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Background: Focal cortical dysplasias (FCDs) are congenital structural abnormalities of the brain, and represent the most common cause of medication-resistant focal epilepsy in children and adults. Recent studies have shown that somatic mutations (i.e. mutations arising in the embryo) in mTOR pathway genes underlie some FCD cases. Specific therapies targeting the mTOR pathway are available. However, testing for somatic mTOR pathway mutations in FCD tissue is not performed on a clinical basis, and the contribution of such mutations to the pathogenesis of FCD remains unknown. Aim: To investigate the feasibility of screening for somatic mutations in resected FCD tissue and determine the proportion and spatial distribution of FCDs which are due to low-level somatic mTOR pathway mutations. Methods: We performed ultra-deep sequencing of 13 mTOR pathway genes using a custom HaloPlexHS target enrichment kit (Agilent Technologies) in 16 resected histologically-confirmed FCD specimens. Results: We identified causal variants in 62.5% (10/16) of patients at an alternate allele frequency of 0.75–33.7%. The spatial mutation frequency correlated with the FCD lesion’s size and severity. Conclusions: Screening FCD tissue using a custom panel results in a high yield, and should be considered clinically given the important potential implications regarding surgical resection, medical management and genetic counselling.
Background: NMDA receptor encephalitis (NMDA-RE) is an autoimmune disorder caused by antibodies to the NR1-NR2B heterodimer of the NMDA receptor. Currently, disease status is tracked primarily by the presence of auto-antibodies in the cerebrospinal fluid (CSF) and serum. Using serological and CSF markers along with clinical parameters to track disease progress can be challenging since patient symptoms and disease progress can vary widely. Methods: EEGs were reviewed in a 31 year old male patient with proven NMDA-RE. EEG data were sampled from various times before and after diagnosis, as well as during various stages of treatment. All analyses were performed using Matlab (Mathworks). Results: We showed that using a simple 1/f model of spectral behaviour (Buzsaki and Draguhn, 2004), we could fit the power spectra of the raw data at various instances during routine EEGs. We have demonstrated that the values of specific fitting parameters vary in relationship to the patient’s clinical status across various stages of illness. Conclusions: The aim of this project was to explore the potential utility of EEG as a complement to the usual clinical metrics used in monitoring NMDA-RE. The analysis techniques presented here highlight the use of EEG as a practical, minimaly-invasive tool to monitor progress and potentially aid in clinical decision making.
We measured biochemical markers of excitability in brain excised for neurosurgical therapy of epilepsy. Intraoperative electrocorticography was used to identify and compare samples from regions of persistent interictal spike discharges and areas of the cerebral convexity which were free of interictal piking. We found that interictal spiking was associated with elevated tissue levels of the excitatory amino acids glutamic acid (26%, p < 0.001) and aspartic acid (25%, p < 0.05). There was also a significant increase in the activity of the enzymes glutamic acid dehydrogenase (20%, p < 0.01) and aspartate acid aminotransferase (18%, p < 0.01) which are involved in their formation. There was no change in the levels of the inhibitory neurotransmitters GABA or taurine. We also found a significant increase in the activity of tyrosine hydroxylase (52%, p < 0.001), the rate controlling enzyme in catecholamine biosynthesis. There was a reduction in the density (Bmax) of cortical alpha-1 adrenoceptors (26%, p < 0.01) and a concommitant diminution of receptor coupled phosphatidylinositide metabolism (21%, p < 0.01). This blunting of inhibitory noradrenergic transmembrane signaling may contribute to a relative imbalance between excitatory and inhibitory mechanisms in epileptogenic neocortex.
The management of uncontrolled partial epilepsy is a process dependent on a multidisciplinary and analytic approach. It is necessary to understand which lesions are epileptogenic, and if they are indeed responsible for the generation of seizures. In addition to localizing seizure onset, the functional and eloquent areas of the brain need to be identified. As in many other centres, we perform resective surgeries on the basis of combined information derived from seizure semiology, EEG abnormalities, neuroimaging and other tests of cerebral function. If surface EEG recording yields inconclusive or ambiguous results, then invasive intracranial techniques using intracerebral depth or subdural electrodes can be used to improve diagnostic or prognostic accuracy. The indications, principles, results and complications of these recording techniques based on extensive experience at two epilepsy surgery centres are reviewed.
Epilepsy is a common medical condition for which physicians perform driver fitness assessments. The Canadian Medical association (CMA) and the Canadian Council of Motor transportation administrators (CCMTA) publish documents to guide Canadian physicians’ driver fitness assessments.
We aimed to measure the consistency of driver fitness counseling among epileptologists in Canada, and to determine whether inconsistencies between national guidelines are associated with greater variability in counseling instructions.
We surveyed 35 epileptologists in Canada (response rate 71%) using a questionnaire that explored physicians’ philosophies about driver fitness assessments and counseling practices of seizure patients in common clinical scenarios. Of the nine scenarios, CCMTA and CMA recommendations were concordant for only two. Cumulative agreement for all scenarios was calculated using Kappa statistic. Agreement for concordant (two) vs. discordant (seven) scenarios were split at the median and analyzed using the Wilcoxon signed rank sum test.
Overall the agreement between respondents for the clinical scenarios was not acceptable (Kappa=0.28). For the two scenarios where CMa and CCMta guidelines were concordant, specialists had high levels of agreement with recommendations (89% each). A majority of specialists disagreed with CMa recommendations in three of seven discordant scenarios. The lack of consistency in respondents’ agreement attained statistical significance (p<0.001).
Canadian epileptologists have variable counseling practices about driving, and this may be attributable to inconsistencies between CMa and CCMta medical fitness guidelines. This study highlights the need to harmonize driving recommendations in order to prevent physician and patient confusion about driving fitness in Canada.
The effect of feeding pigs in a three-phase feeding (3PF) system or a daily-phase feeding (DPF) system on growth performance, body composition, and N and P excretions was studied on 8 pens of 10 pigs each. Feeds for the 3PF and DPF treatments were obtained by mixing two feeds, one with a high nutrient concentration and the other with a low nutrient concentration. The DPF pigs tended (P=0.08) to consume more feed (+3.7%) than the 3PF pigs, but only during the first feeding phase. The DPF pigs consumed 7.3% less protein (P<0.01) but a similar amount of total P. For the whole growing period, the DPF pigs tended (P=0.08) to gain more weight (+2.4%) than the 3PF pigs, mainly because of faster growth (P=0.02) during the first feeding period. At the end of the experiment, total body protein mass was similar in the two treatment groups, but the DPF pigs had 8% more body lipids (P=0.04) than the 3PF pigs. Daily multiphase feeding reduced N excretion by 12% (P<0.01) but did not significantly reduce P excretion. In addition, feed costs, nutrient intake and nutrient excretion under the two feeding strategies were simulated and compared after different approaches were used to formulate complete feeds for each phase of the 3PF system, as well as the two feeds used in the DPF program. Simulated feed intake and growth was similar to those observed in the animal experiment. In comparison with the simulated 3PF system, the feed cost for the DPF pigs was reduced by 1.0%, the simulated N and P intakes were reduced by 7.3% and 4.4%, respectively, and the expected N and P excretions were reduced by 12.6% and 6.6%, respectively. The concomitant adjustment of the dietary concentration of nutrients to match the evaluated requirements of pig populations can be an efficient approach to significantly reduce feeding costs and N and P excretions in pig production systems.