Engineering and Information Technology Collected Works - Research Publications
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ItemAnterior temporal encephaloceles: Elusive, important, and rewarding to treat(WILEY, 2020-12)Objective To investigate the etiology and longitudinal clinical, neuropsychological, psychosocial, and surgical outcome profile of patients with medication refractory epilepsy and temporal encephaloceles with a view to highlight diagnostic clues and management strategies. Methods The comprehensive epilepsy program databases at two surgical epilepsy centers from January 2000 to October 2018 were reviewed for this observational study, to identify patients with encephaloceles causing temporal lobe epilepsy (TLE) and treated with surgical resection. Their clinical, radiological, neuropsychological, psychiatric, and surgical data were obtained. Body mass index (BMI) data were also reviewed due to possible correlation between idiopathic intracranial hypertension and encephaloceles. Results Thirteen patients (eight female) were identified; only three were recognized on initial magnetic resonance imaging (MRI) report. Temporal encephaloceles were identified on the left in eight patients, on the right in three patients, and bilaterally in two patients. One patient had a strong family history of encephaloceles. The median BMI for patients with seizure onset ≤20 years of age was 22.4, whereas for patients with onset >20 years median BMI was 32.6 (P = .06). Five patients underwent a focal lesionectomy, three patients had limited temporal lobectomy, and five patients had standard anterior temporal lobectomy. Median postoperative follow‐up was 5.5 years. All but one patient were free of disabling seizures. Nine of ten neuropsychologically tested patients had no discernable cognitive decline postoperatively. Postoperative psychosocial adjustment features were present in four patients. Significance Genetic factors and a possible association with idiopathic intracranial hypertension (given female predominance and elevated BMI) may contribute to the causation of temporal lobe encephaloceles. It is notable that a targeted surgical approach in the management of patients with TLE associated with encephaloceles has an excellent long‐term clinical and neuropsychological outcome. Subtle encephaloceles should be actively searched for in patients with drug‐resistant TLE because they significantly change surgical strategy and prognostication.
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ItemGlobal Expression Profiling in Epileptogenesis: Does It Add to the Confusion?(WILEY, 2010-01)Since the inception of global gene expression profiling platforms in the mid-1990s, there has been a significant increase in publications of differentially expressed genes in the process of epileptogenesis. In particular for mesial temporal lobe epilepsy, the presence of a latency period between the first manifestation of seizures to chronic epilepsy provides the opportunity for therapeutic interventions at the molecular biology level. Using global expression profiling techniques, approximately 2000 genes have been published demonstrating differential expression in mesial temporal epilepsy. The majority of these changes, however, are specific to laboratory or experimental conditions with only 53 genes demonstrating changes in more than two publications. To this end, we review the current status of gene expression profiling in epileptogenesis and suggest standard guidelines to be followed for greater accuracy and reproducibility of results.
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ItemInterictal and ictal source localization for epilepsy surgery using high-density EEG with MEG: a prospective long-term study(OXFORD UNIV PRESS, 2019-04)Drug-resistant focal epilepsy is a major clinical problem and surgery is under-used. Better non-invasive techniques for epileptogenic zone localization are needed when MRI shows no lesion or an extensive lesion. The problem is interictal and ictal localization before propagation from the epileptogenic zone. High-density EEG (HDEEG) and magnetoencephalography (MEG) offer millisecond-order temporal resolution to address this but co-acquisition is challenging, ictal MEG studies are rare, long-term prospective studies are lacking, and fundamental questions remain. Should HDEEG-MEG discharges be assessed independently [electroencephalographic source localization (ESL), magnetoencephalographic source localization (MSL)] or combined (EMSL) for source localization? Which phase of the discharge best characterizes the epileptogenic zone (defined by intracranial EEG and surgical resection relative to outcome)? Does this differ for interictal and ictal discharges? Does MEG detect mesial temporal lobe discharges? Thirteen patients (10 non-lesional, three extensive-lesional) underwent synchronized HDEEG-MEG (72-94 channel EEG, 306-sensor MEG). Source localization (standardized low-resolution tomographic analysis with MRI patient-individualized boundary-element method) was applied to averaged interictal epileptiform discharges (IED) and ictal discharges at three phases: 'early-phase' (first latency 90% explained variance), 'mid-phase' (first of 50% rising-phase, 50% mean global field power), 'late-phase' (negative peak). 'Earliest-solution' was the first of the three early-phase solutions (ESL, MSL, EMSL). Prospective follow-up was 3-21 (median 12) months before surgery, 14-39 (median 21) months after surgery. IEDs (n = 1474) were recorded, seen in: HDEEG only, 626 (42%); MEG only, 232 (16%); and both 616 (42%). Thirty-three seizures were captured, seen in: HDEEG only, seven (21%); MEG only, one (3%); and both 25 (76%). Intracranial EEG was done in nine patients. Engel scores were I (9/13, 69%), II (2/13,15%), and III (2/13). MEG detected baso-mesial temporal lobe epileptogenic zone sources. Epileptogenic zone OR [odds ratio(s)] were significantly higher for earliest-solution versus early-phase IED-surgical resection and earliest-solution versus all mid-phase and late-phase solutions. ESL outperformed EMSL for ictal-surgical resection [OR 3.54, 95% confidence interval (CI) 1.09-11.55, P = 0.036]. MSL outperformed EMSL for IED-intracranial EEG (OR 4.67, 95% CI 1.19-18.34, P = 0.027). ESL outperformed MSL for ictal-surgical resection (OR 3.73, 95% CI 1.16-12.03, P = 0.028) but was outperformed by MSL for IED-intracranial EEG (OR 0.18, 95% CI 0.05-0.73, P = 0.017). Thus, (i) HDEEG and MEG source solutions more accurately localize the epileptogenic zone at the earliest resolvable phase of interictal and ictal discharges, not mid-phase (as is common practice) or late peak-phase (when signal-to-noise ratios are maximal); (ii) from empirical observation of the differential timing of HDEEG and MEG discharges and based on the superiority of ESL plus MSL over either modality alone and over EMSL, concurrent HDEEG-MEG signals should be assessed independently, not combined; (iii) baso-mesial temporal lobe sources are detectable by MEG; and (iv) MEG is not 'more accurate' than HDEEG-emphasis is best placed on the earliest signal (whether HDEEG or MEG) amenable to source localization. Our findings challenge current practice and our reliance on invasive monitoring in these patients. 10.1093/brain/awz015_video1 awz015media1 6018582479001.
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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.