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Norman Delanty

Publications and source records attributed to Norman Delanty.

13 recordsLinked to original sources
PubMed2006

The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population.

Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs.

INTRODUCTION: Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whether common variation in GABRG2 predisposes to the development of common, complex forms of epilepsy in two large independent cohorts. METHODS: We have applied a tagging single nucleotide polymorphism (tSNP) technique allowing us to satisfactorily represent common variation in the gene. However, to ensure maximal representation of functional variation and in particular in cases of low minor allele frequency (MAF), we have identified and forced known functional variation as tagging SNPs. We examined the association between tagging SNPs and subtypes of epilepsy in two independent cohorts; the first consisted of 677 cases and 384 healthy controls, the second of 684 cases and 277 healthy controls. RESULTS: We failed to detect any variation that conferred an increased risk of disease development in both cohorts. DISCUSSION: Our results suggest that common variants of strong effect in GABRG2 do not appear to play a role in the development of common, complex forms of epilepsy. This report illustrates a number of important features of study design in genetic association studies, including the simultaneous use of map and sequence-based techniques and the necessity of replication before robust conclusions can be drawn from results.

Alleles↗
PubMed2006

A pharmacogenetic exploration of vigabatrin-induced visual field constriction.

INTRODUCTION: Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients. Given the evidence suggesting an idiosyncratic drug response, we set out to detect genetic variation of strong, clinically relevant effect that might guide clinicians in the safe, controlled prescribing of this otherwise usefuldrug. METHODS: Patients with a history of at least 1-year exposure to vigabatrin were enrolled at two independent referral centers. Using Goldmann perimetry, visual fields and the extent of constriction were calculated for each patient. We examined the correlation between the extent of vigabatrin induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1 and GABRR2). We availed of HapMap data and used a tagging SNP technique in an effort to efficiently capture all common variation within these genes. We attempted to replicate any positive associations before drawing conclusions from our results. RESULTS: The degree of visual field constriction correlated with three SNPs and one haplotype in a cohort of 73 patients. However we were unable to replicate these findings in a second independent cohort consisting of 58 patients, suggesting the initial results were possibly false positives, or variants of weak effect. CONCLUSION: Common variants of strong, clinically relevant effect do not appear to reside in the candidate genes studied here. This does not rule out the presence of genetic variants of weak effect in these genes, nor of variants of strong effect in other genes.

4-Aminobutyrate Transaminase↗
PubMed2006

Quantitative MRI: a reliable protocol for measurement of cerebral gyrification using stereology.

Stereology is a sampling technique used to generate mathematically unbiased estimates of geometric properties of three-dimensional structures based on two-dimensional slices of the object. Using this method, volume and surface area estimates may be generated in a robust, reliable and time-efficient manner based on magnetic resonance (MR) image data. We present a method of determining the isoperimetric ratio, which may be used as an index of gyrification of the human cerebrum, using stereological volume and surface area estimates applied to in vivo MR image data. This parameter may be of use in identifying subtle cortical developmental malformations in diseases such as epilepsy and schizophrenia. We also conduct a series of inter- and intrarater repeatability tests based on 20 normal brains, which demonstrated the reliability and robustness of stereological techniques.

Adult↗
PubMed2006

Broadening the phenotype of childhood-onset dopa-responsive dystonia.

BACKGROUND: Dopa-responsive dystonia (DRD) may cause early-onset dystonia, with extrapyramidal or pyramidal tract dysfunction. OBJECTIVE: To broaden the phenotype of DRD. SETTING: Tertiary referral university hospital. PATIENTS: We describe 4 female siblings with genetically confirmed DRD, 3 of whom presented with "unsteadiness" and 1 with scoliosis. All had dystonia and pyramidal tract signs, 3 had additional extrapyramidal features (resting tremor, bradykinesia, or rigidity), and at least 2 had definite signs of cerebellar dysfunction. MAIN OUTCOME MEASURES: The subjective response to treatment with 62.5 mg of a combination product of levodopa and carbidopa 3 times daily was assessed at both 6- and 12-month follow-up visits with the 7-item Patient's Global Impression of Change Scale as very much improved, much improved, a little improved, no different, a little worse, much worse, or very much worse. RESULTS: All patients showed a good response to levodopa therapy 41 to 49 years after symptom onset. CONCLUSION: Cerebellar signs may be observed in patients with DRD and may improve in response to levodopa.

Dystonic Disorders↗
PubMed2006

Use of complementary and alternative medicine in epilepsy.

Complementary and alternative medicine (CAM) has become much in vogue, and CAM practitioners have increased in tandem with this. The trend of using CAM for treating epilepsy does not differ from that in other medical conditions, with nearly one half of patients using CAM. In this article we review the major complementary and alternative medicines used for treatment of epilepsy. They include mind-body medicines such as reiki and yoga; biologic-based medicine such as herbal remedies, dietary supplements, and homeopathy; and manipulative-based medicine such as chiropractic. In the available literature, there is a sense of the merit of these therapies in epilepsy, but there is a paucity of research in these areas. Individualized therapies such as homeopathy and reiki cannot be compared with medicines in a conventional pharmaceutical model. Hence, many studies are inconclusive. In a science of double-blind, randomized controlled trials, appropriate designs and outcome measurements need to be tailored to CAM. This article explains the principles of the major CAM therapies in epilepsy, and discusses peer-reviewed literature where available. More effort needs to be put into future trials, with the assistance of qualified CAM professionals to ensure conformation to their therapeutic principles.

Aromatherapy↗
PubMed2006

Alcohol-related seizures.

Alcohol-related seizures are defined as adult-onset seizures that occur in the setting of chronic alcohol dependence. Alcohol withdrawal is the cause of seizures in a subgroup of these patients; however, concurrent risk factors including pre-existing epilepsy, structural brain lesions, and the use of illicit drugs contribute to the development of seizures in many patients. New onset or a new pattern of alcohol-related seizures, e.g., focal seizures or status epilepticus, should prompt a thorough diagnostic evaluation. This is not indicated if patients have previously completed a comprehensive evaluation and the pattern of current seizures is consistent with past events. Treatment is initially directed at aggressively terminating current seizure activity. This should be followed by prevention of recurrent alcohol-related seizures and progression to status epilepticus during the ensuing 6-h high-risk period. Our purpose is to present recommendations for the diagnostic evaluation, treatment and disposition of these patients based on the current literature.

Alcohol Withdrawal Seizures↗
PubMed2006

Seizure versus syncope.

One of the most common but difficult management problems in medicine is that of patients who present with a paroxysmal loss of consciousness. All too often the underlying diagnosis remains elusive. This has a cost both in terms of mortality and ongoing morbidity and in terms of the financial burden associated with hospitalisation and repeated investigations. We describe a practical approach to this clinical dilemma, which is rooted in adherence to basic principles of history taking and examination, formulation of a reasonable differential diagnosis, followed by an intelligent use of specific investigations and selection of an appropriate treatment. We also discuss the effect of sudden unexpected death in epilepsy and sudden cardiac death. Despite a careful and thorough approach to the patient with a "seizure versus syncope" problem, many will require repeated assessment before a diagnosis is made.

Death, Sudden, Cardiac↗
PubMed2006

Vigabatrin retinopathy in an Irish cohort: lack of correlation with dose.

PURPOSE: The anticonvulsant vigabatrin (VGB) causes irreversible visual-field constriction in 19-92% of patients. It is unclear whether this correlates with dosing, and the natural history of the retinopathy remains obscure. We conducted a retrospective analysis of patients receiving long-term VGB to examine whether toxicity is related to the daily dose, duration of therapy, or cumulative dose. METHODS: Information from 93 patients taking long-term, stable VGB therapy was analyzed. We recorded data on patient demographics, VGB dosing, and all visual-field assessments. We used the mean redial degrees (MRD) from the right eye to compare the amount of constriction with the dose of VGB. RESULTS: The mean number of assessments was two (range, 1-6). Of patients having more than one assessment (n = 65), the mean follow-up time was 2.4 years (range, 0.7-5.6 years); in 52.7%, visual-field constriction developed. Male and female patients were affected equally. We found no correlation between the average MRD and either the maximum dose of VGB taken, the duration of exposure, or the cumulative dose. The shortest exposure time to development of constriction was 1.1 years. All patients with normal fields on initial assessment continued to have normal fields on follow-up. Most patients who had evidence of constriction on initial assessment and remained taking VGB showed no progression on follow-up. One patient had a substantial recovery of vision after discontinuation of VGB. CONCLUSIONS: Development of visual constriction in patients receiving prolonged, standard doses of VGB does not depend on the daily dose, duration of exposure, or cumulative dose. Other contributing factors were not identified. Our data suggest that field defects may develop within the first few years of therapy and possibly remain stable thereafter.

Adult↗
PubMed2005

Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects.

The progressive myoclonic epilepsies (PMEs) are a group of symptomatic generalised epilepsies caused by rare disorders, most of which have a genetic component, a debilitating course, and a poor outcome. Challenges with PME arise from difficulty with diagnosis, especially in the early stages of the illness, and further problems of management and drug treatment. Recent advances in molecular genetics have helped achieve better understanding of the different disorders that cause PME. We review the PMEs with emphasis on updated genetics, diagnosis, and therapeutic options.

Adolescent↗
PubMed2004

Oxidative injury in epilepsy: potential for antioxidant therapy?

Biological ill effects of oxidative injury from excess free radical production are implicated in many human conditions. Epilepsy is a chronic, dynamic neurological disorder associated with ongoing neuronal damage, particularly when uncontrolled. Oxidative injury may play a role in the initiation and progression of epilepsy, and therapies aimed at reducing oxidative stress may ameliorate tissue damage and favorably alter the clinical course. There is abundant in vivo evidence of oxidative injury in animal models of epilepsy and for efficacy of antioxidant therapy in reducing this injury in animal models of epileptogenesis. However, there is sparse direct clinical data on the use of antioxidants in human epilepsy. This review examines the evidence for the role of oxidative injury in epilepsy, the rationale for use of antioxidant therapy in epilepsy and appraises the current clinical performance of the studies of antioxidant therapies.

Antioxidants↗
PubMed2003

Herbal remedies, dietary supplements, and seizures.

The use of herbal remedies and dietary supplements is widespread throughout the world, and use may be increasing. These are taken for a wide range of perceived benefits, such as energy and memory enhancement and treatment of specific conditions. Individuals with and without epilepsy may use these substances and may not inform their treating physician unless specifically asked. Inquiry about herbal medicine and dietary supplement intake should now be part of routine clinical history taking. Anecdotal accounts suggest that some herbal substances may have anticonvulsant effect, but randomised double-blind controlled trails are lacking. Alternatively many herbals and dietary supplements may predispose to seizures in individuals without epilepsy and worsen seizure control in those with epilepsy. In this article, we review the potential anticonvulsant and proconvulsant effects of herbal remedies and dietary supplements and discuss the potential interaction between these herbal substances and conventional anticonvulsant medications.

Animals↗