Medicine (Austin & Northern Health) - Research Publications
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ItemNo Preview AvailableReading difficulty is associated with failure to lateralize temporooccipital function(WILEY-BLACKWELL, 2014-05)OBJECTIVE: Studies of focal epilepsy have revealed abnormalities of language organization; however, little attention has been paid to disorders of reading in this group. We hypothesized that language functional magnetic resonance imaging (fMRI) would reveal differences in language organization between focal epilepsy patients with and without reading difficulties. METHODS: We conducted language fMRI studies of 10 focal epilepsy patients with reading difficulties, 34 focal epilepsy patients without reading difficulties, and 42 healthy controls. RESULTS: We defined regions of interests on the basis of activation patterns on an orthographic lexical retrieval task. Comparison of activations within these ROIs on a second Noun-Verb task revealed epilepsy-related effects (relative to healthy controls: reduced activation in left inferior frontal cortex), as well as greater activation in the right temporooccipital cortex specific to the reading difficulty group. SIGNIFICANCE: These findings identify a focal epilepsy effect in the left frontal region (present in patients with and without reading difficulties), and a functional abnormality specific to the reading difficulty group localized to right temporooccipital cortex-a region implicated in lexicosemantic processing. Our observations suggest a failure of left hemisphere specialization among focal epilepsy patients with reading difficulties.
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ItemNo Preview AvailableEnhanced in vitro CA1 network activity in a sodium channel β1(C121W) subunit model of genetic epilepsy(WILEY-BLACKWELL, 2014-04)OBJECTIVE: A NaV β1(C121W) mouse model of human genetic epilepsy has enhanced neuronal excitability and temperature sensitivity attributed to a decreased threshold for action potential firing in the axon initial segment. To investigate the network consequences of this neuronal dysfunction and to establish a genetic disease state model we developed an in vitro assay to investigate CA1 network properties and antiepileptic drug sensitivity. METHODS: CA1 network oscillations were induced by tetanic stimulation and average number of spikes, interspike interval (ISI), duration, and latency were measured in slices from control and NaV β1(C121W) heterozygous mice in the presence and absence of retigabine or carbamazepine. Retigabine was also tested in a thermogenic seizure model. RESULTS: Oscillations were reliably induced by tetanic stimulation and were maintained after severing connections between CA3 and CA1, suggesting a local recurrent circuit. Blocking α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid receptor A (GABAA ), Ih , and T-type Ca(2+) channels/receptors reduced the number of spikes. Slices from NaV β1(C121W) heterozygous mice displayed several hallmarks of increased network excitability including increases in duration of the oscillation, the number and frequency of spikes and a decrease in their onset latency. The effect of genotype on network excitability was temperature sensitive, as it was seen only at elevated temperatures. Carbamazepine and retigabine were more effective in reducing network excitability in slices from NaV β1(C121W) heterozygous mice. Retigabine appeared to be more effective in suppressing time to thermogenic seizures in NaV β1(C121W) heterozygous mice compared to wild-type (WT) controls. SIGNIFICANCE: Hippocampal networks of the NaV β1(C121W) heterozygous mouse model of genetic epilepsy show enhanced excitability consistent with earlier single neuron studies bridging important scales of brain complexity relevant to seizure genesis. Altered pharmacosensitivity further suggests that genetic epilepsy models may be useful in the development of novel antiepileptic drugs that target disease state pathology. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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ItemNo Preview AvailableTonic seizures of Lennox-Gastaut syndrome: Periictal single-photon emission computed tomography suggests a corticopontine network(WILEY, 2013-12)PURPOSE: Lennox-Gastaut syndrome (LGS) is a severe epileptic disorder with characteristic electroclinical features but diverse etiologies. The shared electroclinical characteristics suggest that common cerebral networks are involved in generating seizures. We sought to reveal these networks by comparing ictal and interictal single-photon emission computed tomography (SPECT). METHODS: We identified 10 ictal-interictal SPECT pairs from seven patients with LGS (median age 11 years; range 1-38) who were studied during video electroencephalography (EEG)-confirmed tonic seizures. We performed a voxel-wise comparison of ictal and interictal SPECT studies across the group. The evolution of blood flow changes was explored by examining early and late injection groups. KEY FINDINGS: Median duration of tonic seizures was 10 s (range 6-29 s), and injection latency from seizure offset was -8 to 48 s. In the early injection group (<10 s; three studies), there was hyperperfusion over pons and cerebellar hemispheres (p < 0.05 cluster corrected family wise error), and hypoperfusion bilaterally over the pericentral region, with a trend toward hyperperfusion over bilateral superior and middle frontal gyri, and lateral parietal cortex. In the late injection group, there was hyperperfusion over midline and lateral cerebellar regions, with hypoperfusion widely over bilateral frontal regions. SIGNIFICANCE: This study suggests that the tonic seizures of LGS result from activity in a network, containing bilateral frontal and parietal association areas and the pons. We postulate that tonic seizures recruit the corticoreticular system, which connects frontal attentional areas to the pontine reticular formation, and is normally responsible for postural tone and orienting behavior.
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ItemNo Preview AvailableNetwork-specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin(WILEY, 2013-07)PURPOSE: A common notion of the mechanism by which the antiepileptic drugs (AEDs) carbamazepine and phenytoin act is that they block sodium channels by binding preferentially to the inactivated state, thereby allowing normal neuronal firing while blocking ictal activity. However, these drugs have unpredictable efficacy and, in some cases, may exacerbate seizures. Previous studies have suggested that reducing sodium channel availability in the dentate gyrus (DG) paradoxically increases excitability. We used a biophysically detailed computer model of the DG to test the hypothesis that AEDs increase excitability by disproportionately reducing negative feedback mechanisms. METHODS: We built a Markov model of sodium channel gating that reproduces responses to voltage clamp experiments in the presence of carbamazepine and phenytoin. We incorporated this validated Markov model into a biophysically realistic computer model of DG neurons and networks. Simulated drug concentrations were similar to those measured in cerebral spinal fluid in medicated patients. Single neuron models were stimulated with current injections, and networks were stimulated with perforant path synaptic input. In the network model, environmental effects were studied by introducing mossy fiber sprouting. KEY FINDINGS: As expected, drugs reduced sodium channel availability, which in turn reduced action potential amplitude. This had only a small effect on action potential (AP) firing rate during brief (100 msec) current injections. Paradoxically, long current injections (2,500 msec) increased AP firing rates. This was caused by reduced calcium entry and consequently reduced activation of calcium activated potassium channels. It is important to note that the main determinant of drug effect was resting membrane potential (RMP) and not action potential firing rate. Binding of phenytoin and carbamazepine is slow and, thus drug effects are largely determined by the long term state of the RMP. This paradoxical AP firing increase was dependent on the unusually large calcium-activated potassium conductances expressed by DG granule cells. This predicts that drug efficacy in a given network will depend on the precise makeup of conductances in the network. RMP is expected to vary with the level of activity in the network. We simulated the effects of drugs on single shot stimulus responses in networks with mossy fiber sprouting and varied the RMP in all neurons as a model for network activity. For an RMP of -50 mV, representing an active network, drugs had no effect, or in some cases, increased excitability. Drugs had an increasingly larger inhibitory effect on network responses as RMP decreased. An important prediction is that drugs will be unable to block ictal activity invading an active network. SIGNIFICANCE: Our key findings are that drug effects depend on both intrinsic properties of the network and its behavioral state. This may explain the paradoxical and unpredictable effects of some AEDs on seizure control in some patients.
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ItemNo Preview AvailableMutations in PRRT2 are not a common cause of infantile epileptic encephalopathies(WILEY, 2013-05)Heterozygous mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Homozygous mutations in PRRT2 have also been reported in two families with intellectual disability (ID) and seizures. Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal-infantile epilepsy. Mutations in KCNQ2 and SCN2A also contribute to severe infantile epileptic encephalopathies (IEEs) in which seizures and intellectual disability co-occur. We therefore hypothesized that PRRT2 mutations may also underlie cases of IEE. We examined PRRT2 for heterozygous, compound heterozygous or homozygous mutations to determine their frequency in causing epileptic encephalopathies (EEs). Two hundred twenty patients with EEs with onset by 2 years were phenotyped. An assay for the common PRRT2 c.649-650insC mutation and high resolution-melt analysis for mutations in the remaining exons of PRRT2 were performed. Neither the common mutation nor any other pathogenic variants in PRRT2 were detected in the 220 patients. Our findings suggest that mutations in PRRT2 are not a common cause of IEEs.
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ItemNo Preview AvailablePsychological trajectories in the year after a newly diagnosed seizure(WILEY-BLACKWELL, 2012-10)PURPOSE: Underdiagnosed depression and anxiety are well-recognized issues in chronic epilepsy, but the evolution of these symptoms after diagnosis is not well understood. We aimed to identify mood trajectories after a first seizure, and to examine factors impacting these trajectories. METHODS: Seventy-four patients were evaluated at 1, 3, and 12 months with (1) the Hospital Anxiety and Depression Scale, and (2) a semistructured interview assessing patients' initial psychological reaction to the seizure at 1 month (limited vs. pervasive loss of control). The SAS Institute's TRAJ data modelling procedure was employed to delineate trajectories. KEY FINDINGS: Two depression and three anxiety trajectories were identified, with significant overlap. The majority of patients (≈ 74%) followed a trajectory with low depression throughout the study, and either low or moderate anxiety. A minority followed trajectories with high depression and anxiety from diagnosis (≈ 16%). Patients with high levels of distress were adversely affected by seizure recurrence and antiepileptic drugs (AEDs), whereas those with low levels were not. Trajectories were predicted by the patient's sense of loss of control early after diagnosis and were weakly related to demographic and medical variables (age, gender, education, relationship status, psychiatric history, and prior epileptic events). SIGNIFICANCE: Methods that account for heterogeneity in patient responses are critical for developing a clinically relevant understanding of adjustment after a newly diagnosed seizure. Most patients appear to be resilient in the face of early seizures, whereas those at risk of longer-term psychological difficulties may be evident from diagnosis. Early screening for depression and anxiety is warranted.
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ItemEpi4K: Gene discovery in 4,000 genomes(WILEY, 2012-08)A major challenge in epilepsy research is to unravel the complex genetic mechanisms underlying both common and rare forms of epilepsy, as well as the genetic determinants of response to treatment. To accelerate progress in this area, the National Institute of Neurological Disorders and Stroke (NINDS) recently offered funding for the creation of a "Center without Walls" to focus on the genetics of human epilepsy. This article describes Epi4K, the collaborative study supported through this grant mechanism and having the aim of analyzing the genomes of a minimum 4,000 subjects with highly selected and well-characterized epilepsy.