinic over 13 years (Paper i). Of these, 312 (57%) became seizure-free on medication. Those with hippocampal sclerosis had the poorest outcome (p<0.01), and a higher incidence of febrile convulsions (p<0.001). Although many patients benefited from AED therapy, results may be biased, given this cross-sectional study analysed data from both newly diagnosed patients, and those with drug-resistant seizures. Many people with epilepsy take more than one AED, although supportive evidence is sparse. Hence, polytherapy outcomes in 2881 patients registered with the Epilepsy Unit database were examined (Paper ii). Of these, 1617 (56%) were seizure-free, with 332 (21%) taking more than one AED (287 on two, 86%; 42 on three, 13%; 3 on four, 1%). There were 40 duotherapy and 28 triple therapy combinations resulting in seizure freedom. Therefore, combining two or three, but rarely four AEDs may be useful for patients not responding to monotherapy. Because this was a retrospective analysis of newly treated patients and those with refractory epilepsy, the analysis was subject to bias. Lack of a control group was also a weakness. Epilepsy Unit staff are therefore now examining similar outcomes in a large population of newly treated patients only. To establish the place of recently marketed AEDs in clinical practice, four studies examined prospectively the efficacy and tolerability of the novel agent, topiramate, in uncontrolled epilepsy. Adjunctive topiramate was administered in 170 patients with refractory seizures (Paper iii). Seizure frequency and adverse events were monitored. Patients were followed-up until seizure freedom for ≥ 6 months, ≥ 50% or <50% seizure reduction, intolerable side-effects, or lack of efficacy occurred. Seizure freedom was achieved in 39 (23%) patients. A ≥50% reduction in seizure frequency was reported in 80 (47%) others. Doses were often lower than those in regulatory studies. Efficacy as monotherapy was also demonstrated. Using the same end-points, topiramate was added to AED regimens of 64 patients with learning disabilities and epilepsy (Paper iv). Remission from seizures was established in 16 (25%). In similar fashion, levetiracetam was started in 156 patients with uncontrolled epilepsy (Paper v). Of these, 40 (26%) became seizure-free, many on low doses. When the drug was added to AED regimens in 64 patients with learning disabilities, 24 (38%) became seizure-free for at least 6 months (Paper vi). Caregiver quality-of-life scores improved significantly with levetiracetam (p<0.001). It is important to recognise that for all four audits results may be biased due to their observational nature, and the fact that they were undertaken at a single centre, with no control group. For patients with learning disabilities, small numbers, and retrospective baseline recordings for some could also have introduced bias. In Papers vii, viii and ix, findings from longitudinal studies in teenagers, people with learning disabilities and epilepsy, and newly diagnosed elderly patients attending the Epilepsy Unit, are reported. At the Teenager Clinic, 301 adolescents were reviewed over four years (Paper vii). Epilepsy was excluded in 135 (45%), five taking AEDs. A single seizure occurred in 22 others. In the 144 with epilepsy, seizure freedom for ≥ 12 months was attained in 76 (53%), but outcomes were poorer than expected. Neuroimaging was abnormal in 27 (43%). Newly diagnosed patients fared better than those taking treatment (p<0.05). More teenagers with primary generalised seizures (60%) attained remission, compared to those with focal-onset seizures (46%) (p<0.02). The retrospective natures of the analysis, and lack of control group may have biased results, thus making statistical conclusions inaccurate. Findings suggested the need for improved services. Over four years, 214 patients with learning disabilities and refractory epilepsy were followed-up (Paper viii). Although it is generally thought these individuals’ seizures are difficult to control, 59 (43%) became seizure-free for ≥ 12 months with AEDs. There was no change in quality-of-life scoring during this time, and no relationship between extent of learning disability and seizure control. The observational nature of the audit, and lack of control group may have biased results. Currently, there are few data on elderly people with epilepsy. Thus, outcomes over a 20-year period in 117 newly diagnosed senior citizens were examined (Paper ix). After starting AED treatment, 93 (79%) became seizure-free for ≥ 12 months, 73 (62%) with their first drug. Prognosis was better than in younger patients, and for those with fewer pre-treatment seizures (p=0.0078). Again bias may have been introduced because of the study’s observational nature and lack of control group. The final studies concentrate on AED-related adverse effects (Papers x, xi and xii). Bone changes have been reported with AED use. Hence, the relationship between bone mineral density, and long-term AED treatment in 78 older adults (47 post-menopausal women, 31 men), taking hepatic enzyme-inducing or non-inducing AEDs, was explored in a case-controlled study (Paper x). Men had significantly lower bone mineral density than controls at the lumbar spine (p<0.01), and neck of femur (p<0.005). Women had statistically reduced bone mineral density at the femoral neck (p<0.05). It was concluded that long-term AED treatment is an independent risk factor for reduced bone mineral density in people with epilepsy. As sodium valproate may be associated with metabolic changes and polycystic ovarian syndrome, hormone profiles were compared in 76 young men and women taking sodium valproate or lamotrigine monotherapy, to assess whether a pharmacological effect of valproate was responsible (Paper xi). Results revealed only four obese females exhibiting biochemical characteristics of polycystic ovarian syndrome (p=0.05), with obese patients of both sexes (p=0.01), and valproate-treated men (p=0.03) having higher insulin concentrations. Results are not significant when corrected for multiple comparisons. It can therefore be concluded that no differences in metabolic indices between patients taking sodium valproate or lamotrigine existed. To examine further effects on androgenic hormones, and the efficacy and tolerability of sodium valproate and lamotrigine monotherapy, a randomised, prospective study in 225 patients was performed (Paper xii). Patients were recruited if they presented with a minimum of two unprovoked seizures of any type, or a single seizure and underlying neuropathology. Of patients with partial-onset seizures, 81 received sodium valproate and 80 were randomised to receive lamotrigine. Of those with idiopathic generalised epilepsies, 30 received sodium valproate and 34 took lamotrigine. Seizure-free rates were identical in both arms at twelve months between the valproate and lamotrigine cohorts. There was a trend towards superiority for valproate (57% seizure-free) over lamotrigine (35% seizure-free) for patients with idiopathic generalised epilepsies (p=0.09), but a converse separation of outcomes for localisation-related epilepsies (43% seizure-free with valproate, 53% seizure-free with lamotrigine, p=0.24). More patients taking sodium valproate withdrew due to adverse events (p=0.046), eight because of weight gain. Neither drug altered testosterone, sex-hormone binding globulin, and androstenedione concentrations, or changed the free androgen index, at six and twelve months, but lack of further formal monitoring may have biased results. These studies report results from different patient populations, including those with refractory epilepsy. Successful pharmacological outcomes were achieved in people with localisation-related epilepsies, and those taking polytherapy. Patients with learning disabilities and elderly individuals fared better than expected, although results were disappointing in adolescents. AEDs, can, however, be associated with adverse effects, and data show how certain patients may require screening for such changes, and/or avoidance of certain drugs. These findings have to be considered in the context that the design of several of the projects may have introduced inherent bias

Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells

The human CD8+ T cell clone 6C5 has previously been shown to recognize the tert-butyl-modified Bax161–170 peptide LLSY(3-tBu)FGTPT presented by HLA-A*02:01. This nonnatural epitope was likely created as a by-product of fluorenylmethoxycarbonyl protecting group peptide synthesis and bound poorly to HLA-A*02:01. In this study, we used a systematic approach to identify and characterize natural ligands for the 6C5 TCR. Functional analyses revealed that 6C5 T cells only recognized the LLSYFGTPT peptide when tBu was added to the tyrosine residue and did not recognize the LLSYFGTPT peptide modified with larger (di-tBu) or smaller chemical groups (Me). Combinatorial peptide library screening further showed that 6C5 T cells recognized a series of self-derived peptides with dissimilar amino acid sequences to LLSY(3-tBu)FGTPT. Structural studies of LLSY(3-tBu)FGTPT and two other activating nonamers (IIGWMWIPV and LLGWVFAQV) in complex with HLA-A*02:01 demonstrated similar overall peptide conformations and highlighted the importance of the position (P) 4 residue for T cell recognition, particularly the capacity of the bulky amino acid tryptophan to substitute for the tBu-modified tyrosine residue in conjunction with other changes at P5 and P6. Collectively, these results indicated that chemical modifications directly altered the immunogenicity of a synthetic peptide via molecular mimicry, leading to the inadvertent activation of a T cell clone with unexpected and potentially autoreactive specificities

Decreased Pulmonary Function Measured in Children Exposed to High Environmental Relative Moldiness Index Homes

Background: Exposures to water-damaged homes/buildings has been linked to deficits in respiratory health. However, accurately quantifying this linkage has been difficult because of the methods used to assess water damage and respiratory health. Purpose: The goal of this analysis was to determine the correlation between the water-damage, as defined by the Environmental Relative Moldiness Index (ERMI) value in an asthmatic child’s home, and the child’s pulmonary function measured by spirometry, “forced expiratory volume in one second, percent predicted” or FEV1%. Methods: This analysis utilized data obtained from the “Heads-off Environmental Asthma in Louisiana” (HEAL) study. The children (n= 109), 6 to 12 years of age, who had completed at least one spirometry evaluation and a dust sample collected for ERMI analysis from the home at approximately the same time as the spirometry testing, were included in the analysis. Statistical evaluation of the correlation between ERMI values and FEV1% was performed using the Spearman’s Rank Correlation analysis. The relationship between ERMI values and FEV1% was performed using B-spline regression. Results: The average ERMI value in the HEAL study homes was 7.3. For homes with ERMI values between 2.5 and 15, there was a significant inverse correlation with the child’s lung function or FEV1% measurement (Spearman’s rho -0.23; p= 0.03), i.e. as the ERMI value increased, the FEV1% value decreased. Conclusions: Measures of water-damage (the ERMI) and clinical assessments of lung function (FEV1%) provided a quantitative assessment of the impact of water-damaged home exposures on children’s respiratory health

The Costs of an Outreach Intervention for Low-Income Women With Abnormal Pap Smears

INTRODUCTION: Follow-up among women who have had an abnormal Papanicolaou (Pap) smear is often poor in public hospitals that serve women at increased risk for cervical cancer. This randomized controlled trial evaluated and compared the total cost and cost per follow-up of a tailored outreach intervention plus usual care with the total cost and cost per follow-up of usual care alone. METHODS: Women with an abnormal Pap smear (n = 348) receiving care at Alameda County Medical Center (Alameda County, California) were randomized to intervention or usual care. The intervention used trained community health advisors to complement the clinic's protocol for usual care. We assessed the costs of the intervention and the cost per follow-up within 6 months of the abnormal Pap smear test result. RESULTS: The intervention increased the rate of 6-month follow-up by 29 percentage points, and the incremental cost per follow-up was $959 (2005 dollars). The cost per follow-up varied by the severity of the abnormality. The cost per follow-up for the most severe abnormality (high-grade squamous intraepithelial lesion) was$681, while the cost per follow-up for less severe abnormalities was higher. CONCLUSION: In a health care system in which many women fail to get follow-up care for an abnormal Pap smear, outreach workers were more effective than usual care (mail or telephone reminders) at increasing follow-up rates. The results suggest that outreach workers should manage their effort based on the degree of abnormality; most effort should be placed on women with the most severe abnormality (high-grade squamous intraepithelial lesion)

Remodelling criminal insanity: Exploring philosophical, legal, and medical premises of the medical model used in Norwegian law

This paper clarifies the conceptual space of discussion of legal insanity by considering the virtues of the ‘medical model’ model that has been used in Norway for almost a century. The medical model identifies insanity exclusively with mental disorder, and especially with psychosis, without any requirement that the disorder causally influenced the commission of the crime. We explore the medical model from a transdisciplinary perspective and show how it can be utilised to systematise and reconsider the central philosophical, legal and medical premises involved in the insanity debate. A key concern is how recent transdiagnostic and dimensional approaches to psychosis can illuminate the law\u27s understanding of insanity and its relation to mental disorder. The authors eventually raise the question whether the medical model can be reconstructed into a unified insanity model that is valid across the related disciplinary perspectives, and that moves beyond current insanity models

The Arab American experience with diabetes: Perceptions, myths and implications for culturally-specific interventions

Culturally-specific lifestyle diabetes prevention programs require an assessment of population disease perceptions and cultural influences on health beliefs and behaviors. The primary objectives were to assess Arab Americans’ knowledge and perceptions of diabetes and their preferences for a lifestyle intervention

Low Temperature Aqueous Electrospray Ionization Mass Spectrometry of Noncovalent Complexes

AbstractIn the present study we describe conditions that permit the characterization of noncovalent protein–substrate complexes in aqueous solution by microspray electrospray ionization-mass spectrometry (ESI-MS), using a heated transfer capillary at low temperature (45 °C). Specifically, we examined the binding of calmodulin to two polypeptides; the calmodulin-binding domain of calmodulin-dependent protein kinase II (CamK-II) and melittin. Calmodulin, a well known calcium-binding protein, binds to a number of small amphipathic peptides in a calcium-dependent manner. Our results directly show that both peptides form equimolar complexes with calmodulin only in the presence of calcium. The stoichiometry necessary for the formation of each complex was 1:1:4 for calmodulin:peptide (melittin or CamK-II):Ca2+, respectively. Furthermore, it is demonstrated that the detection of the complex in ESI-MS is source temperature dependent

Attitudes Toward Breast Cancer Genetic Testing in Five Special Population Groups

Purpose: This study examined interest in and attitudes toward genetic testing in 5 different population groups. Methods: The survey included African American, Asian American, Latina, Native American, and Appalachian women with varying familial histories of breast cancer. A total of 49 women were interviewed in person. Descriptive and nonparametric statistical techniques were used to assess ethnic group differences. Results: Overall, interest in testing was high. All groups endorsed more benefits than risks. There were group differences regarding endorsement of specific benefits and risks: testing to “follow doctor recommendations” (p=0.017), “concern for effects on family” (p=0.044), “distrust of modern medicine” (p=0.036), “cost” (p=0.025), and “concerns about communication of results to others” (p=0.032). There was a significant inverse relationship between interest and genetic testing cost (p Conclusion: Cost may be an important barrier to obtaining genetic testing services, and participants would benefit by genetic counseling that incorporates the unique cultural values and beliefs of each group to create an individualized, culturally competent program. Further research about attitudes toward genetic testing is needed among Asian Americans, Native Americans, and Appalachians for whom data are severely lacking. Future study of the different Latina perceptions toward genetic testing are encouraged

The stellar velocity dispersion in the inner 1.3 disk scale-lengths of the irregular galaxy NGC 4449

We present measurements of the stellar velocity dispersion in the inner 1 arcmin radius (1.3 disk scale-lengths) of the irregular galaxy NGC 4449 determined from long-slit absorption-line spectra. The average observed dispersion is 29 +/-2 km/s, the same as predicted from NGC 4449's luminosity. No significant rotation in the stars is detected. If we assume a maximum rotation speed of the stars from the model determined from the gas kinematics of Hunter et al. (2002), the ratio V_max/sigma_z measured globally is 3. This ratio is comparable to values measured in spiral galaxies, and implies that the stellar disk in NGC 4449 is kinematically relatively cold. The intrinsic minor-to-major axis ratio (b/a)_0 is predicted to be in the range 0.3-0.6, similar to values derived from the distribution of observed b/a of Im galaxies. However, V/sigma_z measured locally is 0.5-1.1, and so the circular velocity of NGC 4449 is comparable or less than the velocity of the stars within the central 1.3 disk scale-lengths of the galaxy.Comment: To be published in ApJ, Nov 200