ORCID Profile
0000-0002-8213-6141
Current Organisations
Royal College of Surgeons in Ireland
,
Universitair Medisch Centrum Utrecht
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Publisher: Wiley
Date: 25-09-2019
DOI: 10.1002/EPI4.12360
Publisher: Elsevier BV
Date: 09-2014
Publisher: Wiley
Date: 31-08-2017
DOI: 10.1111/EPI.13871
Abstract: Mesial temporal lobe epilepsy with hippoc al sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.
Publisher: Wiley
Date: 17-01-2019
DOI: 10.1002/EPI4.12297
Publisher: Wiley
Date: 04-2022
DOI: 10.1111/EPI.17228
Abstract: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All s les were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger s le sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.
Publisher: Wiley
Date: 21-05-2021
DOI: 10.1002/ACN3.51374
Abstract: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of in iduals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. We performed exome sequencing of 1,128 in iduals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 in iduals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-12-2017
DOI: 10.1212/WNL.0000000000004853
Abstract: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. We report an association between a rare variant in the complement factor H–related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10 –11 odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.
No related grants have been discovered for Mark McCormack.