Medicine (RMH) - Research Publications
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ItemConversion to lacosamide monotherapy in the treatment of focal epilepsy: Results from a historical-controlled, multicenter, double-blind study(WILEY, 2014-07)OBJECTIVE: To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy. METHODS: This historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16-70 years on stable doses of 1-2 antiepileptic drugs (AEDs) and experiencing 2-40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier-predicted percentage of patients on 400 mg/day in the full analysis set (FAS) meeting ≥ 1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%). RESULTS: Four hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥ 1 exit criterion; the Kaplan-Meier-predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [CI] 24.6-35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events (TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8-37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity. Seventy-two patients (16.9%) discontinued due to TEAEs. Seventeen patients (4%, all receiving 400 mg/day) experienced serious AEs. SIGNIFICANCE: Lacosamide 400 mg/day monotherapy was effective, with a favorable safety profile in patients with focal epilepsy.
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ItemAltered cortical thickness following prenatal sodium valproate exposure(WILEY-BLACKWELL, 2014-07)Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children.
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ItemIn Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy(PUBLIC LIBRARY SCIENCE, 2014-01-21)PURPOSE: Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [(18)F]-flumazenil ([(18)F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE. METHODS: Dynamic [(18)F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5-25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [(18)F]-FMZ PET scan (3.6-4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [(18)F]-FMZ PET data. KEY FINDINGS: The PSM was found to adequately model [(18)F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [(18)F]-FMZ binding. SIGNIFICANCE: Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [(18)F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [(18)F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.
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Item21.(Elsevier BV, 2014-11)
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ItemHyperphosphorylated Tau is Implicated in Acquired Epilepsy and Neuropsychiatric Comorbidities(SPRINGER, 2014-06)Epilepsy is a common group of neurological diseases. Acquired epilepsy can be caused by brain insults, such as trauma, infection or tumour, and followed by a latent period from several months to years before the emergence of recurrent spontaneous seizures. More than 50% of epilepsy cases will develop chronic neurodegenerative, neurocognitive and neuropsychiatric comorbidities. It is important to understand the mechanisms by which a brain insult results in acquired epilepsy and comorbidities in order to identify targets for novel therapeutic interventions that may mitigate these outcomes. Recent studies have implicated the hyperphosphorylated tubulin-associated protein (tau) in rodent models of epilepsy and Alzheimer's disease, and in experimental and clinical studies of traumatic brain injury. This potentially represents a novel target to mitigate epilepsy and associated neurocognitive and psychiatric disorders post-brain injury. This article reviews the potential role of tau-based mechanisms in the pathophysiology of acquired epilepsy and its neurocognitive and neuropsychiatric comorbidities, and the potential to target these for novel disease-modifying treatments.
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ItemNo Preview AvailableIDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas(WILEY, 2014-09)OBJECTIVE: The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas. METHODS: Thirty consecutive patients with WHO grade II gliomas were analyzed for the presence of the IDH1-R132H mutation using immunohistochemistry. The expression of IDH1 mutation was semiquantified using open-source biologic-imaging analysis software. RESULTS: The percentage of cells positive for the IDH1-R132H mutation was found to be higher in patients with TAE compared to those without TAE (median and interquartile range (IQR) 25.3% [8.6-53.5] vs. 5.2% [0.6-13.4], p = 0.03). In addition, we found a significantly higher median IDH1 mutation expression level in the protoplasmic subtype of low grade glioma (52.2% [IQR 19.9-58.6] vs. 13.8% [IQR 3.9-29.4], p = 0.04). SIGNIFICANCE: Increased expression of the IDH1-R132H mutation is associated with seizures in low grade gliomas and also with the protoplasmic subtype. This supports the hypothesis that this mutation may play a role in the pathogenesis of both TAE and low grade gliomas.
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ItemNo Preview AvailableWeight and fat distribution in patients taking valproate: A valproate-discordant gender-matched twin and sibling pair study(WILEY, 2014-10)OBJECTIVES: Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. METHODS: Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. RESULTS: We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%. SIGNIFICANCE: This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.
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ItemDescribing the genetic architecture of epilepsy through heritability analysis(OXFORD UNIV PRESS, 2014-10)Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.
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ItemThe dynamics of the epileptic bran reveal long-memory processes(FRONTIERS MEDIA SA, 2014)The pattern of epileptic seizures is often considered unpredictable and the interval between events without correlation. A number of studies have examined the possibility that seizure activity respects a power-law relationship, both in terms of event magnitude and inter-event intervals. Such relationships are found in a variety of natural and man-made systems, such as earthquakes or Internet traffic, and describe the relationship between the magnitude of an event and the number of events. We postulated that human inter-seizure intervals would follow a power-law relationship, and furthermore that evidence for the existence of a long-memory process could be established in this relationship. We performed a post hoc analysis, studying eight patients who had long-term (up to 2 years) ambulatory intracranial EEG data recorded as part of the assessment of a novel seizure prediction device. We demonstrated that a power-law relationship could be established in these patients (β = - 1.5). In five out of the six subjects whose data were sufficiently stationary for analysis, we found evidence of long memory between epileptic events. This memory spans time scales from 30 min to 40 days. The estimated Hurst exponents range from 0.51 to 0.77 ± 0.01. This finding may provide evidence of phase-transitions underlying the dynamics of epilepsy.
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ItemEarly life maternal separation stress augmentation of limbic epileptogenesis: The role of corticosterone and HPA axis programming(PERGAMON-ELSEVIER SCIENCE LTD, 2014-04)Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown. Here, we tested whether hypothalamic-pituitary-adrenal (HPA) axis hyper-reactivity induced by MS - specifically the excessive secretion of corticosterone following a seizure - was involved in this vulnerability. In adult female rats subjected to MS from postnatal days 2-14, seizure-induced corticosterone responses were significantly augmented and prolonged for at least two hours post-seizure, compared to control early-handled (EH) rats. This was accompanied by reduced seizure threshold (p<0.05) and increased vulnerability to the kindling-induced progression of seizure duration (p<0.05) in MS rats. Pre-seizure treatment with the corticosterone synthesis inhibitor, metyrapone (MET) (50mg/kgsc) effectively blocked seizure-induced corticosterone responses. When delivered throughout kindling, MET treatment also reversed the MS-induced reduction in seizure threshold and the lengthened seizure duration back to levels of EH rats. These observations suggest that adverse early life environments induce a vulnerability to kindling epileptogenesis mediated by HPA axis hyper-reactivity, which could have relevance for the pathogenesis of MTLE.