Engineering and Information Technology Collected Works - Research Publications
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ItemElectroencephalography in the Diagnosis of Genetic Generalized Epilepsy Syndromes(FRONTIERS MEDIA SA, 2017-09-25)Genetic generalized epilepsy (GGE) consists of several syndromes diagnosed and classified on the basis of clinical features and electroencephalographic (EEG) abnormalities. The main EEG feature of GGE is bilateral, synchronous, symmetric, and generalized spike-wave complex. Other classic EEG abnormalities are polyspikes, epileptiform K-complexes and sleep spindles, polyspike-wave discharges, occipital intermittent rhythmic delta activity, eye-closure sensitivity, fixation-off sensitivity, and photoparoxysmal response. However, admixed with typical changes, atypical epileptiform discharges are also commonly seen in GGE. There are circadian variations of generalized epileptiform discharges. Sleep, sleep deprivation, hyperventilation, intermittent photic stimulation, eye closure, and fixation-off are often used as activation techniques to increase the diagnostic yield of EEG recordings. Reflex seizure-related EEG abnormalities can be elicited by the use of triggers such as cognitive tasks and pattern stimulation during the EEG recording in selected patients. Distinct electrographic abnormalities to help classification can be identified among different electroclinical syndromes.
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ItemCharacteristics of Epileptiform Discharge Duration and Interdischarge Interval in Genetic Generalized Epilepsies(FRONTIERS MEDIA SA, 2018-02-19)We sought to investigate (1) the characteristics of epileptiform discharge (ED) duration and interdischarge interval (IDI) and (2) the influence of vigilance state on the ED duration and IDI in genetic generalized epilepsy (GGE). In a cohort of patients diagnosed with GGE, 24-h ambulatory EEG recordings were performed prospectively. We then tabulated durations, IDI, and vigilance state in relation to all EDs captured on EEGs. We used K-means cluster analysis and finite mixture modeling to quantify and characterize the groups of ED duration and IDI. To investigate the influence of sleep, we calculated the mean, median, and SEM in each population from all subjects for sleep state and wakefulness separately, followed by the Kruskal-Wallis test to compare the groups. We analyzed 4,679 EDs and corresponding IDI from 23 abnormal 24-h ambulatory EEGs. Our analysis defined two populations of ED durations and IDI: short and long. In all populations, both ED durations and IDI were significantly longer in wakefulness. Our results highlight different characteristics of ED populations in GGE and the influence by the sleep-wake cycle.
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ItemDomino-like transient dynamics at seizure onset in epilepsy(PUBLIC LIBRARY SCIENCE, 2020-09)The International League Against Epilepsy (ILAE) groups seizures into "focal", "generalized" and "unknown" based on whether the seizure onset is confined to a brain region in one hemisphere, arises in several brain region simultaneously, or is not known, respectively. This separation fails to account for the rich diversity of clinically and experimentally observed spatiotemporal patterns of seizure onset and even less so for the properties of the brain networks generating them. We consider three different patterns of domino-like seizure onset in Idiopathic Generalized Epilepsy (IGE) and present a novel approach to classification of seizures. To understand how these patterns are generated on networks requires understanding of the relationship between intrinsic node dynamics and coupling between nodes in the presence of noise, which currently is unknown. We investigate this interplay here in the framework of domino-like recruitment across a network. In particular, we use a phenomenological model of seizure onset with heterogeneous coupling and node properties, and show that in combination they generate a range of domino-like onset patterns observed in the IGE seizures. We further explore the individual contribution of heterogeneous node dynamics and coupling by interpreting in-vitro experimental data in which the speed of onset can be chemically modulated. This work contributes to a better understanding of possible drivers for the spatiotemporal patterns observed at seizure onset and may ultimately contribute to a more personalized approach to classification of seizure types in clinical practice.
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ItemAnti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study(ELSEVIER, 2020-05)BACKGROUND: A clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated. METHODS: In this single arm study, five adult subjects, with 29-234 focal onset seizures per month from a seizure focus involving the mesial temporal lobe were implanted with the system (clinicaltrials.gov identifier NCT02899611). Oral valproic acid (VPA) had previously been ineffective in all subjects. Post-surgery, pharmacokinetic studies of CSF infused VPA were performed. Valproic acid doses were increased stepwise in a standardised protocol. FINDINGS: The procedure and implantation were well-tolerated by all subjects. Four subjects responded with > 50% seizure reduction at the highest tested dose of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects reported significant quality of life improvement. No clinical dose limiting side effects were encountered and there was no evidence of local periventricular toxicity in three subjects who were evaluated with imaging (T2 MRI). Side effects included nausea and appetite loss but were not dose-limiting. Mean CSF valproic acid levels were 45 μg per ml (range 20-120 μg per ml), with corresponding serum levels of 4-14 μg per ml. Subjects have received therapy for up to 2.5 years in total . The efficacy analysis presented focuses on the period of time with the current pump with a mean 12.5 months, range 11.5-15 months. Pump failure requiring reimplantation was a significant initial issue in all subjects but resolved with use of pumps suitably compatible with long-term exposure to valproic acid. INTERPRETATION: The study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well-tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal. FUNDING: The study was funded by Cerebral Therapeutics Inc., Suite 137 12635 East Montview Blvd Aurora CO 80045.