ORCID Profile
0000-0002-7198-8621
Current Organisations
University of Melbourne
,
Monash University
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Functional Materials | Nanobiotechnology | Materials Engineering | Metals and Alloy Materials
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in Engineering | Expanding Knowledge in Technology |
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-08-2013
Publisher: Public Library of Science (PLoS)
Date: 21-09-2011
Publisher: Elsevier BV
Date: 08-2023
Publisher: Elsevier BV
Date: 11-2009
Publisher: Oxford University Press (OUP)
Date: 04-12-2019
DOI: 10.1093/IJNP/PYY097
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.EPLEPSYRES.2010.06.003
Abstract: Computer-assisted-telephone-interviewing (CATI), widely used in market research, could be a useful alternative for conducting diagnostic interviews in epilepsy epidemiology. We administered a diagnostic seizure questionnaire by CATI, interpreting the responses with standardized classification guidelines, compared against an epilepsy specialist's assessment, for agreement [Kappa statistic (kappa)], sensitivity, specificity, positive predictive value, negative predictive value and Youden's Index (YI). 99 outpatients with 382 lifetime events participated: 22 generalized-onset epilepsy [16 Idiopathic Generalized Epilepsy (IGE)], 59 partial-onset epilepsy, 12 non-epileptic and 6 uncertain. We observed almost perfect agreement in diagnosing epilepsy (kappa=0.94), seizure-onset types (kappa=0.84), simple or complex partial seizures (kappa=0.87), any generalized non-convulsive seizure (kappa=0.82), and IGE (kappa=0.82). Although substantial, agreement was not as close for secondarily generalized seizures (kappa=0.74), and generalized tonic-clonic seizures (kappa=0.79). This related more to under-recognition of in idual generalized non-convulsive seizures rather than misinterpretation of partial seizures. Epilepsy diagnostic questionnaires administered by CATI and interpreted with standardized diagnostic guidelines can effectively classify epilepsy, most seizure types and IGE in outpatients with suspected seizures. Applying this diagnostic method in 'field' settings will allow firmer conclusions to be drawn on its wider epidemiological utility.
Publisher: ACM
Date: 04-02-2020
Publisher: Oxford University Press (OUP)
Date: 25-06-2014
Publisher: Frontiers Media SA
Date: 29-10-2019
Publisher: BMJ
Date: 04-04-2019
Abstract: Almost 10% of people will experience at least one seizure over a lifetime. Although common, first seizures are serious events and warrant careful assessment and management. First seizures may be provoked by acute or remote symptomatic factors including life-threatening metabolic derangements, drug toxicity or structural brain lesions. An unprovoked first seizure may herald the onset of epilepsy and may be accompanied by medical and psychiatric illnesses. Accidents, injuries and death associated with first seizures are likely under-reported. The cognitive and emotional impact of first seizures is often neglected. Evaluation of a patient presenting with a first seizure requires careful history-taking and early specialist assessment, however optimal management strategies have not been extensively investigated. Further, advances in technology and the role of eHealth interventions such as telemedicine may be of value in the care of patients who have experienced a first seizure. This article reviews the impact and implications of first seizures beyond the scope provided in current guidelines which tend to focus on assessment and management. It examines the effect of first seizures on the well-being of patients assesses morbidity and premature mortality in first seizures and discusses current and future directions to optimise safety and health of people with first seizures, with a focus on adult patients. Recognition of these issues is essential to provide adequate care for people with first seizures.
Publisher: Wiley
Date: 04-05-2018
DOI: 10.1111/EPI.14086
Abstract: The role of ethnicity on pregnancy outcomes of women with epilepsy (WWE) has received little research attention but is important to guide management. The aim of this review is to identify and describe current knowledge of ethnicity for WWE giving birth. Literature searches were performed with the following terms: ethnic/race combined with epilepsy/seizure, antiepileptic drugs (AED), and/or pregnancy, and combined them with congenital malformation, birth outcome, or pregnancy complication, with English language restriction in PubMed, EMBASE, and Web of Science. Both primary studies and review articles were included. Ethnicity disparities exist in specific congenital malformations, pregnancy complications, and birth outcomes among the general population. There is also ethnicity-related ersity of AED disposition. Information on ethnicity is rarely considered in studies about pregnant WWE. The association between ethnicity and pregnancy outcomes of WWE remains to be elucidated. The lack of data relating to ethnicity in pregnancy studies among WWE needs addressing. Knowledge of potential effects of ethnicity on pregnancy outcomes in WWE will help inform better clinical care around the world.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-12-2019
DOI: 10.1212/WNL.0000000000006776
Abstract: To examine the prevalence and risk factors of sleep-disordered breathing (SDB) in in iduals with epilepsy and psychogenic nonepileptic seizures (PNES). We conducted a cross-sectional study of consecutive patients admitted for inpatient video-EEG monitoring at The Royal Melbourne Hospital, Australia, between December 1, 2011, and July 31, 2017. Participants underwent routine clinical investigations during their monitoring period including polysomnography, neurocognitive testing, and screening instruments of daytime somnolence, sleep quality, and quality of life. Our study population consisted of 370 participants who received a diagnosis of epilepsy (n = 255), PNES (n = 93), or both disorders (n = 22). Moderate to severe SDB (defined by an apnea-hypopnea index ≥15) was observed in 26.5% (98/370) of in iduals, and did not differ across subgroups: epilepsy 26.3% (67/255), PNES 29.0% (27/93), or both disorders 18.2% (4/22 p = 0.610). Following adjustment for confounders, pathologic daytime sleepiness predicted moderate to severe SDB in epilepsy (odds ratio [OR] 10.35, 95% confidence interval [CI] 2.09–51.39 p = 0.004). In multivariable analysis, independent predictors for moderate to severe SDB in epilepsy were older age (OR 1.07, 95% CI 1.04–1.10 p 0.001) and higher body mass index (OR 1.06, 95% CI 1.01–1.11 p = 0.029), and in PNES older age (OR 1.10, 95% CI 1.03–1.16 p = 0.002). Polysomnography during inpatient video-EEG monitoring identified a substantial number of patients with undiagnosed SDB. This was remarkable in the subgroup with PNES, who were often female and obese. Identification of risk factors may improve management of SDB in these populations. The association with pathologic daytime sleepiness suggests that SDB may be an important contributor to these common and disabling symptoms in patients with epilepsy.
Publisher: Wiley
Date: 12-01-2015
Publisher: Wiley
Date: 04-03-2008
DOI: 10.1111/J.1528-1167.2008.01554.X
Abstract: Oral lacerations and urinary incontinence have long been considered useful clinical features for the diagnosis of epileptic seizures however, both are also reported in patients with psychogenic nonepileptic seizures (PNES). The aims of the study were (1) to investigate whether the presence and nature of oral lacerations or incontinence during convulsive seizures of patients with epilepsy differed from those with PNES, and (2) whether the side of the oral laceration has any correlation with the epilepsy syndrome or lateralization. Eighty-four consecutive patients who experienced at least one convulsive event during video-EEG monitoring (VEM) were questioned and examined for oral lacerations and incontinence. Seizure classification was determined by a team of epileptologists based on the VEM findings and other clinical and investigational data, blinded to the oral laceration and incontinence information. The presence of oral lacerations among patients with epileptic seizures was 26% (17/66), in contrast it was 0% (0/18) with PNES (p = 0.01). Of the oral lacerations sustained by patients during an epileptic seizure, 14 were to the side of the tongue, one to the tip of the tongue, two to the cheek, and three to the lip. No significant relationships were observed between seizure lateralization and oral lacerations. Incontinence occurred in 23% (15/66) of epilepsy patients and 6% (1/18) of PNES patients (p = 0.09). There was no relationship between epilepsy type or lateralization and the prevalence of incontinence. Despite frequent reports of oral lacerations and incontinence by patients with PNES, objective evidence for this is highly specific to convulsive epileptic seizures.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.NEULET.2015.01.024
Abstract: Epilepsy is a common comorbidity in patients with autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, Neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3(R451C) (NL3(R451C)) and wild type (WT) mice. It has previously been reported that NL3(R451C) mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippoc us and somatosensory cortex. PTZ administration induces absence-seizures at low dose, and generalised convulsive seizures at higher dose. Susceptibility to absence seizures was examined by analysing the frequency and duration of spike-and-wave discharge (SWD) events and accompanying motor seizure activity induced by subcutaneous administration of low dosage (20 or 30mg/kg) PTZ. Susceptibility to generalised convulsive seizures was tested by measuring the response to high dosage (60mg/kg) PTZ using a modified Racine scale. There was no change in the number of SWD events exhibited by NL3(R451C) compared to WT mice following administration of both 20mg/kg PTZ (1.17±0.31 compared to 16.0±11.16 events/30min, NL3(R451C) versus WT, respectively) and 30mg/kg PTZ (7.5±6.54 compared with 27.8±19.9 events/30min, NL3(R451C) versus WT, respectively). NL3(R451C) mice were seizure resistant to generalised convulsive seizures induced by high dose PTZ compared to WT littermates (median latency to first >3s duration clonic seizure 14.5min versus 7.25min, 95% CI: 1.625-2.375, p=0.0009, NL3(R451C) versus WT, respectively). These results indicate that the R451C mutation in the Nlgn3 gene, associated with ASD in humans, confers resistance to induced seizures, suggesting dysfunction of PTZ-sensitive GABAergic signalling in this mouse model of ASD.
Publisher: IEEE
Date: 08-2015
Publisher: Elsevier BV
Date: 11-2023
Publisher: Springer Science and Business Media LLC
Date: 11-11-2019
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1002/EPI4.12386
Publisher: Wiley
Date: 17-10-2016
DOI: 10.1002/EPI4.12020
Publisher: Elsevier BV
Date: 02-2006
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: Patients with medically intractable partial epilepsy and well-defined symptomatic MRI lesions were studied using phase-encoded frequency spectral analysis (PEFSA) combined with low-resolution electromagnetic tomography (LORETA). Ten patients admitted to the epilepsy monitoring unit with MRI-identified lesions and intractable partial epilepsy were studied using 31-electrode scalp EEG. The scalp electrodes were located in three-dimensional space using a magnetic digitizer and coregistered with the patient's MRI. PEFSA was used to obtain a phase-encoded scalp map for the ictal frequencies. The ictal generators were obtained from the scalp map using LORETA. In addition, the generators of interictal epileptogenic spikes were identified using time-domain LORETA. The LORETA generators were rostral to the MRI lesion in 87% (7/8) of patients with temporal lobe lesions, but all were located in the mesial temporal lobe in concordance with the patients' MRI lesions. In patients with frontal lobe epilepsy, the ictal generators at the time that the spectral power was maximal localized to the MRI lesions. Eight of 10 patients had interictal spikes, of which 4 were bilateral independent temporal lobe spikes. Only generators of the interictal spikes that were ipsilateral to seizure onset correlated with the ictal generators. LORETA combined with PEFSA of the ictal discharge can localize ictal EEG discharges accurately and improve correlation with brain anatomy by allowing coregistration of the ictal generator with the MRI. Analysis of interictal spikes was less useful than analysis of the ictal discharge.
Publisher: Wiley
Date: 21-08-2009
Publisher: American Physiological Society
Date: 09-1999
DOI: 10.1152/AJPGI.1999.277.3.G687
Abstract: Central processing of visceral information in humans is incompletely understood. We aimed to demonstrate the feasibility of single photon emission computed tomography (SPECT) and to quantitate the changes in regional cerebral blood flow during rectal distension. Ten healthy volunteers underwent randomized sham and active rectal distensions on separate days, during which cerebral blood flow was assessed by intravenous technetium-99m ethyl cysteinate dimer ( 99m Tc-ECD) SPECT. Three-dimensional coregistration of brain images was used to quantitate activation in four preselected cerebral foci and two control regions. Paired analysis compared blood flow during sham and active distensions. There was increased right anterior cingulate gyrus activity (6.5 ± 2.9%, P = 0.03) with active rectal distension. A 5.4 ± 2.4% reduction in blood flow in the superior parieto-occipital control region ( P = 0.04) suggested blood “redistribution” during stimulation. Marked variability in activation of the frontal cortex, thalamus/basal ganglia complex, and mesiotemporal lobe was noted. Thus rectal distension increases activity in the right anterior cingulate gyrus on average other foci of cerebral activation are quite variable, suggesting a lack of specific cerebral projections during rectal stimulation.
Publisher: Elsevier BV
Date: 2023
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0967-5868(03)00080-8
Abstract: Temporal lobe epilepsy (TLE), the most common form of partial epilepsy in adults is often refractory to medical treatment and in these patients epilepsy surgery is considered. Successful surgery is dependent on accurate localisation and lateralisation of the epileptogenic zone. The preoperative evaluation involves a series of assessments and investigations including detailed clinical history, interictal EEG, video-EEG monitoring, MRI, PET, SPECT, and neuropsychology and neuropsychiatric assessment. The role of each of these investigations and assessments in the preoperative evaluation is discussed. Advanced MR techniques including magnetic resonance spectroscopy, MR diffusion and MR perfusion have recently been assessed and are likely to enhance the pre-surgical evaluation of patients with TLE.The surgical outcome and preoperative investigations performed of 80 consecutive patients who underwent temporal lobe surgery between 1993 and 2002 at Royal Melbourne Hospital were reviewed. All patients had MRI, video-EEG monitoring and neuropsychology assessment and 56% a PET scan. During a mean follow-up of 5.9 years 75% had Class 1 outcome, 22% non-Class 1 outcome and 3% were lost to follow-up. The results of preoperative investigations were correlated with outcome. For interictal EEG, seizure semiology, ictal EEG, PET and neuropsychology assessment the surgical outcome of patients in whom results were concordant to side of surgery was compared with those discordant or non-lateralising. There was no significant difference. In 78 of 80 patients MRI revealed mesial temporal sclerosis or a foreign tissue lesion. The outcome was no different between these two groups. Results suggest that in patients with unilateral temporal lobe lesion on MRI and where ictal EEG is either concordant or non-lateralising, other investigations including PET, provide little additional prognostic information.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.JOCN.2013.11.049
Abstract: The demographic characteristics, details of pregnancies, epilepsies, and treatment of 855 pregnant women with epilepsy enrolled in the Australian Antiepileptic Drugs in Pregnancy Register during 1999-2005 were compared with the corresponding data for the 801 women enrolled from 2006-2012. We estimate that the Register captures approximately 1 in 12 of all pregnancies in Australian women with epilepsy. A number of statistically significant changes were found, with nearly all explained by factors such as re-enrolment of women who had enrolled earlier pregnancies, changes in general population behaviour, altered attitudes to prescribing valproate and using it in lower doses, and the advent of newer antiepileptic drugs which have displaced the use of older agents. It appears that the Register has continued to capture a reasonably representative s le of pregnant Australian women with epilepsy as time has passed.
Publisher: MDPI AG
Date: 22-01-2020
DOI: 10.3390/MPS3010011
Abstract: Glioblastoma is a heterogeneous glial cell malignancy with extremely high morbidity and mortality. Current treatment is limited and provide minimal therapeutic efficacy. Previous studies were reliant on cell lines that do not accurately reflect the heterogeneity of the glioma microenvironment. Developing reliable models of human glioblastoma is therefore essential. Direct culture of human brain tumours is often difficult and there is a limited number of protocols available. Hence, we have developed an effective method for the primary culture of human glioblastoma s les obtained during surgical resection. Culturing tumour tissue direct from human brain is advantageous in that cultures (1) more closely resemble true human disease, relative to the use of cell lines (2) comprise a range of cellular components present in the natural tumour microenvironment and (3) are free of added antibodies and reagents. Additionally, primary glioblastoma cultures are valuable in studies examining the effects of anti-cancer pharmaceuticals and therapeutic agents, and can be further used in live cell imaging, immunocytochemistry, flow cytometry and immunoassay experiments. Via this protocol, cells are maintained in supplemented medium at 37 °C (5% CO2) and are expected to achieve sufficient confluency within 7 days of initial culture.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JNEUROIM.2019.04.010
Abstract: Gliomas are the most prevalent tumours of the central nervous system and present with high morbidity and mortality. The most common and most aggressive form of glioma is glioblastoma multiforme, of which patients have a median survival time of only 12 to 15 months. Current treatment options are limited and have a small impact on clinical outcome and prognosis. There is accumulating evidence that microglia, the immunocompetent cells of the central nervous system, and the purinergic P2X7 receptor (P2X7R) may contribute to tumour progression and pathology. Importantly, P2X7R on both tumour cells and infiltrating microglia is overexpressed in animal and human glioma cultures. Factors released by glioma cells and P2X7R activation recruit microglia into the largely immunosuppressive tumour microenvironment where they have been demonstrated to contribute to either tumour proliferation or tumour suppression. It is likely that P2X7R mediates a range of microglia effector functions in the glioma setting, potentially increasing tumour growth and proliferation. This review evaluates current evidence on the roles of microglia and P2X7R in glioma pathogenesis. Understanding the nature, mechanisms and outcomes of microglia and P2X7R activation in gliomas is necessary for the development of more therapies with increased efficacy and specificity.
Publisher: Frontiers Media SA
Date: 15-09-2020
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.EPLEPSYRES.2008.08.004
Abstract: This study aimed to determine the reliability of clinical history and seizure semiology for distinguishing between frontal lobe seizures (FLS) and temporal lobe seizures (TLS). FLS patients (n=23) were consecutively identified through an epilepsy surgery database. TLS patients (n=27) were selected randomly from 238 patients who had undergone temporal lobe surgery for epilepsy. The criterion standard for seizure localization was the location of resective epilepsy surgery that controlled seizures for a minimum of 2 years. Blinded comparisons of 13 historical information items (HII) and 19 video-recorded semiologic features (VSF) were made. We identified 3 HII (sex, history of febrile convulsions, and history of generalized tonic-clonic seizures) and 2 VSF (fencing posturing and postictal confusion) that significantly distinguished between FLS and TLS. The multivariate analysis model correctly identified 87% of FLS patients and 74% of TLS patients. No single HII or VSF is sufficient for distinguishing between FLS and TLS. A model integrating multiple HII and VSF may assist in this differentiation, but some patients still may be misclassified.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Wiley
Date: 30-11-2019
DOI: 10.1111/EPI.16396
Abstract: Epilepsy is common and carries substantial morbidity, and therefore identifying cost-effective health interventions is essential. Cost-utility analysis is a widely used method for such analyses. For this, health conditions are rated in terms of utilities, which provide a standardized score to reflect quality of life. Utilities are obtained either indirectly using quality of life questionnaires, or directly from patients or the general population. We sought to describe instruments used to estimate utilities in epilepsy populations, and how results differ according to methods used. We undertook a systematic review of studies comparing at least two instruments for obtaining utilities in epilepsy populations. MEDLINE, Embase, ScienceDirect, Cochrane Library, Google Scholar, and gray literature were searched from inception to June 2019. Mean utilities were recorded and compared for each method. Of the 38 unique records initially identified, eight studies met inclusion criteria. Utilities were highest for direct "tradeoff" methods, obtained via instruments including standard gamble (0.93) and time tradeoff (0.92), compared to indirect methods, obtained via instruments including EuroQoL five-dimensional form (range = 0.72-0.86) and Health Utilities Index Mark 3 (range = 0.52-0.71). Visual analog scale (VAS), a direct "nontradeoff" instrument, provided equal or lower utilities (range = 68.0-79.8) compared to indirect instruments. Direct methods, with the important exception of VAS, may provide higher utilities than indirect methods. More studies are needed to identify the most appropriate utility instruments for epilepsy populations, and to investigate whether there is variation between utilities for different types of epilepsy and other patient- and disease-specific factors.
Publisher: Massachusetts Medical Society
Date: 30-06-2011
Publisher: Wiley
Date: 12-04-2020
DOI: 10.1002/EPI4.12391
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-11-2022
Publisher: Mary Ann Liebert Inc
Date: 15-05-2014
Publisher: Mary Ann Liebert Inc
Date: 07-2017
Abstract: Traumatic brain injury (TBI) has been assessed with diffusion tensor imaging (DTI), a commonly used magnetic resonance imaging (MRI) marker for white matter integrity. However, given that the DTI model only fits a single fiber orientation, results can become confounded in regions of "crossing" white matter fibers. In contrast, constrained spherical deconvolution estimates a fiber orientation distribution directly from high angular resolution diffusion-weighted images. Consequently, constrained spherical deconvolution-based measures, such as apparent fiber density (AFD) and track-weighted imaging (TWI) metrics (including tract density imaging, average pathlength mapping, and mean curvature), may be more sensitive than DTI metrics to white matter injury post-TBI. As such, this study administered the lateral fluid percussion injury (FPI) model of TBI, assessed for changes in AFD and TWI metrics, and compared these results to the DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). Rats received either an FPI (n = 11) or sham injury (n = 9) and after a recovery period of 12 weeks underwent MRI. AFD was calculated as described previously and statistical testing was performed using connectivity-based fixel enhancement. TWI and DTI metrics were assessed using voxel-wise nonparametric permutation testing. We found that rats given an FPI had significantly reduced AFD, tract density, average pathlength, and mean curvature when compared to sham-injured rats and significant changes in DTI metrics, including reduced FA and increased MD, RD, and AD. However, the latter DTI metrics identified fewer voxels affected by TBI. Additionally, analysis of AFD with connectivity-based fixel enhancement was the only method that identified damage within the corticospinal tract of rats given an FPI. These results support the use of constrained spherical deconvolution, in conjunction with DTI metrics, to better assess disease progression and treatment post-TBI.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Wiley
Date: 28-03-2020
DOI: 10.1111/EPI.16484
Publisher: Elsevier BV
Date: 09-2023
Publisher: Mary Ann Liebert Inc
Date: 11-2009
Abstract: Traumatic brain injury (TBI) has a high incidence of long-term morbidity. Manganese-enhanced MRI (MEMRI) provides high contrast structural and functional detail of the brain in-vivo. The study utilized serial MEMRI scanning in the fluid percussion injury (FPI) rat's model to assess long-term changes in the brain following TBI. Rats underwent a left-sided craniotomy and a 3.5 atmosphere FPI pulse (n = 23) or sham procedure (n = 22). MEMRI acquisition was performed at baseline, 1 day, 1 month, and 6 months after FPI. Volume changes and MnCl(2) enhancement were measured blindly using region-of-interest analysis and the results analyzed with repeated measures MANOVA. Compared to the shams, FPI animals showed a progressive decrease in brain volume from 1 (right, p = 0.02 left, p = 0.008) to 6 months (right, p = 0.04 left, p = 0.006), with progression over time (F = 7.16, p = 0.00018). Similar changes were found in the cortex and the hippoc us. Conversely, the ventricular volume was increased at 1 (p = 0.02) and 6 months (p = 0.003), with progression over time (F = 7.27, p = 0.0001). There were no differences in thalamic or amygdalae volumes. The severity of the early neuromotor deficits and the T2 signal intensity of the subacute focal lesion were highly predictive of the severity of the long-term hippoc al decrease, and the former was also associated with the degree of neuronal sprouting. Differential MnCl(2) enhancement occurred only in the dentate gyrus at 1 month on the side of trauma (p = 0.04). Progressive functional and structural changes occur in specific brain regions post-FPI. The severity of the neuromotor deficit and focal signal changes on MRI subacutely post-injury are predictive of severity of these long-term neurodegenerative changes.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.JVIR.2019.01.032
Abstract: To investigate the feasibility of single-needle high-frequency irreversible electroporation (SN-HFIRE) to create reproducible tissue ablations in an in vivo pancreatic swine model. SN-HFIRE was performed in swine pancreas in vivo in the absence of intraoperative paralytics or cardiac synchronization using 3 different voltage waveforms (1-5-1, 2-5-2, and 5-5-5 [on-off-on times (μs)], n = 6/setting) with a total energized time of 100 μs per burst. At necropsy, ablation size/shape was determined. Immunohistochemistry was performed to quantify apoptosis using an anticleaved caspase-3 antibody. A numerical model was developed to determine lethal thresholds for each waveform in pancreas. Mean tissue ablation time was 5.0 ± 0.2 minutes, and no cardiac abnormalities or muscle twitch was detected. Mean ablation area significantly increased with increasing pulse width (41.0 ± 5.1 mm SN-HFIRE induces rapid, predictable ablations in pancreatic tissue in vivo without the need for intraoperative paralytics or cardiac synchronization.
Publisher: Wiley
Date: 25-09-2019
DOI: 10.1002/EPI4.12360
Publisher: Elsevier BV
Date: 02-2019
Publisher: American Medical Association (AMA)
Date: 12-2012
DOI: 10.1001/ARCHNEUROL.2012.2203
Abstract: OBJECTIVE To determine whether patients who fail their first antiepileptic drug (AED) have better neuropsychiatric and quality-of-life (QOL) outcomes if substituted to levetiracetam monotherapy compared with a second older AED. DESIGN Randomized comparative trial. Participants with partial epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with levetiracetam or a different older AED. Assessments were performed at baseline, 3 months, and 12 months using questionnaires measuring neuropsychiatric, QOL, seizure control, AED adverse effects, and neurocognitive outcomes. SETTING Epilepsy service of a teaching hospital. PATIENTS Fifty-one patients were randomized to levetiracetam and 48 were randomized to a second older AED (25 to valproate and 23 to carbamazepine). MAIN OUTCOME MEASURES Proportions showing improvements in depression (on the Hospital Anxiety and Depression Scale) and QOL scores (on the 89-item Quality of Life in Epilepsy Inventory) at 3 months. RESULTS There were no differences between the groups in depression scores at 3 months (improvement in 17 of 43 patients [39.5%] in the levetiracetam group and 15 of 44 patients [34.1%] in the older AED group P = .60), but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the levetiracetam group (27 of 38 patients [71.1%] vs 21 of 43 patients [48.8%], respectively P = .04). The QOL, anxiety, and AED adverse effects scores were improved in both groups at 3 and 12 months after randomization. CONCLUSIONS Substitution monotherapy in a patient experiencing ongoing seizures or tolerability issues is associated with sustained improvements in measures of QOL, psychiatric, and adverse events outcomes. Patients switched to levetiracetam do not have better outcomes than those switched to a second older AED. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12606000102572.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.EXPNEUROL.2010.11.001
Abstract: The oscillatory rhythms underlying many physiological and pathological states, including absence seizures, require both the thalamus and cortices for full expression. A co-culture preparation combining cortical and thalamic explants provides a unique model for investigating how such oscillations initiate and spread. Here we investigated the dynamics of synchronized thalamocortical activity by simultaneous measurement of field-potential recordings and rapid imaging of Ca(2+) transients by fluorescence methods. Spontaneous sustained hypersynchronized "seizure-like" oscillations required reciprocal cortico-thalamocortical connections. Isolated cortical explants can independently develop brief discharges, while thalamic explants alone were unable to do so. Rapid imaging of Ca(2+) transients demonstrated deep-layer cortical initiation of oscillatory network activity in both connected and isolated explants. Further, cortical explants derived from a rat model of genetic absence epilepsy showed increased bursting duration consistent with an excitable cortex. We propose that thalamocortical oscillatory network activity initiates in deep layers of the cortex with reciprocal thalamic interconnections enabling sustained hyper-synchronization.
Publisher: Wiley
Date: 07-11-2023
DOI: 10.1111/EPI.17449
Abstract: Childhood trauma has been implicated as a risk factor for the etiology of psychogenic nonepileptic seizures (PNES). Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES. Investigating childhood trauma profiles in these patient groups may identify psychological vulnerabilities that predispose to developing PNES, and aid early diagnoses, prevention, and treatment. Data were collected from two cohorts ( n Retrospective = 203 n Prospective = 209) admitted to video–electroencephalography (EEG) monitoring units in Melbourne Australia. The differences in Childhood Trauma Questionnaire domain score between patient groups were investigated using standardized effect sizes and general linear mixed‐effects models (GLMMs). Receiver‐operating characteristic curves were used to investigate classification accuracy. In the retrospective cohort, patients diagnosed with PNES reported greater childhood emotional abuse, emotional neglect, physical abuse, sexual abuse, and physical neglect relative to patients with epilepsy. These differences were replicated in the prospective cohort, except for physical abuse. GLMMs revealed significant main effects for group in both cohorts, but no evidence for any group by domain interactions. Reported sexual abuse showed the best screening performance of PNES, although no psychometric scores were adequate as isolated measures. Patients with PNES report a greater frequency of childhood trauma than patients with epilepsy. This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES. From a practical perspective, inquiry regarding a history of sexual abuse shows the most promise as a screening measure.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.BBI.2017.08.005
Abstract: Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100mg/kg). Treatments were subcutaneously injected at 1, 6, and 24h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48h post-injury. 12-16 mice/group underwent behavioral testing at 12weeks post-injury and MRI at 14weeks post-injury before being euthanized at 16weeks post-injury. At 48h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.
Publisher: Hindawi Limited
Date: 08-09-2015
DOI: 10.1111/ANE.12479
Abstract: To determine whether being pregnant in its own right alters epileptic seizure control. Study of 148 pregnancies in women who took no antiepileptic drugs before pregnancy and in at least the earlier half of pregnancy, 69 taking none throughout pregnancy. More women (P < 0.01) had seizures of any type during pregnancy (45.9%) than in the prepregnancy year (34.5%), and also convulsive seizures (30.4% vs 12.3%). After excluding potential confounding factors, viz. late prepregnancy drug withdrawal, treatment resumption in pregnancy possibly preventing seizure recurrence, the figures became seizures of any type 56.6% during and 35.5% before pregnancy and convulsive seizures 39.4% during and 18.2% before pregnancy (both P < 0.01). There was a non-statistically significant greater tendency for seizure control to be lost during pregnancy in genetic generalized than in focal epilepsies (54.2% vs 35.5%). Irrespective of its effects on antiepileptic drug disposition, being pregnant per se seems to impair epileptic seizure control.
Publisher: Wiley
Date: 12-03-2013
DOI: 10.1111/BPH.12052
Publisher: Hindawi Limited
Date: 06-03-2013
DOI: 10.1111/ANE.12115
Abstract: To study associations between patterns of fetal malformation and in idual antiepileptic drugs taken during pregnancy. Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy). There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities. The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential.
Publisher: Wiley
Date: 25-03-2014
DOI: 10.1002/NBM.3095
Abstract: This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r² = 0.95, p = 0.002, and r² = 0.97, p < 0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r² = 0.22, p = 0.04) and ratios of Glu to Cr (r² = 0.30, p = 0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 09-02-2018
DOI: 10.1007/S11250-018-1529-3
Abstract: Despite the significant livestock contribution to households' nutrition and incomes in many African smallholder farms, milk productivity remains low. Inadequate feeding is the main reason for the underperformance. To contribute towards addressing this, an on-farm feeding trial was undertaken in Ol-joro-Orok Central Kenya. A feed basket using oat (Avena sativa) cv Conway and vetch (Vicia villosa) was compared to farmers practice. Milk production (kg) and quality parameters, including butterfat, protein, lactose, and density, were monitored, and cost-benefit analysis (CBA) undertaken. Feeding both oat and vetch increased milk production by 21% (morning) and 18%, (evening), equivalent to 1.4 kg/day. Increases (%) in quality were butter fat (18.2), solid-non-fat (16.5), lactose (16.2), and protein (16.1). Concomitantly, the CBA returned positive results, supporting the hypothesis of economic advantage in using oat and vetch in milk production in the area, and possibly in other similar areas.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2019
Publisher: Public Library of Science (PLoS)
Date: 25-08-2009
Publisher: Elsevier BV
Date: 10-2014
Publisher: BMJ
Date: 11-2020
DOI: 10.1136/BMJOPEN-2020-040100
Abstract: Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder often neuropathologically associated with the accumulation of abnormally hyperphosphorylated tau, for which there is currently no disease-modifying treatment. Previous work by our group has shown sodium selenate upregulates the activity of protein phosphatase 2 in the brain, increasing the rate of tau dephosphorylation. The objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying treatment for bvFTD. This will be a multisite, phase IIb, double-blind placebo-controlled trial of sodium selenate. One hundred and twenty participants will be enrolled across 4 Australian academic hospitals. Following screening eligible participants will be randomised (1:1) to sodium selenate (15 mg three times a day) or placebo for 52 weeks. Participants will have regular safety and efficacy visits throughout the study period. The primary study outcome will be percentage brain volume change (PBVC) as measured on MRI over 52 weeks of treatment. This will be analysed with a general linear model (analysis of covariance (ANCOVA)) with the PBVC as an output, the treatment as an input and the baseline brain volume as covariate for adjustment purposes. Secondary outcomes include safety and tolerability measures, and efficacy measures change in cerebrospinal fluid total-tau, Addenbrooke’s Cognitive Examination-III and Cambridge Behavioural Inventory-Revised scores over the 52 weeks of treatment. These will also be analysed with ANCOVA where the corresponding baseline measure will be incorporated in the model. Additional exploratory outcomes will include other imaging, cognitive and biospecimen analyses. The study was approved by the Human Research and Ethics Committee of the lead site as part of the Australian Multisite Ethics approval system. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. ACTRN12620000236998 .
Publisher: American Medical Association (AMA)
Date: 03-2023
DOI: 10.1001/JAMANEUROL.2022.4847
Abstract: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown. To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought. The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred s le, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients’ homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022. Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control. The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control. Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI. Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis. ClinicalTrials.gov Identifier: NCT03834857
Publisher: Hindawi Limited
Date: 22-02-2011
DOI: 10.1002/HUMU.21437
Abstract: BioGrid Australia is a federated data linkage and integration infrastructure that uses the Internet to enable patient specific information to be utilized for research in a privacy protected manner, from multiple databases of various data types (e.g. clinical, treatment, genomic, image, histopathology and outcome), from a range of diseases (oncological, neurological, endocrine and respiratory) and across more than 20 health services, universities and medical research institutes. BioGrid has demonstrated an ability to facilitate powerful research into the causation of human disease and the prediction of disease and treatment outcomes. BioGrid has successfully implemented technology and processes that allow researchers to efficiently extract data from multiple sources, without compromising data security and privacy. This article reviews BioGrid's first seven years and how it has overcome 9 of its top 10 challenges.
Publisher: Wiley
Date: 21-03-2023
DOI: 10.1111/EPI.17584
Abstract: Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The clinical evidence supporting this is derived from patients' subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here, we used genetic absence epilepsy rats from Strasbourg (GAERS), a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures. Adult male GAERS ( n = 38) and nonepileptic control (NEC) rats ( n = 4) were used. First, rats were subjected to 30‐min restraint stress to assess hypothalamic–pituitary–adrenal axis function. Next, we assessed the effects of 30‐min noise stress, and cage tilt stress, on spike–wave discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone, and deoxycorticosterone. GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence ( p .05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence ( p .05). Metyrapone, an inhibitor of corticosterone synthesis, completely abolished seizures in GAERS, and seizures remained suppressed for h. However, deoxycorticosterone, the precursor of corticosterone, increased seizures. These results suggest that GAERS exhibit elevations in stress hormones, and this may contribute to seizures. Inhibiting corticosterone synthesis with metyrapone prevents seizures in GAERS, and shows potential for repurposing this drug as a future antiseizure medication.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1186/S13643-019-1169-3
Abstract: Epilepsy is one of the most common and serious brain conditions, characterised by recurrent unprovoked seizures. It affects about 1% of the population worldwide. Despite a range of antiepileptic drugs being available, one third of the patients do not achieve adequate seizure control. Only a minority of these patients may be suitable to undergo surgical resection of the seizure focus, but this is an invasive and not always successful procedure. There is an urgent need to develop more effective treatment options for uncontrolled seizures. With the recent advances in regenerative and translational medicine, cell therapies could prove to be beneficial. Here we describe the protocol for a proposed systematic review and meta-analysis to assess the effects for cell transplantation in animal models of epilepsy. We will include all preclinical animal models of epilepsy that evaluate the effects of cell transplantation compared to the untreated control. The primary outcome will be the change in frequency and duration of seizures from baseline measured by video electroencephalography (EEG). The secondary outcomes will include histological and neurobehavioural assessments. We will perform an electronic search of MEDLINE via PubMed, Web of Science, and EMBASE. Search results will be screened independently by two reviewers and confirmed by a third reviewer. Data from eligible studies will be extracted and pooled, and the summary estimate of effect size will be calculated using DerSimonian and Laird random effects meta-analysis. Heterogeneity will be explored using sub-group meta-analysis, and meta-regression risk of bias will be assessed by using the CAMARADES checklist for study quality tool. The purpose of this systematic review is to assess and summarise the existing literature in the field of cell transplantation as a treatment for epilepsy in animal models. Efficacy will be measured by evaluating the reduction in seizure intervals, number, and duration, within animal models of epilepsy. Analysis of the existing literature will mark the achievement made in the field and locate the existing gaps, a process that will aid in the search for the next needed step. CRD42018103628
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2022
DOI: 10.1101/2022.05.17.492323
Abstract: There are no pharmacological disease-modifying treatments that can mitigate the seizures and comorbidities associated with established chronic temporal lobe epilepsy (TLE). This study evaluated the effect of sodium selenate in the post-status epilepticus (SE) rat model of chronic drug resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, rats were randomly assigned to receive either sodium selenate, levetiracetam, or vehicle treatments continuously for 4 weeks. To evaluate the effects of the treatments, 1 week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of disease severity. Sodium selenate treatment was able to mitigate disease severity, reducing the number of spontaneous seizures (p 0.05), cognitive dysfunction (p 0.05 in both novel object placement and recognition tasks), and sensorimotor deficits (p 0.01) 8 weeks post-treatment cessation. Moreover, increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening caused by SE (p 0.05). Network medicine integration of multi-omics/ pre-clinical outcomes identified protein-metabolite modules positively correlated with the TLE phenotype. Our results provide evidence that treatment with sodium selenate results in a sustained disease modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.
Publisher: Wiley
Date: 06-05-2021
DOI: 10.1002/EPI4.12490
Abstract: Epilepsy is one of the most common chronic brain diseases and is often associated with cognitive, behavioral, or other medical conditions. The need for therapies that would prevent, ameliorate, or cure epilepsy and the attendant comorbidities is a priority for both epilepsy research and public health. In 2018, the National Institute of Neurological Disease and Stroke (NINDS) convened a workshop titled “Accelerating the Development of Therapies for Antiepileptogenesis and Disease Modification” that brought together preclinical and clinical investigators and industry and regulatory bodies’ representatives to discuss and propose a roadmap to accelerate the development of antiepileptogenic (AEG) and disease‐modifying (DM) new therapies. This report provides a summary of the discussions and proposals of the Preclinical Science working group. Highlights of the progress of collaborative preclinical research projects on AEG/DM of ongoing research initiatives aiming to improve infrastructure and translation to clinical trials are presented. Opportunities and challenges of preclinical epilepsy research, vis‐à‐vis clinical research, were extensively discussed, as they pertain to modeling of specific epilepsy types across etiologies and ages, the utilization of preclinical models in AG/DM studies, and the strategies and study designs, as well as on matters pertaining to transparency, data sharing, and reporting research findings. A set of suggestions on research initiatives, infrastructure, workshops, advocacy, and opportunities for expanding the borders of epilepsy research were discussed and proposed as useful initiatives that could help create a roadmap to accelerate and optimize preclinical translational AEG/DM epilepsy research.
Publisher: American Physiological Society
Date: 02-2015
Abstract: Rapid transmembrane flow of sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated sodium channels (Na V ). Macroscopic currents display rapid activation followed by fast inactivation (I F ) within milliseconds. Slow inactivation (I S ) has been subsequently observed in several preparations including neuronal tissues. I S serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an “intermediate inactivation” (I I ) process in rat hippoc al CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials ( V 0.5 ) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. I I state transitions were observed after opening as well as subthreshold potentials. Entry into I I after opening was relatively insensitive to membrane potential, and recovery of I I became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of I Na decay corresponding to I I and I S with long depolarizations. Dynamic cl revealed attenuation of trains of APs over the 10 2 -ms timescale, suggesting a functional role of I I in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that I I affects important aspects of hippoc al neuron response and may provide a drug target for sodium channel modulation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-03-2023
DOI: 10.1212/WNL.0000000000201671
Abstract: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18–60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ 2 statistics, and logistic regression analyses. A total of 151 (43.5%) patients had a psychiatric diagnosis 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.
Publisher: Wiley
Date: 25-03-2022
DOI: 10.1111/EPI.17217
Abstract: Around 30% of patients undergoing surgical resection for drug‐resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG‐PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. Eighty two patients with drug resistant MTLE were scanned with FDG‐PET pre‐surgery and T1‐weighted MRI pre‐ and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippoc al sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug‐resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow‐up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75–.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59–.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. Collectively, these results indicate that "acceptable" to "good" patient‐specific prognostication for drug‐resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2012
Publisher: IEEE
Date: 08-2015
Publisher: Hindawi Limited
Date: 29-07-2020
DOI: 10.1111/ANE.13315
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.NBD.2013.11.020
Abstract: Due to the high comorbidity of epilepsy and depression, antidepressant treatment is commonly indicated for patients with epilepsy. Studies in humans and animal models suggest that selective serotonin reuptake inhibitors (SSRIs) may reduce seizure frequency and severity, and these drugs are generally considered safe for use in epilepsy. No studies have investigated the effects of SSRIs on epileptogenesis, the neurobiological process underlying the development of the epileptic state. The effect of continuous infusion of the SSRI, fluoxetine (10mg/kg/day sc), versus vehicle control on amygdala kindling was examined in adult male Wistar rats. Seizure threshold and kindling rates were compared between SSRI-treated rats and controls. The study was then repeated examining the effect of a different SSRI, citalopram (10mg/kg/day sc), versus vehicle control. Hippoc al mRNA expression of the serotonin transporter (SERT) and the 5-HT1A receptor was examined in the brains of the rats post-mortem. Treatment with either fluoxetine or citalopram significantly accelerated kindling epileptogenesis, as evidenced by fewer stimulations to reach Class V seizures compared to their respective vehicle-treated group (p 0.05). mRNA analysis did not reveal any molecular changes which were common to both treatments. The rate of epileptogenesis in rats is enhanced by chronic treatment with SSRIs. This could potentially have implications regarding the effect of SSRIs on the development or progression of human epilepsy.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: Wiley
Date: 21-07-2004
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.JOCN.2015.05.002
Abstract: We evaluated the prevalence of epilepsy in a cohort of patients who suffered a sudden unexpected death (SUDEP), and determined the proportion of the deaths that were related to an identifiable underlying familial cardiac pathology. Epilepsy is common in people who experience a sudden unexpected death, with approximately a quarter having identifiable familial electrophysiological abnormalities. Familial cardiac pathology may be an important cause of SUDEP. A retrospective evaluation was performed of 74 families that were referred to the Royal Melbourne Hospital Cardiac Genetic Clinic over a 5 year period for investigation following a family member's sudden, presumed cardiac, death. This state-wide referral clinic includes all patients who have died from a sudden unexpected death in whom the cause of death is unascertained. An epilepsy diagnosis was categorised as either definite, probable, possible or unlikely. The family members underwent comprehensive clinical evaluations and investigations in an attempt to identify a familial cardiac cause for the sudden unexpected death. Our findings suggest that systematic referral to a cardiac genetics service is warranted for the first degree relatives of people with epilepsy who experience a sudden unexplained death, for further evaluation and to identify those who are at higher risk for sudden death. Interventions may then be instituted to potentially reduce this risk.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.SEIZURE.2010.07.019
Abstract: Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N = 118), the incidences for LTG (N = 243), carbamazepine (CBZ) (N = 302) and VPA (N = 224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs.
Publisher: Informa UK Limited
Date: 16-03-2019
DOI: 10.1080/07357907.2019.1582060
Abstract: Glioma stem cells (GSCs) play major roles in drug resistance, tumour maintenance and recurrence of glioblastoma. We investigated inhibition of the GTPase dynamin 2 as a therapy for glioblastoma. Glioma cell lines and patient-derived GSCs were treated with dynamin inhibitors, Dynole 34-2 and CyDyn 4-36. We studied about cell viability, and GSC neurosphere formation in vitro and orthotopic tumour growth in vivo. Dynamin inhibition reduced glioblastoma cell line viability and suppressed neurosphere formation and migration of GSCs. Tumour growth was reduced by CyDyn 4-36 treatment. Dynamin 2 inhibition therefore represents a novel approach for stem cell-directed Glioblastoma therapy.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2018
Publisher: Elsevier BV
Date: 12-1999
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.JOCN.2006.04.025
Abstract: We report progress in the accumulation of data by the Australian Pregnancy Register over 64 months, confirming the rise in enrollment and the predominantly epileptic indication for taking antiepileptic drugs. Eighty percent of the enrollment was prospective. The focus of the current report is the observation that as a possible result of education and dissemination of information about the risks of exposure to high-dose valproate, there has been a decline in the drug's doses prescribed in Australia, as well as a decline in the proportion of patients prescribed this drug in pregnancy. The risk of teratogenicity associated with valproate in doses in excess of 1100 mg/day was confirmed, and the incidence of lamotrigine-related malformations was comparable to that associated with exposure to phenytoin and carbamazepine. Reporting of data for this paper took into account the 12 months follow-up period for each pregnancy outcome, thus in effect making the evaluation period 21 months for each pregnancy and its outcome.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.JOCN.2006.10.015
Abstract: The aim of this study was to determine how valid 68 first-trimester pregnancies of untreated epileptic women would prove as an internal control group for investigating foetal malformation rates in 709 simultaneously collected antiepileptic drug-exposed pregnancies in an Australian register of pregnancies in epileptic women. We carried out comparisons of values for parameters relating to personal details, obstetric aspects, and epilepsies prior to and during pregnancy in the drug-exposed and drug-unexposed pregnancies, with observations on subpopulations within the drug-unexposed group. Statistically significant (p<0.05) differences existed for only seven of more than 50 parameters compared. None of these seven parameters had a statistically significant influence on foetal malformation rates in the whole dataset. In 23 of the 65 epileptic pregnancies unexposed to antiepileptic drugs, therapy had been ceased shortly prior to pregnancy and was often resumed after the first trimester. In the remaining 42, therapy had been ceased earlier, often despite continuing seizures. Planned withdrawal of therapy did not appear to produce additional hazards for mothers and foetuses in the former subgroup. In the data collection studied, there did not appear to be evidence of statistically significant differences between untreated pregnancies and treated epileptic pregnancies that would be likely to invalidate the former group as an internal control for the latter, at least when assessing foetal malformation rates.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.NBD.2017.04.022
Abstract: Alterations in white matter integrity have been well documented in chronic epilepsy and during epileptogenesis. However, the relationship between white matter integrity and a predisposition towards epileptogenesis has been understudied. The FAST rat strain exhibit heightened susceptibility towards kindling epileptogenesis whereas SLOW rats are highly resistant. FAST rats also display behavioral phenotypes reminiscent of those observed in neurodevelopmental disorders that commonly comorbid with epilepsy. In this study, we aim to identify differences in white matter integrity that may contribute to a predisposition towards epileptogenesis and its associated comorbidities in 6month old FAST (n=10) and SLOW (n=10) male rats. Open field and water consumption tests were conducted to confirm the behavioral phenotype difference between FAST and SLOW rats followed by ex-vivo diffusion-weighted magnetic resonance imaging to identify differences in white matter integrity. Diffusion tensor imaging scalar values namely fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were compared in the anterior commissure, corpus callosum, external capsule, internal capsule, fimbria and optic tract. Electron microscopy was used to evaluate microstructural alterations in myelinated axons. Behavioral phenotyping confirmed higher activity levels (distance moved on days 2-4, p<0.001 number of rearings on days 2 and 4, p<0.05 at both days) and polydipsia (p<0.001) in FAST rats. Comparative analysis of diffusion tensor imaging scalars found a significant decrease in fractional anisotropy in the corpus callosum (p<0.05) of FAST versus SLOW rats. Using electron microscopy, alterations in myelinated axons including increased axon diameter (p<0.001) and reduced g-ratio (p<0.001) in the midline of the corpus callosum in 6month old FAST (n=3) versus SLOW (n=4) male rats. These findings suggest that differences in white matter integrity between FAST and SLOW rats could be a contributing factor to the differential seizure susceptibility and behavioral phenotypes observed in these strains.
Publisher: Oxford University Press (OUP)
Date: 02-2007
DOI: 10.1093/BRAIN/AWL232
Abstract: A significant minority of patients undergoing surgery for medically refractory non-lesional temporal lobe epilepsy (TLE) continue to have seizures, but the reasons for this are uncertain. Fluorodeoxyglucose (FDG) PET shows hypometabolism in a majority of patients with non-lesional TLE, even in the absence of hippoc al atrophy. We examined whether the extent of resection of the area of FDG-PET hypometabolism influenced outcome following surgery for non-lesional TLE. Twenty-six patients who underwent temporal lobectomy for medically refractory TLE with at least 12 months follow-up were studied. The preoperative FDG-PET was compared with 20 non-epileptic controls using SPM99 to identify regions of significant hypometabolism (P 200). This image was then co-registered to the postoperative MRI scan. The volume of the FDG-PET hypometabolism that lay within the area of the resected temporal lobe was calculated. The volume of temporal lobe resected was also calculated. Patients with a good outcome had a greater proportion of the total FDG-PET hypometabolism volume resected than those with a poor outcome (24.1% versus 11.8%, P = 0.02). There was no significant difference between the groups in the volume of temporal lobe resected (P = 0.86). Multivariate regression demonstrated that the extent of resection of the hypometabolism significantly correlated with outcome (P = 0.03), independent of the presence of hippoc al sclerosis (P = 0.03) and total brain volume of hypometabolism (P = 0.45). The extent of resection of the region of hypometabolism on the preoperative FDG-PET is predictive of outcome following surgery for non-lesional TLE. Strategies that tailor resection extent to regional hypometabolism may warrant further evaluation.
Publisher: Public Library of Science (PLoS)
Date: 21-01-2014
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0967-5868(03)00158-9
Abstract: Most women with epilepsy need to take antiepileptic drugs (AEDs) in pregnancy to prevent the potentially harmful effects of seizures. Retrospective studies have demonstrated an increased chance of having a child with a birth defect (BD) in women with epilepsy taking AEDs. It is uncertain how much of this risk is directly caused by the AEDs and whether certain drugs or combinations are associated with a greater risk. To establish a register to evaluate prospectively the incidence of adverse pregnancy outcomes in women exposed to specific AEDs to determine whether certain AEDs or combinations were associated with a greater risk and to determine whether other factors influenced the risk. An Australia-wide, prospective, voluntary, telephone-interview based, observational register. Three groups of pregnant women were enrolled: those with epilepsy taking AEDs, those with epilepsy not taking AEDs, and those taking AEDs for a non-epileptic indication. The pregnancy outcomes were evaluated by follow-up interviews and by reference to hospital and treating doctors' records. Over the first 30 months of the study (till December 2001) 334 eligible women were enrolled, with all states and territories being represented. Two hundred and ninety two pregnancies had been completed, of which 256 (88%) resulted in a healthy live birth, 19 (6.5%) a live birth with a birth defect, four an induced abortion because of a detected malformation on ultrasound, one premature labour with a stillbirth and 12 (4%) spontaneous abortions. Of the completed pregnancies, 269 were exposed to at least one AED during the first trimester. The incidence of birth defects in relation to specific AEDs was: valproate (16.7%), phenytoin (10.5%), lamotrigine (7.7%) and carbamazepine (3.3%), none of which was significantly different from that in women with epilepsy not taking an AED (4.3%, n.s.). The dose of valproate taken was higher in pregnancies with BD compared to those without (mean 2081 mg vs. 1149 mg, p<0.0001). The incidence of folate supplementation being taken prior to conception did not differ for pregnancy outcomes with or without BD (70% vs. 66%, n.s.). The model for the Australian Pregnancy Register appears to be successful, with strong enrolment from all regions over the first 30 months. The study is prospective and includes reference to all new AEDs approved in Australia over the past decade. Analysis of the pregnancy outcomes to date may reveal early trends, but numbers are still to small for any definitive conclusions to be made regarding the relative risk in pregnancy of in idual AEDs.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2018
DOI: 10.1038/S41598-018-33839-4
Abstract: Invasive Brain-Computer Interfaces (BCIs) require surgeries with high health-risks. The risk-to-benefit ratio of the procedure could potentially be improved by pre-surgically identifying the ideal locations for mental strategy classification. We recorded high-spatiotemporal resolution blood-oxygenation-level-dependent (BOLD) signals using functional MRI at 7 Tesla in eleven healthy participants during two motor imagery tasks. BCI diagnostic task isolated the intent to imagine movements, while BCI simulation task simulated the neural states that may be yielded in a real-life BCI-operation scenario. Imagination of movements were classified from the BOLD signals in sub-regions of activation within a single or multiple dorsal motor network regions. Then, the participant’s decoding performance during the BCI simulation task was predicted from the BCI diagnostic task. The results revealed that drawing information from multiple regions compared to a single region increased the classification accuracy of imagined movements. Importantly, systematic unimodal and multimodal classification revealed the ideal combination of regions that yielded the best classification accuracy at the in idual-level. Lastly, a given participant’s decoding performance achieved during the BCI simulation task could be predicted from the BCI diagnostic task. These results show the feasibility of 7T-fMRI with unimodal and multimodal classification being utilized for identifying ideal sites for mental strategy classification.
Publisher: Wiley
Date: 06-2010
DOI: 10.1111/J.1528-1167.2009.02516.X
Abstract: Bone disease and fractures are common with chronic antiepileptic drug (AED) therapy, but the underlying mechanisms are poorly understood. This study aimed to characterize adverse bone effects of valproate and to identify mouse strains either resistant or sensitive to these effects. Seven mouse strains (n = 40/strain 10/diet) were screened for the effect of chronic (8 weeks) valproate treatment (0, 2, 4, and 6 g/kg food) on total bone mineral content (BMC, by dual energy x-ray absorptiometry). In a confirmatory study the effect of valproate (0 or 4 g/kg food) over 16 weeks was assessed in five of the mouse strains (n = 60/strain 30/diet) identified in the screening phase as either sensitive or resistant. Ex vivo volumetric bone measures and structural changes were assessed using peripheral quantitative computed tomography (pQCT) and histomorphometry. Chronic valproate treatment reproducibly affected bone in C3H/HeJ mice, with a 9.1% (p < 0.01) reduction in total BMC and a 10.7% (p < 0.01) reduction in trabecular volumetric density, indicating a sensitive strain to AED-induced bone loss. Histomorphometry was consistent, revealing reductions in trabecular volume (19.6%, p < 0.05) and number (14.3%, p < 0.04), and a 19.9% (p < 0.05) increase in trabecular separation. In contrast the A/J mice were reproducibly resistant to the bone effects. Mouse strains sensitive and resistant to the adverse bone effects of chronic valproate treatment were identified. The strain-specific effects suggest a role of genetic factors in the pathogenesis of AED-induced bone disease. This novel model provides a new, powerful tool to investigate the pathophysiology and therapy of AED-associated bone disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-12-2009
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.YEBEH.2012.11.002
Abstract: Epilepsy and autism spectrum disorder (ASD) share many primary and comorbid symptoms. The degree of clinical overlap is believed to signify a 'spectrum of vulnerability' that arises out of an early common dysfunction in central nervous system development. However, research into the underlying, and potentially shared, etiopathological mechanisms is challenging given the extensive comorbidity profiles. Adding to the degree of difficulty is the frequently evolving recompartmentalization of diagnostic criteria within each disorder. This review discusses potential preclinical strategies that, through the use of animal models, are designed to gain insight into the biological basis of the overlap between epilepsy and autism and to foster a rapid clinical translation of the insights gained.
Publisher: Elsevier BV
Date: 2019
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NBD.2019.104625
Abstract: NMDAr antagonists induce disturbances to gamma frequency oscillations, including increasing ongoing gamma activity and reducing evoked gamma oscillations. We sought to investigate the role parvalbumin (PV+) neurons and CaMKIIα+ pyramidal cells in NMDAr antagonist-induced disturbances in gamma oscillatory activity and relate these to common behavioural consequences of these drugs by selectively deleting the obligatory GluN1 subunit from these cells in mice. Adult mice (total n = 99) with GluN1 deleted from PV interneurons (PV:GluN1 KO) or CaMKIIα+ pyramidal cells (CaMKIIα:GluN1 KO), and WT littermates, were used. We assessed effects of the NMDAr antagonist MK-801 on prepulse inhibition (PPI) and locomotor behaviour. Then, mice were implanted with electrodes in the prefrontal cortex (mPFC) and hippoc us (dHPC), and the effects of MK-801 on gamma oscillations assessed. In WT mice, MK-801 increased ongoing gamma power, reduced evoked gamma power and increased gamma coherence. These changes were accompanied by hyperlocomotion and deficient PPI. The consequences of NMDAr antagonism were differentially regulated in the transgenic mice. The MK-801-induced increase in ongoing gamma power was significantly attenuated in both transgenic strains, but deficits to evoked gamma activity were unaffected by genotype. Deficient PPI was not affected by genotype, and only in PV:GluN1 KO mice was the hyperlocomotor phenotype of MK-801 attenuated. The emergence of abnormal gamma band hyperconnectivity between the mPFC and dHPC was absent in CaMKIIα:GluN1 KO mice. This study suggests that the effects of NMDAr antagonism on gamma band responses and behaviour have complex relationships, and rely on different populations of neurons.
Publisher: Wiley
Date: 07-12-2022
DOI: 10.1111/EPI.17441
Abstract: Alprazolam administered via the Staccato® breath‐actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE‐E‐001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision. Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double‐blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h. A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double‐blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg ( n = 38 p = .0392) and 2.0 mg ( n = 38 p = .0392), compared with 42.5% for Staccato placebo ( n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity there were no treatment‐related serious AEs. Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting.
Publisher: Hindawi Limited
Date: 18-07-2014
DOI: 10.1111/ANE.12280
Abstract: To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate. Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester. Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure. Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.CLINPH.2004.06.023
Abstract: We investigated the feasibility of electroencephalography (EEG) dipole source localisation of interictal epileptiform discharges from data acquired during routine clinical inpatient video-EEG monitoring (VEM) and compared a 19-channel 'routine montage' with a 29-channel 'surgical montage' that includes an additional row of 10 inferior temporal electrodes. Twenty consecutive patients who had VEM for the presurgical evaluation of medically refractory partial epilepsy were screened. Thirteen of the patients had focal interictal spikes recorded, and in 11 (85%) these were technically satisfactory for source localisation. Fourteen spike foci were analysed as 3 patients had bilateral independent spikes. EEG data was acquired with 29 electrodes including an inferior temporal row (surgical montage). For comparison, the 10 additional electrodes were excluded from analysis (routine montage). Using NEUROSCAN Source 2.0 software, a computed dipole source localisation of averaged spikes was performed utilising a magnetic resonance imaging-based finite element model. Dipole localisation was compared with that of the Comprehensive Epilepsy Program (CEP) evaluation. Using the surgical montage dipole source localisation was consistent with the CEP spike localisation for 13/14 spikes (93%, P<0.005), compared with only 5/14 spikes (36%) using the routine montage. Data derived from routine clinical inpatient VEM using a routine montage can yield accurate EEG dipole source localisation, but significantly more accurate localisation is obtained using the surgical montage.
Publisher: Oxford University Press (OUP)
Date: 11-06-2016
DOI: 10.1093/BRAIN/AWW116
Abstract: There are no treatments in clinical practice known to mitigate the neurobiological processes that convert a healthy brain into an epileptic one, a phenomenon known as epileptogenesis. Downregulation of protein phosphatase 2A, a protein that causes the hyperphosphorylation of tau, is implicated in neurodegenerative diseases commonly associated with epilepsy, such as Alzheimer's disease and traumatic brain injury. Here we used the protein phosphatase 2A activator sodium selenate to investigate the role of protein phosphatase 2A in three different rat models of epileptogenesis: amygdala kindling, post-kainic acid status epilepticus, and post-traumatic epilepsy. Protein phosphatase 2A activity was decreased, and tau phosphorylation increased, in epileptogenic brain regions in all three models. Continuous sodium selenate treatment mitigated epileptogenesis and prevented the biochemical abnormalities, effects which persisted after drug withdrawal. Our studies indicate that limbic epileptogenesis is associated with downregulation of protein phosphatase 2A and the hyperphosphorylation of tau, and that targeting this mechanism with sodium selenate is a potential anti-epileptogenic therapy.
Publisher: Wiley
Date: 27-10-2004
Publisher: Hindawi Limited
Date: 08-07-2021
DOI: 10.1111/ANE.13499
Publisher: BMJ
Date: 18-08-2020
Abstract: To evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE). Phase 3, double-blind, randomised, placebo-controlled trial (SP0982 NCT02408523 ) in patients with IGE and PGTCS taking 1–3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment. 242 patients were randomised and received ≥1 dose of trial medication (lacosamide lacebo: n=121/n=121). Patients (mean age: 27.7 years 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6% myoclonic 38.8% absence 37.2%). Median treatment duration with lacosamide lacebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37% HR 0.540, 95% CI 0.377 to 0.774 p .001 n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide ( % of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide lacebo was 31.3%/17.2% (difference 14.1% p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial. Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.
Publisher: Wiley
Date: 28-11-2006
DOI: 10.1111/J.1528-1167.2006.00860.X
Abstract: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery. We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n=9) versus those who did not (n=14) and between those in whom postoperative depression developed (n=13) versus those in whom it did not (n=10). A significant region of hypometabolism was set at p or=20 contiguous voxels. Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t=4.64 p<0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t=5.10 p<0.001). Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JAUT.2018.10.014
Abstract: To perform a systematic review of the current scientific literature in order to identify variables associated with patient prognosis in autoimmune encephalitis. We performed a systematic literature search using MEDLINE, Embase, PubMed and PsychInfo databases. We selected studies that explored the correlation between early clinical and paraclinical findings, and patient outcomes. Data was extracted, analyzed and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Forty four publications detailing 2823 subjects matched our inclusion criteria. There was considerable heterogeneity in methodology, patient profile, investigation results and clinical outcome measures. Findings were often discrepant for cases of anti-NMDAR encephalitis when compared with other causes of autoimmune encephalitis. Delay in immunotherapy contributed to a variety of worse outcomes for patients with different subsets of autoimmune encephalitis. Altered consciousness, ICU admission and no use of immunotherapy were variables associated with poor prognosis in anti-NMDAR encephalitis. Older age, sex, the presence of status epilepticus, CSF abnormalities and MRI changes were unlikely to have significant prognostic value. The influence of antibody titers, autonomic dysfunction and underlying malignancy was unclear. A number of variables were identified to have potential predictive value for outcomes in autoimmune encephalitis. Heterogeneous study design, size and quality were major limiting factors in this review.
Publisher: Elsevier BV
Date: 2021
Publisher: Informa UK Limited
Date: 16-09-2019
DOI: 10.1080/02699052.2019.1667539
Abstract: This study characterized the acute and chronic effects of tau reduction in traumatic brain injury (TBI). A fluid percussion injury (FPI) or a sham-injury was administered to wild type (WT) or tau knockout (Tau-/-) mice. Mice were assigned to a one-week or twelve-week recovery period before behavioral testing and analysis of brain tissue. Mice were tested on the elevated-plus maze, the Y-maze, and rotarod. The twelve-week recovery mice underwent in vivo MRI. Phosphorylated tau in brain tissue was analyzed post-mortem using western blots. FPI mice, regardless of genotype, had abnormalities on the elevated-plus maze (a task to assess anxiety-like behavior) at one-week post-injury. However, after twelve-weeks recovery, the Tau-/- mice that were given an FPI were less anxious and had improved motor function compared to their WT counterparts. MRI analysis found that while all FPI mice had brain damage, the Tau-/- mice had larger hippoc al volumes. The WT+FPI mice also had increased phosphorylated tau compared to WT+sham mice at both the one-week and twelve-week recovery times. These findings suggest that tau may play an important role in some of the consequences of TBI, particularly the long-term functional deficits.
Publisher: IOP Publishing
Date: 03-08-2010
DOI: 10.1088/0031-9155/55/16/013
Abstract: The use of THz radiation as a potential tool for medical imaging is of increasing interest. In this paper three methods of analysis of THz spectroscopic information for diagnosis of tissue pathologies at THz frequencies are presented. The frequency-dependent absorption coefficients, refractive indices and Debye relaxation times of pure water and pure lipids were measured and used as prior knowledge in the different theoretical methods for the determination of concentration. Three concentration analysis methods were investigated: (a) linear spectral decomposition, (b) spectrally averaged dielectric coefficient method and (c) the Debye relaxation coefficient method. These methods were validated on water and lipid emulsions by determining the concentrations of phantom chromophores and comparing to the known composition. The accuracy and resolution of each method were determined to assess the potential of each method as a tool for medical diagnosis at THz frequencies.
Publisher: Wiley
Date: 31-12-2016
DOI: 10.1111/EPI.13291
Abstract: We report on a quantitative analysis of data from a study that acquired continuous long-term ambulatory human electroencephalography (EEG) data over extended periods. The objectives were to examine the seizure duration and interseizure interval (ISI), their relationship to each other, and the effect of these features on the clinical manifestation of events. Chronic ambulatory intracranial EEG data acquired for the purpose of seizure prediction were analyzed and annotated. A detection algorithm identified potential seizure activity, which was manually confirmed. Events were classified as clinically corroborated, electroencephalographically identical but not clinically corroborated, or subclinical. K-means cluster analysis supplemented by finite mixture modeling was used to locate groupings of seizure duration and ISI. Quantitative analyses confirmed well-resolved groups of seizure duration and ISIs, which were either mono-modal or multimodal, and highly subject specific. Subjects with a single population of seizures were linked to improved seizure prediction outcomes. There was a complex relationship between clinically manifest seizures, seizure duration, and interval. These data represent the first opportunity to reliably investigate the statistics of seizure occurrence in a realistic, long-term setting. The presence of distinct duration groups implies that the evolution of seizures follows a predetermined course. Patterns of seizure activity showed considerable variation between in iduals, but were highly predictable within in iduals. This finding indicates seizure dynamics are characterized by subject-specific time scales therefore, temporal distributions of seizures should also be interpreted on an in idual level. Identification of duration and interval subgroups may provide a new avenue for improving seizure prediction.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1007/S10334-018-0690-Z
Abstract: Ultra-high-field functional MRI (UHF-fMRI) allows for higher spatiotemporal resolution imaging. However, higher-resolution imaging entails coverage limitations. Processing partial-coverage images using standard pipelines leads to sub-optimal results. We aimed to develop a simple, semi-automated pipeline for processing partial-coverage UHF-fMRI data using widely used image processing algorithms. We developed automated pipelines for optimized skull stripping and co-registration of partial-coverage UHF functional images, using built-in functions of the Centre for Functional Magnetic Resonance Imaging of the Brain's (FMRIB's) Software library (FSL) and advanced normalization tools. We incorporated the pipelines into the FSL's functional analysis pipeline and provide a semi-automated optimized partial-coverage functional analysis pipeline (OPFAP). Compared to the standard pipeline, the OPFAP yielded images with 15 and 30% greater volume of non-zero voxels after skull stripping the functional and anatomical images, respectively (all p = 0.0004), which reflected the conservation of cortical voxels lost when the standard pipeline was used. The OPFAP yielded the greatest Dice and Jaccard coefficients (87 and 80%, respectively all p < 0.0001) between the co-registered participant gyri maps and the template gyri maps, demonstrating the goodness of the co-registration results. Furthermore, the greatest volume of group-level activation in the most number of functionally relevant regions was observed when the OPFAP was used. Importantly, group-level activations were not observed when using the standard pipeline. These results suggest that the OPFAP should be used for processing partial-coverage UHF-fMRI data for detecting high-resolution macroscopic blood oxygenation level-dependent activations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-03-2007
DOI: 10.1212/01.WNL.0000256375.39476.BE
Abstract: We report three patients with reflex toothbrushing-induced epilepsy associated with small circumscribed structural lesions in the primary somatosensory cortex in close proximity to the hand and speech motor areas. Sensory symptoms were observed at clinical onset with localizing focal ictal and interictal epileptiform discharges on EEG. These cases refine the localization, possible mechanisms of epileptogenesis, and classification of this reflex epilepsy.
Publisher: Cold Spring Harbor Laboratory
Date: 20-12-2019
DOI: 10.1101/2019.12.19.883405
Abstract: The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre s le of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippoc al sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p .001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippoc al sclerosis in the ipsilateral parahippoc al cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippoc al sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata . Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippoc al sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.
Publisher: Frontiers Media SA
Date: 25-05-2018
Publisher: Wiley
Date: 21-02-2018
DOI: 10.1111/EPI.14018
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.NEUBIOREV.2019.12.027
Abstract: Neurological conditions such as traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis, and Alzheimer's disease are serious clinical problems that affect millions of people worldwide. The majority of clinical trials for these common conditions have failed, and there is a critical need to understand why treatments in preclinical animal models do not translate to patients. Many patients with these conditions are middle-aged or older, however, the majority of preclinical studies have used only young-adult animals. Considering that aging involves biological changes that are relevant to the pathobiology of neurological diseases, the lack of aged subjects in preclinical research could contribute to translational failures. This paper details how aging affects biological processes involved in neurological conditions, and reviews aging research in the context of traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis, and Alzheimer's disease. We conclude that aging is an important, but often overlooked, factor that influences biology and outcomes in neurological conditions, and provide suggestions to improve our understanding and treatment of these diseases in aged patients.
Publisher: Public Library of Science (PLoS)
Date: 11-01-2017
Publisher: Cambridge University Press (CUP)
Date: 06-03-2018
DOI: 10.1017/S0963180117000640
Abstract: A new generation of implantable brain–computer interfaces (BCI) devices have been tested for the first time in a human clinical trial, with significant success. These intelligent implants detect specific neuronal activity patterns, such as an epileptic seizure, and provide information to help patients to respond to the upcoming neuronal events. By forecasting a seizure, the technology keeps patients in the decisional loop the device gives control to patients on how to respond and decide on a therapeutic course ahead of time. Being kept in the decisional loop can positively increase patients’ quality of life however, doing so does not come free of ethical concerns. There is currently a lack of evidence concerning the various impacts of closed-loop system BCIs on patients’ decisionmaking processes, especially how being in the decisional loop impacts patients’ sense of autonomy. This article addresses these gaps by providing data that we obtained from a first-in-human clinical trial involving patients implanted with advisory brain devices. This article explores ethical issues related to the risks involved in being kept in the decisional loop.
Publisher: Wiley
Date: 27-05-2023
DOI: 10.1111/EPI.17644
Abstract: Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug‐resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta‐analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre‐ and post‐epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta‐analysis assessed the postsurgery change in QoL. Meta‐regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre‐ and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory–31 item (QOLIE‐31) meta‐analysis included six studies, and QOLIE‐89 meta‐analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE‐31 (95% confidence interval [CI] = 10.9–30.1, I 2 = 95.5) and 12.1 for QOLIE‐89 (95% CI = 8.0–16.1, I 2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta‐regression demonstrated a higher postoperative QOLIE‐31 score as well as change in pre‐ and postoperative QOLIE‐31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an in idual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between in idual studies and high risk of bias.
Publisher: Wiley
Date: 17-03-2017
DOI: 10.1002/EPI4.12049
Publisher: Impact Journals, LLC
Date: 03-06-2015
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1016/S0378-4347(99)00043-2
Abstract: The method involves precipitation of plasma proteins with acetonitrile and analysis of the supernatant by high-performance liquid chromatography using a 5 microm Zorbax C8 column. Quantitation was performed by measurement of the UV absorbance at a wavelength of 306 nm. The method was linear in the range of 1-20 microg/ml, with a mean coefficient of determination (r2=0.998). The limit of detection was 0.6 microg/ml and the lower limit of quantitation was 1 microg/ml using 200 microl of plasma. Within- and between-day accuracy and precision were below 6% at all analysed concentrations except at the limit of quantitation. No interfering peaks were found by commonly monitored antiepileptic drugs. Recovery was found to be > or =99%. Satisfactory performance was obtained in the evaluation of epileptic patient s les, whose results of plasma concentration measurements are briefly discussed. We conclude that this is a reliable method for the routine monitoring of lamotrigine concentration in plasma in the clinical setting.
Publisher: Hindawi Limited
Date: 14-08-2018
DOI: 10.1111/ANE.13005
Abstract: To gain insight into the main advantages and disadvantages that might result from valproate being unavailable for women who intend to become pregnant. Analysis of data from the Australian Pregnancy Register concerning pregnancies exposed to valproate (N = 501) and pregnancies where previous valproate intake had been ceased before pregnancy (N = 101). The risk of foetal malformation associated with valproate exposure during pregnancy was dose-related, and there was a tendency for the more major malformations, including those often managed by therapeutic abortion, for ex le spina bifida, to occur at higher valproate doses. Had there been no exposure to valproate during pregnancy, some 80% of the foetal malformations that occurred might have been avoided. Cessation of previous valproate therapy before pregnancy was associated with an increased hazard of seizure-affected pregnancy. This was particularly the case for women with generalized epilepsies, in whom the incidence of seizure-affected pregnancy was increased by 50% to nearly 100%. Avoiding valproate intake during pregnancy is likely to reduce the incidence of foetal malformation, but at a cost of worsened maternal epilepsy control. In idualization of treatment is particularly important in considering withdrawal of valproate in the light of the fact that it is much more widely used in generalized epilepsy, there being fewer alternative drugs than for focal epilepsy and withdrawal is not without risk for both mother and baby. This study may provide a quantitative basis for assessing the balance between benefit and disadvantage for in idual women with valproate-treated epilepsy who are considering pregnancy.
Publisher: Frontiers Media SA
Date: 18-10-2022
DOI: 10.3389/FNINS.2022.1021131
Abstract: Alzheimer’s disease (AD) is a highly damaging disease that affects one’s cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as in iduals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world ePVS may be able to fulfill this role and therefore merit further research.
Publisher: Wiley
Date: 10-2000
DOI: 10.1111/J.1528-1157.2000.TB04611.X
Abstract: Purpose: To determine the incidence of cerebellar atrophy (CA) in patients with intractable temporal lobe epilepsy, whether any clinical factors are significantly associated with CA, whether CA is unilateral or asymmetric and whether this feature has any relationship to the side of epileptogenicity, and whether the presence of CA is related to epilepsy surgery outcome. Methods: We developed a magnetic resonance imaging method of measuring the presurgical volumes of the cerebellar hemispheres of 185 patients who underwent temporal lobectomy for intractable epilepsy and of 80 control subjects. In addition, cerebellar volumes were normalized to the total brain volumes. CA was determined as being present when the measured volume was smaller than two standard deviations from the mean value found in control subjects. Results: Both absolute and normalized cerebellar volumes were found to be significantly reduced in the epilepsy patients compared with the control subjects. Without normalization of the cerebellar volumes, CA was present in 25.9% of the epilepsy patients with normalization, it was present in only 16.2%. The atrophy was symmetric between the cerebellar hemispheres, and there was no significant difference in volume between the hemisphere ipsilateral and the hemisphere contralateral to the side of the temporal lobectomy. The duration of epilepsy was significantly longer and the age at onset of epilepsy was younger in patients with CA than in those without CA. The presence of CA was not associated with the outcome of temporal lobectomy. Conclusions: CA is symmetric and common in patients with intractable temporal lobe epilepsy. However, the results suggest that the atrophy in one third of patients with CA also proportionately affects the cerebral hemispheres. The duration of epilepsy and the age at onset of epilepsy are associated with the occurrence of CA. Seizure control after temporal lobectomy is not influenced by the presence of CA.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.EPLEPSYRES.2016.08.007
Abstract: Alterations in cardiac electrophysiology are an established consequence of long-standing drug resistant epilepsy. Patients with chronic epilepsy display abnormalities in both sinoatrial node pacemaker current as well as ventricular repolarizing current that places them at a greater risk of developing life-threatening cardiac arrhythmias. The development of cardiac arrhythmias secondary to drug resistant epilepsy is believed to be a key mechanism underlying the phenomenon of Sudden Unexpected Death in EPilepsy (SUDEP). Though an increasing amount of studies examining both animal models and human patients have provided evidence that chronic epilepsy can detrimentally affect cardiac function, the underlying pathophysiology remains unclear. Recent work has shown the expression of several key cardiac ion channels to be altered in animal models of genetic and acquired epilepsies. This has led to the currently held paradigm that cardiac ion channel expression may be secondarily altered as a consequence of seizure activity-resulting in electrophysiological cardiac dysfunction. Furthermore, cortical autonomic dysfunction - resulting from seizure activity-has also been suggested to play a role, whereby seizure activity may indirectly influence cardiac function via altering centrally-mediated autonomic output to the heart. In this review, we discuss various cardiac dysrhythmias associated with seizure events-including tachycardia, bradycardia and QT prolongation, both ictally and inter-ictally, as well as the role of the autonomic nervous system. We further discuss key ion channels expressed in both the heart and the brain that have been shown to be altered in epilepsy and may be responsible for the development of cardiac dysrhythmias secondary to chronic epilepsy.
Publisher: Oxford University Press (OUP)
Date: 30-01-2018
DOI: 10.1093/BRAIN/AWX341
Publisher: Elsevier BV
Date: 03-2019
Publisher: Wiley
Date: 07-2000
DOI: 10.1111/J.1528-1157.2000.TB00251.X
Abstract: To identify factors that predict the outcome in seizure control after frontal lobe epilepsy surgery (FLES). FLES is the second most frequent type of epilepsy surgery, but the results are generally not as good as those after anterior temporal lobectomy. Our cohort consisted of 68 consecutive patients whose first epilepsy surgery involving the frontal lobe occurred between 1987 and 1994. Clinical history and results of imaging and electroencephalographic studies were reviewed in detail. Excellent outcome was defined as being seizure free or having only nondisabling seizures at last follow up. Forty of the 68 patients (58.8%) had an excellent outcome none of the patients with a history of childhood febrile seizures had an excellent outcome, whereas outcome was excellent in 63% of those without that history (p </= 0.01). The other significant presurgical factor was the presence of a potentially epileptogenic lesion in the frontal lobe on neuroimaging (excellent outcome in 72% when present versus 41% when absent, p </= 0.001). The only significant postsurgical factor was early postoperative seizure control in the first year (excellent outcome in 96% with early control versus 25% without, p </= 0.01). History of childhood febrile seizures is a poor prognostic factor in FLES patients. It may suggest that the structural basis of all or some of the patients' intractable seizures is mesial temporal sclerosis. On the other hand, neuroimaging detection of a potentially epileptogenic frontal lobe lesion and early postoperative seizure control are associated with subsequent excellent outcome.
Publisher: Mary Ann Liebert Inc
Date: 03-2018
Abstract: This study used oculomotor, cognitive, and multi-modal magnetic resonance imaging (MRI) measures to assess for neurological abnormalities in current asymptomatic amateur Australian rules footballers (i.e., Australia's most participated collision sport) with a history of sports-related concussion (SRC). Participants were 15 male amateur Australian rules football players with a history of SRC greater than 6 months previously, and 15 sex-, age-, and education-matched athlete control subjects that had no history of neurotrauma or participation in collision sports. Participants completed a clinical interview, neuropsychological measures, and oculomotor measures of cognitive control. MRI investigation involved structural imaging, as well as diffusion tensor imaging and resting-state functional MRI sequences. Despite no group differences on conventional neuropsychological tests and multi-modal MRI measures, Australian rules football players with a history of SRC performed significantly worse on an oculomotor switch task: a measure of cognitive control that interleaves the response of looking towards a target (i.e., a prosaccade) with the response of looking away from a target (i.e., an antisaccade). Specifically, Australian footballers performed significantly shorter latency prosaccades and found changing from an antisaccade trial to a prosaccade trial (switch cost) significantly more difficult than control subjects. Poorer switch cost was related to poorer performance on a number of neuropsychological measures of inhibitory control. Further, when comparing performance on the cognitively more demanding switch task with performance on simpler, antisaccade rosaccades tasks which require a single response, Australian footballers demonstrated a susceptibility to increased cognitive load, compared to the control group who were unaffected. These initial results suggest that current asymptomatic amateur Australian rules football players with a history of SRC may have persisting, subtle, cognitive changes, which are demonstrable on oculomotor cognitive measures. Future studies are required in order to further elucidate the full nature and clinical relevance of these findings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1998
DOI: 10.1097/00006231-199801000-00006
Abstract: Computer-aided subtraction of the co-registered and normalized interictal from the ictal single photon emission tomography (SPET) scan, followed by co-registration to the magnetic resonance image, may improve the utility of ictal SPET in the localization of partial epilepsy. This paper describes and technically validates our method. The SPET to SPET co-registration was tested using six sequential 99Tc(m) brain phantom SPET images of different known positions (15 matches). The registration error was determined by multiplying the calculated match transformation matrix by the inverse of the known transformation matrix. The 'worst case' co-registration error was less that one voxel diameter in all cases (median 3.2 mm, range 1.2-4.8 mm). For interictal to ictal SPET registrations in 10 consecutive intractable partial epilepsy patients, a similar root mean square distance (RMSD) between corresponding points on the matched scans was found as for the phantom studies (median 2.2 vs 2.6 mm). The appropriateness of our normalization was studied by comparing the pixel intensity distributions between the matched scans, and by analysing the subtraction pixel intensity distribution. The pixel intensity distribution for both the normalized phantom, and paired normalized patient studies, were closely matched to each other except for the extreme values, which in clinical situations likely represent regions of ictal activation or depression. The subtraction image intensity distributions were symmetrically centred on zero for all values up to at least within the 5th to 95th centile range, confirming good normalization for the 'non-activated' pixels. Also, a linear relationship was demonstrated between the measured pixel intensity on the phantom scans and the true changes in 99Tc(m) activity based on its decay constant. The results of this study demonstrate that our method produces accurate SPET to SPET co-registration, and appropriate SPET normalization, thereby allowing a valid ictal subtraction image to be derived.
Publisher: Wiley
Date: 29-08-2019
DOI: 10.1111/EPI.16329
Abstract: Epidemiological data and gene association studies suggest a genetic predisposition to developing epilepsy after an acquired brain insult, such as traumatic brain injury. An improved understanding of genetic determinants of vulnerability is imperative for early disease diagnosis and prognosis prediction, with flow‐on benefits for the development of targeted antiepileptogenic treatments as well as optimal clinical trial design. In the laboratory, one approach to investigate why some in iduals are more vulnerable to acquired epilepsy than others is to examine unique rodent models exhibiting either vulnerability or resistance to epileptogenesis. This review focuses on the most well‐characterized of these models, the FAST (seizure‐prone) and SLOW (seizure‐resistant) rat strains, which were derived by selective breeding for differential amygdala electrical kindling rates. We describe how these strains differ in their seizure profiles, neuroanatomy, and neurobehavioral phenotypes, both at baseline and after a brain insult, with this knowledge proving fruitful to identify common pathological abnormalities associated with seizure susceptibility and psychiatric comorbidities. It is important to note that accruing data on strain differences in multiple biological processes provides insight into why some in iduals may be more vulnerable to epileptogenesis, although future studies are evidently needed to identify the precise molecular and genetic risk factors. Together, the FAST and SLOW rat strains, and other similar experimental models, are invaluable neurobiological tools to investigate the effect of genetic background on acquired epilepsy risk, as well as the poorly understood relationship between epilepsy development and associated comorbidities.
Publisher: Wiley
Date: 17-01-2019
DOI: 10.1002/EPI4.12297
Publisher: Wiley
Date: 20-01-2016
DOI: 10.1111/EPI.13299
Abstract: Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy (MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment (EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms. At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys n = 43) or standard housing (SH standard laboratory cages n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects. EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes. We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE.
Publisher: Wiley
Date: 11-2000
Publisher: BMJ
Date: 03-2020
DOI: 10.1136/BMJOPEN-2019-032567
Abstract: To investigate whether sex, age, medical specialty and seasonal variations in serum concentration of 25-hydroxy vitamin D (25(OH)D) are evident among an Australian patient population. Retrospective study analysing the results of serum 25(OH)D lab tests and vitamin D supplementation from Royal Melbourne Hospital (RMH) between 2014 and 2017. Tertiary healthcare centre in Victoria, Australia. 30 023 patients (inpatient and outpatient) who had their serum 25(OH)D levels measured at RMH between 2014 and 2017. Serum 25(OH)D levels stratified according to patients’ sex, age and medical specialty admitted to, as well as the season and year (2014 to 2017) 25(OH)D level was measured. Mean serum 25(OH)D level of study population was 69.9 nmol/L (95% CI 69.5 to 70.2). Only 40.2% patients in this cohort were sufficient in vitamin D ( nmol/L). On average, 25(OH)D levels in male patients were 6.1 units (95% CI 5.4 to 6.9) lower than in females. Linear regression analysis found that 25(OH)D levels increased by 0.16 unit (95% CI 0.14 to 0.18) for every year increase in age. One-way analysis of variance showed patients from neurology had the highest average 25(OH)D level, 76.8 nmol/L (95% CI 74.2 to 79.3) compared with other medical specialties. Mean 25(OH)D level during winter, 64.9 nmol/L (95% CI 64.2 to 65.6) was significantly lower compared with other seasons despite supplementation. Average 25(OH)D level measured in 2014, 71.5 nmol/L (95 CI% 70.8 to 72.2) was significantly higher than levels measured in 2016–2017. There is a sex, age, medical specialty, seasonal and yearly variation in vitamin D status in an Australian patient population. The association between low vitamin D status and winter despite supplementation suggests other interventions are required to boost serum 25(OH)D levels.
Publisher: Elsevier BV
Date: 11-2000
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.NEUBIOREV.2017.06.002
Abstract: In recent years, sheep (Ovis aries) have emerged as a useful animal model for neurological research due to their relatively large brain and blood vessel size, their cortical architecture, and their docile temperament. However, the functional anatomy of sheep brain is not as well studied as that of non-human primates, rodents, and felines. For ex le, while the location of the sheep motor cortex has been known for many years, there have been few studies of the somatotopy of the motor cortex and there were a range of discrepancies across them. The motivation for this review is to provide a definitive resource for studies of the sheep motor cortex. This work critically reviews the literature examining the organization of the motor cortex in sheep, utilizing studies that have applied direct electrical stimulation and histological methods A clearer understanding of the sheep brain will facilitate and progress the use of this species as a scientific animal model for neurological research.
Publisher: Oxford University Press (OUP)
Date: 17-02-2016
DOI: 10.1093/BRAIN/AWW019
Abstract: We report on a quantitative analysis of electrocorticography data from a study that acquired continuous ambulatory recordings in humans over extended periods of time. The objectives were to examine patterns of seizures and spontaneous interictal spikes, their relationship to each other, and the nature of periodic variation. The recorded data were originally acquired for the purpose of seizure prediction, and were subsequently analysed in further detail. A detection algorithm identified potential seizure activity and a template matched filter was used to locate spikes. Seizure events were confirmed manually and classified as either clinically correlated, electroencephalographically identical but not clinically correlated, or subclinical. We found that spike rate was significantly altered prior to seizure in 9 out of 15 subjects. Increased pre-ictal spike rate was linked to improved predictability however, spike rate was also shown to decrease before seizure (in 6 out of the 9 subjects). The probability distribution of spikes and seizures were notably similar, i.e. at times of high seizure likelihood the probability of epileptic spiking also increased. Both spikes and seizures showed clear evidence of circadian regulation and, for some subjects, there were also longer term patterns visible over weeks to months. Patterns of spike and seizure occurrence were highly subject-specific. The pre-ictal decrease in spike rate is not consistent with spikes promoting seizures. However, the fact that spikes and seizures demonstrate similar probability distributions suggests they are not wholly independent processes. It is possible spikes actively inhibit seizures, or that a decreased spike rate is a secondary symptom of the brain approaching seizure. If spike rate is modulated by common regulatory factors as seizures then spikes may be useful biomarkers of cortical excitability.
Publisher: American Chemical Society (ACS)
Date: 16-10-2020
Publisher: Wiley
Date: 22-10-2012
DOI: 10.1111/J.1528-1167.2012.03720.X
Abstract: The origin of bilateral synchronous spike-and-wave discharges (SWDs) that underlie absence seizures has been widely debated. Studies in genetic rodent models suggest that SWDs originate from a restricted region in the somatosensory cortex. The properties of this initiation site remain unknown. Our goal was to characterize the interictal, preictal and ictal neuronal activity in the primary and secondary cortical regions (S1, S2) and in the adjacent insular cortex (IC) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). We performed electroencephalography (EEG) recordings in combination with multisite local field potential (LFP) and single cell juxtacellular recordings, and cortical electrical stimulations, in freely moving rats and those under neurolept-anesthesia. The onset of the SWDs was preceded by 5-9 Hz field potential oscillations, which were detected earlier in S2 and IC than in S1. Sustained SWDs could be triggered by a 2-s train of 7-Hz electrical stimuli at a lower current intensity in S2 than in S1. In S2 and IC, subsets of neurons displayed rhythmic firing (5-9 Hz) in between seizures. S2 and IC layers V and VI neurons fired during the same time window, whereas in S1 layer VI, neurons fired before layer V neurons. Just before the spike component of each SW complex, short-lasting high-frequency oscillations consistently occurred in IC ∼20 msec before S1. Our findings demonstrate that the S2/IC cortical areas are a critical component of the macro-network that is responsible for the generation of absence-related SWDs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 08-11-2007
DOI: 10.1007/S00198-006-0185-Z
Abstract: Epilepsy is a common chronic neurological disorder, usually requiring long-term treatment with anti-epileptic drugs (AED). Many studies have reported that AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures. There remains uncertainty about the type(s) of bone disease due to AED treatment, and the pathogenesis of AED-associated fractures. Deficits in bone mineral density (BMD) are widely reported in AED-treated patient populations. However, much of the research conducted to date has been limited by factors such as small s le size, potentially biased subject selection, a lack of selection of appropriate control data, and failure to take account of important confounding influences. The pathogenesis of AED-associated fractures is likely to be multifactorial, due to factors including reduced BMD, impaired bone quality (due to osteoporosis and/or osteomalacia), increased propensity to fall, and fractures associated with seizures or loss of consciousness. Patients receiving long-term AED should be monitored for indices of bone health, including BMD and vitamin D status. Lifestyle factors should be optimized, vitamin D status maintained, and fall prevention strategies introduced as appropriate. Good seizure control is important. The use of additional, specific osteoporosis therapy is not evidence-based in this setting, but would appear reasonable in patients with clinically significant decreases in BMD, applying current treatment guidelines for osteoporosis. There is a pressing need for improved understanding of the pathogenesis of AED-associated bone disease, for better definition of the risk associated with specific AED regimens, and for the development of evidence-based preventive and treatment approaches in this common but neglected disorder.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.NBD.2011.01.003
Abstract: Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.
Publisher: Wiley
Date: 29-07-2019
DOI: 10.1111/EPI.16301
Abstract: There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes. Specifically, seizure activity has been shown to alter the messenger RNA (mRNA) and protein expression of voltage-gated sodium channels (Na
Publisher: Hindawi Limited
Date: 03-2012
DOI: 10.1111/J.1600-0404.2011.01499.X
Abstract: To estimate the prevalence and demographic distribution of treated epilepsy in a community-based population. We surveyed all residents in Tasmania, Australia, who were supplied at least one antiepileptic drug prescription between July 1, 2001 and June 30, 2002, recorded on the national prescription database. We adjusted for the effect of disease-related non-response bias by imputation methods. After three mail contacts, 54.0% (4072/7541) responded, with 1774 (43.6%) indicating treatment for epilepsy, representing 86.0% of the estimated total possible cases in Tasmania. The adjusted treated epilepsy prevalence was 4.36 per 1000 (95% CI 4.34, 4.39) lower in women (prevalence ratio 0.92 (95% CI 0.84, 1.00)) greater with increasing age (P < 0.001) similar in the three main geographic regions and similar with socioeconomic status of postcode of residence. Although our estimates are likely to be affected by access to health services, overall treated epilepsy prevalence of 4.4 per 1000 is similar to previous studies. Our finding of high elderly prevalence has been reported in a few recent studies in developed countries and has important clinical and public health implications in populations with similar aging demographics.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Oxford University Press (OUP)
Date: 05-2020
Abstract: Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer’s disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer’s disease pathology. Twenty-six patients (n = 12 with clinically probable Alzheimer’s dementia and n = 14 with amyloid-positive mild cognitive impairment) and 29 healthy control subjects underwent baseline assessment with 18F-AV-1451 PET, 11C-PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke’s Cognitive Examination. Regional grey matter volumes, and regional binding of 18F-AV-1451 and 11C-PK11195 were derived from 15 temporo-parietal regions characteristically affected by Alzheimer’s disease pathology. A principal component analysis was used on each imaging modality separately, to identify the main spatial distributions of pathology. A latent growth curve model was applied across the whole s le on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the in iduals’ estimated rate of cognitive decline on the neuroimaging components and examined univariable predictive models with single-modality predictors, and a multi-modality predictive model, to identify the independent and combined prognostic value of the different neuroimaging markers. Principal component analysis identified a single component for the grey matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-s le, the single-modality models indicated significant correlations between the rate of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer’s disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer’s disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer’s disease.
Publisher: Wiley
Date: 07-2015
DOI: 10.1111/EPI.13029
Publisher: Springer Science and Business Media LLC
Date: 03-02-2016
DOI: 10.1007/S00223-016-0109-7
Abstract: Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0 % p < 0.001 in levetiracetam vs. -9.8 % p < 0.001 in older AED group), FA (-1.46 % p < 0.001 vs. -0.96 % p < 0.001, respectively) and radial trabecular BMD (-1.46 % p = 0.048 and -2.31 % p = 0.013, respectively). C-terminal telopeptides of type I collagen (βCTX bone resorption marker) decreased in both groups (-16.1 % p = 0.021 vs. -15.2 % p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP bone formation marker) decreased in older AED group (-27.3 % p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover.
Publisher: Frontiers Media SA
Date: 04-02-2020
Publisher: Springer Science and Business Media LLC
Date: 17-03-2021
DOI: 10.1186/S12974-021-02114-1
Abstract: Traumatic brain injury (TBI) is a major cause of disability in young children, yet the factors contributing to poor outcomes in this population are not well understood. TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization, and such infections may modify TBI pathobiology and recovery. In this study, we hypothesized that a peripheral immune challenge such as lipopolysaccharide (LPS)—mimicking a hospital-acquired infection—would worsen outcomes after experimental pediatric TBI, by perpetuating the inflammatory immune response. Three-week-old male mice received either a moderate controlled cortical impact or sham surgery, followed by a single LPS dose (1 mg/kg i.p.) or vehicle (0.9% saline) at 4 days post-surgery, then analysis at 5 or 8 days post-injury (i.e., 1 or 4 days post-LPS). LPS-treated mice exhibited a time-dependent reduction in general activity and social investigation, and increased anxiety, alongside substantial body weight loss, indicating transient sickness behaviors. Spleen-to-body weight ratios were also increased in LPS-treated mice, indicative of persistent activation of adaptive immunity at 4 days post-LPS. TBI + LPS mice showed an impaired trajectory of weight gain post-LPS, reflecting a synergistic effect of TBI and the LPS-induced immune challenge. Flow cytometry analysis demonstrated innate immune cell activation in blood, brain, and spleen post-LPS however, this was not potentiated by TBI. Cytokine protein levels in serum, and gene expression levels in the brain, were altered in response to LPS but not TBI across the time course. Immunofluorescence analysis of brain sections revealed increased glia reactivity due to injury, but no additive effect of LPS was observed. Together, we found that a transient, infection-like systemic challenge had widespread effects on the brain and immune system, but these were not synergistic with prior TBI in pediatric mice. These findings provide novel insight into the potential influence of a secondary immune challenge to the injured pediatric brain, with future studies needed to elucidate the chronic effects of this two-hit insult.
Publisher: Wiley
Date: 08-2013
DOI: 10.1111/EPI.12298
Publisher: Wiley
Date: 10-07-2012
DOI: 10.1111/J.1528-1167.2012.03585.X
Abstract: We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected in iduals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.JOCN.2009.03.012
Abstract: The aim of this study was to report the safety and efficacy of tailored cortical resection based on image guided subdural electrode implantations in eight patients with medically refractory epilepsy. The patients were selected for multimodality image guided subdural grid implantation, inpatient invasive electroencephalography video monitoring and surgical resection of epileptogenic foci. All patients had frequent disabling, medically refractory seizures pre-operatively. At a minimum of 10 months post-resection all patients had a worthwhile improvement in seizure frequency, with 7 of the 8 (87.5%) having an excellent outcome (Engel Class I). Short-term complications of grid implantation were: one patient with a post-operative subdural haemorrhage and one patient with a transient fluctuating dysphasia. The only long-term complication was a mild, non-disabling dysarthria following resection near eloquent speech cortex in one patient. We conclude that tailored cortical resection following image-guided insertion of subdural grids is a reliable, safe and highly effective method for the treatment of medically refractory epilepsy in carefully selected patients.
Publisher: Wiley
Date: 16-05-2020
DOI: 10.1111/EPI.16536
Abstract: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA‐induced birth defects. We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures inbred Non‐Epileptic Controls (NEC) and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same‐strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C‐section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements. VPA‐exposed pups showed significant reductions in weight, length, and whole‐body development compared with controls of all three strains ( P .0001). Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100% NEC, 95% Wistar, 80%), more frequently than in controls (9%, 13%, 19%). Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA‐induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug–induced birth defects.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.EPLEPSYRES.2017.06.015
Abstract: 1) To study the breastfeeding initiation, duration and exclusivity rates, and common reasons for early weaning in Chinese mothers with epilepsy (MWE) 2) To identify potential perinatal breastfeeding correlations with selected sociodemographic and clinical factors. A semi-structured questionnaire was administered to 281 MWE attending hospitals in South-west China from February 2014 to July 2015. Data about breastfeeding behaviors, sociodemographic, obstetric, and epileptic variables were collected. Descriptive analyses, followed by univariate and multivariate logistic regression analyses, were utilized to examine associations with breastfeeding, its duration and exclusivity. Breastfeeding initiation rate in MWE was 59.4%. At 3 months post partum total breastfeeding rate was 49.5% and exclusive breastfeeding rate was 36.3%. At 6 months, about one third (33.1%) of MWE had continued breastfeeding their babies and 12.8% of enrolled infants were exclusively breastfed. During lactation, fear of exposure of the babies to antiepileptic drugs (AEDs) via breast milk, frequent seizures, and insufficient breast milk supply were the commonest reasons for early cessation of breastfeeding. Mothers with epilepsy who had babies delivered at full term were more inclined to breastfeed their babies. Mothers who had gestational non-active epilepsy were more likely to engage in long-term breastfeeding. AED polytherapy was associated with poor breastfeeding behaviors in all aspects. MWE in our study had a lower prevalence of breastfeeding than what would be expected in the general population, where approximately 95% breastfeed. Good seizure control and optimal antiepileptic therapy during gestation and lactation were associated with a higher rate of breastfeeding. Targeted intervention programs enhancing antenatal care services and breastfeeding consultation are needed.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2018
DOI: 10.1038/NRDP.2018.24
Abstract: Epilepsy affects all age groups and is one of the most common and most disabling neurological disorders. The accurate diagnosis of seizures is essential as some patients will be misdiagnosed with epilepsy, whereas others will receive an incorrect diagnosis. Indeed, errors in diagnosis are common, and many patients fail to receive the correct treatment, which often has severe consequences. Although many patients have seizure control using a single medication, others require multiple medications, resective surgery, neuromodulation devices or dietary therapies. In addition, one-third of patients will continue to have uncontrolled seizures. Epilepsy can substantially impair quality of life owing to seizures, comorbid mood and psychiatric disorders, cognitive deficits and adverse effects of medications. In addition, seizures can be fatal owing to direct effects on autonomic and arousal functions or owing to indirect effects such as drowning and other accidents. Deciphering the pathophysiology of epilepsy has advanced the understanding of the cellular and molecular events initiated by pathogenetic insults that transform normal circuits into epileptic circuits (epileptogenesis) and the mechanisms that generate seizures (ictogenesis). The discovery of >500 genes associated with epilepsy has led to new animal models, more precise diagnoses and, in some cases, targeted therapies.
Publisher: Elsevier
Date: 2017
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.EPLEPSYRES.2014.04.005
Abstract: The data collected in the Australian Register of antiepileptic drugs in pregnancy have been studied in the hope of defining simple items of information that could be recorded at initial interview of pregnant women with epilepsy, and which might allow estimation of the risk of the pregnancy resulting in a malformed foetus. Analysis of the data showed that dose of valproate, but not intake of other commonly used antiepileptic drugs, in the current pregnancy, and a past history of a pregnancy involving a malformed foetus, statistically significantly increased the malformation hazard in the current pregnancy, and that continuing alcohol intake might decrease it. Plotting the hazard against valproate dose in monotherapy, with or without histories of (i) previous pregnancies with foetal malformations (FMs), and (ii) continuing alcohol intake, provided quantitative information concerning the degree of increased risk. It is hoped that this information may help in advising about the risk of foetal malformation (FM) in in idual pregnancies.
Publisher: Wiley
Date: 18-07-2011
DOI: 10.1002/JMRI.22669
Abstract: To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI) model. Two groups of adult male Wistar rats (n = 72) were studied with either MEMRI, whereby rats receive MnCl(2) (100 mg/kg intraperitoneally) 24 hours prior to scanning, or standard MRI (sMRI) with no contrast agent. Rats from both groups underwent FPI or sham injury and were longitudinally assessed for 6 months for neurological toxicity using behavioral tests, EEG recording, and MRI scanning. Regardless of whether they received FPI, MEMRI animals showed progressive signs of cerebral toxicity compared with sMRI rats, including significantly reduced weight gain, progressive brain volume decrease, and increased anxiety and depressive-like behaviors. Long-term structural and functional consequences of using manganese as a contrast agent for MRI can confound experimental outcomes and must be taken into account when designing longitudinal imaging studies using manganese-enhanced MRI.
Publisher: BMJ
Date: 10-10-2008
Abstract: To compare hippoc al surface structure, using large deformation high dimensional mapping (HDM-LD), in subjects with temporal lobe epilepsy (TLE) with (HS+ve) and without (HS-ve) hippoc al sclerosis. The study included 30 HS-ve subjects matched with 30 HS+ve subjects from the previously reported epilepsy patient cohort. To control for normal right-left asymmetries of hippoc al surface structure, subjects were regrouped based on laterality of onset of epileptic seizures and presence of HS. Gender ratio, age, duration of epilepsy and seizure frequency were calculated for each of the four groups. Final HDM-LD surface maps of the right and left TLE groups were compared to define differences in subregional hippoc al involvement within the groups. There were no significant differences in comparisons of the left TLE (left HS-ve compared with HS+ve) or right TLE (right HS-ve compared with HS+ve) groups with respect to age, duration of epilepsy or seizure severity scores. HDM-LD maps showed accentuated surface changes over the lateral hippoc al surface, in the region of the Sommer sector, in the hippoc i affected by HS. However, HS-ve hippoc i showed maximal surface changes in a different pattern, and did not involve the region of Sommer sector. We conclude that differences in segmental volume loss between the HS-ve and HS+ve groups are suggestive that the underlying pathophysiology of hippoc al changes in the two groups is different, and not related to chronic seizure duration or severity.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.SEIZURE.2018.12.006
Abstract: This paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data. Over 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analysed using conventional statistical techniques, confidence interval methods, and logistic regression. By 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy. There were (i) dose-related increased incidences of pregnancies carrying foetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (P < .05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the foetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that pre-conception folate supplementation reduced the hazard of AED-associated foetal malformation. AED polytherapy did not increase foetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard. If it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.EXPNEUROL.2019.112979
Abstract: High mobility group box protein-1 (HMGB1) has been implicated as a key mediator of neuroinflammation and neurodegeneration in a range of neurological conditions including traumatic brain injury (TBI) and epilepsy. To date, however, most studies have examined only acute outcomes, and the adult brain. We have recently demonstrated HMGB1 release after experimental TBI in the pediatric mouse. This study therefore examined the chronic consequences of acute HMGB1 inhibition in the same model, to test the hypothesis that HMGB1 is a pivotal mediator of neuropathological, neurobehavioral, and epilepsy outcomes in pediatric TBI. HMGB1 was inhibited by treatment with 50 mg/kg i.p. Glycyrrhizin (Gly), compared to vehicle controls, commencing 1 h prior to moderate TBI or sham surgery in post-natal day 21 mice. We first demonstrated that Gly reduced brain HMGB1 levels and brain edema at an acute time point of 3 days post-injury. Subsequent analysis over a chronic time course found that pediatric TBI resulted in short-term spatial memory and motor learning deficits alongside an apparent increase in hippoc al microglial reactivity, which was prevented in Gly-treated TBI mice. In contrast, Gly treatment did not reduce the severity of evoked seizures, the proportion of animals exhibiting chronic spontaneous seizure activity, or cortical tissue loss. Together, our findings contribute to a growing appreciation for HMGB1's role in neuropathology and associated behavioral outcomes after TBI. However, further work is needed to fully elucidate the contribution of HMGB1 to epileptogenesis in this context.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.BBI.2019.04.034
Abstract: Traumatic brain injury (TBI) is a serious global health issue, being the leading cause of death and disability for in iduals under the age of 45, and one of the largest causes of global neurological disability. In addition to the brain injury itself, it is increasingly appreciated that a TBI may also alter the systemic immune response in a way that renders TBI patients more vulnerable to infections in the acute post-injury period. Such infections pose an additional challenge to the patient, increasing rates of mortality and morbidity, and worsening neurological outcomes. Hospitalization, surgical interventions, and a state of immunosuppression induced by injury to the central nervous system (CNS), may all contribute to the high rate of infections seen in the population with TBI. Ongoing research to better understand the immunomodulators that underlie TBI-induced immunosuppression may aid in the development of effective therapeutic strategies to improve the recovery trajectory for patients. This review first describes the clinical scenario, posing the question of whether TBI patients are more susceptible to infections such as pneumonia, and if so, why? We then consider how cross-talk between the injured brain and the systemic immune system occurs, and further, how the additional immune challenge of an acquired infection can contribute to ongoing neuroinflammation and neurodegeneration after a TBI. Experimental models combining TBI with infection are discussed, as well as current treatment options available for this double-barreled insult. The aims of this review are to summarize current understanding of the bidirectional relationship between the CNS and the immune system when faced with a mechanical trauma combined with a concomitant infection, and to highlight key outstanding questions that remain in the field.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JOCN.2013.08.005
Abstract: We present a case of tuberous sclerosis complex (TSC) diagnosed in adulthood in a man initially referred for specialist neuropsychiatric assessment with psychosis and obsessive-compulsive symptoms (OCS) on a background of epilepsy and intellectual disability. To our knowledge, this is the first reported patient with TSC featuring both psychosis and OCS. This patient highlights the importance of comprehensive re-evaluation of atypical presentations of intellectual disability, epilepsy and associated neuropsychiatric symptoms, even in adulthood. This is particularly relevant in the context of significant advances in genetics, neuroscience, imaging and treatments for heritable neurogenetic disorders.
Publisher: Wiley
Date: 07-2009
DOI: 10.1111/J.1528-1167.2009.02059.X
Abstract: The association between a specific polymorphism (3435C>T) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy. Data were collected on demographics, medication details, and seizure control after 12 months of treatment. The distribution of ABCB1 3435C>T genotypes was compared between patients with and without recurrent unprovoked seizures. Five hundred forty-two newly treated patients were enrolled (212 from Australia, 285 from Scotland, and 45 from Hong Kong). A total of 38.4% had recurrent unprovoked seizures after starting antiepileptic drug (AED) treatment. Genotype frequencies and ethnicity did not differ between the Scottish and Australian cohorts, but both were significantly different in the Hong Kong cohort. There was no significant relationship between the ABCB1 3435C>T genotype and the rate of recurrence of unprovoked seizures in the three cohorts in idually or combined however the epilepsy syndrome and a greater number of seizures pretreatment was associated with an increased risk of seizure recurrence. The ABCB1 3435C>T genotype does not have a major role in determining the efficacy of seizure control with initial AED therapy. The study highlights issues that arise in combining pharmacogenetic datasets from different ethnic regions and health systems, an approach that is essential to advance this field.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2011
DOI: 10.1158/1535-7163.MCT-11-0067
Abstract: Inhibitors of mitotic proteins such as Aurora kinase and polo-like kinase have shown promise in preclinical or early clinical development for cancer treatment. We have reported that the MiTMAB class of dynamin small molecule inhibitors are new antimitotic agents with a novel mechanism of action, blocking cytokinesis. Here, we examined 5 of the most potent of a new series of dynamin GTPase inhibitors called dynoles. They all induced cytokinesis failure at the point of abscission, consistent with inhibition of dynamin while not affecting other cell cycle stages. All 5 dynoles inhibited cell proliferation (MTT and colony formation assays) in 11 cancer cell lines. The most potent GTPase inhibitor, dynole 34-2, also induced apoptosis, as revealed by cell blebbing, DNA fragmentation, and PARP cleavage. Cell death was induced specifically following cytokinesis failure, suggesting that dynole 34-2 selectively targets iding cells. Dividing HeLa cells were more sensitive to the antiproliferative properties of all 5 dynoles compared with non iding cells, and nontumorigenic fibroblasts were less sensitive to cell death induced by dynole 34-2. Thus, the dynoles are a second class of dynamin GTPase inhibitors, with dynole 34-2 as the lead compound, that are novel antimitotic compounds acting specifically at the abscission stage. Mol Cancer Ther 10(9) 1553–62. ©2011 AACR.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.BBI.2019.04.038
Abstract: Initial studies suggest that increased age is associated with worse outcomes after traumatic brain injury (TBI), though the pathophysiological mechanisms responsible for this remain unclear. Immunosenescence (i.e., dysregulation of the immune system due to aging) may play a significant role in influencing TBI outcomes. This study therefore examined neurological outcomes and immune response in young-adult (i.e., 10 weeks old) compared to middle-aged (i.e., 1 year old) rats following a TBI (i.e., fluid percussion) or sham-injury. Rats were euthanized at either 24 h or one-week post-injury to analyze immune cell populations in the brain and periphery via flow cytometry, as well as telomere length (i.e., a biomarker of neurological health). Behavioral testing, as well as volumetric and diffusion-weighted MRI, were also performed in the one-week recovery rats to assess for functional deficits and brain damage. Middle-aged rats had worse sensorimotor deficits and shorter telomeres after TBI compared to young rats. Both aging and TBI independently worsened cognitive function and cortical volume. These changes occurred in the presence of fewer total leukocytes, fewer infiltrating myeloid cells, and fewer microglia in the brains of middle-aged TBI rats compared to young rats. These findings indicate that middle-aged rats have worse sensorimotor deficits and shorter telomeres after TBI than young rats, and this may be related to an altered neuroimmune response. Although further studies are required, these findings have important implications for understanding the pathophysiology and optimal treatment strategies in TBI patients across the life span.
Publisher: Wiley
Date: 05-09-2022
DOI: 10.1111/EPI.17400
Abstract: Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippoc us and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation. Analyses included 36 cases (age = 14–64 years, age at epilepsy onset = 0–51 years, epilepsy duration = 2–53 years, PGES duration = 0–93 s), with 13 cases in all hippoc al analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippoc us ( n = 16) and temporal cortex ( n = 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters. In hippoc us, 5HT2A protein by Western blot positively correlated with PGES duration ( p = .0024, R 2 = .52), but 5HT1A did not ( p = .87, R 2 = .0020). In temporal cortex, 5HT1A and 5HT2A had lower expression and did not correlate with PGES duration. Histologically, PGES duration did not correlate with 5HT1A or 5HT2A expression in hippoc al CA4, dentate gyrus, or temporal cortex. RNAseq identified two serotonin receptors with expression that correlated with PGES duration in an exploratory analysis: HTR3B negatively correlated ( p = .043, R 2 = .26) and HTR4 positively correlated ( p = .049, R 2 = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts ( p = .040, Pearson correlation r = .52), particularly potassium channels ( KCNA4 , KCNC4 , KCNH1 , KCNIP4 , KCNJ3 , KCNJ6 , KCNK1 ). No modules were associated with serotonin receptor signaling. Higher hippoc al 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk.
Publisher: Wiley
Date: 28-01-2018
DOI: 10.1111/EPI.14013
Abstract: Aberrant myelination and developmental delay have been reported in epilepsy. However, it is unclear whether these are linked to intrinsic mechanisms that support a predisposition toward seizures and the development of epilepsy. Thus, we compared rates of myelination and neurodevelopment in male rats selectively bred for enhanced susceptibility to kindling epileptogenesis (FAST) with male rats bred for resistance (SLOW). Myelin-specific gene expression was compared in the brainstem, cerebellum, and cerebral hemisphere of FAST and SLOW rats on postnatal days (PNDs) 5, 11, 17, 23, and 90 to determine strain-specific myelination rates. Myelin protein levels were also compared at PNDs 5 and 23 in the brainstem. Relative rates of neurodevelopment were evaluated between PNDs 5 and 21 using physical growth landmarks and neuromotor tests including righting reflex, cliff avoidance, negative geotaxis, and locomotor activity. Myelin-specific mRNA expression was significantly down-regulated in FAST rats on PNDs 5 and 11 in all 3 brain structures, indicating relatively delayed myelination. Likewise, corresponding protein levels were significantly lower in FAST brainstem on PND 5. Developmental delay was evident in the FAST strain such that only 9% of FAST pups, compared to 81% of SLOW, had open eyes by PND 13, locomotor activity was significantly reduced between PNDs 12 and 16, and neuromotor task acquisition was delayed between PNDs 5 and 10. Relative delays in myelination and neurodevelopment co-occurred in the seizure-prone FAST strain in the absence of seizures. These findings suggest these symptoms are not seizure-induced and may be mechanistically linked to an underlying pathophysiology supporting a predisposition toward developing epilepsy.
Publisher: Wiley
Date: 29-08-2018
DOI: 10.1111/EPI.14496
Abstract: To describe the demographics, etiologies, types of status epilepticus (SE), and outcomes in people with refractory and super-refractory SE from around the world, we prospectively collected cases of refractory SE (RSE) treated with continuous intravenous anesthetic drugs in an intensive care unit setting through online questionnaires using "active surveillance." We collected information about 776 cases of RSE in 50 countries over 4 years. Control of SE was achieved in 74% of the cases. Neurologic outcomes were poor in 41% of patients, and 24% died. Good outcome was associated with younger age and a history of epilepsy. Etiology strongly influenced the outcome. Patients from Asia were younger, more frequently presented with convulsive SE, and were more frequently affected by infectious etiologies when compared with patients from Europe and the Americas. Despite these differences, outcomes were similar in all countries. Demographics of patients with RSE in a global audit are similar to those in prior single center series, providing evidence of generalizability of those studies. Important differences exist among patients with RSE from different regions of the world, but these do not seem to significantly influence patient outcomes.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2020
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.BBR.2016.10.045
Abstract: Chronic social behavior problems after pediatric traumatic brain injury (TBI) significantly contribute to poor quality of life for survivors. Using a well-characterized mouse model of early childhood TBI, we have previously demonstrated that young brain-injured mice develop social deficits by adulthood. As biological sex may influence both normal and aberrant social development, we here evaluated potential sex differences in post-TBI psychosocial deficits by comparing the behavior of male and female mice at adulthood (8 weeks post-injury). Secondly, we hypothesized that pediatric TBI would influence neuronal morphology identified by Golgi-Cox staining in the hippoc us and prefrontal cortex, regions involved in social cognition and behavior, before the onset of social problems (3 weeks post-injury). Morphological analysis of pyramidal neurons in the ipsilateral prefrontal cortex and granule cells of the hippoc al dentate gyrus revealed a reduction in dendritic complexity after pediatric TBI. This was most apparent in TBI males, whereas neurons from females were less affected. At adulthood, consistent with previous studies, TBI males showed deficits in sociability and social recognition. TBI females also showed a reduction in sociability, but intact social recognition and increased sociosexual avoidance. Together, these findings indicate that sex is a determinant of regional neuroplasticity and social outcomes after pediatric TBI. Reduced neuronal complexity in the prefrontal cortex and hippoc us, several weeks after injury in male mice, appears to precede the subsequent emergence of social deficits. Sex-specific alterations in the social brain network are thus implicated as an underlying mechanism of social dysfunction after pediatric TBI.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.YEBEH.2018.10.008
Abstract: The literature suggests that cesarean delivery or birth is carried out more often in pregnant women with epilepsy (WWE) than in pregnant women in the general population. Data were utilized from the Australian Pregnancy Register (APR) for Women on Antiepileptic Medication to investigate this issue in Australia. Over almost two decades, the mean CS rate in 1900 APR women was 39.2%, but was only 29.9% in women in the general population (relative risk (R.R.) = 1.31, 95% confidence interval (C.I.) 1.24, 1.39). Rates for forceps and suction-assisted delivery were similar in the two datasets. The 9.3% excess CS rate was almost entirely accounted for by operations carried out prior to the onset of labor. The rates for CS during labor were very similar. Only 11.0% of the WWE knew the indication for their prelabor CS, whereas 69.8% knew why theirs had been carried out during labor (odds ratio (O.R.) = 0.054 99% C.I. 0.032, 0.089). Slightly older mothers and increased proportions of primipara probably made small contributions to the increased prelabor CS rate in the Australian WWE, but most of the excess could not be accounted for in the Register data. Australian obstetricians may have tended to regard prelabor CS as a preferable course of action in managing delivery in WWE, even in the absence of other indications.
Publisher: Frontiers Media SA
Date: 11-09-2020
Publisher: Society of Nuclear Medicine
Date: 23-12-2016
DOI: 10.2967/JNUMED.114.141713
Abstract: Neuroinflammation is implicated in the pathogenesis of a wide range of neurologic and neuropsychiatric diseases. For over 20 years, (11)C-PK11195 PET, which aims to image expression of the translocator protein (TSPO) on activated microglia in the brain, has been used in preclinical and clinical research to investigate neuroinflammation in vivo in patients with brain diseases. However, (11)C-PK11195 suffers from two major limitations: its low brain permeability and high nonspecific and plasma binding results in a low signal-to-noise ratio, and the use of (11)C restricts its use to PET research centers and hospitals with an on-site cyclotron. In recent years, there has been a great deal of work into the development of new TSPO-specific PET radiotracers. This work has focused on fluorinated radiotracers, which would enable wider use and improved signal-to-noise ratios. These radiotracers have been utilized in preclinical and clinical studies of several neurologic diseases with varying degrees of success. Unfortunately, the application of these second-generation TSPO radiotracers has revealed additional problems, including a polymorphism that affects TSPO binding. In this review, the developments in TSPO imaging are discussed, and current limitations and suggestions for future directions are explored.
Publisher: BMJ
Date: 30-04-2201
Publisher: Wiley
Date: 14-12-2020
DOI: 10.1111/EPI.16788
Abstract: Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed.
Publisher: EDP Sciences
Date: 2023
DOI: 10.1051/E3SCONF/202337400024
Abstract: The study was to produce natural isotonic made from natural sources for Cihateup’s ducks in a dry maintenance system. Ducklings were ided into five replications and four treatments. The ratios used were 17 % protein and 2 900 kcal kg −1 of metabolic energy. The composition of natural isotonic (treatment) is as follows: T0=Water T1=Water + 7 % Sugar + 2 % Lime Juice + 25 mg Celery Extract + 0.8 g Salt T2 =Water + 7 % Sugar + 3 % Lime Juice + 50 mg Celery Extract + 0.9 g Salt T3=Water + 7 % Sugar + 4 % Lime Juice + 75 mg Celery Extract + 1 g Salt. Experiment design using a completely randomized design with four treatments and five replications. The results showed a significant decrease in leukocyte and platelet levels in T2. It indicated that the use of natural isotonic at these levels had an immune effect on local ducks. Hematocrit, hemoglobin, and erythrocyte levels also showed a decrease in T2 but were not significant. While the lowest number of duck platelets was also shown by T2. These platelets are indicators of inflammation, which means that T2 can keep ducks from disease.
Publisher: Oxford University Press (OUP)
Date: 19-08-2013
DOI: 10.1093/HMG/DDT403
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 21-05-2021
DOI: 10.1002/ACN3.51374
Abstract: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of in iduals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. We performed exome sequencing of 1,128 in iduals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 in iduals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
Publisher: Wiley
Date: 13-01-2020
DOI: 10.1111/EPI.16424
Abstract: Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti-inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti-inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells-brain-resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro- and anti-inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain-resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.PNEUROBIO.2019.101677
Abstract: We evaluated whether pharmacologically targeting T-type Ca
Publisher: Wiley
Date: 28-08-2007
DOI: 10.1111/J.1528-1167.2007.01242.X
Abstract: The neurobiological processes that result in epilepsy, known as epileptogenesis, are incompletely understood. Moreover, there is currently no therapy that effectively halts or impedes the development or progression of the condition. Positron Emission Tomography (PET) provides valuable information about the function of the brain in vivo, and is playing a central role in both clinical practice and research. This technique reliably reveals functional abnormalities in many epilepsy syndromes, particularly temporal lobe epilepsy. Unfortunately, epileptogenesis is extremely difficult to study in human patients who usually present with established epilepsy, rather than at the early stages of the process. Animal models offer the advantage of permitting the assessment of the pre-, developing, and chronic epileptic states. However, traditional techniques (e.g., histology) are only able to examine the brain at one time point during epileptogenesis in any one in idual. Recent advances in dedicated small animal PET (saPET) allow researchers for the first time to study in vivo biomolecular changes in the brain during epileptogenesis by means of serial acquisitions in the same animal. Repeated application of in vivo imaging modalities in the same animal also decreases the effect of biological inter-in idual variability and the number of animals to be used. The availability of novel PET tracers permits the investigation of a broad range of biochemical and physiological processes in the brain. Besides research on epileptogenesis, saPET can also be applied to investigate in vivo the biological effect of novel treatment strategies. saPET is widely used in many fields of pathophysiological investigation and is likely to significantly enhance epilepsy research.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41467-018-07524-Z
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 in iduals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have erse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Publisher: MDPI AG
Date: 09-11-2019
Abstract: Epilepsy is a common chronic consequence of traumatic brain injury (TBI), contributing to increased morbidity and mortality for survivors. As post-traumatic epilepsy (PTE) is drug-resistant in at least one-third of patients, there is a clear need for novel therapeutic strategies to prevent epilepsy from developing after TBI, or to mitigate its severity. It has long been recognized that seizure activity is associated with a local immune response, characterized by the activation of microglia and astrocytes and the release of a plethora of pro-inflammatory cytokines and chemokines. More recently, increasing evidence also supports a causal role for neuroinflammation in seizure induction and propagation, acting both directly and indirectly on neurons to promote regional hyperexcitability. In this narrative review, we focus on key aspects of the neuroinflammatory response that have been implicated in epilepsy, with a particular focus on PTE. The contributions of glial cells, blood-derived leukocytes, and the blood–brain barrier will be explored, as well as pro- and anti-inflammatory mediators. While the neuroinflammatory response to TBI appears to be largely pro-epileptogenic, further research is needed to clearly demonstrate causal relationships. This research has the potential to unveil new drug targets for PTE, and identify immune-based biomarkers for improved epilepsy prediction.
Publisher: Wiley
Date: 12-09-2011
Publisher: Oxford University Press (OUP)
Date: 15-04-2021
Abstract: Sports-related concussion (SRC) is a serious health concern. However, the temporal profile of neuropathophysiological changes after SRC and how these relate to biological sex are still poorly understood. This preliminary study investigated whether diffusion-weighted magnetic resonance imaging (dMRI) was sensitive to neuropathophysiological changes following SRC whether these changes were sex-specific and whether they persisted beyond the resolution of self-reported symptoms. Recently concussed athletes (n = 14), and age- and education-matched nonconcussed control athletes (n = 16), underwent MRI 24–48-h postinjury and again at 2-week postinjury (i.e., when cleared to return-to-play). Male athletes reported more symptoms and greater symptom severity compared with females. dMRI revealed white matter differences between athletes with SRC and their nonconcussed counterparts at 48-h postinjury. These differences were still present at 2-week postinjury, despite SRC athletes being cleared to return to play and may indicate increased cerebral vulnerability beyond the resolution of subjective symptoms. Furthermore, we identified sex-specific differences, with male SRC athletes having significantly greater white matter disruption compared with female SRC athletes. These results have important implications for the management of concussion, including guiding return-to-play decisions, and further improve our understanding regarding the role of sex in SRC outcomes.
Publisher: Wiley
Date: 29-01-2010
DOI: 10.1111/J.1528-1167.2009.02254.X
Abstract: Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED-discordant, twin and sibling matched-pair approach, and assessed clinically relevant subgroups: AED polytherapy longer-duration AED and falls history. Twenty-nine same-sex (mean age 44.9 years, 59% female), ambulatory, community-dwelling twin and sibling pairs, discordant for AED exposure (and AED-indication), were recruited. Validated clinical and laboratory tests of strength, gait, and balance were performed. Relevant AED levels, and fasting serum s les for 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and immunoreactive parathyroid hormone (iPTH) levels were taken. There were significant mean within-pair differences in tests of static and dynamic balance, with the AED user having poorer balance function than the AED nonuser. No difference was seen in lower limb strength or gait measures. Increased duration of AED therapy and AED polytherapy were independent predictors of increased sway. No significant within-pair differences were seen in fasting serum levels of 1,25(OH)(2)D, 25OHD and iPTH after Bonferroni correction. Balance performance is impaired in AED users compared to their matched nonuser siblings. Pairs where the AED users took AED polytherapy, or had a longer duration of AED use, had more impaired balance performance. These balance deficits may contribute to the increased rate of fractures in this population.
Publisher: Society of Nuclear Medicine
Date: 11-2010
DOI: 10.2967/JNUMED.110.078626
Abstract: Traumatic brain injury (TBI) has a high incidence of long-term neurologic and neuropsychiatric morbidity. Metabolic and structural changes in rat brains were assessed after TBI using serial (18)F-FDG PET and 3-dimensional MRI in vivo. Rats underwent lateral fluid percussion injury (FPI n = 16) or a sham procedure (n = 11). PET and MR images were acquired at 1 wk and at 1, 3, and 6 mo after injury. Morphologic changes were assessed using MRI-based regions of interest, and hippoc al shape changes were assessed with large-deformation high-dimensional mapping. Metabolic changes were assessed using region-of-interest analysis and statistical parametric mapping with the flexible factorial analysis. Anxiety-like behavior and learning were assessed at 1, 3, and 6 mo after injury. PET analyses showed widespread hypometabolism in injured rats, in particular involving the ipsilateral cortex, hippoc us, and amygdalae, present at 1 wk after FPI, most prominent at 1 mo, and then decreasing. Compared with the sham group, rats in the FPI group had decreased structural volume which progressively increased over 3-6 mo, occurring in the ipsilateral cortex, hippoc us, and ventricles after FPI (P < 0.05). Large-deformation high-dimensional mapping showed evolving hippoc al shape changes across the 6 mo after FPI. Injured rats displayed increased anxiety-like behavior (P < 0.05), but there were no direct correlations between the severity of the behavior abnormalities and functional or structural imaging changes. In selected brain structures, FPI induces early hypometabolism and delayed progressive atrophic changes that are dynamic and continue to evolve for months. These findings have implications for the understanding of the pathophysiology and evolution of long-term neurologic morbidity following TBI, and indicate an extended window for targeted neuroprotective interventions.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.SEIZURE.2014.08.008
Abstract: To determine the outcomes in regards to seizure control and foetal malformation in pregnant women with epilepsy not treated with antiepileptic drugs (AEDs). Analysis of data from the Australian Register of AEDs in Pregnancy on 148 women with epilepsy who were not receiving AEDs before and during at least the first trimester of pregnancy. Seizure control was less likely to be maintained in AED-untreated pregnancies. Whether AED therapy had been ceased in preparation for pregnancy, or had not been employed for long periods before pregnancy, made no statistically significant difference to seizure control outcomes, but those who ceased therapy in preparation for pregnancy were more likely to again be taking AED therapy by term. Foetal malformation rates were reasonably similar in untreated pregnancies, and in treated pregnancies if pregnancies exposed to known AED teratogens (valproate and probably topiramate) were excluded from consideration. Leaving epilepsy untreated during pregnancy appears disadvantageous from the standpoint of seizure control: it also does not reduce the hazard of foetal malformation unless it avoids valproate or topiramate intake during pregnancy.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-11-2019
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 10-2005
DOI: 10.3171/JNS.2005.103.4.0768
Abstract: Object. The syndrome of medial temporal lobe epilepsy (MTLE) may occur in patients in whom magnetic resonance (MR) images demonstrate normal findings. In these patients, there is no evidence of hippoc al sclerosis on neuroimaging, and histopathological examination of the resected hippoc us does not reveal significant neuron loss. In this paper the authors describe the distinct clinical features of this MTLE subtype, referred to as paradoxical temporal lobe epilepsy (PTLE). Methods. The authors selected 12 consecutive patients with preoperative findings consistent with MTLE in whom MR imaging did not demonstrate any hippoc al abnormality. Onset of hippoc al seizure was confirmed by long-term intracranial monitoring. There were six female and six male patients with a mean age of 32 ± 11 years (mean ± standard deviation [SD]) at presentation. These patients' seizure histories, available hippoc al volumetric measurements, and hippoc al cell densities in different subfields were reviewed. Sharp electrode recordings from dentate granule cells that had been maintained in hippoc al slices provided a measure of excitation and inhibition in the tissue. We compared these data with those of a cohort of 50 randomly selected patients who underwent anteromedial temporal resection for medial temporal sclerosis (MTS) during the same time period (1987–1999). The durations of follow up (means ± SDs) for the PTLE and MTS groups were 51 ± 59 months and 88 ± 44 months, respectively. A history of febrile seizure was present less frequently in the PTLE group (8%) than in the MTS group (34%). Other risk factors for epilepsy such as trauma, meningoencephalitis, or perinatal injuries were present more frequently in the PTLE group (50%) than in the MTS cohort (36%). In patients in the PTLE group the first seizure occurred later in life (mean age at seizure onset 14 years in the PTLE group compared with 9 years in the MTS group, p = 0.09). Ten patients (83%) in the PTLE cohort and 23 patients (46%) in the MTLE cohort had secondary generalization of their seizures. Among patients with PTLE, volumetric measurements (five patients) and randomized blinded visual inspection (seven patients) of the bilateral hippoc i revealed no atrophy and no increased T 2 signal change on preoperative MR images. All patients with PTLE underwent anteromedial temporal resection (amygdalohippoc ectomy, in five patients on the left side and in seven on the right side). Electrophysiological studies of hippoc al slices demonstrated that dentate granule cells from patients with PTLE were significantly less excitable than those from patients with MTS. The mean pyramidal cell loss in the CA1 subfield in patients in the PTLE group was 20% (range 0–59%) and that in patients in the MTS group was 75% (range 41–90%) (p 0.001). Maximal neuron loss (mean loss 38%) occurred in the CA4 region in six patients with PTLE (end folium sclerosis). At the last follow-up examination, six patients (50%) in the PTLE group were seizure free compared with 38 patients (76%) in the MTS group. Conclusions. Clinical PTLE is a distinct syndrome with clinical features and surgical outcomes different from those of MTS.
Publisher: BMJ
Date: 28-10-2020
DOI: 10.1136/NEURINTSURG-2020-016862
Abstract: Implantable brain–computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation. Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks. Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%–100.00%) (trial mean (median, Q1–Q3)) at a rate of 13.81 (13.44, 10.96–16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%–100.00%) at 20.10 (17.73, 12.27–26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants. We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 04-08-2023
DOI: 10.1111/EPI.17727
Abstract: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient , and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p = .0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = −.007 to −.005, p .0001). For male participants, the ratio was .011 less than for female participants (95% CI = −.014 to −.007, p .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.
Publisher: Wiley
Date: 31-08-2015
DOI: 10.1111/EPI.13127
Abstract: Up to half of patients assessed for suspected new-onset epileptic seizures report previous undiagnosed events. This suggests that delay to timely and expert assessment is a major issue. Very little is known about the degree of delay or nature of the undiagnosed events, impacting on our understanding of new-onset epilepsy. In this study we aimed to examine events that occur before presentation, as well as the extent and risk factors for delay to assessment. Included in this retrospective study were 220 patients diagnosed at the First Seizure Clinic (Austin Health, Australia) between 2003 and 2006 with an epileptic index seizure. Patients with a prior diagnosis of epileptic seizures were excluded. Chart review was undertaken, including detailed interviews conducted by an epileptologist at first assessment. Logistic regression assessed risk factors for delay from first event to presentation, including event characteristics, socioeconomic disadvantage, employment, and distance to medical facility. Forty-one percent (n = 90) of patients had one or more event before their index seizure. Of these, 50% had multiple or more than five prior events and 28% experienced one or more convulsive event before the index seizure. Of the total 220 patients, 36% had delayed presentation >4 weeks, 21% delayed >6 months, and 14% delayed >2 years. First events without convulsions or features likely to disrupt behaviour were strongly associated with delay (p = <0.001). Relative socioeconomic disadvantage was also associated with delay to presentation (p = 0.04). Our findings suggest a gap in early diagnosis and care in a sizable proportion of new-onset cases, despite a "first world" urban environment and the availability of free basic medical care. Delay appears particularly likely when events are nonconvulsive or low-impact, suggesting that these seizure types may be underrepresented in studies of new-onset epilepsy. This has implications for our understanding of the incidence, evolution, impact, and treatment response of new-onset epilepsy.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.BBI.2018.01.007
Abstract: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and typically involves a robust immune response. Although a great deal of preclinical research has been conducted to identify an effective treatment, all phase III clinical trials have been unsuccessful to date. These translational shortcomings are in part due to a failure to recognize and account for the heterogeneity of TBI, including how extracranial factors can influence the aftermath of TBI. For ex le, most preclinical studies have utilized isolated TBI models in young adult males, while clinical trials typically involve highly heterogeneous patient populations (e.g., different mechanisms of injury, a range of ages, presence of polytrauma or infection). This paper will review the current, albeit limited literature related to how TBI is affected by common concomitant immunological stressors. In particular, discussion will focus on whether extracranial trauma (i.e., polytrauma), infection, and age/immunosenescence can influence TBI pathophysiology, and thereby may result in a different brain injury than what would have occurred in an isolated TBI. It is concluded that these immunological stressors are all likely to be TBI modifiers that should be further studied and could impact translational treatment strategies.
Publisher: Wiley
Date: 11-05-2015
DOI: 10.1111/EPI.13007
Abstract: The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26 7.7%), two to carbamazepine monotherapy (2/34 5.9%), and seven to valproate in polytherapy (7/15 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the s le. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.
Publisher: Wiley
Date: 13-05-2020
DOI: 10.1111/EPI.16515
Abstract: Epilepsy is a common neurological disorder that increases the risk of morbidity and mortality. Autoimmune epilepsy is a subset of epilepsy that occurs in the setting of autoimmunity, such as in autoimmune encephalitis (AIE). AIE is an autoimmune disorder characterized by immune‐mediated neuroinflammation resulting in a variety of neurological symptoms, including psychiatric disturbance, cognitive dysfunction, and seizures. Seizures in AIE are thought to be a result of antibodies directed against neuronal cell‐surface proteins involved in synaptic transmission. The role of blood‐brain barrier dysfunction, myeloid cell infiltration, and the initiation of proinflammatory cascades in epileptogenesis has been shown to be important in animal models and human patients with epilepsy. Epileptogenesis in AIE is likely to arise from the synergistic effect of both innately driven neuroinflammation and antibody‐induced hyperexcitability. Together, these processes produce persistent drug‐resistant seizures that contribute to the morbidity seen in AIE. Understanding the proinflammatory pathways involved in this process may improve diagnostics and provide alternative treatment targets in AIE.
Publisher: Cambridge University Press (CUP)
Date: 12-2007
DOI: 10.1111/J.1601-5215.2007.00238.X
Abstract: We describe the presentation of a young woman with long-standing complex partial seizures with occasional secondary generalization, who presented with complex visual hallucinations (CVHs) and delusions. Routine biological workup including magnetic resonance imaging revealed an area of significant left-sided occipital gliosis. Video telemetry monitoring revealed a left occipital focus for the origin of the electrographic seizure discharge. CVHs occur in a range of organic states, including epilepsy, and can be understood in terms of the underpinning neuroanatomy and neurotransmitter systems of the visual system.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.EPLEPSYRES.2013.02.015
Abstract: Up to 13% of patients with epilepsy have moderate or severe sleep-disordered breathing, in particular obstructive sleep apnea (OSA), a disorder associated with reduced quality of life, worsened seizure control, and increased cardiovascular morbidity and mortality. Combining video-EEG monitoring with polysomnography (VPSG) provides the opportunity to diagnose clinically significant OSA as well as relate the occurrence of seizures and the epilepsy diagnosis to the presence and severity of sleep-disordered breathing. We have established routine VPSG in our inpatient video-EEG monitoring unit and present our findings in 87 patients. Clinically significant sleep-disordered breathing was diagnosed in 19 of 87 (22%) patients. Patients with psychogenic non-epileptic seizures (PNES) had poorer sleep quality compared to patients with epilepsy and those with neither diagnosis, whereas the prevalence of clinically significant sleep-disordered breathing in patients with PNES (29%) did not differ significantly compared to patients with epilepsy (21%) and those with neither diagnosis (22%). The differences in sleep quality are not explained by differences in body mass index (BMI) or anti-epileptic drug (AED) effects.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.NEUROSCIENCE.2017.03.012
Abstract: The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug-resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti-inflammatory effects in the CNS. During acute seizures in rats, PACAP and microglia produce sympathoprotective effect at the intermediolateral cell column (IML), whereas their action on the presympathetic rostral ventrolateral medulla (RVLM) neurons mediates proarrhythmogenic changes. We evaluated the effect of PACAP and microglia at the IML on sympathetic nerve activity (SNA), cardiovascular reflex responses, and electrocardiographic changes in the post-status epilepticus (SE) model of acquired epilepsy, and control rats. Chronic spontaneous seizures in rats produced tachycardia with profound proarrhythmogenic effects (prolongation of QT interval). Antagonism of microglia, but not PACAP, significantly reduced the SNA and the corrected QT interval in post-SE rats. PACAP and microglia antagonists did not change baroreflex and peripheral or central chemoreflex responses with varied effect on somatosympathetic responses in post-SE and control rats. We did not notice changes in microglial morphology or changes in a number of M2 phenotype in epileptic nor control rats in the vicinity of RVLM neurons. Our findings establish that microglial activation, and not PACAP, at the IML accounts for higher SNA and proarrhythmogenic changes during chronic epilepsy in rats. This is the first experimental evidence to support a neurotoxic effect of microglia during chronic epilepsy, in contrast to their neuroprotective action during acute seizures.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2016
DOI: 10.1038/TP.2016.51
Abstract: Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N -methyl- d -aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with erse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI. We hypothesized that antipsychotic-mediated improvement of PPI deficits would be accompanied by a normalization of gamma oscillatory activity. Wistar rats were implanted with extradural electrodes to facilitate recording of electroencephalogram during PPI behavioural testing. In each session, the rats were administered haloperidol (0.25 mg kg −1 ), clozapine (5 mg kg −1 ), olanzapine (5 mg kg −1 ), LY379268 (3 mg kg −1 ), NFPS (sarcosine, 1 mg kg −1 ), d -serine (1800 mg kg −1 ) or vehicle, followed by the NMDAr antagonists MK-801(0.16 mg kg −1 ), ketamine (5 mg kg −1 ) or vehicle. Outcome measures were auditory-evoked, as well as ongoing, gamma oscillations and PPI. Although treatment with all the clinically validated antipsychotic drugs reduced ongoing gamma oscillations, clozapine was the only compound that prevented the sensory-evoked gamma deficit produced by ketamine and MK-801. In addition, clozapine was also the only antipsychotic that attenuated the disruption to PPI produced by the NMDAr antagonists. We conclude that disruptions to evoked, but not ongoing, gamma oscillations caused by NMDAr antagonists are functionally relevant, and suggest that compounds, which restore sensory-evoked gamma oscillations may improve sensory processing in patients with schizophrenia.
Publisher: Wiley
Date: 12-2012
DOI: 10.1111/EPI.12034
Abstract: Synaptic transmission is the communication between a presynaptic and a postsynaptic neuron, and the subsequent processing of the signal. These processes are complex and highly regulated, reflecting their importance in normal brain functioning and homeostasis. Sustaining synaptic transmission depends on the continuing cycle of synaptic vesicle formation, release, and endocytosis, which requires proteins such as dynamin, syndapin, synapsin, and synaptic vesicle protein 2A. Synaptic transmission is regulated by erse mechanisms, including presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors and signaling, and modulators of neurotransmission. Neurotransmitters released presynaptically can bind to their postsynaptic receptors, the inhibitory γ-aminobutyric acid (GABA)ergic receptors or the excitatory glutamate receptors. Once released, glutamate activates a variety of postsynaptic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), kainate, and metabotropic receptors. The activation of the receptors triggers downstream signaling cascades generating a vast array of effects, which can be modulated by a numerous auxiliary regulatory subunits. Moreover, different neuropeptides such as neuropeptide Y, brain-derived neurotrophic factor (BDNF), somatostatin, ghrelin, and galanin, act as regulators of erse synaptic functions and along with the classic neurotransmitters. Abnormalities in the regulation of synaptic transmission play a critical role in the pathogenesis of numerous brain diseases, including epilepsy. This review focuses on the different mechanisms involved in the regulation of synaptic transmission, which may play a role in the pathogenesis of epilepsy: the presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors, and modulators of neurotransmission, including the mechanism by which drugs can modulate the frequency and severity of epileptic seizures.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2005
DOI: 10.1097/01.WNF.0000159955.87511.BC
Abstract: The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the in idual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.NBD.2020.105151
Abstract: A history of mild traumatic brain injury (mTBI) is linked to a number of chronic neurological conditions, however there is still much unknown about the underlying mechanisms. To provide new insights, this study used a clinically relevant model of repeated mTBI in rats to characterize the acute and chronic neuropathological and neurobehavioral consequences of these injuries. Rats were given four sham-injuries or four mTBIs and allocated to 7-day or 3.5-months post-injury recovery groups. Behavioral analysis assessed sensorimotor function, locomotion, anxiety, and spatial memory. Neuropathological analysis included serum quantification of neurofilament light (NfL), mass spectrometry of the hippoc al proteome, and ex vivo magnetic resonance imaging (MRI). Repeated mTBI rats had evidence of acute cognitive deficits and prolonged sensorimotor impairments. Serum NfL was elevated at 7 days post injury, with levels correlating with sensorimotor deficits however, no NfL differences were observed at 3.5 months. Several hippoc al proteins were altered by repeated mTBI, including those associated with energy metabolism, neuroinflammation, and impaired neurogenic capacity. Diffusion MRI analysis at 3.5 months found widespread reductions in white matter integrity. Taken together, these findings provide novel insights into the nature and progression of repeated mTBI neuropathology that may underlie lingering or chronic neurobehavioral deficits.
Publisher: IEEE
Date: 08-2016
Publisher: Springer Science and Business Media LLC
Date: 21-12-2023
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/11772719211053449
Abstract: Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries. Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI n = 11) peripheral injuries (muscle crush + fracture + sham-TBI n = 12) TBI-only (sham-muscle crush + sham-fracture + TBI n = 13) and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer. Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats. Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion).
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.YEBEH.2019.07.003
Abstract: The objective of the study was to identify where epilepsy or seizures may be the underlying cause of death but not identified by the death certification process in the Australian coronial system and to better characterize such deaths. Australian National Coronial Information System (NCIS) closed cases for the Australian Capital Territory (ACT) (population average 348,000) over 13 years were searched using cause of death, and a text search of police and autopsy reports, to identify all deaths where epilepsy or seizures were mentioned. Deaths where the underlying cause of death was not seizures or epilepsy were excluded (including suicide). The remaining cases (75) were categorized by the circumstances of death. Suspected sudden unexpected death in epilepsy (SUDEP) cases were further classified using the unified definition of SUDEP of Nashef and colleagues (2012). Of the final 75 cases, only 44 were found by the cause of death search. Key word document searches found another 31. Cases were classified as Definite SUDEP (37), Definite SUDEP Plus (10), Probable SUDEP (1), Possible SUDEP (3), Near SUDEP (4), Near SUDEP Plus (1), Asphyxia (3), Treatment-related (1), Head injury (2), Drowning (2), motor vehicle accident (MVA) (1), deaths related to a single convulsive seizure (6), and status epilepticus (SE) (4). Cases were 80% male. Epilepsy and seizure-related deaths are underreported in the Australian Coronial system. Enhanced documentation of the causal chain of events leading to deaths would increase recognition. Using the unified SUDEP definition would expand SUDEP identification.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2016
Publisher: Elsevier BV
Date: 09-2014
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.JOCN.2014.02.012
Abstract: Tumour associated epilepsy (TAE) is common, debilitating and often not successfully controlled by surgical resection of the tumour and administration of multiple anti-epileptic drugs. It represents a cause of significant lost quality of life in an incurable disease and is therefore an important subject for ongoing research. The pathogenesis of TAE is likely to be multifactorial and involve, on the microscopic level, the interaction of genetic factors, changes in the peritumoural microenvironment, alterations in synaptic neurotransmitter release and re-uptake, and the excitotoxic effects of glutamate. On a macroscopic level, the occurrence of TAE is likely to be influenced by tumour size, location and interaction with environmental factors. The optimal treatment of TAE requires a multi-disciplinary approach with input from neurosurgeons, neurologists, radiologists, pathologists and basic scientists. This article reviews the current literature regarding the incidence, treatment, and aetiology of TAE.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2016
DOI: 10.1038/SREP28713
Abstract: Repeated mild traumatic brain injuries (mTBI) may lead to serious neurological consequences, especially if re-injury occurs within the period of increased cerebral vulnerability (ICV) triggered by the initial insult. MRI and blood proteomics might provide objective measures of pathophysiological changes in mTBI and indicate when the brain is no longer in a state of ICV. This study assessed behavioral, MRI and blood-based markers in a rat model of mTBI. Rats were given a sham or mild fluid percussion injury (mFPI) and behavioral testing, MRI and blood collections were conducted up to 30 days post-injury. There were cognitive impairments for three days post-mFPI, before normalizing by day 5 post-injury. In contrast, advanced MRI (i.e., tractography) and blood proteomics (i.e., vascular endothelial growth factor) detected a number of abnormalities, some of which were still present 30 days post-mFPI. These findings suggest that MRI and blood proteomics are sensitive measures of the molecular and subtle structural changes following mTBI. Of particular significance, this study identified novel tractography measures that are able to detect mTBI and may be more sensitive than traditional diffusion-tensor measures. Furthermore, the blood and MRI findings may have important implications in understanding ICV and are translatable to the clinical setting.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Oxford University Press (OUP)
Date: 28-07-2004
DOI: 10.1093/BRAIN/AWH257
Publisher: Public Library of Science (PLoS)
Date: 14-08-2015
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.JNEUMETH.2013.06.010
Abstract: Single neuronal juxtacellular recording with simultaneous cortical electroencephalogram (EEG) in whole-animal preparations in vivo has allowed the study of the behaviour of in idual neurons in relation to whole brain activity. Data on single neuron firing, neural synchrony, network behaviour and their responses to pharmacological agents can be obtained with dual recordings. However, pharmacological effects on cellular and network activity during paired single-unit recordings have not been possible due to the difficulties in maintaining recordings of two cells for a prolonged period. Here, we describe a method of maintaining stable dual cell juxtacellular recordings from distinct brain regions, allowing the assessment of single unit activity before, during and after the intracerebroventricular (ICV) injection of drugs. Data collection using this technique allows correlation both between the two cells and with whole-brain EEG, and their responses to pharmacological interventions. This is particularly useful for the investigation of the effects of anti-epileptic drugs on animal models of epilepsy, where single unit activity of two cells from distinct regions can be correlated with each other and with whole-brain activity during pre-ictal, ictal and interictal states. We also describe standardised analytical methods of quantifying cell firing patterns, the rhythmicity of in idual neurons and the synchronicity of firing between two neurons in ictal and interictal periods and their responses to drug exposure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-08-2015
Publisher: SAGE Publications
Date: 2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1998
DOI: 10.1097/00004691-199811000-00008
Abstract: Previous descriptions of the subclinical rhythmic electrographic discharges of adults (SREDA) have been based entirely on visual analysis of analog electroencephalographic (EEG) recordings. The introduction of digital electroencephalograms (EEGs) and advances in digital signal processing provide an opportunity to restudy in more depth the nature of SREDA. We identified nine patients who had SREDA diagnosed on a routine EEG recording since the introduction of digital EEG to our laboratory in August 1995. Following careful rereview using standard montages, six of these patients were determined to fulfill the traditional requirements for the diagnosis of SREDA, whereas three were believed to have other benign discharges. Review with Laplacian montages demonstrated that the site of the SREDA activity was maximal in the parietal region or parietocentrotemporal regions, whereas it was maximal in the temporal or frontotemporal regions in the non-SREDA discharges. Frequency analysis, using both the conventional fast Fourier transform (FFT) and time-frequency mapping with the Wigner FFT variant, demonstrated that the SREDA consisted of a complex mixture of multiple rapidly shifting frequencies which showed little spatial and temporal correlation. In contrast, the non-SREDA all consisted of a single dominant well-organized rhythmic frequency spectrum that remained stable throughout space and time.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 10-2019
Publisher: SAGE Publications
Date: 10-2020
Abstract: Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood–brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2015
DOI: 10.1038/NRNEUROL.2014.255
Abstract: In 2014, novel, large-scale collaborative efforts and frameworks resulted in major advances in the epilepsy field, from publication of a new definition of epilepsy to important discoveries regarding aetiology, pathophysiology and management. These collaborative works provide a platform from which further advances are anticipated, and a model for future research.
Publisher: Wiley
Date: 08-2013
DOI: 10.1111/EPI.12293
Publisher: Proceedings of the National Academy of Sciences
Date: 06-03-2007
Abstract: Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor ( Drd1a )+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P , and dynorphin expression is progressively lost, whereas D2 dopamine receptor ( Drd2 ) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippoc al dentate gyrus. This study specifically implicates Drd1a + cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2018
DOI: 10.1038/S41598-018-36257-8
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Publisher: Wiley
Date: 11-08-2023
DOI: 10.1111/EPI.17735
Abstract: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild‐to‐moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ‐aminobutyric acid transporter‐1, and to test its seizure suppression effects in a rat model of chronic MTLE. We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood s ling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid‐induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video‐electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. Plasma levels following continuous infusion of E2730 showed a clear dose‐related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose‐dependent manner, with 65% of rats becoming seizure‐free at the highest dose tested. Mean seizure class did not differ between the treatment groups. This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose‐dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 29-10-2015
DOI: 10.1111/EPI.13136
Abstract: To investigate cross-sectional and longitudinal differences in static and dynamic standing balance measures and lower limb muscle strength in patients who are treated chronically with antiepileptic drugs (AEDs). Twenty-six AED exposure-discordant same-gender twin and sibling pairs were studied. Clinical and laboratory balance examinations were conducted twice, separated by at least 1 year. The mean within-pair differences in balance measures were calculated cross-sectionally at baseline and follow-up, and longitudinally. No significant mean within-pair difference was found at baseline in age (44 years), weight, and height (p > 0.05). Between study assessments, the median (interquartile range [IQR]) interval was 3.0 (2.1-4.3) years in users and 2.9 (2.0-4.4) years in nonusers. The median duration of AED therapy was 19 (11-21) years. At baseline and follow-up, cross-sectional sway measures from posturography (Chattecx Balance System) and clinical static balance tests showed poorer performance in users compared to nonusers on several test conditions (p = 0.002-0.032). At follow-up, the users took longer than nonusers to complete the Four-Square-Step Test (p = 0.005) and Five-Times-Sit-to-Stand Test (p = 0.018). A greater annual rate of deterioration in sway was found in users compared to nonusers using posturography on the anteroposterior tilting platform task with distraction (p = 0.032). In both groups, higher baseline sway predicted greater annual deterioration in sway in all platform conditions (β = 0.3-0.5, p < 0.001-0.013). The annual change in measures did not differ between groups in the clinical balance and lower limb strength assessments. In this longitudinal twin and sibling study, chronic AED users had poorer standing balance compared to nonusers. Users showed greater deterioration in postural sway with one dynamic platform condition. AEDs may progressively impair balance mechanisms, although this requires further investigations. Repeated dynamic posturography could provide a basis for preventive trials for maintaining or improving balance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-11-2000
Abstract: The authors retrospectively examined the role of SPECT in 65 children undergoing video-EEG telemetry. SPECT was concordant in most children whose lesions were already localized by MRI and epilepsy syndrome and provided localizing data in more than half not localized by these modalities. Ictal SPECT provided no additional prognostic benefit in patients undergoing epilepsy surgery (n = 23) who have a localized MRI lesion. In patients without lesions, however, ictal SPECT provides useful additional localization that may be used as a guide to intracranial implantation.
Publisher: Elsevier BV
Date: 2018
Publisher: Royal College of Psychiatrists
Date: 06-2008
DOI: 10.1192/BJP.BP.107.046664
Abstract: Previous work has identified elevated prevalence rates for psychiatric disorders in in iduals with medically refractory focal epilepsy, particularly temporal lobe epilepsy. Many studies were undertaken before the advent of video electroencephalogram monitoring (VEM) and magnetic resonance imaging (MRI). To investigate which characteristics of the focal epilepsy syndromes are associated with the presence of depression or psychosis. Three hundred and nineteen in iduals with focal epilepsy admitted for VEM were seen over an 11-year period. The lifetime history of depression and psychosis, epileptic site, laterality and type of lesion were determined by clinical assessment, VEM and MRI scan. There was a significant association between the prevalence of depressive symptoms and non-lesional focal epilepsy. There were no significant differences in prevalence of neuropsychiatric disorders between the groups with temporal lobe epilepsy and those with extratemporal lobe epilepsy. These findings contrast with previous findings in smaller cohorts. The association between non-lesional focal epilepsy and depression may be due to the effects of a more diffuse epileptogenic area.
Publisher: IEEE
Date: 08-2016
Publisher: Elsevier BV
Date: 12-2018
Publisher: Oxford University Press (OUP)
Date: 22-06-2020
Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All s les were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JOCD.2016.07.008
Abstract: Antiepileptic drug (AED) therapy is associated with decreased bone mineral density however, the time course for this development is unclear. The aim of this study was to evaluate bone mineral changes during the initial years of AED therapy in AED-naive, newly diagnosed epilepsy patients compared with non-AED users. In 49 epilepsy patients newly started on AEDs and in 53 non-AED users of both genders, bone mineral density (BMD) and bone mineral content were measured using dual-energy X-ray absorptiometry at baseline (within the first year of therapy) and at least 1 yr later. Bone changes between the 2 assessments, adjusted for age, height, and weight, were calculated as the annual rate of change. The median duration of AED therapy was 3.5 mo at baseline and 27.6 mo at follow-up. No overall difference was found in mean BMD and bone mineral content measures between user and nonuser cohorts in both cross-sectional baseline and the annual rate of change (p > 0.05). However, users on carbamazepine monotherapy (n = 11) had an increased annual rate of total hip (-2.1% vs -0.8%, p = 0.020) and femoral neck BMD loss (-2.1% vs -0.6%, p = 0.032) compared to nonusers. They also had a marginally higher rate of femoral neck BMD loss (-2.1%, p = 0.049) compared with valproate (-0.1%, n = 13) and levetiracetam users (+0.6%, n = 13). During the initial years of AED treatment for epilepsy, no difference was found in bone measures between AED users as a group and nonuser cohorts. However, the data suggested that carbamazepine monotherapy was associated with increased bone loss at the hip regions, compared to users of levetiracetam or valproate and nonusers. Larger studies of longer duration are warranted to better delineate the bone effects of specific AEDs, with further consideration of the role of early dual-energy X-ray absorptiometry scanning and careful AED selection in potentially minimizing the impact on bone health in these patients.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.NEUROIMAGE.2008.12.019
Abstract: Imaging studies of epilepsy patients with comorbid affective disturbance demonstrate morphometric changes in limbic brain regions implicated in psychiatric disease. Genetic Absence Epilepsy Rats from Strasbourg (GAERS), specifically bred for their epilepsy phenotype, also exhibit elevated anxiety-like behaviors suggesting a common causality. Here we examined whether relevant cerebral morphological alterations exist in this rat strain using volumetric measurements and large deformation high dimensional mapping (HDM-LD), a tool recently validated to produce accurate three-dimensional surface representations of the hippoc us. Volumetric MRI and the Open Field test of anxiety were performed in adult female GAERS (n=12) and Non-Epileptic Controls (NEC n=11). The volumes of selected brain regions, including cortex, hippoc us, amygdala, thalamus, hypothalamus and lateral ventricles, were measured using Region-Of-Interest analysis from the MRI data and total volumes compared between the two strains. GAERS had increased amygdala (right: p=0.003 left p<0.001), cortices (right: p=0.006 left p=0.012) and ventricular volumes (p=0.002) when compared with NEC rats. Further, HDM-LD showed GAERS to have hippoc al volume loss in two regions: the medial hippoc al surface immediately caudal to the hippoc al commissure, and the lateral hippoc al surface over the mid-portion of the septotemporal axis. GAERS exhibited increased anxiety in the Open Field compared with NEC rats: reduced distance traveled (p<0.001) and reduced time in the centre area (p=0.042). Morphometric brain changes in GAERS could be relevant to their hyperanxious and epileptic phenotypes. This model may be useful in illuminating the pathogenesis of affective disorders generally, as well as modeling psychiatric comorbidities of epilepsy.
Publisher: IEEE
Date: 07-2018
Publisher: Elsevier BV
Date: 07-1999
Publisher: Elsevier BV
Date: 05-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-12-2005
DOI: 10.1212/01.WNL.0000195888.51845.80
Abstract: To analyze seizure control and treatment in pregnant women with epilepsy. Seizure control and treatment were recorded prospectively in 1,956 pregnancies of 1,882 women with epilepsy participating in EURAP, an international antiepileptic drugs (AEDs) and pregnancy registry. Of all cases, 58.3% were seizure-free throughout pregnancy. Occurrence of any seizures was associated with localization-related epilepsy (OR: 2.5 1.7 to 3.9) and polytherapy (OR: 9.0 5.6 to 14.8) and for tonic-clonic seizures, with oxcarbazepine monotherapy (OR: 5.4 1.6 to 17.1). Using first trimester as reference, seizure control remained unchanged throughout pregnancy in 63.6%, 92.7% of whom were seizure-free during the entire pregnancy. For those with a change in seizure frequency, 17.3% had an increase and 15.9% a decrease. Seizures occurred during delivery in 60 pregnancies (3.5%), more commonly in women with seizures during pregnancy (OR: 4.8 2.3 to 10.0). There were 36 cases of status epilepticus (12 convulsive), which resulted in stillbirth in one case but no cases of miscarriage or maternal mortality. AED treatment remained unchanged in 62.7% of the pregnancies. The number or dosage of AEDs were more often increased in pregnancies with seizures (OR: 3.6 2.8 to 4.7) and with monotherapy with lamotrigine (OR: 3.8 2.1 to 6.9) or oxcarbazepine (OR: 3.7 1.1 to 12.9). The majority of patients with epilepsy maintain seizure control during pregnancy. The apparently higher risk of seizures among women treated with oxcarbazepine and the more frequent increases in drug load in the oxcarbazepine and lamotrigine cohorts prompts further studies on relationships with pharmacokinetic changes. Risks associated with status epilepticus appear to be lower than previously reported.
Publisher: Wiley
Date: 21-07-2016
DOI: 10.1111/EPI.13474
Abstract: Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage-gated sodium (NaV ) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels. Immunocytochemistry was performed on primary calvarial osteoblasts extracted from neonatal C57BL/6J mice and additional RNA sequencing (RNASeq) was included to confirm expression of NaV . Whole-cell patch-cl recordings were made to identify the native currents expressed and to assess the actions of carbamazepine (50 μm) or phenytoin (50 μm). NaV expression was demonstrated with immunocytochemistry, RNA sequencing, and functionally, with demonstration of robust tetrodotoxin-sensitive and voltage-activated inward currents. Application of carbamazepine or phenytoin resulted in significant inhibition of current litude for carbamazepine (31.6 ± 5.9%, n = 9 p < 0.001), and for phenytoin (35.5 ± 6.9%, n = 7 p < 0.001). Mouse osteoblasts express NaV , and native NaV currents are blocked by carbamazepine and phenytoin, supporting our hypothesis that AEDs can directly influence osteoblast function and potentially affect bone strength.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.ORCP.2006.11.001
Abstract: Validation of dual-energy X-ray absorptiometry (DXA) with the Hologic QDR 4500A (QDR 4500) Fan Beam X-ray densitometer for in vivo assessment of body fat content in mice. Precision of DXA fat measurement was assessed by repeated in vivo scanning and re-positioning of different sized mice (17.6, 24.6, 34.2 g). DXA fat and total mass measurements were correlated with dissected tissue weights in 240 female adult mice of seven strains (mean weights 21.9-26.8 g). Accuracy of DXA fat tissue measurements was assessed by chemical analysis in a subgroup of 40 female decapitated mice (mean weights 19.6-28.4 g). Precision of the DXA measurements for fat mass was dependent on body weight (mean coefficient of variation, CV, 34.2 g mouse: 7.53 ± 0.13% 24.6 g mouse: 32.16 ± 0.17% 17.6 g mouse: 40.64 ± 0.06%). A moderate to high correlation with the dissected fat tissue weights was found for all seven strains: r = 0.52, p ≤ 0.01 (AJ) to r = 0.83, p ≤ 0.01 (CBA, both mean weight = 22 g). The correlation of DXA measurements with the chemical analysis of the carcass was good to excellent (r = 0.80, p ≤ 0.01). The results demonstrate that the QDR 4500A DXA can be utilised for in vivo measurements of fat content in mice weighing as little as 20 g, with excellent correlations between tissue dissections and chemical analysis demonstrating high consistency of the measurements. DXA values were consistently slightly lower than those by direct chemical analysis however, the limits of agreement (mean difference 0.96 g) demonstrated good concordance between the two methods.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.YEBEH.2011.02.025
Abstract: Cognitive impairment is not uncommon in patients with epilepsy, and may relate to the underlying pathophysiology of epilepsy, the effects of seizures, or epilepsy treatment. Formal neuropsychological testing is not available in many centers, and few cognitive screening tools have been validated in an epilepsy population. We aimed to ascertain the reliability and validity of a multidimensional cognitive screening instrument, the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), in a mixed epilepsy population. One hundred sixty-one of 177 consecutive patients admitted to a video telemetry unit were assessed with the NUCOG and classified with respect to seizure semiology, and a subset (n=33) were formally neuropsychologically assessed. Scores did not differ between patients with epileptiform, those with nonepileptiform, and those with mixed EEGs on the NUCOG, nor between patients with focal and those with generalized epilepsies. Patients with a temporal lobe focus performed more poorly in general, and in memory specifically, than patients with an extratemporal focus. Scores on the NUCOG subscales Memory, Attention, and Executive Functioning correlated significantly with neuropsychological testing of these same domains, although patients were not impaired on measures of language or spatial function. The NUCOG appears to correlate strongly with neuropsychological functioning in a number of key cognitive areas affected in patients with epilepsy, and appears to robustly detect memory impairment in patients with temporal lobe epilepsy.
Publisher: Wiley
Date: 14-06-2018
DOI: 10.1111/EPI.14436
Abstract: There is little detailed phenotypic characterization of bilateral hippoc al sclerosis (HS). We therefore conducted a multicenter review of people with pharmacoresistant epilepsy and bilateral HS to better determine their clinical characteristics. Databases from 11 EPIGEN centers were searched. For identified cases, clinicians reviewed the medical notes, imaging, and electroencephalographic (EEG), video-EEG, and neuropsychometric data. Data were irretrievably anonymized, and a single database was populated to capture all phenotypic information. These data were compared with phenotyped cases of unilateral HS from the same centers. In total, 96 patients with pharmacoresistant epilepsy and bilateral HS were identified (43 female, 53 male age range = 8-80 years). Twenty-five percent had experienced febrile convulsions, and 27% of patients had experienced status epilepticus. The mean number of previously tried antiepileptic drugs was 5.32, and the average number of currently prescribed medications was 2.99 44.8% of patients had cognitive difficulties, and 47.9% had psychiatric comorbidity 35.4% (34/96) of patients continued with long-term medical therapy alone, another 4 being seizure-free on medication. Sixteen patients proceeded to, or were awaiting, neurostimulation, and 11 underwent surgical resection. One patient was rendered seizure-free postresection, with an improvement in seizures for 3 other cases. By comparison, of 201 patients with unilateral HS, a significantly higher number (44.3%) had febrile convulsions and only 11.4% had experienced status epilepticus. Importantly, 41.8% (84/201) of patients with unilateral HS had focal aware seizures, whereas such seizures were less frequently observed in people with bilateral HS, and were never observed exclusively (P = .002 Fisher's exact test). The current work describes the phenotypic spectrum of people with pharmacoresistant epilepsy and bilateral HS, highlights salient clinical differences from patients with unilateral HS, and provides a large platform from which to develop further studies, both epidemiological and genomic, to better understand etiopathogenesis and optimal treatment regimes in this condition.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.NBD.2022.105863
Abstract: Malformations of cortical development (MCDs) are common causes of drug-resistant epilepsy. The mechanisms underlying the associated epileptogenesis and ictogenesis remain poorly elucidated. EEG can help in understanding these mechanisms. We systematically reviewed studies reporting scalp or intracranial EEG features of MCDs to characterise interictal and seizure-onset EEG patterns across different MCD types. We conducted a systematic review in accordance with PRISMA guidelines. MEDLINE, PubMed, and Cochrane databases were searched for studies describing interictal and seizure-onset EEG patterns in MCD patients. A classification framework was implemented to group EEG features into 20 predefined patterns, comprising nine interictal (five, scalp EEG four, intracranial EEG) and 11 seizure-onset (five, scalp EEG six, intracranial EEG) patterns. Logistic regression was used to estimate the odds ratios (OR) of each seizure-onset pattern being associated with specific MCD types. Our search yielded 1682 studies, of which 27 comprising 936 MCD patients were included. Of the nine interictal EEG patterns, five (three, scalp EEG two, intracranial EEG) were detected in ≥2 MCD types, while four (rhythmic epileptiform discharges type 1 and type 2 on scalp EEG repetitive bursting spikes and sporadic spikes on intracranial EEG) were seen only in focal cortical dysplasia (FCD). Of the 11 seizure-onset patterns, eight (three, scalp EEG five, intracranial EEG) were found in ≥2 MCD types, whereas three were observed only in FCD (suppression on scalp EEG delta brush on intracranial EEG) or tuberous sclerosis complex (TSC focal fast wave on scalp EEG). Among scalp EEG seizure-onset patterns, paroxysmal fast activity (OR = 0.13 95% CI: 0.03-0.53 p = 0.024) and repetitive epileptiform discharges (OR = 0.18 95% CI: 0.05-0.61 p = 0.036) were less likely to occur in TSC than FCD. Among intracranial EEG seizure-onset patterns, low-voltage fast activity was more likely to be detected in heterotopia (OR = 19.3 95% CI: 6.22-60.1 p 0.001), polymicrogyria (OR = 6.70 95% CI: 2.25-20.0 p = 0.004) and TSC (OR = 4.27 95% CI: 1.88-9.70 p = 0.005) than FCD. Different MCD types can share similar interictal or seizure-onset EEG patterns, reflecting common underlying biological mechanisms. However, selected EEG patterns appear to point to distinct MCD types, suggesting certain differences in their neuronal networks.
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/EPI.16854
Abstract: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene‐level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion‐deletion (indel) variants, and copy number variants present in leukocyte‐derived DNA. Across the cohort of 86 in iduals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2 , including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome‐wide threshold of significance in the gene‐level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2 , we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62 , all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy‐associated and neurodevelopmental disease‐associated genes ( SCN2A in two in iduals, GRIA3 , CACNA1C ) and a 597‐kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio‐based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A , GRIA3 , CACNA1C , and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
Publisher: Public Library of Science (PLoS)
Date: 29-12-2020
DOI: 10.1371/JOURNAL.PONE.0244491
Abstract: The default mode network (DMN) is the main large-scale network of the resting brain and the PCC recuneus is a major hub of this network. Glutamate and GABA (γ-amino butyric acid) are the main excitatory and inhibitory neurotransmitters in the CNS, respectively. We studied glutamate and GABA concentrations in the PCC recuneus via magnetic resonance spectroscopy (MRS) at 7T in relation to age and correlated them with functional connectivity between this region and other DMN nodes in ten healthy right-handed volunteers ranging in age between 23–68 years. Mean functional connectivity of the PCC recuneus to the other DMN nodes and the glutamate/GABA ratio significantly correlated with age ( r = 0.802, p = 0.005 and r = 0.793, p = 0.006, respectively) but not with each other. Glutamate and GABA alone did not significantly correlate with age nor with functional connectivity within the DMN. The glutamate/GABA ratio and functional connectivity of the PCC recuneus are, therefore, independent age-related biomarkers of the DMN and may be combined in a multimodal pipeline to study DMN alterations in various disease states.
Publisher: Oxford University Press (OUP)
Date: 25-07-2014
DOI: 10.1093/BRAIN/AWU206
Publisher: Wiley
Date: 28-10-2020
DOI: 10.1111/EPI.16731
Publisher: Wiley
Date: 06-2018
DOI: 10.1111/EPI.14435
Abstract: Patients with epilepsy often have mood disorders, and these are commonly treated with antidepressant drugs. Although these drugs are often successful in mitigating depressive symptoms, how they affect the epileptogenic processes has been little studied. Recent evidence has demonstrated that treatment with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs adversely promotes epileptogenesis, which may be of great concern considering the number of patients exposed to these drugs. This study investigated 5-HT
Publisher: BMJ
Date: 20-09-2019
Abstract: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippoc us are aetiologically important. Despite decades of investigation, it is unclear whether hippoc al volume is reduced in POE, perhaps due to small s le sizes and methodological limitations of past research. In this study, we examined the volume of the total hippoc us, and the hippoc al head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippoc al volumes were manually traced and compared between (1) POE and EC (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). Compared with EC the POE group had smaller total left hippoc us volume (13.5% decrease, p .001), and smaller left hippoc al body (13.3% decrease, p=0.002), and left (41.5% decrease, p .001) and right (36.4% decrease, p .001) hippoc al tail volumes. Hippoc al head volumes did not differ between groups. Posterior hippoc al volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippoc al head. Posterior hippoc al atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippoc al atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.
Publisher: American Chemical Society (ACS)
Date: 18-09-2019
DOI: 10.1021/ACSCHEMNEURO.9B00460
Abstract: Emerging findings point toward an important interconnection between epilepsy and Alzheimer's disease (AD) pathogenesis. Patients with epilepsy (PWE) commonly exhibit cognitive impairment similar to AD patients, who in turn are at a higher risk of developing epilepsy compared to age-matched controls. To date, no disease-modifying treatment strategy is available for either epilepsy or AD, reflecting an immediate need for exploring common molecular targets, which can delineate a possible mechanistic link between epilepsy and AD. This review attempts to disentangle the interconnectivity between epilepsy and AD pathogenesis via the crucial contribution of Tau protein. Tau protein is a microtubule-associated protein (MAP) that has been implicated in the pathophysiology of both epilepsy and AD. Hyperphosphorylation of Tau contributes to the different forms of human epilepsy and inhibition of the same exerted seizure inhibitions and altered disease progression in a range of animal models. Moreover, Tau-protein-mediated therapy has demonstrated promising outcomes in experimental models of AD. In this review, we discuss how Tau-related mechanisms might present a link between the cause of seizures in epilepsy and cognitive disruption in AD. Untangling this interconnection might be instrumental in designing novel therapies that can minimize epileptic seizures and cognitive deficits in patients with epilepsy and AD.
Publisher: Society for Neuroscience
Date: 19-07-2017
Publisher: Springer Science and Business Media LLC
Date: 29-09-2016
DOI: 10.1038/SREP34491
Abstract: Concomitant traumatic brain injury (TBI) and long bone fracture are commonly observed in multitrauma and polytrauma. Despite clinical observations of enhanced bone healing in patients with TBI, the relationship between TBI and fracture healing remains poorly understood, with clinical data limited by the presence of several confounding variables. Here we developed a novel trauma model featuring closed-skull weight-drop TBI and concomitant tibial fracture in order to investigate the effect of TBI on fracture healing. Male mice were assigned into Fracture + Sham TBI (FX) or Fracture + TBI (MULTI) groups and sacrificed at 21 and 35 days post-injury for analysis of healing fractures by micro computed tomography (μCT) and histomorphometry. μCT analysis revealed calluses from MULTI mice had a greater bone and total tissue volume and displayed higher mean polar moment of inertia when compared to calluses from FX mice at 21 days post-injury. Histomorphometric results demonstrated an increased amount of trabecular bone in MULTI calluses at 21 days post-injury. These findings indicate that closed head TBI results in calluses that are larger in size and have an increased bone volume, which is consistent with the notion that TBI induces the formation of a more robust callus.
Publisher: American Medical Association (AMA)
Date: 05-2013
Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.PSYNEUEN.2007.05.011
Abstract: We have previously demonstrated that low-dose corticosterone (CS) administration, used as a model of the effect of chronic stress, accelerates epileptogenesis in the electrical amygdala kindling rat model of temporal lobe epilepsy (TLE). This current study examined the relative contributions to this effect of mineralocorticoid (MR) and glucocorticoid (GR) subtypes of glucocorticoid receptors. Female non-epileptic wistar rats 10-13 weeks of age were implanted with a bipolar electrode into the left amygdala. Five treatment groups were subjected to rapid amygdala kindling: water-control (n=9), CS treated (6 mg/100 ml added to drinking water n=9), CS+spironolactone (MR antagonist, 50 mg/kg sc n=9), CS+mifepristone (GR antagonist, 25 mg/kg sc n=9), and CS+both antagonists (n=7). Rats were injected with vehicle or the relevant antagonist twice daily for the entire kindling period. Experimental groups differed significantly in the number of stimulations required to reach the 'fully kindled state' (Racine, 1972) ANOVA, F(4,38)=2.73, p=0.04). Amygdala kindling was accelerated in the CS-treated group compared with water controls (mean stimulations for full kindling: 45.2 vs. 86.5, p<0.01). This acceleration was inhibited by both the MR and GR antagonist treatments (mean stimulations: 69.6 and 70.4, p=0.04 and 0.04 vs. CS group, respectively), with the kindling rates in these groups not significantly different from water-treated subjects (p=0.26 and 0.29, respectively). The kindling rates in the MR and GR antagonist treatment groups did not significantly differ from each other (p=0.93), nor from the combined treatment group (mean stimulations: 62.8, p=0.59 and 0.54, respectively). This study demonstrates that activation of both high-affinity (MR) and low-affinity (GR) glucocorticoid receptors are involved in mediating CS-induced acceleration of amygdala kindling epileptogenesis.
Publisher: Wiley
Date: 06-2010
DOI: 10.1111/J.1528-1167.2009.02430.X
Abstract: To assess the outcomes from temporal lobectomy for hippoc al sclerosis in patients 50 years or older. Controversy exists as to the suitability of older patients for epilepsy surgery, with most of the previous studies demonstrating a correlation between increasing age and poor outcome. However, the inclusion of temporal lobe epilepsy of multiple etiologies has confounded many previous studies of this age group. Twenty-one patients aged 50 years or older (mean 54.9 years) at the time of surgery were included in the study group. All patients had a pathologic diagnosis of hippoc al sclerosis. A retrospective analysis was performed comparing seizure outcomes following a standardized anterior temporal lobectomy with those from 103 patients younger than 50 (mean age 34.7 years) operated upon over the same time period. The mean follow-up period for the study was 9.57 years. Twenty of the 21 patients in the older group (95.2%) had a satisfactory seizure outcome (Engel classes I and II) compared with 90.3% of the younger patients. There was no statistically significant difference in the outcomes between the two groups (p = 0.719). Across both groups of patients combined, there was no significant difference between the mean age in the patients with a satisfactory seizure outcome compared to those with an unsatisfactory outcome (38.3 vs. 34.7 years, p = 0.213). Patients 50 years or older with intractable seizures from hippoc al sclerosis have seizure outcomes following temporal lobectomy that are comparable to young patients over the long term. Older patients should not be denied treatment on the basis of age.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2005
Abstract: Mesial temporal lobe epilepsy (MTLE) is associated with high rates of depression and anxiety. A bidirectional causal relationship has been suggested, with these psychiatric comorbidities themselves enhancing epileptogenesis, possibly via hypercortisolemia. We examined the effects on epileptogenesis of chronic supplementation with low-dose corticosterone (CS) in the electrical amygdala kindling rat model. Adult Wistar rats were ovariectomized and implanted with bipolar electrodes into the left amygdala. After 1 week recovery, one group (n=7) had CS (3 mg/100 ml--approx. 4.5 mg/kg/day) and a control group saline (n=7) added to their drinking water, and both groups underwent twice daily electrical stimulations. Rats were culled 2 weeks after reaching the fully kindled state. A stereological optical fractionator technique was used to estimate the number of CA1 pyramidal cells in the hippoc us ipsilateral to the stimulations. Fewer stimulations were required in the CS-supplemented rats than in controls to reach the fully kindled state (32 vs 81, p<0.03, Student's t-test) and the first Class V seizure (14 vs 57, p<0.05). The mean after-discharge length was greater in the CS group (p=0.03, repeated measures analysis of variance). There was no difference in the mean number of CA1 neurons (1.05 x 10(5) vs 1.04 x 10(5), p=0.98). These data demonstrate that low-dose CS enhances epileptogenesis in this model of MTLE. This provides support for the hypothesis that chronic hypercortisolemia, as a result of stress, anxiety, and/or depression, may facilitate the development and progression of epilepsy in patients with MTLE. The lack of difference in hippoc al CA1 neurons indicates that the mechanism does not primarily involve pyramidal cell loss.
Publisher: Oxford University Press (OUP)
Date: 06-09-2013
DOI: 10.1093/BRAIN/AWT233
Publisher: Springer Science and Business Media LLC
Date: 16-06-2016
DOI: 10.1007/S11060-016-2169-Y
Abstract: To examine the impact of glutamate on post-operative seizures and survival in a cohort of patients with grade II to IV supratentorial glioma. A retrospective analysis was performed on 216 patients who underwent surgery for supratentorial gliomas. Primary explanatory variables were peritumoural and/or tumoural glutamate concentrations, glutamate transporter expression (EAAT2 and SXC). Univariate and multivariate survival analysis was performed with primary outcomes of time to first post-operative seizure and overall survival. Subgroup analysis was performed in patients with de novo glioblastomas who received adjuvant chemoradiotherapy. 47 (21.8 %), 34 (15.8 %) and 135 (62.5 %) WHO grade II, III and IV gliomas respectively were followed for a median of 15.8 months. Following multivariate analysis, there was a non-significant association between higher peritumoural glutamate concentrations and time to first post-operative seizure (HR 2.07, CI 0.98-4.37, p = 0.06). In subgroup analysis of 81 glioblastoma patients who received adjunct chemoradiotherapy, peritumoural glutamate concentration was significantly associated with time to first post-operative seizure (HR 3.10, CI 1.20-7.97, p = 0.02). In both the overall cohort and subgroup analysis no glutamate cycle biomarkers were predictive of overall survival. Increased concentrations of peritumoural glutamate were significantly associated with shorter periods of post-operative seizure freedom in patients with de novo glioblastomas treated with adjuvant chemoradiotherapy. No glutamate cycle biomarkers were predictive of overall survival. These results suggest that therapies targeting glutamate may be beneficial in tumour associated epilepsy.
Publisher: Wiley
Date: 02-2007
DOI: 10.1111/J.1460-9568.2007.05348.X
Abstract: Neuropeptide Y (NPY) potently suppresses absence seizures in a model of genetic generalized epilepsy, genetic absence epilepsy rats of Strasbourg (GAERS). Here we investigated the Y-receptor subtype(s) on which NPY exerts this anti-absence effect. A dual in vivo approach was used: the cumulative duration of seizures was quantified in adult male GAERS in 90-min electroencephalogram recordings following intracerebroventricular (i.c.v.) injection of: (i) subtype-selective agonists of Y1 ([Leu31Pro34]NPY, 2.5 nmol), Y2 (Ac[Leu(28,31)]NPY24-36, 3 nmol), Y5 receptors [hPP1(-17),Ala31,Aib32]NPY, 4 nmol), NPY (3 nmol) or vehicle and following (ii) i.c.v. injection of antagonists of Y1 (BIBP3226, 20 nmol), Y2 (BIIE0246, 20 nmol) and Y5 (NPY5RA972, 20 nmol) receptors or vehicle, followed by NPY (3 nmol). Injection of the Y1- and Y5-selective agonists resulted in significantly less mean seizure suppression (37.4% and 53.9%, respectively) than NPY (83.2% P < 0.05), while the Y2 agonist had similar effects to NPY (62.3% suppression, P = 0.57). Food intake was not increased following injection of the Y2 agonist, while significant increases in food intake were seen following NPY and the other Y-subtype agonists. Compared with vehicle, NPY injection suppressed seizures following the Y1 and Y5 antagonists (45.3% and 80.1%, respectively, P < 0.05), but not following the Y2 antagonist (5.1% suppression, P = 0.46). We conclude that NPY Y2 receptors are more important than Y1 and Y5 receptors in mediating the effect of NPY to suppress absence seizures in a genetic rat model. Y2 receptor agonists may represent targets for novel drugs against genetic generalized epilepsies without resulting in appetite stimulation.
Publisher: IEEE
Date: 04-2015
Publisher: Elsevier BV
Date: 06-2000
DOI: 10.4065/75.6.615
Abstract: Peri-ictal single-photon emission computed tomography (SPECT) of the brain is increasingly used in localizing the seizure focus in presurgical evaluation of patients with partial epilepsy. However, traditional side-by-side visual interpretation of ictal and interictal SPECT films is h ered by differences in slice location and tracer activity. Precise correlation of the seizure focus with a high-quality image of the underlying brain anatomy can improve the physician's understanding of seizure neurophysiology and assist in surgical planning. Computer-based methods have been developed for aligning, normalizing, and subtracting digital ictal and interictal SPECT images of the patient's brain to produce a map of the blood flow changes occurring between the seizure and resting states. These maps are then aligned with a high-resolution magnetic resonance image (MRI) of the patient's brain anatomy and fused to identify anatomical regions involved in the seizure. The purpose of this article is to review the technical components and clinical implementation of subtraction ictal SPECT, as well as to discuss recent technological advances that could extend and improve the diagnostic and localizing capacity of this method.
Publisher: Wiley
Date: 06-12-2013
DOI: 10.1111/EJN.12441
Abstract: A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)-thalamocortical (TC) network, more specifically on CT 5-9-Hz and TC spindle (10-16-Hz) oscillations. Two to three successive 5-9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5-9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5-9-Hz depolarizing wave-hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately -70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5-9-Hz waves can trigger TC spindles.
Publisher: Wiley
Date: 20-06-2018
DOI: 10.1111/EPI.14451
Abstract: Neuropeptide Y (NPY) potently suppresses spike-wave discharges (SWDs) in a genetic rat model of absence epilepsy (GAERS), but the underlying neurophysiologic mechanisms are not clear. We therefore sought to determine the in vivo effects of NPY on neuronal firing in the cortico-thalamo-cortical network activity, known to play a critical role in the generation of SWDs in these rats. NPY was administered intracerebroventricularly (ICV) or in separate experiments locally on the neurons of caudal thalamic reticular nucleus (NRT) by use of juxtacellular iontophoresis in triple-barrel electrodes in male GAERS aged 12-15 weeks, in vivo under neuroleptic anesthesia. Drug infusions and electroencephalography (EEG) monitoring were performed simultaneously with juxtacellular single neuronal recordings. Effect of NPY on electrically induced SWD induction threshold were also measured. NPY administration ICV led to a decrease in the total length of SWDs in EEG recordings. Both ICV administration and iontophoresis of NPY on NRT neurons led to an increase in interictal neuronal firing of NRT neurons. During ictal periods, ICV NPY administration reduced the number of thalamic action potentials per SWDs, as well as reduced waveform correlations between field potentials within the NRT and the cortical EEG. NPY administration ICV did not significantly alter the firing patterns of relay thalamic neurons interictally and cortical neurons during ictal and interictal periods. In addition, SWD induction threshold in the S2 region of the cortex was significantly increased after NPY administration. Our results show alterations in cortico-thalamo-cortical local and network properties following ICV administration of NPY, suggesting mechanisms of SWD suppression in GAERS. Cellular and network alteration of NRT activity, resulting from a direct action of NPY, may be a contributor to this effect.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.YEBEH.2017.10.027
Abstract: Isocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II-IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency. This was a retrospective study. Patients with grades II-IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A - postoperative seizure freedom Group B - 1-11 seizures over 12months (less than one seizure per month) and Group C - greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data. One hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p=0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p=0.032) and Group B (RR 9.70, p=0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p=0.004). In patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy.
Publisher: Wiley
Date: 18-03-2021
DOI: 10.1111/EPI.16871
Abstract: This study was undertaken to identify factors that predict discordance between the screening instruments Neurological Disorders Depression Inventory for Epilepsy (NDDI‐E) and Generalized Anxiety Disorder scale (GAD‐7), and diagnoses made by qualified psychiatrists among patients with seizure disorders. Importantly, this is not a validation study rather, it investigates clinicodemographic predictors of discordance between screening tests and psychiatric assessment. Adult patients admitted for inpatient video‐electroencephalographic monitoring completed eight psychometric instruments, including the NDDI‐E and GAD‐7, and psychiatric assessment. Patients were grouped according to agreement between the screening instrument and psychiatrists’ diagnoses. Screening was "discordant" if the outcome differed from the psychiatrist's diagnosis, including both false positive and false negative results. Bayesian statistical analyses were used to identify factors associated with discordance. A total of 411 patients met inclusion criteria mean age was 39.6 years, and 55.5% ( n = 228) were female. Depression screening was discordant in 33% of cases ( n = 136/411), driven by false positives ( n = 76/136, 56%) rather than false negatives ( n = 60/136, 44%). Likewise, anxiety screening was discordant in one third of cases ( n = 121/411, 29%) due to false positives ( n = 60/121, 50%) and false negatives ( n = 61/121, 50%). Seven clinical factors were predictive of discordant screening for both depression and anxiety: greater dissociative symptoms, greater patient‐reported adverse events, subjective cognitive impairment, negative affect, detachment, disinhibition, and psychoticism. When the analyses were restricted to only patients with psychogenic nonepileptic seizures (PNES) or epilepsy, the rate of discordant depression screening was higher in the PNES group ( n = 29, 47%) compared to the epilepsy group ( n = 70, 30%, Bayes factor for the alternative hypothesis = 4.65). Patients with seizure disorders who self‐report a variety of psychiatric and other symptoms should be evaluated more thoroughly for depression and anxiety, regardless of screening test results, especially if they have PNES and not epilepsy. Clinical assessment by a qualified psychiatrist remains essential in diagnosing depressive and anxiety disorders among such patients.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 08-08-2006
Abstract: Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood. GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures. The hypothesis that CBZ aggravates absence seizures by acting at the VB thalamus via a GABA(A) receptor-mediated mechanism was investigated in a genetic rat model, generalized absence epilepsy rats from Strasbourg (GAERS). Seizure activity was quantified by a 90-min electroencephalogram recording postdrug injection. Intracerebroventricular injections of CBZ (15 microg in 4 microl) resulted in seizure aggravation versus vehicle treatment, with a mean increase in seizure time of 40%. This indicates that CBZ acts directly, rather than via a metabolite, on the brain to aggravate seizures. Seizure aggravation also occurred following bilateral microinjection of CBZ (0.75 microg in 0.2 microl) into the VB (53%) but not following injection into the Rt (-9%). However, seizure aggravation was blocked when the GABA(A) receptor antagonist, bicuculline (BIC, 0.04 microg in 0.2 microl), was coinjected with CBZ into the VB. Injection of BIC alone (versus vehicle) into the VB also blocked seizure aggravation following systemic administration of CBZ (15 mg/kg i.p.). In vitro studies in Xenopus oocytes expressing recombinant GABA(A) receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1-100 microM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABA(A) receptors is critical to this effect.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.NBD.2010.08.021
Abstract: Reduced GABA(A)/central benzodiazepine receptor (GABA(A)/cBZR) density, mossy fibre sprouting (MFS) and hippoc al cell loss are well described pathological features of human temporal lobe epilepsy (TLE), and animal models thereof. However, the temporal relationship of their development, and their roles in the emergence of the epilepsy, are uncertain. This was investigated in the kainic acid (KA)-induced post-status epilepticus (SE) model of TLE. Male Wistar rats (7 weeks, n=53) were randomised into control and KA groups. At 24h, 2, 4 or 6 weeks sham and KA post-SE animals were euthanised, brains extracted and GABA(A)/cBZR density, neuronal loss and MFS measured in hippoc al sub-regions. GABA(A)/cBZR density (B(max)) was measured by saturation-binding analysis using [(3)H]-flumazenil. At 24h post-SE GABA(A)/cBZR density was increased in almost all hippoc al subregions, but was decreased at the later time points with the exception of the dentate gyrus. There was significant neuronal loss in the CA3 SPc region (-24 ± 9.3%, p<0.05) at 24h, which remained stable at the later time points associated with an elevated GABA(A)/cBZR density per surviving neuron at 24h post-SE (+56.4% p<0.05) which returned to control levels by 6 weeks post-SE. MFS in the dentate gyrus progressively increased over the 6 weeks following SE (+70.6% at 6 weeks), at which time there was a significant inverse relationship with GABA(A)/cBZR binding (r(2)=0.87 p=0.02). The temporal evolution of GABA(A)/cBZR density changes post-KA-induced SE, and the relationship with decreases in hippoc al pyramidal cell numbers and MFS, may point to a key role for these changes in the pathogenesis of acquired limbic epileptogenesis.
Publisher: Wiley
Date: 13-03-2019
DOI: 10.1111/EPI.14691
Abstract: Prolonged electroencephalographic (EEG) monitoring in chronic epilepsy rodent models has become an important tool in preclinical drug development of new therapies, in particular those for antiepileptogenesis, disease modification, and treating drug-resistant epilepsy. We have developed an easy-to-use, reliable, computational tool for automated detection of electrographic seizures from prolonged EEG recordings in rodent models of epilepsy. We applied a novel method based on advanced time-frequency analysis that detects EEG episodes with excessive activity in certain frequency bands. The method uses an innovative technique of short-term spectral analysis, the Similar Basis Function algorithm. The method was applied for offline seizure detection from long-term EEG recordings from four spontaneously seizing, chronic epilepsy rat models: the fluid percussion injury (n = 5 rats, n = 49 seizures) and post-status epilepticus models (n = 119 rats, n = 993 seizures) of acquired epilepsy, and two genetic models of absence epilepsy, Genetic Absence Epilepsy Rats from Strasbourg and Wistar Albino Glaxo from Rijswijk (n = 41 and 14 rats, n = 8733 and 825 seizures, respectively). Our comparative analysis revealed that the EEG litude spectra of these four rat models are remarkably similar during epileptiform activity and have a single expressed peak within the 17- to 25-Hz frequency range. Focusing on this band, our computer program detected all seizures in the 179 rats. A quick semiautomated user inspection of the EEGs for the period of each identified event allowed quick rejection of artifact events. The overall processing time for 12-day-long recordings varied from a few minutes (5-10) to 30 minutes, depending on the number of artifact events, which was strongly correlated with the signal quality of the raw EEG data. Our automated seizure detection tool provides high sensitivity, with acceptable specificity, for long- and short-term EEG recordings from both acquired and genetic chronic epilepsy rat models. This tool has the potential to improve the efficiency and rigor of preclinical research and therapy development using these models.
Publisher: Wiley
Date: 07-08-2015
DOI: 10.1111/EPI.13116
Publisher: Wiley
Date: 07-2022
DOI: 10.1111/AOR.14007
Abstract: Over the last few decades, biomedical implants have successfully delivered therapeutic electrical stimulation to reduce the frequency and severity of seizures in people with drug‐resistant epilepsy. However, neurostimulation approaches require invasive surgery to implant stimulating electrodes, and surgical, medical, and hardware complications are not uncommon. An endovascular approach provides a potentially safer and less invasive surgical alternative. This article critically evaluates the feasibility of endovascular closed‐loop neuromodulation for the treatment of epilepsy. By reviewing literature that reported the impact of direct electrical stimulation to reduce the frequency of epileptic seizures, we identified clinically validated extracranial, cortical, and deep cortical neural targets. We identified veins in close proximity to these targets and evaluated the potential of delivering an endovascular implant to these veins based on their diameter. We then compared the risks and benefits of existing technology to describe a benchmark of clinical safety and efficacy that would need to be achieved for endovascular neuromodulation to provide therapeutic benefit. For the majority of brain regions that have been clinically demonstrated to reduce seizure occurrence in response to delivered electrical stimulation, vessels of appropriate diameter for delivery of an endovascular electrode to these regions could be achieved. This includes delivery to the vagus nerve via the 13.2 ± 0.9 mm diameter internal jugular vein, the motor cortex via the 6.5 ± 1.7 mm diameter superior sagittal sinus, and the cerebellum via the 7.7 ± 1.4 mm diameter sigmoid sinus or 6.2 ± 1.4 mm diameter transverse sinus. Deep cerebral targets can also be accessed with an endovascular approach, with the 1.9 ± 0.5 mm diameter internal cerebral vein and 1.2‐mm‐diameter thalamostriate vein lying in close proximity to the anterior and centromedian nuclei of the thalamus, respectively. This work identified numerous veins that are in close proximity to conventional stimulation targets that are of a diameter large enough for delivery and deployment of an endovascular electrode array, supporting future work to assess clinical efficacy and chronic safety of an endovascular approach to deliver therapeutic neurostimulation.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 21-04-2020
DOI: 10.1111/EPI.16505
Publisher: Mary Ann Liebert Inc
Date: 12-0004
Abstract: Few studies have investigated the influence of traumatic brain injury (TBI) on bone homeostasis however, pathophysiological mechanisms involved in TBI have potential to be detrimental to bone. The current study assessed the effect of experimental TBI in rats on the quantity and quality of two different weight-bearing bones, the femur and humerus. Rats were randomly assigned into either sham or lateral fluid percussion injury (FPI) groups. Open-field testing to assess locomotion was conducted at 1, 4, and 12 weeks post-injury, with the rats killed at 1 and 12 weeks post-injury. Bones were analyzed using peripheral quantitative computed tomography (pQCT), histomorphometric analysis, and three-point bending. pQCT analysis revealed that at 1 and 12 weeks post-injury, the distal metaphyseal region of femora from FPI rats had reduced cortical content (10% decrease at 1 week, 8% decrease at 12 weeks p < 0.01) and cortical thickness (10% decrease at 1 week, 11% decrease at 12 weeks p < 0.001). There was also a 23% reduction in trabecular bone volume ratio at 1 week post-injury and a 27% reduction at 12 weeks post-injury in FPI rats compared to sham (p < 0.001). There were no differences in bone quantity and mechanical properties of the femoral midshaft between sham and TBI animals. There were no differences in locomotor outcomes, which suggested that post-TBI changes in bone were not attributed to immobility. Taken together, these findings indicate that this rat model of TBI was detrimental to bone and suggests a link between TBI and altered bone remodeling.
Publisher: JMIR Publications Inc.
Date: 18-10-2022
Abstract: hina is facing a rapidly expanding aging population. Insights into the health status of older adults are of great significance for health resource allocation and health care provision to this population. ith the goal of providing a comprehensive understanding of the health status of older adults and to inform potential interventions, we investigated the level of disability and identified risk factors associated with disability among the older population (aged ≥60 years) living in China. total of 8467 older adults living in the Chinese city of Shenzhen were enrolled in this cross-sectional study. We used a multidimensional ability assessment survey, which assessed their activities of daily living (ADL including eating, bathing, grooming, dressing, defecation control, urination control, using a toilet unaided, transfer, flat-ground walking, stair activity), mental status (including cognitive function, aggressive behavior, depression symptoms), sensory and communication (including consciousness level, vision, hearing, communication), and social participation (including living, working, time/space orientation, distinguish persons, social communication) abilities. The impact of demographic risk factors on ability levels was analyzed using ordinal logistic regression. The correlations between the four dimensions of ability mentioned above were analyzed using Spearman correlation analysis. total of 7766 participants were effectively assessed. The participants’ average age was 70.64 (SD 8.46) years comprising 56.53% females. The overall ability level was classified as mildly, moderately, and severely impaired for 27.57% (n=2141), 2.83% (n=220), and 4.28% (n=332) of the 7766 participants, respectively. With increasing age, the proportion of impaired participants increased from 17.62% (365/2071) in the age group 60-64 years to 91.3% (253/277) in the age group above 90 years ( i P /i & .001), corresponding to an approximate 10% rise for every 5-year age increment. The odds of having more severe overall ability impairment in females was 1.15 times that in males (odds ratio [OR] 1.15, 95% CI 1.04-1.28). Participants who were orced or widowed had a higher risk of more severe overall ability impairment than those currently married (OR 1.98, 95% CI 1.68-2.33). Participants living with nonrelatives had an increased risk of more severe overall ability impairment than those living alone (OR 2.38, 95% CI 1.46-3.91). Higher education level was a protective factor of overall ability impairment (college degree or above: OR 0.32, 95% CI 0.24-0.42). The four dimensions of ability assessed were significantly correlated a low score for ADL was significantly correlated with poorer mental status, sensory and communication, and social participation (all i P /i & .001). he proportion of disability among Chinese older adults increases with age, being female, having lower education levels, being orced or widowed, and living with nonrelatives. Impairment in ADL ability is significantly correlated with poor mental status, social participation, and sensory and communication abilities. A holistic approach to improving the health of the older population is recommended in China.
Publisher: Public Library of Science (PLoS)
Date: 09-09-2013
Publisher: Springer Science and Business Media LLC
Date: 08-02-2016
DOI: 10.1038/NBT.3428
Abstract: High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.
Publisher: Wiley
Date: 22-04-2009
DOI: 10.1002/JMRI.21766
Abstract: To report the detection of structural and functional biological changes in living animals using small animal in vivo MRI that complements traditional ex vivo histological techniques. We report the development and validation of the application of large deformation high dimensional mapping (HDM-LD) segmentation for the hippoc us in the rat. High resolution volumetric T2 weighted MRI images were acquired at 4.7 Tesla from six male in-breed nonepileptic Wistar rats. Two HDM-LD segmentations of the hippoc us (automated 1 and automated 2) were compared with the manual segmentations of two investigators who independently segmented the hippoc i (manual 1 and manual 2). The mean overlap for the hippoc i between automated 1 and automated 2 for the right hippoc i was 94.4% (SD 1.0) and for the left hippoc i was 94.3% (SD 2.5), while the mean overlap between automated 1 and manual 1 for the right hippoc i was 91.4% (SD 1.3) and for the left hippoc i was 91.9% (SD 1.4). Mean values for absolute differences for comparisons of all the segmentations were the following: automated 1 versus automated 2, 3.2% (SD 1.0) manual 1 versus manual 2 6.82% (SD 5.22) automated 1 versus manual 1 13.0% (SD 1.8). HDM-LD can be applied to obtain accurate and reproducible three-dimensional segmentations of the hippoc us from rat MR images. HDM-LD will be a useful tool for investigations of hippoc al structural changes in vivo in rat models of human disease.
Publisher: Massachusetts Medical Society
Date: 28-10-2010
DOI: 10.1056/NEJMC1008255
Publisher: Elsevier BV
Date: 02-2019
Publisher: Elsevier BV
Date: 02-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-10-2018
DOI: 10.1212/WNL.0000000000006472
Abstract: To identify clinical and EEG biomarkers of drug resistance in adults with idiopathic generalized epilepsy. We conducted a case-control study consisting of a discovery cohort and a replication cohort independently assessed at 2 different centers. In each center, patients with the idiopathic generalized epilepsy phenotype and generalized spike-wave discharges on EEG were classified as drug-resistant or drug-responsive. EEG changes were classified into predefined patterns and compared between the 2 groups in the discovery cohort. Factors associated with drug resistance in multivariable analysis were tested in the replication cohort. The discovery cohort included 85 patients (29% drug-resistant and 71% drug-responsive). Their median age at assessment was 32 years and 50.6% were female. Multivariable analysis showed that higher number of seizure types ever experienced (3 vs 1: odds ratio [OR] = 31.1, 95% confidence interval [CI]: 4.5–214, p 0.001 3 vs 2: OR = 14.6, 95% CI: 2.3–93.1, p = 0.004) and generalized polyspike train (burst of generalized rhythmic spikes lasting less than 1 second) during sleep were associated with drug resistance (OR = 10.8, 95% CI: 2.4–49.4, p = 0.002). When these factors were tested in the replication cohort of 80 patients (27.5% drug-resistant and 72.5% drug-responsive 71.3% female median age 27.5 years), the proportion of patients with generalized polyspike train during sleep was also higher in the drug-resistant group (OR = 4.0, 95% CI: 1.35–11.8, p = 0.012). Generalized polyspike train during sleep may be an EEG biomarker for drug resistance in adults with idiopathic generalized epilepsy.
Publisher: American Medical Association (AMA)
Date: 03-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2000
DOI: 10.1097/00004691-200001000-00003
Abstract: Single photon emission computed tomography (SPECT) has increasingly been used as a diagnostic procedure for localizing epileptic seizure foci and as a research tool for investigating the physiologic mechanisms underlying seizure activity. With increasing use of SPECT in localizing the seizure focus for epilepsy surgery, there arises a need to critically assess its current role in the evaluation of patients for epilepsy surgery, especially as it relates to other clinical and laboratory data used in presurgical evaluation. Ictal EEG discharge has traditionally been used as the "gold standard" against which SPECT studies are compared in assessing the latter's localizing value. However, this practice presents a major challenge because SPECT studies are often reserved for patients with nonlocalizing EEG or magnetic resonance imaging findings. Nonetheless, SPECT studies in evaluation for epilepsy surgery should always be performed with the knowledge of the patient's EEG activity preceding, during, and after the injection of the radiotracer. The advent of techniques such as subtraction SPECT with co-registration on magnetic resonance imaging (SISCOM) and computer image-guided surgery has great potential in enhancing the clinical electrophysiologic evaluation of SPECT-detected abnormalities in epilepsy. These techniques permit accurate spatial correlation between intracranial EEG activity and SPECT perfusion patterns. The techniques can also be used to evaluate the effect of the extent of EEG focus resection compared with that of SISCOM focus resection to determine which has more prognostic importance in postsurgical control of seizures. Both animal and human studies are warranted to advance our knowledge of the electrophysiology associated with the various SPECT perfusion patterns.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.NBD.2008.04.012
Abstract: Stargazin is membrane bound protein involved in trafficking, synapse anchoring and biophysical modulation of AMPA receptors. A quantitative trait locus in chromosome 7 containing the stargazin gene has been identified as controlling the frequency and duration of absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Furthermore, mutations in this gene result in the Stargazer mouse that displays an absence epilepsy phenotype. GAERS stargazin mRNA expression is increased 1.8 fold in the somatosensory cortex and by 1.3 fold in the thalamus. The changes were present before and after the onset of absence seizures indicating that increases are not a secondary consequence of the seizures. Stargazin protein expression was also significantly increased in the somatosensory cortex after the onset of spontaneous seizures. The results are of significant importance beyond the GAERS model, as they are the first to show that an increase in stargazin expression may be pro-epileptic.
Publisher: Society of Nuclear Medicine
Date: 15-07-2013
DOI: 10.2967/JNUMED.112.107359
Abstract: Studies report that (11)C-flumazenil (FMZ) PET more specifically localizes the epileptogenic zone in patients with medically refractory focal epilepsy than (18)F-FDG PET. However, practical aspects of (11)C use limit clinical application. We report a phase I/IIa study assessing the clinical use of (18)F-FMZ PET for the localization of the epileptogenic zone in patients with drug-resistant temporal lobe epilepsy (TLE). Receptor binding was quantified using kinetic modeling that did not require arterial s ling. Dynamic (18)F-FMZ PET and static interictal (18)F-FDG PET scans were compared in healthy controls (n = 17 for (18)F-FMZ and n = 20 for (18)F-FDG) and TLE patients with mesial temporal sclerosis on MR imaging (MTS, n = 12) and with normal MR imaging (NL TLE, n = 19). Masked visual assessment of images was undertaken. Parametric images of (18)F-FMZ binding potential (BPND) were generated using the simplified reference tissue model. Region-of-interest analysis on coregistered MR images and statistical parametric mapping were used to quantify (18)F-FMZ BPND and (18)F-FDG uptake in the temporal lobe. The visual assessment of static standardized uptake value images showed (18)F-FMZ PET to have high specificity (16/17 [94%]) and moderate sensitivity (21/31 [68%]) for the localization of the epileptogenic zone, with a more restricted abnormality than (18)F-FDG PET. However, the (18)F-FMZ standardized uptake value images were falsely localizing in 3 of 31 patients (10%). Region-of-interest analysis demonstrated reductions in ipsilateral hippoc al (18)F-FMZ BPND in patients with either MTS or NL TLE, compared with controls subjects. Ipsilateral hippoc al (18)F-FMZ BPND was independent of both hippoc al volume and (18)F-FDG uptake, whereas ipsilateral hippoc al volume was correlated with (18)F-FDG uptake (r(2) = 0.69, P < 0.0001). Statistical parametric mapping analysis demonstrated decreased uptake in 14 of 31 (45%) cases with (18)F-FMZ PET and 18 of 29 (62%) with (18)F-FDG PET. Cluster size was significantly smaller on (18)F-FMZ than (18)F-FDG images (37 vs. 160 voxels, P < 0.01). (18)F-FMZ PET has potential as a clinical tool for the localization of the epileptogenic zone in the presurgical evaluation of drug-resistant TLE, providing information complementary to (18)F-FDG PET, with a more restricted region of abnormality.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JMGM.2021.108116
Abstract: Oxidative stress is one of the pathophysiological mechanisms implicated in drug-resistant epilepsy. Recurrent seizures and prolonged treatment with anti-seizure medicines (ASMs) can produce reactive oxygen species (ROS) resulting in neuronal cell damage, cell toxicity, and cell death. This damage may contribute to the loss of efficacy of anti-seizure medicines. Add-on therapy with antioxidants, neuroimmunophilins, and polyphenols may thus be beneficial in drug-resistant epilepsy. In vitro and in vivo studies have shown a significant improvement in drug efficacy and seizure suppression using co-treatment of anti-seizure medication with naturally available antioxidants including alpha-lipoic acid (α-lipoic acid) from walnut however, the underlying mechanisms of action remain to be fully understood. We undertook molecular docking and molecular dynamics simulations to determine whether alpha-lipoic acid and related analogues interacted with the human manganese superoxide dismutase (MnSOD) protein, a member of the oxidative metabolic pathway. The 3D structure of the compounds and the protein were retrieved from protein and chemical databases, binding sites were identified and ligand-protein interactions were performed. Alpha-lipoic acid and various analogues docked within a human MnSOD binding region. Docking results were validated by molecular dynamic simulation. The CMX-2043 analogue showed strong binding with MnSOD compared to alpha-lipoic acid and other analogues. Our findings provide new insights into additional mechanisms of action, which may in part, account for the antioxidant properties associated with alpha-lipoic acid and related analogues. The results support further in vitro and in vivo evaluation of these compounds to better understand their potential as add-on therapy for ASM treatment in epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2020
DOI: 10.1038/S41598-020-77975-2
Abstract: Neurovascular injury has been proposed as a universal pathological hallmark of traumatic brain injury (TBI) with molecular markers of angiogenesis and endothelial function associated with injury severity and morbidity. Sex differences in the neurovasculature response post-TBI may contribute to the differences seen in how males and females respond to injury. Steady-state contrast enhanced magnetic resonance imaging (SSCE-MRI) can be used to non-invasively assess the neurovasculature and may be a useful tool in understanding and predicting outcomes post-TBI. Here we used SSCE-MRI to investigate the neurovasculature of male and female rats at 48 h after an experimental TBI, and how these changes related to neuromotor function at 1-week post-TBI. In addition to TBI induced changes, we found that female rats had greater vessel density, greater cerebral blood volumes and performed better on a neuromotor task than their male counterparts. These results suggest that acute post-TBI cerebrovascular function is worse in males, and that this may contribute to the greater functional deficits observed post-injury. Furthermore, these results highlight the potential of SSCE-MRI to provide insights into the cerebral microvasculature post-TBI. Future studies, incorporating both males and females, are warranted to investigate the evolution of these changes and the underlying mechanisms.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.JOCN.2014.09.001
Abstract: The established role of glutamate in the pathogenesis of glioma-associated seizures (GAS) led us to investigate a novel treatment method using an established drug class, peroxisome proliferator activated receptor (PPAR) gamma agonists. Previously, sulfasalazine has been shown to prevent release of glutamate from glioma cells and prevent GAS in rodent models. However, raising protein mediated glutamate transport via excitatory amino acid transporter 2 (EAAT2) has not been investigated previously to our knowledge. PPAR gamma agonists are known to upregulate functional EAAT2 expression in astrocytes and prevent excitotoxicity caused by glutamate excess. These agents are also known to have anti-neoplastic mechanisms. Herein we discuss and review the potential mechanisms of these drugs and highlight a novel potential treatment for GAS.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Wiley
Date: 31-01-2012
Publisher: Hindawi Limited
Date: 29-08-2016
DOI: 10.1111/ANE.12672
Abstract: Some recent studies have found an association between foetal malformations in earlier antiepileptic drug (AED)-exposed pregnancies and an increased hazard of such malformations in subsequent pregnancies. We investigated this matter further, and also considered the possible role of spontaneous abortions in previous pregnancies, in this situation. Analysis of foetal malformation data for current and previous pregnancies in women taking AEDs and women with untreated epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy (APR) from 1999 to late 2014. Antiepileptic drug-treated women with either a malformed foetus or a spontaneous abortion in their previous pregnancy had a statistically significant twofold to threefold increased risk of foetal malformation in their next pregnancy, compared with similarly treated women with normal offspring in their previous pregnancy. This was not seen in the same circumstances in women with untreated epilepsy. On AED treatment, the women were more likely to have spontaneous abortions than in their previous untreated pregnancies. Possibly some of the increased abortion rate resulted from drug-related malformations that were incompatible with continuing intrauterine survival. In assessing the hazard of an AED-treated woman having a malformed foetus, it is important to know both the AEDs being taken and, if there had been a previous pregnancy, whether a foetal malformation or a spontaneous abortion occurred in it.
Publisher: Wiley
Date: 24-08-2018
DOI: 10.1111/EPI.14539
Abstract: To study interactions between first-trimester exposure to antidepressant drugs (ADDs) and antiepileptic drugs (AEDs), and a history of clinical depression and/or anxiety, on pregnancy outcomes and seizure control in pregnant women with epilepsy (WWE). We examined data from the Australian Pregnancy Register of Antiepileptic Drugs in Pregnancy, collected from 1999 to 2016. The register is an observational, prospective database, from which this study retrospectively analyzed a cohort. Among the AED-exposed outcomes, comparisons were made among 3 exposure groups: (1) pregnancy outcomes with first-trimester exposure to ADDs (2) outcomes with mothers diagnosed with depression and/or anxiety but who were not medicated with an ADD and (3) those with mothers who were not diagnosed with depression and/or anxiety and were not medicating with ADD. Prevalence data was analyzed using Fisher's exact test. A total of 2124 pregnancy outcomes were included in the analysis 1954 outcomes were exposed to AEDs in utero, whereas 170 were unexposed. Within the group of WWE taking AEDs, there was no significant difference in the prevalence of malformations in infants who were additionally exposed to ADDs (10.2%, 95% confidence interval [CI] 3.9-16.6), compared to in iduals in the non-ADD-medicated depression and/or anxiety group (7.7%, 95% CI 1.2-14.2), or those without depression or anxiety (6.9%, 95% CI 5.7-8.1 P = 0.45). The malformation rates in pregnancy outcomes unexposed to AEDs were also similar in the above groups (P = 0.27). In WWE medicated with AEDs and ADDs, the frequency of convulsive seizures (P = 0.78), or nonconvulsive seizures (P = 0.45) throughout pregnancy, did not differ across comparative groups. Co-medicating with ADDs in WWE taking AEDs does not appear to confer a significant added teratogenic risk, and it does not affect seizure control.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.NEUROIMAGE.2017.03.002
Abstract: Recent developments in accelerated imaging methods allow faster acquisition of high spatial resolution images. This could improve the applications of functional magnetic resonance imaging at 7 Tesla (7T-fMRI), such as neurosurgical planning and Brain Computer Interfaces (BCIs). However, increasing the spatial and temporal resolution will both lead to signal-to-noise ratio (SNR) losses due to decreased net magnetization per voxel and T
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JOCN.2018.07.002
Abstract: Sport-related concussion is a common form of mild traumatic brain injury that is now recognised as a serious health issue. Growing evidence suggests concussion may result in long-term and severe neurological disabilities. Recent research into the diagnosis and management of concussion may provide new approaches to concussion management that limit the potential long-term adverse effects of concussion. This paper summarises the problem of sport-related concussion and reviews key factors (sex, age, genetics) that may modify concussion outcomes. Current sport-related concussion tools are described. Analysis of emerging methods of acute concussion diagnosis using objective fluid and neuroimaging biomarkers is provided. These new concussion biomarkers have the potential to change management of sport-related concussion.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JOCN.2018.07.003
Abstract: Australian Rules Football is a collision sport that is associated with increased sport-related concussion risk. Sport-related concussion is a common form of mild traumatic brain injury that is now recognised as a serious health issue. This study measured the concussion incidence rate for amateur Australian Rules players over 3 seasons (2015-2017) by athlete exposures-a metric used widely in the literature. This study also reported concussion incidence based on player match hours, a less common yet more accurate method of reporting concussion incidence which takes match duration into account. Accurate concussion incidence reporting in amateur Australian Rules Football quantifies the problem of concussion in this sport. This may be necessary to inform players of their concussion injury risk and to help guide rule changes to protect players from this injury.
Publisher: Mary Ann Liebert Inc
Date: 07-2021
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.EPLEPSYRES.2010.05.008
Abstract: This study assessed the comparative efficacy of pregabalin for refractory partial seizures. Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day. During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21% p=.007) and lamotrigine (36% vs 24% p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.
Publisher: Mary Ann Liebert Inc
Date: 10-2023
Publisher: Public Library of Science (PLoS)
Date: 14-07-2017
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2016
Publisher: Elsevier BV
Date: 02-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2020
DOI: 10.1212/WNL.0000000000009855
Abstract: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0–3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4–19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and “epilepsy” was recorded as the cause of death in 24%. Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.
Publisher: AME Publishing Company
Date: 08-2017
Publisher: Elsevier BV
Date: 02-2021
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.NEULET.2011.02.039
Abstract: The idiopathic generalized epilepsies (IGEs), constituting approximately a quarter of all epilepsy cases, are presumed to arise primarily from genetic abnormalities. A minority of cases have been identified to be caused by mutations in a single gene, but in the vast majority, mutations in multiple genes are presumed to contribute to the development of epilepsy. Two rat models of IGE with absence seizures, the Genetic Epilepsy Rats from Strasbourg (GAERS) and Wistar Albino Glaxo from Rijswijk (WAG/Rij), have proven valuable for translational research. These models closely mimic the behavioural, electrophysiological, and pharmacological aspects of the human condition, with the epilepsy phenotype for both likely to have polygenic determinants. Research in these models, using molecular and in vivo imaging approaches, has provided important insights into the pathophysiology of IGE. Molecular and imaging techniques have the potential to provide researchers with tangible biomarkers of disease progression and the effects of intervention, and also to provide fundamental information about the causation and epileptogenic processes associated with IGE. This review discusses the published literature concerning the molecular changes and morphometric abnormalities identified in these models, as well as their potential relevance for human IGE.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.SEIZURE.2022.02.004
Abstract: Between 16-77% of patients with newly diagnosed epilepsy report seizures before diagnosis but little is known about the risk factors for diagnostic delay. Here, we examined the association between prior seizures and neuroimaging findings in newly diagnosed focal epilepsy. Adults diagnosed with focal epilepsy at First Seizure Clinics (FSC) at the Royal Melbourne Hospital or Austin Health, Melbourne, Australia, between 2000 and 2010 were included. Medical records were audited for seizure history accrued from the detailed FSC interview. Potentially epileptogenic brain abnormality type, location and extent was determined from neuroimaging. Statistical analysis comprised multivariate logistic regression. Of 735 patients, 44% reported seizure/s before the index seizure. Among the 260 in iduals with a potentially epileptogenic brain imaging abnormality, 34% reported prior seizures. Of 475 in iduals with no abnormality, 50% reported prior seizures (p 50 years had lower odds compared to those 18-30 years (OR 0.5, p = 0.01). A history of prior seizures is less common in patients with newly diagnosed focal epilepsy associated with antecedent stroke or high-grade tumor than in those without a lesion, and is also less common in older in iduals. These findings may be related to age, biological mechanisms or aspects of diagnosis and assessment of these events.
Publisher: Wiley
Date: 02-11-2020
DOI: 10.1111/EPI.16727
Publisher: Cold Spring Harbor Laboratory
Date: 19-01-2023
DOI: 10.1101/2023.01.16.524331
Abstract: Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing s le sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 in iduals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each in idual’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences. We present a global effort to devise harmonization procedures necessary to meaningfully leverage big data.
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.NEUROIMAGE.2012.11.054
Abstract: The neurobiological processes resulting in epilepsy, known as epileptogenesis, are incompletely understood. Manganese-enhanced MRI (MEMRI) can potentially aide in this quest as it provides superior tissue contrast, particularly of the hippoc al subregions. This longitudinal study aims to characterise the changes in the hippoc us of the post kainic acid-induced status epilepticus (KASE) rat model of mesial temporal lobe epilepsy using MEMRI in vivo. Serial acquisition of T(1)-weighted MEMRI images were taken before, 2 days and 6 weeks after KASE (10-30 mg/kg, i.p.) in 14 rats and in 11 control rats, while a second cohort of control (N=6) and epileptic animals (N=10) was imaged at 2 months post KASE only. MnCl(2) (50 mM, 10 μl) was administered in the right lateral ventricle 1 day before scanning. Regions of interest were drawn around the hippoc us and several subregions of the hippoc us (CA1, CA3 and dentate gyrus). Markers of epilepsy such as spontaneous recurrent seizures, hippoc al neuronal loss and mossy fiber sprouting were quantified. A persistent increase in MEMRI signal intensity was found in the hippoc us, CA1 and dentate gyrus in the KASE group compared to the control group (ANOVA P<0.05). The intensity signal in the hippoc us and subregions correlated inversely with the frequency of spontaneous recurrent seizures in the chronic epileptic phase, however there was no relationship observed between histopathological changes such as cell loss and mossy fiber sprouting with seizures. This study demonstrates that MEMRI is able to detect imaging changes in the hippoc us during the course of epileptogenesis relevant for seizure expression. These data strongly indicate a relationship between manganese enhancement and spontaneous seizure outcome, suggesting that MEMRI could provide a preclinical biomarker for the severity of epileptogenesis in vivo in animal models.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1998
DOI: 10.1212/WNL.50.2.445
Abstract: Traditional side-by-side visual interpretation of ictal and interictal single-photon emission computed tomography (SPECT) scans can be difficult in identifying the surgical focus, particularly in patients with extratemporal or otherwise unlocalized intractable epilepsy. Computer-aided subtraction ictal SPECT co-registered to MRI (SISCOM) may improve the clinical usefulness of SPECT in localizing the surgical seizure focus. We studied 51 consecutive intractable partial epilepsy patients who had interictal and ictal scans. The SPECT studies were blindly reviewed and classified as either localizing to 1 of 16 sites in the brain or as nonlocalizing. SISCOM images were localizing in 45 of 51 (88.2%) compared with 20 of 51 (39.2%) for traditional side-by-side inspection of ictal and interictal SPECT images (p < 0.0001). Inter-rater agreement for two independent reviewers was better for SISCOM (84.3% versus 41.2%, kappa = 0.83 versus 0.26 p 45 seconds), but not secondary generalization of the seizure, was associated with a falsely localizing or nonlocalizing SISCOM. Epilepsy surgery patients whose SISCOM localization was concordant with a falsely localizing or nonlocalizing SISCOM. Epilepsy surgery patients whose SISCOM localization was concordant with the surgical site were more likely to have excellent outcome than patients with nonconcordant or nonlocalizing findings (62.5% [10/16] versus 20% [2/10] p < 0.05). On the other hand, seizure localization by the traditional method of SPECT inspection had no significant association with postsurgical outcome. We conclude that SISCOM improves the sensitivity and the specificity of SPECT in localizing the seizure focus for epilepsy surgery. Concordance between SISCOM localization and site of surgery is predictive of postsurgical improvement in seizure outcome.
Publisher: Oxford University Press (OUP)
Date: 31-01-2018
DOI: 10.1093/SLEEP/ZSY015
Abstract: Epilepsy is a group of neurological conditions in which there is a pathological and enduring predisposition to generate recurrent seizures. Evidence over the last few decades suggests that epilepsy may be associated with increased sleep-disordered breathing, which may contribute towards sleep fragmentation, daytime somnolence, reduced seizure control, and cardiovascular-related morbidity and mortality. Chronic sleep-disordered breathing can result in loss of gray matter and cause deficits to memory and global cognitive function. Sleep-disordered breathing is a novel and independent predictor of sudden cardiac death and, as such, may be involved in the mechanisms leading to sudden unexpected death in epilepsy. Despite this, the long-term consequences of sleep-disordered breathing in epilepsy remain unknown, and there are no guidelines for screening or treating this population. There is currently insufficient evidence to indicate continuous positive airway pressure (CPAP) for the primary or secondary prevention of cardiovascular disease, and recent evidence has failed to show any reduction of fatal or nonfatal cardiovascular endpoints. Treatment of sleep-disordered breathing may potentially improve seizure control, daytime somnolence, and neurocognitive outcomes, but few studies have examined this relationship. In this review, we examine sleep-disordered breathing in epilepsy, and discuss the potential effect of epilepsy treatments. We consider the role of CPAP and other interventions for sleep-disordered breathing and discuss their implications for epilepsy management.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2000
Abstract: To determine whether localization of extratemporal epilepsy with subtraction ictal SPECT coregistered with MRI (SISCOM) is predictive of outcome after resective epilepsy surgery, whether SISCOM images provide prognostically important information compared with standard tests, and whether blood flow change on SISCOM images is useful in determining site and extent of excision required. The value of SISCOM in predicting surgical outcome for extratemporal epilepsy is unknown, especially if MRI findings are nonlocalizing. SISCOM images in 36 consecutive patients were classified by blinded reviewers as "localizing and concordant with site of surgery," "localizing but nonconcordant with site of surgery," or "nonlocalizing." SISCOM images were coregistered with postoperative MRI, and reviewers visually determined whether cerebral cortex underlying the SISCOM focus had been completely resected, partially resected, or not resected. Twenty-four patients (66.7%) had localizing SISCOM, including 13 (76.5%) of those without a focal MRI lesion. Eleven of 19 patients (57.9%) with localizing SISCOM concordant with the surgical site, compared with 3 of 17 (17.6%) with nonlocalizing or nonconcordant SISCOM, had an excellent outcome (p < 0.05). With logistic regression analysis, SISCOM findings were predictive of postsurgical outcome, independently of MRI or scalp ictal EEG findings (p < 0.05). The extent of resection of the cortical region of the SISCOM focus was significantly associated with the rate of excellent outcome (100% with complete resection, 60% with partial resection, and 20% with nonresection, p < 0.05). SISCOM images may be useful in guiding the location and extent of resection in extratemporal epilepsy surgery.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.JOCN.2005.04.018
Abstract: Herein, we present the case of a 67-year-old grazier who was bitten by a tiger snake and developed coagulopathy and respiratory distress. The patient required intubation and ventilation in intensive care. There was delayed detection of snake envenomation and administration of antivenom. On extubation several days later, gross external ocular paresis was noted. Clinical testing indicated that the ocular pathology was secondary to neurotoxin-mediated presynaptic blockade. The paresis was partially resolved by the time of discharge one week later. The present case report discusses the possible mechanisms for the delayed development of ophthalmoplegia.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.YEBEH.2019.106481
Abstract: Data from 2182 pregnancies in the Australian Register of antiepileptic drugs in pregnancy that were followed to term, with 1965 followed for another year, were analyzed to ascertain whether preexisting illness influenced i. the hazard of fetal malformations, and ii. seizure control during pregnancy. Fetal malformation occurred in 74 of the 842 pregnancies associated with preexisting illness (8.8%) and in 84 of the 1340 comparator pregnancies (6.27%), Relative Risk (R.R.) = 1.402 (95% Confidence Interval (C.I.) = 1.038, 1.893). Logistic regression showed statistically significant effects of preexisting maternal drug-treated psychiatric illness, untreated psychiatric illness, and use of citalopram, carbamazepine, valproate, and topiramate in increasing hazard of fetal malformation. Preexisting nonpsychiatric illness and other antiepileptic drugs and drugs prescribed for psychiatric illness, mainly antidepressants, had no such effect. Seizures occurred during 405 of the 842 pregnancies associated with preexisting illness, and during 593 of 1340 comparison pregnancies (48.1% v 44.3% R.R. = 1.087 95% C.I. = 0.991, 1.192). There were no statistically significant relationships between preexisting nonpsychiatric and psychiatric illnesses separately and seizure control during pregnancy. Thus, apart from consequences of antiepileptic drug exposure, preexisting maternal psychiatric illness, in its own right, or when treated with citalopram, appears to be associated with increased hazards of fetal malformation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
Publisher: Mary Ann Liebert Inc
Date: 02-05-2023
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.EPLEPSYRES.2019.106234
Abstract: Similarities in clinical presentations between epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES) produces a risk of misdiagnosis. Video-EEG monitoring (VEM) is the diagnostic gold standard, but involves significant cost and time commitment, suggesting a need for efficient screening tools. 628 patients were recruited from an inpatient VEM unit 293 patients with ES, 158 with PNES, 31 both ES and PNES, and 146 non-diagnostic. Patients completed the SCL-90-R, a standardised 90-item psychopathology instrument. Bayesian linear models were computed to investigate whether SCL-90-R domain scores or the overall psychopathology factor p differed between groups. Receiver operating characteristic (ROC) curves were computed to investigate the PNES classification accuracy of each domain score and p. A machine learning algorithm was also used to determine which subset of SCL-90-R items produced the greatest classification accuracy. Evidence was found for elevated scores in PNES compared to ES groups in the symptom domains of anxiety (b = 0.47, 95%HDI = [0.10, 0.80]), phobic anxiety (b = 1.32, 95%HDI = [0.98, 1.69]), somatisation (b = 0.84, 95%HDI = [0.49, 1.20]), and the general psychopathology factor p (b = 1.35, 95%HDI = [0.86, 1.82]). Of the SCL-90-R domain scores, somatisation produced the highest classification accuracy (AUC = 0.74, 95%CI = [0.69, 0.79]). The genetic algorithm produced a 6-item subset from the SCL-90-R, which produced comparable classification accuracy to the somatisation scores (AUC = 0.73, 95%CI = [0.64, 0.82]). Compared to patients with ES, patients with PNES report greater symptoms of somatisation, general anxiety, and phobic anxiety against a background of generally elevated psychopathology. While self-reported psychopathology scores are not accurate enough for diagnosis in isolation, elevated psychopathology in these domains should raise the suspicion of PNES in clinical settings.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 09-06-2005
DOI: 10.1002/AJMG.A.30355
Abstract: We report a three-generation Caucasian family of Macedonian origin with dentatorubral-pallidoluysian atrophy (DRPLA), manifesting as very mild elderly onset, severe young adult onset, and severe childhood onset presentations in the three generations. The grandparental trinucleotide expansion size (52 repeats) is the smallest overtly pathogenic mutation yet reported. This 67-year-old man displayed only subtle neurological and cognitive deficits on formal examination and very slight signs on MRI. His son had developed a choreiform disorder at age 32 years, and by his 40s suffered severe dementia and motor decline. The grandson, the proband, presented as a teenager with progressive myoclonic epilepsy, dysarthria, ataxia, and cognitive decline, having manifesting learning difficulties from the age 5 years. Atrophin-1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the three patients, respectively. Given an absence of any other indicative history in the family, we speculate that the mutation may have expanded from a 'high-end' normal allele to a pathogenic size at the grandfather's conception, or that one of his parents may have had a pathogenic mutation at the lowest end of the expanded range.
Publisher: Wiley
Date: 07-08-2007
DOI: 10.1111/J.1528-1167.2007.01246.X
Abstract: Early life stress has enduring behavioral and neuroendocrine effects, particularly in hippoc us and amygdala. This may be relevant to mesial temporal lobe epilepsy (MTLE) that arises from these structures. In rats, we tested the hypothesis that early postnatal stress, in the form of maternal separation (MS), creates vulnerability to limbic epileptogenesis in adult life. On postnatal days 2-14, we exposed male and female nonepileptic rats to either MS for 180 min/day, or early handling (EH) and brief separation (15 min/day). At 7 weeks of age, rats of both genders exposed to MS displayed significantly increased anxiety, as evidenced by reduced time spent in the open arms of the elevated plus maze compared with EH rats. For epileptogenesis experiments, separate cohorts of rats, similarly exposed to either early life MS or EH, were implanted with bipolar electrodes into the left amygdala and one week later rapid electrical kindling performed until fully kindled (five Class V seizures, Racine scale). In females, fewer stimulations were required following MS than EH to reach the fully kindled state (39.6 +/- 6.4 vs. 67.1 +/- 9.4 p < 0.0001) no differences were observed in males (MS: 49.1 +/- 5.1 EH: 53.7 +/- 6.6 stimulations). We conclude that, while postnatal MS stress increases anxiety in both genders, this early life stressor results in persisting vulnerability to limbic epileptogenesis only in females. This has implications for human MTLE and its psychiatric comorbidities, suggesting a common causation model and the involvement of gender-specific factors such as sex hormones.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-09-2010
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.YEBEH.2019.106631
Abstract: People with epilepsy (PWE) have high rates of comorbid anxiety disorders and depressive disorders, from 25% in general population cohorts to rates of 55% in people with treatment resistant epilepsy. High rates are also seen in patients with psychogenic nonepileptic seizures (PNES). Depressive disorders and anxiety disorders in PWE are associated with decreased quality of life measures and are the strongest risk factors for increased suicidality, rates of which are markedly elevated in PWE, at 12%, compared to the general Australian population (1.8%). The Hospital Anxiety and Depression Scale (HADS) is one of the more commonly used screening tools in medical populations. Past studies of the HADS in general outpatient populations with epilepsy have demonstrated promising validity for detecting depression. The following were the objectives of the study: 1. To examine the validity of HADS in detecting depressive disorders and anxiety disorders in an inpatient population of patients admitted for video monitoring. 2. To investigate the measurement structure of the HADS across the diagnosis groups of epilepsy subtypes and PNES. This was a retrospective cohort study of 485 patients admitted to a tertiary epilepsy video electroencephalography (EEG) monitoring unit. All patients received clinical neurological, neuropsychiatric, and neuroimaging assessments to arrive at consensus epilepsy and psychiatric diagnoses. Clinical psychiatric diagnosis of depressive disorders and anxiety disorders, based on the assessment of a neuropsychiatrist, were compared to accepted HADS cutoff scores for these conditions. Of the 485 patients, 229 patients were with epilepsy, 28 had both epilepsy and PNES, and 121 had PNES. In 107 cases, no definite diagnosis could be made. At a cutoff score of 7 HADS was able to significantly classify patients with depression (area under the curve [AUC] = 0.79, 95% confidence interval [CI] = 0.72-0.82) with a sensitivity of 70% and a specificity of 83%. A similar result was observed for anxiety disorders a cutoff score of 7 (AUC = 0.75, 95% CI = 0.72-0.81) was able to significantly classify anxiety disorders in patients with a sensitivity of 88% and specificity of 54%. This study has found that HADS measures two separate, yet correlated, constructs of anxiety disorders and depressive disorders. Our results indicate that while the HADS is sensitive to distress in this population, relatively low cutoff scores would be required to achieve highly sensitive screening. This s le includes patients with a diagnosis of epilepsy and/or PNES, and thus, the findings have clinical applicability to screening in tertiary epilepsy video-EEG monitoring units where both these conditions frequently co-occur.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2019
DOI: 10.1038/S41598-019-51267-W
Abstract: A single mild traumatic brain injury (mTBI) typically causes only transient symptoms, but repeated mTBI (RmTBI) is associated with cumulative and chronic neurological abnormalities. Clinical management of mTBI is challenging due to the heterogeneous, subjective and transient nature of symptoms, and thus would be aided by objective biomarkers. Promising biomarkers including advanced magnetic resonance imaging (MRI) and plasma levels of select proteins were examined here in a rat model of RmTBI. Rats received either two mild fluid percussion or sham injuries administered five days apart. Rats underwent MRI and behavioral testing 1, 3, 5, 7, and 30 days after the second injury and blood s les were collected on days 1, 7, and 30. Structural and diffusion-weighted MRI revealed that RmTBI rats had abnormalities in the cortex and corpus callosum. Proteomic analysis of plasma found that RmTBI rats had abnormalities in markers indicating axonal and vascular injury, metabolic and mitochondrial dysfunction, and glial reactivity. These changes occurred in the presence of ongoing cognitive and sensorimotor deficits in the RmTBI rats. Our findings demonstrate that RmTBI can result in chronic neurological abnormalities, provide insight into potential contributing pathophysiological mechanisms, and supports the use of MRI and plasma protein measures as RmTBI biomarkers.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.SEIZURE.2018.02.009
Abstract: Antiepileptic drugs (AEDs), particularly valproate (VPA), are known to be teratogens when taken by women with epilepsy (WWE), but the risk in women who take these drugs for indications other than epilepsy have been little studied. This study aims to investigate the incidence of birth defects in children born to mothers taking AEDs for non-epilepsy indications. The Australian Pregnancy Register (APR), established in 1998, is a prospective observational study operating with ethical approval and informed written consent for participation. Of the 2066 pregnancies enrolled in the Register, 98% are WWE and the remainder received AEDs for other indications. Data from this Register was analysed to study the rates of congenital malformations (CM) in infants exposed to AEDs in utero in WWE compared to those women taking AEDs for other indications. The malformation rates in pregnancies of WWE taking AEDs (5%), is higher than the rates of infants born to untreated WWE (2%). There were 32 pregnancies enrolled from 29 mothers taking AEDs for indications other than epilepsy (2 women/2 pregnancies were lost to follow up). Out of 30 pregnancies, 9 of which were exposed to VPA, 1 resulted in a child with a malformation (3%) (cleft palate) on 1700 mg/day of valproate. This is the first attempt to assess the use of AEDs in a prospective study of women who are pregnant but do not have active epilepsy. Although underpowered, this study suggests that women taking AEDs for non-epilepsy indications have a similar risk of having a child with a CM as compared with women taking AEDs for epilepsy. Larger numbers are required to investigate the risk of AED-associated malformations in this important group.
Publisher: Wiley
Date: 07-2014
DOI: 10.1002/ACN3.74
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.JNEUMETH.2005.02.008
Abstract: To validate a method for the chronic implantation of micro-cannulae to examine the effect of drug administration to two small brain regions critical to the control of generalised seizures, the reticular nucleus of the thalamus (Rt) and the ventrobasal thalamus (VB), in a genetically epileptic rat model. Micro-cannulae guides (length 9 mm, 26G, i.d. 0.24 mm, o.d. 0.46 mm) were implanted bilaterally into either the Rt or the VB of 11- to 13-week-old Genetic Absence Epilepsy Rats from Strasbourg (GAERS) using a stereotaxic head frame. After a seven-day recovery period the animals were injected with 0.2 microl of methylene blue. The animals were allowed to move freely in their cages for a further 90 min while a post-drug EEG recording was acquired and then brains were perfused with 4% paraformaldehyde and extracted. Twenty-micrometer slices were cut on a cryostat and the site and extent of the methylene blue staining in the brain determined. The implantation co-ordinates were adjusted accordingly, and then a validation study was performed on a further cohort of rats (n=8 Rt, n=7 VB). The co-ordinates that were found to most accurately localise the Rt were: AP -3mm, ML 3.6mm, DV -5.8mm (relative to Bregma). Those that accurately localised the VB were: AP -3mm, ML 2.6mm, DV -5.5mm. In the validation study, the dye staining was measured to diffuse an average radius of 520+/-120 microm from the centre of the injection site for the 0.2 microl injection in both brain hemispheres. For the VB injections the dye remained confined within the structure, however, for the smaller Rt there was spread to surrounding structures in the axial plane. The radial diffusion for the 0.5 microl injection was similar, but more of the dye was found to spread back up the cannula tract away from the target zone. These studies have validated a method for accurate and localised injection of drugs into the VB and Rt for neuropharmacological studies in a rat model of generalised epilepsy. This method allows the measurement of localised drug effects on EEG and generalised seizure activity at these sites.
Publisher: Wiley
Date: 02-07-2016
DOI: 10.1111/CNS.12571
Publisher: Frontiers Media SA
Date: 11-12-2018
Publisher: Elsevier BV
Date: 04-1996
DOI: 10.1016/S0967-5868(96)90012-0
Abstract: We report two cases of unrelated female heterozygotes for adrenoleukodystrophy (ALD) who have developed progressive neurological disease. Both presented with a progressive myelopathy in midlife and one has since also developed a peripheral neuropathy. Both women had elevated very long chain fatty acid (VLCFA) levels. One patient has been on Lorenzo's oil for 2 years with normalisation of her plasma VLCFA assays but her condition has progressed relentlessly and the second discontinued Lorenzo's oil after 1 month due to unacceptable weight loss. Review of the literature reveals that significant neurological symptoms develop in 15-20% of female heterozygotes and that abnormalities on neurological examination occur in up to 55%. Despite a not excessively rare estimated gene frequency of 1 20,000 the diagnosis of a symptomatic heterozygote for ALD is rarely made in the absence of an affected male relative with most patients misdiagnosed as suffering from multiple sclerosis.
Publisher: American Physiological Society
Date: 10-2016
Abstract: The antiepileptic drug phenytoin (PHT) is thought to reduce the excitability of neural tissue by stabilizing sodium channels (Na V ) in inactivated states. It has been suggested the fast-inactivated state (I F ) is the main target, although slow inactivation (I S ) has also been implicated. Other studies on local anesthetics with similar effects on sodium channels have implicated the Na V voltage sensor interactions. In this study, we reexamined the effect of PHT in both equilibrium and dynamic transitions between fast and slower forms of inactivation in rat hippoc al CA1 pyramidal neurons. The effects of PHT were observed on fast and slow inactivation processes, as well as on another identified “intermediate” inactivation process. The effect of enzymatic removal of I F was also studied, as well as effects on the residual persistent sodium current ( I NaP ). A computational model based on a gating charge interaction was derived that reproduced a range of PHT effects on Na V equilibrium and state transitions. No effect of PHT on I F was observed rather, PHT appeared to facilitate the occupancy of other closed states, either through enhancement of slow inactivation or through formation of analogous drug-bound states. The overall significance of these observations is that our data are inconsistent with the commonly held view that the archetypal Na V channel inhibitor PHT stabilizes fast inactivation states, and we demonstrate that conventional slow activation “I S ” and the more recently identified intermediate-duration inactivation process “I I ” are the primary functional targets of PHT. In addition, we show that the traditional explanatory frameworks based on the “modulated receptor hypothesis” can be substituted by simple, physiologically plausible interactions with voltage sensors. Additionally, I NaP was not preferentially inhibited compared with peak I Na at short latencies (50 ms) by PHT.
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.NBD.2009.05.009
Abstract: Alterations in hippoc al GABA(A)/central benzodiazepine receptor (GABA(A)/cBZR) expression and mossy fibre sprouting (MFS) may have aetiological significance in temporal lobe epileptogenesis. Their relationship with each other is also unknown. We utilised [3H]-flumazenil autoradiography to quantify changes in GABA(A)/cBZR density and affinity in all hippoc al laminae, and Timm's staining for MFS at different stages of epileptogenesis in the amygdala kindling rat model (after 24 stimulations, 48 stimulations and two weeks post-kindling). During kindling, receptor density was significantly elevated within the dentate stratum moleculare and granulosum, but decreased within the stratum radiatum of CA3 and CA2. Two weeks post-kindling, receptor density remained upregulated in the dentate stratum moleculare and was also upregulated in CA3 stratum oriens and CA1 stratum moleculare. MFS was significantly increased in the dentate stratum moleculare at two weeks post-kindling, with a strong inverse correlation between MFS and GABA(A)/cBZR density in this region. No changes in GABA(A)/cBZR binding affinity were detected for any hippoc al subregion at any time point. Our results demonstrate that changes in hippoc al GABA(A)/cBZR expression are lamina- and time-specific. Within the dentate gyrus, receptor density is upregulated throughout epileptogenesis, whilst within the hippoc us proper, receptor density is downregulated early in epileptogenesis but upregulated at the chronic phase. A novel association between MFS and GABA(A)/cBZR density has been demonstrated by this study, which could represent an important compensatory or pathological mechanism associated with epileptogenesis.
Publisher: Cambridge University Press (CUP)
Date: 09-2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-06-2012
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2022
DOI: 10.1101/2022.08.22.22278046
Abstract: Prenatal exposure to certain antiseizure medications (ASMs) has been associated with increased risk of adverse neurodevelopmental outcomes in offspring. While the cognitive and intellectual outcomes of ASM-exposed offspring have been well-described, the long-term behavioural and functional sequalae in these children have received less attention. This systematic review aims to synthesise evidence on the relationship between prenatal ASM exposure and postnatal adverse neurodevelopmental outcomes, focusing on non-cognitive and intellectual domains of neurodevelopment including reduced social, emotional, behavioural, and adaptive functioning, as well as the frequency of neurodevelopmental and psychiatric disorders. This will have meaningful clinical implications for how we counsel women taking ASMs in pregnancy. Studies reporting predefined neurodevelopmental outcomes will be identified by electronic searches of MEDLINE, PsychINFO, EMBASE, as well as additional manual and grey literature searches. Eligible studies will report outcomes of offspring exposed to ASMs in utero either prospectively or retrospectively from 1990 to present, with screening performed in duplicate. We will use the Newcastle-Ottawa Scale to conduct methodological quality assessments of included observational studies. A narrative synthesis will be used to report on the review findings. Meta-analysis is not anticipated. Ethics clearance is not required for the current study. The systematic review will be prepared as a journal article and published in a peer-reviewed journal upon completion. PROSPERO CRD42021281919 Strengths and limitations of this study This protocol was developed and written according to the PRISMA-P guidelines Publication of this protocol ensures transparency and reproducibility of the methods of the systematic review, as well as reduces the likelihood of review duplication Restricting publications to English only may introduce bias whereby some relevant data is not included Meta-analysis is not likely to be possible due to heterogeneity in study methodology, reducing the strength of the conclusions that can be drawn Targeting psychosocial and behavioural outcomes allows for a more nuanced understanding of the long-term clinical consequences of prenatal ASM-exposure
Publisher: Frontiers Media SA
Date: 22-11-2019
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.YEBEH.2022.108960
Abstract: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 % from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p 1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-11-2005
DOI: 10.1212/01.WNL.0000180910.72487.18
Abstract: Long-term antiepileptic drug (AED) use has been associated with bone disease, but many previous studies have been limited by inadequate control subjects. We used a cotwin affected sib-pair model to investigate this issue. The authors studied 31 female twin (15 monozygous and 16 dizygous) and four sibling pairs ( 12 months of AED treatment. Areal bone mineral density (ABMD, g/cm2) was measured at the lumbar spine (LS), total hip (TH), femoral neck (FN), and total forearm (FA). Three primary a priori defined subgroups were analyzed: a) use for > 2 years, b) use of enzyme-inducing AEDs, or c) age older than 40 years. For all pairs (n = 35), there were no significant within-pair differences in any ABMD measure. However, in Subgroup a (n = 27), there was a within-pair difference at the FA (0.513 vs 0.534, -3.9%, p = 0.016). In Subgroup b (n = 29), there was also a within-pair difference at the FA for AED user vs nonuser (0.508 vs 0.529, -3.8%, p = 0.010). In Subgroup c (n = 15), there were within-pair differences at the FA (0.492 vs 0.524, -6.1%, p = 0.017) and the LS (0.884 vs 0.980, -9.8%, p = 0.036). Patients using AEDs for > 2 years, in particular those taking enzyme-inducing AEDs and those older than 40 years, have significantly lower bone mineral density at clinically relevant fracture risk sites.
Publisher: Wiley
Date: 16-02-2023
DOI: 10.1002/EPI4.12704
Abstract: Electroencephalogram (EEG) datasets from epilepsy patients have been used to develop seizure detection and prediction algorithms using machine learning (ML) techniques with the aim of implementing the learned model in a device. However, the format and structure of publicly available datasets are different from each other, and there is a lack of guidelines on the use of these datasets. This impacts the generatability, generalizability, and reproducibility of the results and findings produced by the studies. In this narrative review, we compiled and compared the different characteristics of the publicly available EEG datasets that are commonly used to develop seizure detection and prediction algorithms. We investigated the advantages and limitations of the characteristics of the EEG datasets. Based on our study, we identified 17 characteristics that make the EEG datasets unique from each other. We also briefly looked into how certain characteristics of the publicly available datasets affect the performance and outcome of a study, as well as the influences it has on the choice of ML techniques and preprocessing steps required to develop seizure detection and prediction algorithms. In conclusion, this study provides a guideline on the choice of publicly available EEG datasets to both clinicians and scientists working to develop a reproducible, generalizable, and effective seizure detection and prediction algorithm.
Publisher: Wiley
Date: 28-08-2007
Publisher: American Veterinary Medical Association (AVMA)
Date: 04-2016
Abstract: OBJECTIVE To develop representative MRI atlases of the canine brain and to evaluate 3 methods of atlas-based segmentation (ABS). ANIMALS 62 dogs without clinical signs of epilepsy and without MRI evidence of structural brain disease. PROCEDURES The MRI scans from 44 dogs were used to develop 4 templates on the basis of brain shape (brachycephalic, mesaticephalic, dolichocephalic, and combined mesaticephalic and dolichocephalic). Atlas labels were generated by segmenting the brain, ventricular system, hippoc al formation, and caudate nuclei. The MRI scans from the remaining 18 dogs were used to evaluate 3 methods of ABS (manual brain extraction and application of a brain shape–specific template [A], automatic brain extraction and application of a brain shape–specific template [B], and manual brain extraction and application of a combined template [C]). The performance of each ABS method was compared by calculation of the Dice and Jaccard coefficients, with manual segmentation used as the gold standard. RESULTS Method A had the highest mean Jaccard coefficient and was the most accurate ABS method assessed. Measures of overlap for ABS methods that used manual brain extraction (A and C) ranged from 0.75 to 0.95 and compared favorably with repeated measures of overlap for manual extraction, which ranged from 0.88 to 0.97. CONCLUSIONS AND CLINICAL RELEVANCE Atlas-based segmentation was an accurate and repeatable method for segmentation of canine brain structures. It could be performed more rapidly than manual segmentation, which should allow the application of computer-assisted volumetry to large data sets and clinical cases and facilitate neuroimaging research and disease diagnosis.
Publisher: Mary Ann Liebert Inc
Date: 11-2008
Abstract: Mood disturbances, including depression and anxiety disorders, are common and disabling long-term sequelae of traumatic brain injury (TBI). These psychiatric conditions have generally been considered psychosocial consequences of the trauma, but neurobiological alterations and causes have also been implicated. Using a rat model of TBI (lateral fluid-percussion injury), this longitudinal study seeks to assess anxiety and depression-like behaviors following experimental TBI. Male Wistar rats (n = 20) received a severe (approximately 3.5 atmosphere) pressure pulse directed to the right sensorimotor cortex, or sham surgery (n = 15). At 1, 3, and 6 months following injury, all rats underwent four assessments of anxiety and depression-like behaviors: exposure to an open field, elevated plus maze test, the forced swim test, and the sucrose preference test. Injured animals displayed increased anxiety-like behaviors throughout the study, as evidenced by reduced time spent (p = 0.014) and reduced entries (p < 0.001) into the center area of the open field, and reduced proportion of time in the open arms of the plus maze (p = 0.015), compared to sham-injured controls. These striking changes were particularly evident 1 and 3 months after injury. No differences were observed in depression-like behaviors in the forced swim test (a measure of behavioral despair) and the sucrose preference test (a measure of anhedonia). This report provides the first evidence of persistent anxiety-like disturbances in an experimental model of TBI. This finding indicates that the common occurrence of these symptoms in human sufferers is likely to have, at least in part, a neurobiological basis. Studies in this model could provide insight into the mechanisms underlying affective disturbance in brain-injured patients.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.BRAINRES.2004.11.022
Abstract: Evidence from studies in rodents and humans support an anti-seizure action of neuropeptide Y (NPY) in focal, acquired epilepsy. However, the effects of NPY in generalized genetic epilepsy remain unexplored. In this study, adult male Genetic Absence Epilepsy Rats of Strasbourg (GAERS) were implanted with extradural electrodes and an intracerebroventricular (icv) cannula. Six and 12 nmol NPY or vehicle was administered icv in a random order (n=6), and the effect of NPY on seizure activity quantitated from a 90-min EEG recording. A rapid onset and sustained seizure suppression was observed following NPY treatment compared to vehicle, with both 6 and 12 nmol NPY having a significantly decreased mean percentage time in seizure (5.7 +/- 1.4% and 5.0 +/- 1.7% vs. 15.8 +/- 3.4%) and mean number of seizures per minute (0.5 +/- 0.1 and 0.4 +/- 0.1 vs. 1.1 +/- 0.1). There was no significant difference between the degree of seizure suppression after 6 and 12 nmol NPY. The results of this study demonstrate that NPY suppresses absence seizures in GAERS. This suggests that NPY modulates pathological oscillatory thalamocortical activity and may represent a new therapeutic approach for the treatment of generalized epilepsies.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2006
DOI: 10.1007/S11307-006-0073-0
Abstract: Some patients with temporal lobe epilepsy (TLE) lack evidence of hippoc al sclerosis (HS) on MRI (HS-ve). We hypothesized that this group would have a different pattern of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) hypometabolism than typical mesial TLE/HS patients with evidence of hippoc al atrophy on magnetic resonance imaging (MRI) (HS+ve), with a lateral temporal neocortical rather than mesial focus. Thirty consecutive HS-ve patients and 30 age- and sex-matched HS+ve patients with well-lateralized EEG were identified. FDG-PET was performed on 28 HS-ve patients and 24 HS+ve patients. Both groups were compared using statistical parametric mapping (SPM), directly and with FDG-PET from 20 healthy controls. Both groups showed lateralized temporal hypometabolism compared to controls. In HS+ve, this was antero-infero-mesial (T = 17.13) in HS-ve the main clustering was inferolateral (T = 17.63). When directly compared, HS+ve had greater hypometabolism inmesial temporal/hippoc al regions (T = 4.86) HS-ve had greater inferolateral temporal hypometabolism (T = 4.18). These data support the hypothesis that focal hypometabolism involves primarily lateal neocortical rather than mesial temporal structures in 'MRI-negative PET-positive TLE.'
Publisher: Wiley
Date: 27-03-2014
DOI: 10.1111/EPI.12592
Abstract: The co‐occurrence of absence and mesial temporal lobe epilepsy is rare in both humans and animal models. Consistent with this, rat models of absence epilepsy, including genetic absence epilepsy rats from Strasbourg ( GAERS ), are resistant to experimental temporal lobe epileptogenesis, in particular by amygdala kindling. Structures within the cortical‐thalamocortical system are critically involved in the generation and maintenance of the electrographic spike‐and‐wave discharges (SWDs) that characterize absence seizures. Using in vivo electrophysiologic recordings, this study investigated the role of thalamocortical circuitry in the generalization of amygdala‐kindling induced seizures in the GAERS and the nonepileptic control ( NEC ) strain of Wistar rats. GAERS and NEC rats were implanted with a stimulating electrode in amygdala and stimulated at afterdischarge threshold twice daily to a maximum number of 30 stimulations. Thereafter extracellular single neuron recordings were performed in vivo under neuroleptanesthesia in the thalamocortical network. In NEC rats, amygdala kindling induced convulsive class V seizures and altered characteristics of neuronal activity in the thalamic reticular nucleus ( TRN ), in particular decreased firing rates and increased burst firing patterns. Less marked changes were seen in other regions examined: the ventroposteromedial nucleus of thalamus ( VPM ), the CA 3 region of the hippoc us, and the deep layers (V/ VI ) of the cortex. GAERS did not progress beyond class II seizures, with a matched number of kindling stimulations, and the thalamic neuronal firing alterations observed in NEC rats were not seen. These data suggest that the TRN plays an important role in kindling resistance in GAERS and is central to the control of secondary generalization of limbic seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .
Publisher: Elsevier BV
Date: 10-2019
Publisher: BMJ
Date: 12-2020
DOI: 10.1136/BMJNO-2020-000102
Abstract: Continuous electroencephalography (cEEG) is increasingly used to detect non-convulsive seizures in critically ill patients but is not widely practised in Australasia. Use of cEEG is also influencing the management of status epilepticus (SE), which is rapidly evolving. We aimed to survey Australian and New Zealand cEEG use and current treatment of SE A web-based survey was distributed to Epilepsy Society of Australia (ESA) members, between October and November 2019. Adult and paediatric neurologists/epileptologists with ESA membership involved in clinical epilepsy care and cEEG interpretation were invited to participate. Thirty-five paediatric/adult epileptologists completed the survey, 51% with over 10 years of consultant experience. cEEG was always available for only 31% of respondents, with the majority having no or only ad hoc access to cEEG. Lack of funding (74%) and personnel (71%) were the most common barriers to performing cEEG. Although experience with SE was common, responses varied regarding treatment approaches for both convulsive and non-convulsive SE. Escalation to anaesthetic treatment of convulsive SE tended to occur later than international guideline recommendations. There was general agreement that formal training in cEEG and national guidelines for SE/cEEG were needed. cEEG availability remains limited in Australia, with lack of funding and resourcing being key commonly identified barriers. Current opinions on the use of cEEG and treatment of SE vary reflecting the complexity of management and a rapidly evolving field. An Australian-based guideline for the management of SE, including the role of cEEG is recommended.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.NBD.2018.01.016
Abstract: Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippoc us can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures. Three cohorts of GAERS were injected bilaterally into the thalamus (short term n = 14 and long term n = 8) or the somatosensory cortex (n = 26) with rAAV-NPY or rAAV-empty. EEG recordings were acquired weekly post-treatment and seizure expression was quantified. Anxiety levels were tested using elevated plus maze and open field test. NPY and NPY receptor mRNA and protein expression were evaluated using quantitative PCR, immunohistochemistry and immunofluorescence. Viral overexpression of human NPY in the thalamus and somatosensory cortex in GAERS significantly reduced the time spent in seizure activity and number of seizures, whereas seizure duration was only reduced after thalamic NPY overexpression. Human and rat NPY and rat Y2 receptor mRNA expression was significantly increased in the somatosensory cortex. NPY overexpression in the thalamus was observed in rAAV-NPY treated rats compared to controls in the long term cohort. No effect was observed on anxiety behaviour. We conclude that virally-mediated human NPY overexpression in the thalamus or somatosensory cortex produces sustained anti-epileptic effects in GAERS. NPY gene therapy may represent a novel approach for the treatment of patients with genetic generalised epilepsies.
Publisher: Wiley
Date: 26-09-2016
DOI: 10.1111/EPI.13562
Abstract: The patterns of postoperative seizure control and response to antiepileptic drugs (AEDs) in tumor-associated epilepsy (TAE) are poorly understood. We aim to document these characteristics in patients with supratentorial gliomas. This was a retrospective analysis of 186 patients with supratentorial gliomas. Seizure patterns were classified into four groups: A, no postoperative seizure B, early postoperative seizure control within 6 months C, fluctuating seizure control and D, never seizure-free. Rates and duration of seizure freedom, subsequent seizure relapse, and response to AED were analyzed. Among patients included, 49 (26.3%) had grade II, 28 (15.1%) had grade III, and 109 (58.6%) had grade IV glioma. Outcome pattern A was observed in 95 (51.1%), B in 22 (11.8%), C in 45 (24.2%), and D in 24 (12.9%). One hundred nineteen patients had at least one seizure and were classified as having TAE. Compared to pattern A, pattern B was predicted by histologic progression pattern C by tumor grade, preoperative seizure, and histologic progression, and pattern D by preoperative seizure and gross total resection. Among patients with TAE, 57.5% of grade II, 68.2% of grade III, and 26.3% of grade IV experienced a period of 12-month seizure freedom. After first 12-month seizure remission, 39.1%, 60.0%, and 13.3% of grade II, III, and IV gliomas, respectively, experienced subsequent seizure 22.6% of those with TAE reached terminal seizure freedom of at least 12 months on their first postoperative AED regimen, 6.5% on their second regimen, and 5.4% on subsequent regimens. Distinct patterns of postoperative seizure control exist in gliomas they have specific risk factor profiles, and we hypothesize these correspond to unique pathogenic mechanisms. Twelve-month seizure freedom with subsequent relapse is frequent in grade II-III gliomas. Response to AEDs is markedly poorer than with non-TAE, highlighting the complex epileptogenicity of gliomas.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.YEBEH.2016.08.022
Abstract: The neurobiological factors underlying a predisposition towards developing epilepsy and its common behavioral comorbidities are poorly understood. FAST rats are a strain that has been selectively bred for enhanced vulnerability to kindling, while the SLOW strain has been bred to be resistant to kindling. FAST rats also exhibit behavioral traits reminiscent of those observed in neurodevelopmental disorders (autism spectrum disorder (ASD)/attention-deficit/hyperactivity disorder (ADHD)) commonly comorbid with epilepsy. In this study, we aimed to investigate neuroanatomical differences between these strains that may be associated with a differential vulnerability towards these interrelated disorders. Ex vivo high-resolution magnetic resonance imaging on adult male FAST and SLOW rat brains was performed to identify morphological differences in regions of interest between the two strains. Behavioral examination using open-field, water consumption, and restraint tests was also conducted on a subgroup of these rats to document their differential ASD/ADHD-like behavior phenotype. Using optical stereological methods, the volume of cerebellar granule, white matter, and molecular layer and number of Purkinje cells were compared in a separate cohort of adult FAST and SLOW rats. Behavioral testing demonstrated hyperactivity, impulsivity, and polydipsia in FAST versus SLOW rats, consistent with an ASD/ADHD-like phenotype. Magnetic resonance imaging analysis identified brain structural differences in FAST compared with SLOW rats, including increased volume of the cerebrum, corpus callosum, third ventricle, and posterior inferior cerebellum, while decreased volume of the anterior cerebellar vermis. Stereological measurements on histological slices indicated significantly larger white matter layer volume, reduced number of Purkinje cells, and smaller molecular layer volume in the cerebellum in FAST versus SLOW rats. These findings provide evidence of structural differences between the brains of FAST and SLOW rats that may be mechanistically related to their differential vulnerability to kindling and associated comorbid ASD/ADHD-like behaviors.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.JOCN.2004.03.027
Abstract: To report 3 cases with focal lesional epilepsy that had non-convulsive status epilepticus (NCSE) induced by treatment with tiagabine (TGB) and review the previously published cases. Drugs that enhance GABAnergic transmission are recognised to promote absence seizures in patients with generalised epilepsy syndromes and may on occasions even induce NCSE. However, that TGB can also induce NCSE in focal lesional epilepsy is not widely recognised in clinical practice. The clinical history, EEG and MRI findings were reviewed in 3 patients with lesional focal epilepsy who presented to our epilepsy programs over a 12 month period with TGB-induced NCSE. All previously reported cases in the English medical literature were reviewed. The three patients had longstanding complex partial and secondarily generalised seizures refractory to multiple different anti-epileptic drugs. In two cases, MRI demonstrated a focal malformation of cortical development in the left parieto-occipital region and in the third left mesial temporal sclerosis. Following commencement of TGB in one patient and dose escalation in two, prolonged episodes of confusion and poor responsiveness were noted. Prolonged EEG monitoring demonstrated continuous high litude, generalised, 2-4 Hz delta activity with intermingled spikes during the episodes of unresponsiveness, consistent with NCSE. The clinical and EEG activity normalised following the administration of IV clonazepam followed by dose reduction or withdrawal of the TGB. Eleven previously reported cases of patients with partial epilepsy and a focal underlying lesion on MRI were identified, all of whom had similar features to that seen in our cases. These cases illustrate that TGB may induce generalised NCSE in patients with focal lesional epilepsy, in addition to those with generalised syndromes. We hypothesise that patients may have developed an acquired alteration in the sensitivity of their thalamocortical circuitry that renders them more sensitive to the effects of drugs that enhance GABAnergic activity.
Publisher: Elsevier
Date: 2012
Publisher: AMPCo
Date: 30-06-2019
DOI: 10.5694/MJA2.50246
Publisher: Wiley
Date: 1997
DOI: 10.1111/J.1528-1157.1997.TB01080.X
Abstract: The pathophysiologic basis for the [18F]fluorodeoxyglucose positron-emission tomography (FDG-PET) temporal lobe hypometabolism in patients with hippoc al sclerosis (HS) is uncertain. We tested the hypothesis that hippoc al atrophy, which is strongly correlated with hippoc al cell loss, is largely responsible for the regional hypometabolism in HS. Regions of interest (ROIs) on FDG-PET scanning were determined in the medial, lateral, and posterior temporal lobe, thalamus, and basal ganglia. A right/left asymmetry index for each ROI was calculated. These results were correlated with hippoc al magnetic resonance imaging (MRI) volume ratios. There was no correlation between the magnitudes of the FDG-PET asymmetry index and the MRI volume ratio for the mesial or lateral temporal regions (r = -0.09, r = -0.04). When the right/left asymmetry index was compared with the right/left hippoc al volume ratio, correlations for the mesial temporal ROI (r = 0.79, p < 0.0001) and lateral temporal ROI (r = 0.57, p < 0.0005) were found. These, however, simply indicated that both tests accurately reflect the side of the epileptogenic region. The concordance of the side of relative hypometabolism of the FDG-PET with the side of the hippoc al atrophy was higher for the mesial temporal region (100%) than for the lateral (77.5%). The lack of correlation between the magnitudes of the ratios argues against hippoc al atrophy and cell loss having a central role in the FDG-PET temporal hypometabolism.
Publisher: Wiley
Date: 29-05-2013
DOI: 10.1111/EPI.12223
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 04-2017
DOI: 10.3171/2016.11.JNS161754
Abstract: Neural interface technology may enable the development of novel therapies to treat neurological conditions, including motor prostheses for spinal cord injury. Intracranial neural interfaces currently require a craniotomy to achieve implantation and may result in chronic tissue inflammation. Novel approaches are required that achieve less invasive implantation methods while maintaining high spatial resolution. An endovascular stent electrode array avoids direct brain trauma and is able to record electrocorticography in local cortical tissue from within the venous vasculature. The motor area in sheep runs in a parasagittal plane immediately adjacent to the superior sagittal sinus (SSS). The authors aimed to develop a sheep model of cerebral venography that would enable validation of an endovascular neural interface. Cerebral catheter venography was performed in 39 consecutive sheep. Contrast-enhanced MRI of the brain was performed on 13 animals. Multiple telescoping coaxial catheter systems were assessed to determine the largest wide-bore delivery catheter that could be delivered into the anterior SSS. Measurements of SSS diameter and distance from the motor area were taken. The location of the motor area was determined in relation to lateral and superior projections of digital subtraction venography images and confirmed on MRI. The venous pathway from the common jugular vein (7.4 mm) to the anterior SSS (1.2 mm) was technically challenging to selectively catheterize. The SSS coursed immediately adjacent to the motor cortex ( 1 mm) for a length of 40 mm, or the anterior half of the SSS. Attempted access with 5-Fr and 6-Fr delivery catheters was associated with longer procedure times and higher complication rates. A 4-Fr catheter (internal lumen diameter 1.1 mm) was successful in accessing the SSS in 100% of cases with no associated complications. Complications included procedure-related venous dissection in two major areas: the torcular herophili, and the anterior formation of the SSS. The bifurcation of the cruciate sulcal veins with the SSS was a reliable predictor of the commencement of the motor area. The ovine model for cerebral catheter venography has generalizability to the human cerebral venous system in relation to motor cortex location. This novel model may facilitate the development of the novel field of endovascular neural interfaces that may include preclinical investigations for cortical recording applications such as paralysis and epilepsy, as well as other potential applications in neuromodulation.
Publisher: Hindawi Limited
Date: 29-01-2009
DOI: 10.1111/J.1600-0404.1996.TB00200.X
Abstract: A patient who developed an acute brainstem syndrome following Mycoplasma pneumoniae respiratory infection is reported. MRI showed changes consistent with brainstem demyelination. Clinical features and laboratory investigations support an immune mediated mechanism with no evidence of direction CNS invasion. On the basis of this case and a review of the literature, we postulate two mechanisms for the development of M. pneumoniae associated CNS disease: direct CNS invasion causing meningitis and an immune-mediated acute disseminated encephalomyelitis (ADEM). This has obvious therapeutic implications.
Publisher: Wiley
Date: 05-02-2021
DOI: 10.1111/EPI.16827
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 07-1998
DOI: 10.1016/S0887-8994(98)00019-8
Abstract: Peri-ictal brain single-photon emission computed tomography (SPECT) is increasingly being established as a useful test in localizing partial epilepsy in adults. However, obtaining an ictal injection and acquiring the SPECT images poses a greater challenge in pediatric patients, and few reports have specifically addressed the practical use of this technique in children. The Mayo Clinic experience of peri-ictal SPECT in the evaluation of children with partial epilepsy is reported here. Peri-ictal SPECT was attempted during 71 admissions involving 59 patients (median age 12 years, range 1 year 6 months-17 years). A peri-ictal SPECT injection was performed on 48 (67.6%) of these admissions in 43 (72.9%) patients, and only two patients could not be scanned. Of the 46 peri-ictal images successfully obtained, 30 (65.2%) were from ictal injection and 16 (34.8%) from post-ictal injections. Forty-two (91.3%) of the successfully obtained SPECT images, in 38 patients (92.3%), were classified as localizing (15 temporal, 24 extratemporal). We conclude that, with the appropriate unit setup and well-trained staff, peri-ictal SPECT scans can be obtained in most pediatric partial epilepsy patients. Moreover, the procedure provides specific localizing information in a high proportion of these patients.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2021
Publisher: Springer Science and Business Media LLC
Date: 10-02-2009
DOI: 10.1007/S00259-009-1066-4
Abstract: [(11)C]Flumazenil shows promise as a clinical and research PET radiotracer to image changes in GABA(A) central benzodiazepine receptor (cBZR), but its widespread use has been limited by practical limitations of [(11)C]. This study evaluated the imaging characteristics of two fluorinated PET radiotracers in rats in vivo: [(18)F]fluoroflumazenil ([(18)F]FFMZ) and [(18)F]flumazenil ([(18)F]FMZ). PET acquisitions were performed on a small-animal scanner following injection of [(18)F]FFMZ in nine rats and [(18)F]FMZ in eight rats. The following treatments were investigated: (1) injection of the tracer dose, (2) presaturation then injection of the tracer dose, and (3) injection of the tracer dose followed by a displacement injection. Unchanged tracer was measured in plasma and brain structures in four animals 10 and 30 min after injection, and ex-vivo autoradiography was also performed. For both [(18)F]FFMZ and [(18)F]FMZ maximal brain activity peaked rapidly, and was highest in the hippoc us (1.12+/-0.06 SUV, 1.24+/-0.10 SUV, respectively), and lowest in the pons (1.00+/-0.07 SUV, 1.03+/-0.09 SUV, respectively). By 50 min after injection, maximal uptake for [(18)F]FFMZ and [(18)F]FMZ had decreased in the hippoc us to 18+/-3% and 80+/-1% (p 70% of the signal in the brain, which resulted in well-defined regional binding on autoradiography. These results demonstrate that [(18)F]FMZ is a superior radiotracer to [(18)F]FFMZ for in-vivo PET imaging of the GABA(A)/cBZR, having slower metabolism and leading to lower concentrations of metabolites in the brain that results in a substantially better signal-to-noise ratio.
Publisher: SAGE Publications
Date: 03-07-2023
DOI: 10.1177/00048674231180509
Abstract: Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on in idual medical practitioners. Through the examination of international ex les and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and in idualised treatments (2) active triage of complexity, acuity and treatment readiness (3) integrated interdisciplinary teams that in idualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.
Publisher: BMJ
Date: 09-10-2020
DOI: 10.1136/BMJ.M3658
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-02-2012
DOI: 10.1126/SCITRANSLMED.3003120
Abstract: Two high-affinity T-type calcium channel blockers attenuate neural activity in the thalamus and suppress seizures in a genetic model of absence epilepsy.
Publisher: Wiley
Date: 10-06-2014
DOI: 10.1111/EPI.12681
Publisher: Elsevier BV
Date: 05-2023
DOI: 10.1016/J.TRSL.2022.11.008
Abstract: A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, in iduals may return to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognised as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. Given this hypothesis is difficult to test clinically, we used a two-hit model of mTBI in rats and staggered inter-injury intervals by 1-, 3-, 7- or 14-days. Repeat-mTBI rats were dichotomised into NfL
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.YEBEH.2017.10.017
Abstract: The objective of the study was to assess whether the type of seizure disorder present in the prospective mother with epilepsy, her use of antiepileptic drugs (AEDs) in early pregnancy, and her seizure control before pregnancy help predict her prospects for seizure freedom throughout pregnancy. This paper is based on data accumulated in the Australian Pregnancy Register (APR) between 1998 and late 2016. Information was analyzed concerning epileptic seizure occurrence and AED therapy taken before and during pregnancy, using simple statistical and confidence interval (C.I.) methods, mainly relative risk (R.R.) calculations. After excluding pregnancies lost to follow-up, and those that ended prematurely because of spontaneous abortion or stillbirth, 1939 pregnancies were available for study. Seizures had occurred during pregnancy in 829 (42.8%), and convulsive seizures in 385 (19.9%). Seizures of any type occurred in 78.4% of pregnancies where seizures had occurred in the previous year (active epilepsy) and in 22.3% of those associated with inactive epilepsy. Seizures of any type had occurred in 54.9% of pregnancies initially unexposed to AEDs and in 45.5% of those treated with AEDs throughout. The corresponding figures for convulsive seizures during pregnancy were 31.7% and 22.3%. There was statistically significant evidence that, in women with epilepsy (WWE), having a seizure disorder that was active in the prepregnancy year and one untreated in early pregnancy was associated with decreased prospects of seizure freedom during pregnancy. Decreased chances of seizure-free pregnancies in women with focal epilepsies and those treated with multiple AEDs were probably explained by greater frequencies of active seizure disorders in these patient categories. Women with epilepsy who experience seizures in the year prior to pregnancy appear 3 or 4 times more likely to continue to have seizures during pregnancy than women whose seizures are fully controlled prior to pregnancy. Not taking AEDs in early pregnancy also increases the hazard for seizure occurrence in pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2018
Publisher: Elsevier BV
Date: 08-2023
Publisher: Wiley
Date: 17-01-2019
DOI: 10.1002/ANA.25405
Abstract: We investigated the relationship between the interictal metabolic patterns, the extent of resection of Eighty-two patients with hippoc al sclerosis or normal magnetic resonance imaging (MRI) findings, concordant Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019 1-10 ANN NEUROL 2019 :241-250.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 08-1998
DOI: 10.3171/JNS.1998.89.2.0177
Abstract: Object. Recurrence of seizures immediately following epilepsy surgery can be emotionally devastating, and raises concerns about the chances of successfully attaining long-term seizure control. The goals of this study were to investigate the frequency of acute postoperative seizures (APOS) occurring in the 1st postoperative week following anterior temporal lobectomy (ATL) to identify potential risk factors and to determine their prognostic significance. Methods. One hundred sixty consecutive patients who underwent an ATL for intractable nonlesional temporal lobe epilepsy were retrospectively studied. Acute postoperative seizures occurred in 32 patients (20%). None of the following factors were shown to be significantly associated with the occurrence of APOS: age at surgery, duration of epilepsy, side of surgery, extent of neocortical resection, electrocorticography findings, presence of mesial temporal sclerosis, and hippoc al volume measurements (p 0.05). Patients who suffered from APOS overall had a lower rate of favorable outcome with respect to seizure control at the last follow-up examination than patients without APOS (62.5% compared with 83.6%, p 0.05). The type of APOS was of prognostic importance, with patients whose APOS were similar to their preoperative habitual seizures having a significantly worse outcome than those whose APOS were auras or were focal motor and/or generalized tonic—clonic seizures (excellent outcome: 14.3%, 77.8%, and 75%, respectively, p 0.05). Only patients who had APOS similar to preoperative habitual seizures were less likely to have an excellent outcome than patients without APOS (14.3% compared with 75%, p 0.05). Timing of the APOS and identification of a precipitating factor were of no prognostic importance. Conclusions. The findings of this study may be useful in counseling patients who suffer from APOS following ATL for temporal lobe epilepsy.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NBD.2016.05.005
Abstract: The absence epilepsies are presumed to be caused by genetic factors, but the influence of environmental exposures on epilepsy development and severity, and whether this influence is transmitted to subsequent generations, is not well known. We assessed the effects of environmental enrichment on epilepsy and anxiety outcomes in multiple generations of GAERS - a genetic rat model of absence epilepsy that manifests comorbid elevated anxiety-like behaviour. GAERS were exposed to environmental enrichment or standard housing beginning either prior to, or after epilepsy onset, and underwent EEG recordings and anxiety testing. Then, we exposed male GAERS to early enrichment or standard housing and generated F1 progeny, which also underwent EEG recordings. Hippoc al CRH mRNA expression and DNA methylation were assessed using RT-PCR and pyrosequencing, respectively. Early environmental enrichment delayed the onset of epilepsy in GAERS, and resulted in fewer seizures in adulthood, compared with standard housed GAERS. Enrichment also reduced the frequency of seizures when initiated in adulthood. Anxiety levels were reduced by enrichment, and these anti-epileptogenic and anxiolytic effects were heritable into the next generation. We also found reduced expression of CRH mRNA in GAERS exposed to enrichment, but this was not due to changes in DNA methylation. Environmental enrichment produces disease-modifying effects on genetically determined absence epilepsy and anxiety, and these beneficial effects are transferable to the subsequent generation. Reduced CRH expression was associated with these phenotypic improvements. Environmental stimulation holds promise as a naturalistic therapy for genetically determined epilepsy which may benefit subsequent generations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1999
DOI: 10.1212/WNL.52.1.137
Abstract: To determine whether the detection of focal hypoperfusion by subtraction SPECT co-registered to MRI (SISCOM) improves the sensitivity and specificity of postictal SPECT in intractable partial epilepsy. Postictal SPECT injections are easier to perform than are ictal injections, but the images are more difficult to interpret and have been reported to have lower sensitivity and specificity. Thirty-five consecutive intractable partial epilepsy patients who had postictal SPECT studies were evaluated. The following sets of SPECT images were separately interpreted by three blinded reviewers and classified as either localizing to 1 of 16 possible sites in the brain or as nonlocalizing: unsubtracted postictal and interictal images for conventional side-by-side comparison, SISCOM images of hyperperfusion, SISCOM images of hypoperfusion, and both sets of SISCOM hyperperfusion and hypoperfusion images (combined SISCOM evaluation). Significantly higher proportions of the hyperperfusion SISCOM images (65.7%), the hypoperfusion SISCOM images (74.3%), and the combined SISCOM evaluation (82.9%) were localizing than were the conventional method of side-by-side comparison of unsubtracted images (31.4% p < 0.0001). Concordance with the discharge diagnosis was higher for the combined SISCOM evaluation than it was for either the hyperperfusion or the hypoperfusion SISCOM images alone (both p < 0.05). For the hypoperfusion SISCOM and the combined SISCOM evaluations, concordance of the localization with the site of epilepsy surgery was associated with a greater probability of an excellent outcome than were nonconcordant/nonlocalizing images (both p < 0.05). The use of SISCOM to detect focal cerebral hypoperfusion, in addition to focal hyperperfusion, improves the sensitivity and specificity of postictal SPECT in intractable partial epilepsy.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.SEIZURE.2010.10.011
Abstract: Controlled-release formulations of Valproate (VPA) reduce side effects by minimizing peak plasma VPA concentrations in patients with epilepsy. However, the impact of this on anti-seizure efficacy has not been thoroughly explored. Here the pharmacokinetics and pharmacodynamics of chronic intermittent (consequently, peak VPA concentrations) and continuous VPA administration were directly compared in two rat models of epilepsy. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) received a single acute bolus of VPA (100 mg/kg intravenously) combined with electroencephalography (EEG) and/or blood s ling for 180 min post-injection. GAERS and epileptic rats post-kainic acid-induced status epilepticus were chronically infused intravenously (3-5 days, respectively) with (i) saline followed by in random order (ii) intermittent and (iii) continuous VPA (42 mg/kg/h), separated by two days of wash-out. Seizures were quantified using video-EEG monitoring and VPA levels measured in brain, cerebrospinal fluid and plasma. Following acute VPA administration seizure suppression in GAERS persisted after plasma VPA levels became very low. Chronic intermittent and continuous VPA significantly suppressed seizures in both models (p<0.01) with no difference between administration regimens. In GAERS, the pattern of seizure suppression during intermittent treatment was constant, in contrast to the fluctuating VPA plasma and brain levels. There was discordance between the temporal pattern of plasma, brain VPA levels and seizure suppression efficacy in GAERS. Administration regimes that result in fluctuating VPA blood levels achieve equivalent sustained seizure suppression as those that maintain steady mid-range concentrations.
Publisher: Wiley
Date: 05-01-2012
DOI: 10.1111/J.1528-1167.2011.03370.X
Abstract: Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocortical circuit that NPY acts to suppress seizures in genetic absence epilepsy rats from Strasbourg (GAERS). In conscious freely moving GAERS, NPY was administered via intracerebral microcannulae implanted bilaterally into one of the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), the primary motor cortex (M1), caudal nucleus reticular thalamus (nRT), or ventrobasal thalamus (VB). Animals received vehicle and up to three doses of NPY, in a randomized order. Electroencephalography (EEG) recordings were carried out for 30 min prior to injection and 90 min after the injection of NPY or vehicle. Focal microinjections of NPY into the S2 cortex suppressed seizures in a dose-dependent manner, with the response being significantly different at the highest dose (1.5 mm) compared to vehicle for total time in seizures postinjection (7.2 ± 3.0% of saline, p < 0.01) and average number of seizures (9.4 ± 4.9% of saline, p < 0.05). In contrast NPY microinjections into the VB resulted in an aggravation of seizures. NPY produces contrasting effects on absence-like seizures in GAERS depending on the site of injection within the thalamocortical circuit. The S2 is the site at which NPY most potently acts to suppress absence-like seizures in GAERS, whereas seizure-aggravating effects are seen in the VB. These results provide further evidence to support the proposition that these electroclinically "generalized" seizures are being driven by a topographically restricted region within the somatosensory cortex.
Publisher: Elsevier BV
Date: 06-2013
Publisher: Wiley
Date: 09-12-2019
DOI: 10.1111/EPI.14619
Abstract: To investigate the characteristics of motor manifestation during convulsive epileptic and psychogenic nonepileptic seizures (PNES), captured using a wrist-worn accelerometer (ACM) device. The main goal was to find quantitative ACM features that can differentiate between convulsive epileptic and convulsive PNES. In this study, motor data were recorded using wrist-worn ACM-based devices. A total of 83 clinical events were recorded: 39 generalized tonic-clonic seizures (GTCS) from 12 patients with epilepsy, and 44 convulsive PNES from 7 patients (one patient had both GTCS and PNES). The temporal variations in the ACM traces corresponding to 39 GTCS and 44 convulsive PNES events were extracted using Poincaré maps. Two new indices-tonic index (TI) and dispersion decay index (DDI)-were used to quantify the Poincaré-derived temporal variations for every GTCS and convulsive PNES event. The TI and DDI of Poincaré-derived temporal variations for GTCS events were higher in comparison to convulsive PNES events (P < 0.001). The onset and the subsiding patterns captured by TI and DDI differentiated between epileptic and convulsive nonepileptic seizures. An automated classifier built using TI and DDI of Poincaré-derived temporal variations could correctly differentiate 42 (sensitivity: 95.45%) of 44 convulsive PNES events and 37 (specificity: 94.87%) of 39 GTCS events. A blinded review of the Poincaré-derived temporal variations in GTCS and convulsive PNES by epileptologists differentiated 26 (sensitivity: 70.27%) of 44 PNES events and 33 (specificity: 86.84%) of 39 GTCS events correctly. In addition to quantifying the motor manifestation mechanism of GTCS and convulsive PNES, the proposed approach also has diagnostic significance. The new ACM features incorporate clinical characteristics of GTCS and PNES, thus providing an accurate, low-cost, and practical alternative to differential diagnosis of PNES.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-08-2013
Publisher: Mary Ann Liebert Inc
Date: 15-04-2021
Abstract: The topic of potential long-term neurological consequences from having multiple concussions during a career in collision sports is controversial. We sought to investigate white matter microstructure using diffusion tensor imaging (DTI) in retired professional Australian National Rugby League (NRL) players (
Publisher: Springer Science and Business Media LLC
Date: 28-08-2014
Publisher: Elsevier BV
Date: 03-2018
Publisher: Wiley
Date: 26-07-2017
DOI: 10.1002/ACN3.441
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.PSYNEUEN.2014.01.009
Abstract: 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.
Publisher: Society of Nuclear Medicine
Date: 15-05-2008
DOI: 10.2967/JNUMED.107.048207
Abstract: This study applied decision tree analysis to evaluate the sensitivity, specificity, and cost-effectiveness of clinical algorithms that incorporate 18F-FDG PET. A cohort of 176 patients was studied. The localization rate, accuracy, therapeutic impact on the presurgical decision-making process, and correlation with the postsurgical outcome were assessed for the tests commonly performed for seizure localization. Decision tree sensitivity analysis compared 3 imaging strategies with a baseline strategy of medical therapy for all: video-electroencephalography monitoring (VEM)/MRI strategy, in which patients underwent VEM and brain MRI only, and +SPECT and +PET strategies, in which patients with an indeterminate VEM/MRI result underwent ictal SPECT or interictal 18F-FDG PET, respectively. The localization rates for VEM, MRI, 18F-FDG PET, ictal SPECT, and intracranial electroencephalography (EEG) were 62.2%, 35.8%, 75.0%, 60.0%, and 93.8%. The VEM/MRI strategy had the lowest cost per class I/II outcome, but the additional costs per class I/II outcome for the +PET and +SPECT strategies were always below the minimum reported cost savings for a class I/II outcome. There were no valid conditions in which the +SPECT strategy had a lower cost per class I/II outcome than the +PET strategy. Within the range of cost savings estimated to be associated with a class I/II outcome, all decision strategies produced net cost savings however, these were significantly higher for the +PET and the +SPECT strategies. 18F-FDG PET is cost-effective in the presurgical evaluation, particularly when used in patients with a nonlocalizing or nonconcordant VEM or MRI result.
Publisher: Informa UK Limited
Date: 2002
DOI: 10.1080/02688690220131886
Abstract: Over recent years frameless stereotactic systems have begun replacing framed systems for many neurosurgical procedures. However, little has been published regarding the use of these systems to guide intracranial electrode implantation for epilepsy surgery patients. Here we report our experience utilising such a system to insert depth electrodes and subdural grid electrodes. The SteathStation Image-Guided System (SSIGS) (Sofamor Danek, Memphis TN.) was used to insert bilateral depth electrodes in 13 patients, of whom 5 also underwent the insertion of subdural grids or strip electrodes. Initially, a surgical plan based on an entry and target point on axial and sagittal images was performed for the insertion of electrodes. Navigational views, using three-planar images, were then performed to determine which structures the electrodes would pass through to be correctly placed in the amygdala and hippoc us. The correct site of electrode implantation was confirmed post-operatively by spiral CT scans in 4 patients (which were then co-registered to the pre-implantation MRI using a surface matching technique) and the other 9 patients by post-implantation MRI. The SSIGS was found to have a mean registration error of 2.0 mm (range 1.8-2.5) in 10 cases in the 3 cases where the error was greater than 2.5 mm a surfacemerge technique was used with a mean error 0.9 (0.8-1.00). The post-implantation MRI or CT-MRI co-registration confirmed an accurate electrode placement in the mesial temporal region in all cases. Seizure onset lateralisation was achieved in 11 patients, all of whom went onto formal resections based on these results. The only long-term complication was a case of osteomyelitis which required removal of the bone flap. 73% of patients had an excellent seizure outcome. Frameless stereotactic systems can be safely used to intracranial electrodes, avoid the disadvantages of the framed system and have the added advantage of the surgeon being able to visualise the trajectory and to adjust this to avoid vital structures. As well they eliminate surgical obstruction to the insertion of subdural grids at the same operation, which may be caused by a framed system.
Publisher: MDPI AG
Date: 13-09-2009
DOI: 10.3390/MOLECULES27185931
Abstract: (1) Background: [18F]Flumazenil 1 ([18F]FMZ) is an established positron emission tomography (PET) radiotracer for the imaging of the gamma-aminobutyric acid (GABA) receptor subtype, GABAA in the brain. The production of [18F]FMZ 1 for its clinical use has proven to be challenging, requiring harsh radiochemical conditions, while affording low radiochemical yields. Fully characterized, new methods for the improved production of [18F]FMZ 1 are needed. (2) Methods: We investigate the use of late-stage copper-mediated radiofluorination of aryl stannanes to improve the production of [18F]FMZ 1 that is suitable for clinical use. Mass spectrometry was used to identify the chemical by-products that were produced under the reaction conditions. (3) Results: The radiosynthesis of [18F]FMZ 1 was fully automated using the iPhase FlexLab radiochemistry module, affording a 22.2 ± 2.7% (n = 5) decay-corrected yield after 80 min. [18F]FMZ 1 was obtained with a high radiochemical purity ( %) and molar activity (247.9 ± 25.9 GBq/µmol). (4) Conclusions: The copper-mediated radiofluorination of the stannyl precursor is an effective strategy for the production of clinically suitable [18F]FMZ 1.
Publisher: Cold Spring Harbor Laboratory
Date: 20-07-2019
DOI: 10.1101/19002717
Abstract: The primary aim of the study was to determine whether patients with psychogenic non-epileptic seizures (PNES) have different personality profiles compared to patients with epileptic seizures (ES). The secondary aim was to determine whether any such personality differences could be used to efficiently screen for PNES in clinical settings. PNES and ES are often difficult to differentiate, leading to incorrect or delayed diagnosis. While the current gold-standard investigation is video-EEG monitoring (VEM), it is resource intensive and not universally available. Although some research has investigated the differential psychological profiles of PNES and ES patients, most studies have focused on symptoms of psychopathology. The lack of research using modern personality models in PNES and ES presents a gap in knowledge that this study aimed to address. A retrospective collection of data was conducted on patients who completed the NEO-Five Factor Inventory questionnaire during a VEM admission to the Royal Melbourne Hospital between 2002-2017. Patients were classified as either ES or PNES based on clinical consensus diagnosis. For patients with ES, type of epilepsy and laterality of seizure focus were also recorded. Personality differences were investigated using Bayesian linear mixed effects models. Receiver operating characteristic curve analysis was also performed to generate sensitivities and specificities of in idual personality scores. 305 patients were included in the study. The ‘openness to experience’ domain was the only personality factor demonstrating strong evidence for a group difference (BF 10 = 21.55, d = −0.43 [95% CI −0.71, −0.17]), with patients in the PNES group having higher scores compared to the ES group. Within the openness to experience domain, only the ‘aesthetic interest’ facet showed evidence for a group difference (BF 10 = 7.98, d = −0.39 [95% CI −0.66, −0.12]). ES patients had lower scores on these measures compared to the normal population, while PNES patients did not. Both openness to experience and aesthetic interest, however, showed poor sensitivities (53%, 46% respectively) and specificities (69%, 46% respectively) for classifying PNES and ES patients. There were no differences between personality profiles in Temporal Lobe Epilepsy (TLE) and non-TLE patients, or in laterality in TLE. Patients with ES exhibit lower openness to experience and aesthetic interest compared to patients with PNES and compared to the general population. Despite these differences, the relatively low sensitivity and specificity of these instruments suggests their use is limited in a clinical setting. Nevertheless, these findings open up new avenues of research using modern personality models to further understand patients with epilepsy and related presentations.
Publisher: Wiley
Date: 05-06-2016
DOI: 10.1111/EPI.13415
Abstract: To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined. An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014). Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64% odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025). The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.
Publisher: Wiley
Date: 04-03-2014
DOI: 10.1111/EPI.12563
Abstract: Evidence from animal and human studies indicates that epilepsy can affect cardiac function, although the molecular basis of this remains poorly understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate pacemaker activity and modulate cellular excitability in the brain and heart, with altered expression and function associated with epilepsy and cardiomyopathies. Whether HCN expression is altered in the heart in association with epilepsy has not been investigated previously. We studied cardiac electrophysiologic properties and HCN channel subunit expression in rat models of genetic generalized epilepsy (Genetic Absence Epilepsy Rats from Strasbourg, GAERS) and acquired temporal lobe epilepsy (post-status epilepticus SE). We hypothesized that the development of epilepsy is associated with altered cardiac electrophysiologic function and altered cardiac HCN channel expression. Electrocardiography studies were recorded in vivo in rats and in vitro in isolated hearts. Cardiac HCN channel messenger RNA (mRNA) and protein expression were measured using quantitative PCR and Western blotting respectively. Cardiac electrophysiology was significantly altered in adult GAERS, with slower heart rate, shorter QRS duration, longer QTc interval, and greater standard deviation of RR intervals compared to control rats. In the post-SE model, we observed similar interictal changes in several of these parameters, and we also observed consistent and striking bradycardia associated with the onset of ictal activity. Molecular analysis demonstrated significant reductions in cardiac HCN2 mRNA and protein expression in both models, providing a molecular correlate of these electrophysiologic abnormalities. These results demonstrate that ion channelopathies and cardiac dysfunction can develop as a secondary consequence of chronic epilepsy, which may have relevance for the pathophysiology of cardiac dysfunction in patients with epilepsy.
Publisher: Oxford University Press (OUP)
Date: 15-05-2014
Publisher: Wiley
Date: 2009
DOI: 10.1111/J.1528-1167.2008.01759.X
Abstract: Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of gamma aminobutyric acid (GABA(A)) receptor activity is a critical mechanism in the aggravation of seizures by carbamazepine (CBZ). We examined whether structural analogs of CBZ, oxcarbazepine (OXC), and its active metabolite, monohydroxy derivative (MHD), also potentiate GABA(A) receptor current and aggravate seizures. In vitro studies in Xenopus oocytes compared the three drugs' effect on GABA(A) receptor currents. In vivo studies compared seizure activity in GAERS after intraperitoneal drug administration. OXC potentiated GABA(A) receptor current and aggravated seizures in GAERS, similarly to the effect of CBZ. Conversely, MHD showed only a minor potentiation of GABA(A) receptor current and did not aggravate seizures. A hydroxyl group at the C-10 position on the CBZ tricyclic structure in MHD reduces GABA(A) receptor potentiation and seizure aggravation. Reports of the aggravation of absence seizures in patients taking OXC may result from circulating unmetabolized OXC rather than MHD.
Publisher: Wiley
Date: 03-05-2013
DOI: 10.1111/EPI.12207
Abstract: A definite diagnosis of psychogenic nonepileptic seizures (PNES) usually requires in-patient video-electroencephalography (EEG) monitoring. Previous research has shown that convulsive psychogenic nonepileptic seizures (PNES) demonstrate a characteristic pattern of rhythmic movement artifact on the EEG. Herein we sought to examine the potential for time-frequency mapping of data from a movement-recording device (accelerometer) worn on the wrist as a diagnostic tool to differentiate between convulsive epileptic seizures and PNES. Time-frequency mapping was performed on accelerometer traces obtained during 56 convulsive seizure-like events from 35 patients recorded during in-patient video-EEG monitoring. Twenty-six patients had PNES, eight had epileptic seizures, and one had both seizure types. The time-frequency maps were derived from fast Fourier transformations to determine the dominant frequency for sequential 2.56-s blocks for the course of each event. The coefficient of variation (CoV) of limb movement frequency for the PNES events was less than for the epileptic seizure events (median, 17.18% vs. 52.23% p < 0.001). A blinded review of the time-frequency maps by an epileptologist was accurate in differentiating between the event types, that is, 38 (92.7%) of 41 and 6 (75%) of 8 nonepileptic and epileptic seizures, respectively, were diagnosed correctly, with seven events classified as "nondiagnostic." Using a CoV cutoff score of 32% resulted in similar classification accuracy, with 42 (93%) of 45 PNES and 10 (91%) of 11 epileptic seizure events correctly diagnosed. Time-frequency analysis of data from a wristband movement monitor could be utilized as a diagnostic tool to differentiate between epileptic and nonepileptic convulsive seizure-like events.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2017
Publisher: Elsevier BV
Date: 10-2020
Publisher: Hindawi Limited
Date: 24-05-2018
DOI: 10.1111/ANE.12965
Abstract: To study seizure control and rates of foetal malformation in pregnancies of women with epilepsy treated with antiepileptic drug polytherapy. The use of conventional statistical methods to analyse the Australian Pregnancy Register records of 1810 pregnancies in women with epilepsy, 508 treated with antiepileptic drug polytherapy. Polytherapy-treated pregnancies were less often seizure free than monotherapy-treated ones, for both focal (36.0% vs 51.9%: P < .05) and primary generalized epilepsies (41.1% vs 69.3% P < .05). Drug combinations with dissimilar and similar mechanisms of action achieved similar rates of seizure freedom during pregnancy (36.3% vs 38.3%). The increased rate of malformed foetuses in polytherapy pregnancies depended on valproate or topiramate being in the drug combinations. The combinations of lamotrigine and levetiracetam offered the chance of seizure control and foetal safety. In pregnancy, the use of antiepileptic drug combinations is not necessarily disadvantageous to mother and foetus if valproate and topiramate are avoided.
Publisher: Oxford University Press (OUP)
Date: 03-06-2016
Abstract: The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in cortical and subcortical structures, including the thalamus. The underlying mechanisms are unknown. The goal of the present study was to determine whether a ketamine-induced psychotic-relevant state disturbs the functional state of the corticothalamic (CT) pathway. Multisite field recordings were performed in the somatosensory CT system of the sedated rat. Baseline activity was challenged by activation of vibrissa-related prethalamic inputs. The sensory-evoked thalamic response was characterized by a short-latency (∼4 ms) prethalamic-mediated negative sharp potential and a longer latency (∼10 ms) CT-mediated negative potential. Following a single subcutaneous injection of ketamine (2.5 mg/kg), spontaneously occurring and sensory-evoked thalamic gamma oscillations increased and decreased in power, respectively. The power of the sensory-related gamma oscillations was positively correlated with both the litude and the area under the curve of the corresponding CT potential but not with the prethalamic potential. The present results show that the layer VI CT pathway significantly contributes in thalamic gamma oscillations, and they support the hypothesis that reduced NMDAR activation disturbs the functional state of CT and corticocortical networks.
Publisher: Wiley
Date: 18-02-2004
DOI: 10.1111/J.0013-9580.2004.35903.X
Abstract: To examine long-term seizure and quality-of-life outcome in a homogeneous group of patients after temporal lobectomy with pathologically proven hippoc al sclerosis (HS). Previous research has had limited follow-up (generally or=2 years' follow-up. All patients were sent a postal survey concerning seizure activity, quality of life (QOLIE-89), and antiepileptic drug (AED) use. The mean follow-up was 5.8 years (range, 2-9.2). The rate of complete postoperative seizure freedom was 82% at 12 months, 76% at 24 months, and 64% at 63 months (no further seizure recurrences observed after this time). A class I seizure outcome was achieved by 83.3% of patients. Patients with better seizure outcome had significantly better quality of life (Kendall's tau =-234, p or=2 years after surgery. Long-term quality of life is dependent on seizure outcome.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2016
Publisher: Springer Science and Business Media LLC
Date: 02-2014
Publisher: Springer Science and Business Media LLC
Date: 10-12-2013
DOI: 10.1007/S12035-013-8601-9
Abstract: 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.
Publisher: Wiley
Date: 12-2013
DOI: 10.1111/EPI.12414
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2023
Publisher: Springer Netherlands
Date: 2014
DOI: 10.1007/978-94-017-8914-1_17
Abstract: Neuronal voltage-gated ion channels and ligand-gated synaptic receptors play a critical role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks in the brain. Changes in expression of voltage-gated ion channels, in particular sodium, hyperpolarization-activated cyclic nucleotide-gated (HCN) and calcium channels, and ligand-gated synaptic receptors, in particular GABA and glutamate receptors, have been reported in many types of both genetic and acquired epilepsies, in animal models and in humans. In this chapter we review these and discuss the potential pathogenic role they may play in the epilepsies.
Publisher: Wiley
Date: 22-04-2010
DOI: 10.1111/J.1528-1167.2009.02336.X
Abstract: To compare the risks of fetal malformation during pregnancy associated with antiepileptic drug (AED) polytherapy and monotherapy. Statistical analysis of malformation rate and antiepileptic drug exposure data from the Australian Register of Antiepileptic Drugs in Pregnancy, and from the literature. The calculated relative risk (RR) value for AED polytherapy compared with monotherapy was below 1.0 in only 3 of 14 literature publications. In the register, at 1 year postnatally there were fetal malformations in 5.32% of 282 AED polytherapy pregnancies, and in 7.84% of 791 AED monotherapy pregnancies, an RR of 0.68 [95% confidence interval (CI) 0.39-1.17). For pregnancies exposed to valproate, the RR of fetal malformation (0.39, 95% CI 0.20-0.89) was lower in polytherapy (7.26%) than in monotherapy (17.9%) the difference did not depend on valproate dosage. The RR values for fetal malformation were not significantly different for AED polytherapy and monotherapy when valproate was not involved. Logistic regression suggested that coadministration of lamotrigine may have reduced the malformation risk from valproate. The fetal hazard of AED polytherapy relative to monotherapy may depend more on the degree of exposure to valproate than on the fact of polytherapy per se. Coadministration with lamotrigine may lower the fetal risk of valproate therapy.
Publisher: Wiley
Date: 27-10-2004
DOI: 10.1111/J.0013-9580.2004.04704.X
Abstract: Approximately 30% of patients admitted for video-EEG monitoring have psychogenic nonepileptic seizures (PNES). Differentiation of "convulsive" PNES from convulsive seizures can be difficult. The EEG often displays rhythmic movement artifact that may resemble seizure activity and confound the interpretation. We sought to determine whether time-frequency mapping of the rhythmic EEG artifact during "convulsive" PNES reveals a pattern that differs from that of epileptic seizures. EEGs from 15 consecutive patients with "convulsive" PNESs were studied with time-frequency mapping by using NEUROSCAN and compared with 15 patients with convulsive epileptic seizures. Fast Fourier transforms (FFTs) were performed to determine the dominant frequency for 1- to 2-s windows every 2 s through the seizures. The dominant frequency remained stable within a narrow range for the duration of the PNES, whereas in the epileptic seizures, it evolved through a wide range. The coefficient of variation of the frequency during the seizures was considerably less for patients without epilepsy (median, 15.0% range, 7.2-23.7% vs. median, 58.0% range, 34.8-92.1% p < 0.001). The median frequency did not differ significantly between groups (4.2 vs. 4.6 Hz p = 0.290). "Convulsive" PNES display a characteristic pattern on time-frequency mapping of the EEG artifact, with a stable, nonevolving frequency that is different from the evolving pattern seen during an epileptic seizure.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.YEBEH.2016.09.015
Abstract: Exposure to early life childhood trauma has been implicated as resulting in a vulnerability to epileptic and psychogenic nonepileptic seizures (PNES), hippoc al atrophy, and psychiatric disorders. This study aimed to explore the relationships between childhood trauma, epilepsy, PNES, and hippoc al volume in patients admitted to a video-electroencephalogram monitoring (VEM) unit. One hundred thirty-one patients were recruited from the Royal Melbourne Hospital VEM unit. The diagnostic breakdown of this group was: temporal lobe epilepsy (TLE) (32), other epilepsy syndromes (35), PNES (47), other nonepileptic syndromes (5), both epilepsy and PNES (6), and uncertain diagnosis (6). All patients completed a questionnaire assessing exposure to childhood trauma, the Childhood Trauma Questionnaire (CTQ), as well as questionnaires assessing psychiatric symptomatology (SCL-90-R), Anxiety and Depression (HADS), quality of life (QOLIE-98) and cognition (NUCOG). Volumetric coronal T1 MRI scans were available for 84 patients. Hippoc al volumes were manually traced by a blinded operator. The prevalence of childhood trauma in patients with PNES was higher than in patients with other diagnoses (p=0.005), and the group with PNES overall scored significantly higher on the CTQ (p=0.002). No association was found between CTQ scores and hippoc al volumes however, patients with a history of sexual abuse were found to have smaller left hippoc al volumes than patients who had not (p=0.043). Patients reporting having experienced childhood trauma scored lower on measures of quality of life and higher on measures of psychiatric symptomatology. Patients with PNES report having experienced significantly more childhood trauma than those with epileptic seizures, and in both groups there was a relationship between a history of having experienced sexual abuse and reduced left hippoc al volume. Patients with PNES and those with epilepsy who have a history of childhood trauma have overall worse quality of life and more psychiatric symptomatology.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.PSYNEUEN.2012.06.005
Abstract: Psychiatric disorders associated with elevated stress levels, such as depression, are present in many epilepsy patients, including those with mesial Temporal Lobe Epilepsy (mTLE). Evidence suggests that these psychiatric disorders can predate the onset of epilepsy, suggesting a causal/contributory role. Prolonged exposure to elevated corticosterone, used as a model of chronic stress/depression, accelerates limbic epileptogenesis in the amygdala kindling model. The current study examined whether exposure to repeated stress could similarly accelerate experimental epileptogenesis. Female adult non-epileptic Wistar rats were implanted with a bipolar electrode into the left amygdala, and were randomly assigned into stressed (n=18) or non-stressed (n=19) groups. Rats underwent conventional amygdala kindling (two electrical stimulations per day) until 5 Class V seizures had been experienced ('the fully kindled state'). Stressed rats were exposed to 30min restraint immediately prior to each kindling stimulation, whereas non-stressed rats received control handling. Restraint stress increased circulating corticosterone levels (pre-stress: 122±17ng/ml post-stress: 632±33ng/ml), with no habituation observed over the experiment. Stressed rats reached the 'fully kindled state' in significantly fewer stimulations than non-stressed rats (21±1 vs 33±3 stimulations p=0.022 ANOVA), indicative of a vulnerability to epileptogenesis. Further, seizure durations were significantly longer in stressed rats (p<0.001 ANOVA). These data demonstrate that exposure to repeated experimental stress accelerates the development of limbic epileptogenesis, an effect which may be related to elevated corticosterone levels. This may have implications for understanding the effects of chronic stress and depression in disease onset and progression of mTLE in humans.
Publisher: Oxford University Press (OUP)
Date: 1996
Abstract: This study aims to determine whether there are important clinico-electrical differences between patients with temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS) and those with TLE secondary to a discrete temporal neocortical lesion (NL). The case histories, interictal EEG, seizure semiology, ictal EEG and postoperative outcome of 46 pathologically proven patients (31 MTS and 15 NL) were compared. A history of febrile convulsions (FC) was more common in MTS patients (58% versus 26%, P < 0.05), as was a history of a significant cerebral event at < 4 years of age (22% versus 0%, P < 0.05). There were no statistically significant differences in the incidence or nature of auras. No statistically significant differences between the groups were found in the interictal-EEG. With ictal semiology dystonic posturing occurred more frequently in MTS patients (mean 52% versus 26%, P < 0.05). Facial grimacing/ twitching occurred earlier in the seizures of NL patients (median 19 s versus 35 s, P 4 Hz) in the ictal-EEG of MTS patients (mean 81% versus 60%, P = 0.05). The patients with NL developed bilateral ictal EEG changes more often (mean 55% versus 26%, P < 0.05) and more rapidly (mean 23 s versus 74 s, P < 0.005). The onset of ictal EEG seizure activity was bilateral more often in patients with NL (20% versus 4%, P < 0.005). There were no significant differences between the two groups for any of the video-EEG features, in terms of whether or not the feature occurred at least once in an in idual patients. There was a tendency for MTS patients to have a higher seizure-free postsurgical outcome (87% versus 60%, P = 0.057). However, all the NL patients who were not free of seizures had had an incomplete lesion resection. We conclude that there are a number of clinico-electrical differences between patients with mesial TLE (MTLE) and patients with neocortical TLE (NCTLE), but that none of these are sufficient to allow a distinction to be made in an in idual patient.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 11-1994
DOI: 10.3171/JNS.1994.81.5.0780
Abstract: ✓ Isolated amyloidomas may, albeit rarely, involve the central nervous system. There are three previous reports of amyloidomas that involved the gasserian ganglion and caused unilateral trigeminal neuropathies. The authors report the case of a 49-year-old woman with apparently isolated amyloidomas that caused slowly progressive bilateral trigeminal neuropathies. Magnetic resonance imaging of the brain revealed mild swelling of the left trigeminal nerve within the cavernous sinus and uniform enhancement with gadolinium throughout the length of the nerve. At craniotomy, the trigeminal nerve and ganglion were observed to be infiltrated by a tumor-like mass. Biopsy showed extensive infiltration of the nerve and ganglion by amyloid. Immunocytochemical studies of the amyloid were negative for immunoglobulins, κ and λ light chains, β-amyloid A4 protein, transthyretin, β 2 -microglobulin, cystatin C, and gelsolin, but weak focal immunoreactivity with antiamyloid AA antibody was seen in the amyloid in vessels and in some intraneural deposits. Extensive investigations failed to reveal evidence of either systemic amyloidoses or an underlying inflammatory disorder or malignancy.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.NBD.2021.105505
Abstract: This study aimed to prospectively examine cardiac structure and function in the kainic acid-induced post-status epilepticus (post-KA SE) model of chronic acquired temporal lobe epilepsy (TLE), specifically to examine for changes between the pre-epileptic, early epileptogenesis and the chronic epilepsy stages. We also aimed to examine whether any changes related to the seizure frequency in in idual animals. Four hours of SE was induced in 9 male Wistar rats at 10 weeks of age, with 8 saline treated matched control rats. Echocardiography was performed prior to the induction of SE, two- and 10-weeks post-SE. Two weeks of continuous video-EEG and simultaneous ECG recordings were acquired for two weeks from 11 weeks post-KA SE. The video-EEG recordings were analyzed blindly to quantify the number and severity of spontaneous seizures, and the ECG recordings analyzed for measures of heart rate variability (HRV). PicroSirius red histology was performed to assess cardiac fibrosis, and intracellular Ca All 9 post-KA SE rats were demonstrated to have spontaneous recurrent seizures on the two-week video-EEG recording acquired from 11 weeks SE (seizure frequency ranging from 0.3 to 10.6 seizures/day with the seizure durations from 11 to 62 s), and none of the 8 control rats. Left ventricular wall thickness was thinner, left ventricular internal dimension was shorter, and ejection fraction was significantly decreased in chronically epileptic rats, and was negatively correlated to seizure frequency in in idual rats. Diastolic dysfunction was evident in chronically epileptic rats by a decrease in mitral valve deceleration time and an increase in E/E` ratio. Measures of HRV were reduced in the chronically epileptic rats, indicating abnormalities of cardiac autonomic function. Cardiac fibrosis was significantly increased in epileptic rats, positively correlated to seizure frequency, and negatively correlated to ejection fraction. The cardiac fibrosis was not a consequence of direct effect of KA toxicity, as it was not seen in the 6/10 rats from separate cohort that received similar doses of KA but did not go into SE. Cardiomyocyte length, width, volume, and rate of cell lengthening and shortening were significantly reduced in epileptic rats. The results from this study demonstrate that chronic epilepsy in the post-KA SE rat model of TLE is associated with a progressive deterioration in cardiac structure and function, with a restrictive cardiomyopathy associated with myocardial fibrosis. Positive correlations between seizure frequency and the severity of the cardiac changes were identified. These results provide new insights into the pathophysiology of cardiac disease in chronic epilepsy, and may have relevance for the heterogeneous mechanisms that place these people at risk of sudden unexplained death.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
DOI: 10.1038/S41551-018-0321-Z
Abstract: Direct electrical stimulation of the brain can alleviate symptoms associated with Parkinson's disease, depression, epilepsy and other neurological disorders. However, access to the brain requires invasive procedures, such as the removal of a portion of the skull or the drilling of a burr hole. Also, electrode implantation into tissue can cause inflammatory tissue responses and brain trauma, and lead to device failure. Here, we report the development and application of a chronically implanted platinum electrode array mounted on a nitinol endovascular stent for the localized stimulation of cortical tissue from within a blood vessel. Following percutaneous angiographic implantation of the device in sheep, we observed stimulation-induced responses of the facial muscles and limbs of the animals, similar to those evoked by electrodes implanted via invasive surgery. Proximity of the electrode to the motor cortex, yet not its orientation, was integral to achieving reliable responses from discrete neuronal populations. The minimally invasive endovascular surgical approach offered by the stent-mounted electrode array might enable safe and efficacious stimulation of focal regions in the brain.
Publisher: Wiley
Date: 10-2008
DOI: 10.1111/J.1528-1167.2008.01593.X
Abstract: Studies in animal models and patients have implicated changes in hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) expression in the pathogenesis of temporal lobe epilepsy (TLE). However, the nature of HCN changes during the epileptogenic process and their commonality across different TLE models is unknown. Here HCN1 and HCN2 mRNA expression was quantitatively measured at different time points during epileptogenesis in two distinct animal models of TLE the kainic acid (KA)-induced status epilepticus (SE) and amygdala kindling models. Hippoc al subregions (CA1, CA3, and dentate gyrus [DG]) and entorhinal cortex were dissected at different time-points. For KA-induced SE animals this was 24 h, 7 days (preepileptic), and 6 weeks (epileptic) post status. For amygdala kindling animals this was 2 weeks after reaching either "partially kindled" (one class II/III seizure) or "fully kindled" (five class V seizures) states. Quantification of regional hippoc al neuronal loss in the KA-treated animals was done using NeuN immunofluorescence and confocal microscopy. HCN mRNA levels decreased in an isoform and region specific manner at all time points after KA-induced SE. The decrease in neuronal number could not account for all reductions in HCN mRNA levels post-KA insult, implicating transcriptional changes. A reduction in HCN2 mRNA levels was also observed in fully kindled animals in the CA3 region. A reduction in HCN mRNA levels is present in two different models of TLE. This supports the case that a reduction in HCN channel expression is an accompaniment of epileptogenesis in different adult models of TLE.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.NBD.2011.12.005
Abstract: Tau hyperphosphorylation has been implicated in the pathogenesis of a variety of forms of human epilepsy. Here we investigated whether treatment with sodium selenate, a drug which reduces pathological hyperphosphorylated tau by enhancement of PP2A activity, would inhibit seizures in rodent models. In vitro, sodium selenate reduced tau phosphorylation in human neuroblastoma cells and reversed the increase in tau phosphorylation induced by the PP2A inhibitor, okadaic acid. Sodium selenate treatment was then tested against three different rodent seizure models. Firstly the propensity of 6-Hz electrical corneal stimulation to induce seizures in adult mice was assessed following acute treatment with different doses of sodium selenate. Secondly, the number of seizures induced by pentylenetetrazole (PTZ) was quantified in rats following chronic sodium selenate treatment via drinking water. Finally, amygdala kindled rats were chronically treated with sodium selenate in drinking water and the length and the severity of the seizures evoked by stimulation of the amygdala recorded. The results demonstrated a dose-dependent protection of sodium selenate against 6-Hz stimulation induced seizures, and significant reduction in the total number of seizures following PTZ injection. Amygdala kindled rats chronically treated with sodium selenate had significantly shorter seizure duration compared controls, with more pronounced effects observed as the duration of treatment increased. The results of this study indicate that targeting hyperphosphorylated tau by treatment with sodium selenate has anti-seizure effects in a broad range of rodent models, and may represent a novel approach to treatment of patients with epilepsy.
Publisher: Hindawi Limited
Date: 02-2009
DOI: 10.1111/J.1600-0404.2009.01260.X
Abstract: To trace the pattern of antiepileptic drug (AED) use in pregnant Australian women annually from 1999 to 2007, and correlate it with the pattern of AED use in the wider community. Analysis of data from the Australian Register of AEDs in Pregnancy, related to Australian population data for AED prescriptions. Over the study period, prescribing of carbamazepine, phenytoin and valproate for pregnant women decreased, and prescribing of lamotrigine, topiramate and levetiracetam increased. These changes tended to parallel prescribing trends in the wider community, except for valproate, whose prescribing in the overall community increased as its prescribing, and its dosage prescribed, decreased in pregnancy. Concomitant with this, there was a trend towards fewer births of foetuses with abnormalities. While otherwise following national AED prescribing trends, Australian prescribers are reducing the use and dose of valproate in pregnant women, likely in recognition of the teratogenic hazards of this drug.
Publisher: Wiley
Date: 31-08-2017
DOI: 10.1111/EPI.13871
Abstract: Mesial temporal lobe epilepsy with hippoc al sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.
Publisher: Wiley
Date: 05-06-2014
DOI: 10.1111/EPI.12662
Abstract: 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. 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. 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). 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.
Publisher: Wiley
Date: 08-2013
DOI: 10.1111/EPI.12300
Abstract: There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy. Here we propose and discuss a strategy for implementing a "phase II" multicenter preclinical drug trial model based on clinical phase II/III studies designed to generate more rigorous preclinical data for efficacy. The goal is to improve the evidence resulting from preclinical studies for investigational new drugs that have shown strong promise in initial preclinical "phase I" studies. This should reduce the risk for expensive clinical studies in epilepsy and therefore increase the appeal for funders (industry and government) to invest in their clinical development.
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.JOCN.2006.07.003
Abstract: To undertake a pilot study to assess whether magnetic resonance (MR) contrast-enhanced perfusion imaging (CEPI) and diffusion-weighted imaging (DWI) provide lateralizing information in medically refractory temporal lobe epilepsy (TLE),and to compare this to standard quantitative hippoc al assessments (volumetric measurements and T2 relaxometry). Ten patients with 'non-lesional' TLE and 10 control subjects were studied. Quantification of the relative cerebral blood flow (rCBF) and apparent diffusion coefficient (ADC) was performed for the hippoc al regions. The ratios of the ipsilateral-to-contralateral side (to the EEG lateralization) were compared with the side-to-side ratios in the controls. Six patients (60%) had an ADC ratio outside the control range (the larger ADC ipsilateral to the EEG lateralization in all cases). The CBF ratios were outside the control range in all eight patients (100%) in whom CEPI was performed (the lower value ipsilateral to the EEG lateralization in all cases). The magnitude of the hippoc al volume (HV) ratios showed no significant correlation with the magnitude of the ADC ratios (R=-0.03, p=0.93) or CBF ratios (R=0.36, p=0.39). There was a closer relationship with the T2 relaxometry ratios, but this was also not significant (R=-0.40, p=0.32 R=0.58, p=0.08). DWI and CEPI show potential as reliable tools for the lateralization of non-lesional TLE. Further studies with larger numbers are necessary to determine whether these techniques provide independent data to established MR quantitative measures.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 03-2004
DOI: 10.3171/JNS.2004.100.3.0452
Abstract: Object. The aim of this study was to review seizure outcome, imaging modalities used, and complications following surgery in patients with epilepsy who had undergone multimodality image-guided surgery at our institution. Methods. Data from patients with epilepsy who had undergone surgery between April 1999 and October 2001 were reviewed. During this time period, 116 operations were performed in 109 patients with medically refractory epilepsy. Among these patients, 22 were selected to undergo multimodality image-guided surgery primarily on the basis of whether they had no lesion visible on conventional magnetic resonance (MR) imaging sequences, multiple lesions, or one very large lesion that could not be completely resected without the risk of significant postoperative morbidity. A fourth group of patients in whom there was a single lesion in the eloquent cortex, a location associated with a significant risk of postoperative morbidity, was also included in the analysis. This latter group was assessed with the aid of intracranial grid electrodes that were coregistered to the MR image and were used intraoperatively to minimize electrode position error. Other imaging modalities used included positron emission tomography (PET), fluid-attenuated inversion recovery (FLAIR) MR imaging, and subtracted ictal–interictal single-photon positron emission computerized tomography (SPECT) coregistered with MR imaging (SISCOM). After coregistration, images were then downloaded onto an image-guided surgical system and the epileptogenic area was then resected. The mean patient age was 33 years (range 17–46 years), and there was a mean follow up of 27 months (range 14–41 months). Multimodality coregistrations used were as follows: nine PET scans, seven subdural electrode grids, four SISCOM studies, one FLAIR MR image, and one combined PET/subdural grid. Seizure outcome was excellent in 17 patients (77%) and not excellent in five (23%), or favorable in 19 (86%) and unfavorable in three (14%). Six patients (27%) had a transient neurological deficit, one patient (5%) a permanent major deficit, and three patients (15%) a permanent minor deficit. Five patients (24%) had a transient psychiatric problem postoperatively. Conclusions. Multimodality image-guided surgery offers a new perspective in surgery for epilepsy. Functional imaging modalities previously lateralized and often localized a seizure focus, but did not provide enough anatomical information to resect the epileptogenic zone confidently and safely. The coregistration of these modalities to a volumetric MR image and their incorporation into an image-guided system has allowed surgeons to offer surgery to patients who may not previously have been considered eligible, with outcomes comparable to those in patients with more straightforward lesional epilepsy.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.JNEUMETH.2009.01.024
Abstract: Electroencephalography (EEG) recording and drug administration is commonly used for neurological experiments in rats, but is typically cumbersome due the use of multiple lines. We have developed a unique system, which allows long-term simultaneous video-electroencephalography recording, drug infusion and blood s ling in rats. The vEEG/drug infusion system was designed and tested on two contrasting animal models of epilepsy. Animals were implanted with EEG-electrodes and a jugular vein cannula fixed in a head cap, avoiding an additional cable for tethering. In an acute infusion study (n=16), repeated blood s les were taken after i.v. bolus injection of valproate. In a subset of these rats (n=10), paired blood s les were removed from the jugular vein and the heart after valproate administration. In a chronic infusion study (n=38), heparinised (4IU/h) saline or valproate (42mg/kg/h) was infused continuously for up to 17 days. In the acute study, repeated blood s les showed a decrease in plasma valproate levels over time following bolus injection. In the chronic study, high quality continuous EEG was achieved and 79% of animals were successfully infused throughout the planned infusion period (13-17 days), with 66% of projected blood s les able to be taken during the infusion. There was a high correlation between the jugular vein and cardiac plasma levels of valproate (Spearman test, r=0.69 p<0.05). This system is ideal for pharmacokinetic/dynamic studies and long-term drug infusion where simultaneous EEG and/or frequent blood s ling are desired.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 28-08-2007
DOI: 10.1111/J.1528-1167.2007.01245.X
Abstract: The past decade has seen a surge in the utilization of small animal imaging for epilepsy research. In vivo imaging studies have the potential to provide important insights into the structural and functional correlates of the development and progression of epilepsy in these models. However, the small size of the rodent brain means that anatomic resolution is often relatively poor for many imaging modalities, particularly those providing functional information such as positron emission tomography. Coregistration of these images with those of higher structural resolution, such as MRI, provides an attractive approach to this problem, and also allows correlations between structural and functional imaging data. Image coregistration is commonly utilized in clinical research and practice. However, its application for small animal images has been, to date, relatively under utilized and largely unvalidated. The current review aims to provide an overview of image coregistration methods, particularly for MRI and PET, and their application to imaging of small animal models of epilepsy. Methodological advantages and potential traps are highlighted.
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.JOCN.2006.08.015
Abstract: Internal comparisons using the data of the Australian Register of Antiepileptic Drugs in Pregnancy as of November 2005, and comparisons with Australian population data, were carried out. It was found that (i) except for under-representation of mothers of Asian origin, the demography of the register population was reasonably representative of the Australian situation (ii) except for more pregnancies terminated for foetal malformation, malformation rates were similar in retrospectively and non-retrospectively enrolled pregnancies (iii) some 21% of foetal malformations would have been excluded by not including malformations first recognised after the neonatal period and (iv) in practice, the comparator against which malformation rates were expressed made little difference to the rates found. It is desirable to have available such analyses of pregnancy register data before comparing the findings of different registers.
Publisher: Oxford University Press (OUP)
Date: 23-11-2022
Abstract: More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7–11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9–2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8–0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9–1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63–0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64–0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.
Publisher: IOP Publishing
Date: 10-2022
Abstract: Automated interictal epileptiform discharge (IED) detection has been widely studied, with machine learning methods at the forefront in recent years. As computational resources become more accessible, researchers have applied deep learning (DL) to IED detection with promising results. This systematic review aims to provide an overview of the current DL approaches to automated IED detection from scalp electroencephalography (EEG) and establish recommendations for the clinical research community. We conduct a systematic review according to the PRISMA guidelines. We searched for studies published between 2012 and 2022 implementing DL for automating IED detection from scalp EEG in major medical and engineering databases. We highlight trends and formulate recommendations for the research community by analyzing various aspects: data properties, preprocessing methods, DL architectures, evaluation metrics and results, and reproducibility. The search yielded 66 studies, and 23 met our inclusion criteria. There were two main DL networks, convolutional neural networks in 14 studies and long short-term memory networks in three studies. A hybrid approach combining a hidden Markov model with an autoencoder was employed in one study. Graph convolutional network was seen in one study, which considered a montage as a graph. All DL models involved supervised learning. The median number of layers was 9 (IQR: 5–21). The median number of IEDs was 11 631 (IQR: 2663–16 402). Only six studies acquired data from multiple clinical centers. AUC was the most reported metric (median: 0.94 IQR: 0.94–0.96). The application of DL to IED detection is still limited and lacks standardization in data collection, multi-center testing, and reporting of clinically relevant metrics (i.e. F1, AUCPR, and false-positive/minute). However, the performance is promising, suggesting that DL might be a helpful approach. Further testing on multiple datasets from different clinical centers is required to confirm the generalizability of these methods.
Publisher: Society for Neuroscience
Date: 14-01-2009
DOI: 10.1523/JNEUROSCI.5295-08.2009
Abstract: Low-voltage-activated, or T-type, calcium (Ca 2+ ) channels are believed to play an essential role in the generation of absence seizures in the idiopathic generalized epilepsies (IGEs). We describe a homozygous, missense, single nucleotide (G to C) mutation in the Ca v 3.2 T-type Ca 2+ channel gene ( Cacna1h ) in the genetic absence epilepsy rats from Strasbourg (GAERS) model of IGE. The GAERS Ca v 3.2 mutation ( gcm ) produces an arginine to proline (R1584P) substitution in exon 24 of Cacna1h , encoding a portion of the III–IV linker region in Ca v 3.2. gcm segregates codominantly with the number of seizures and time in seizure activity in progeny of an F1 intercross. We have further identified two major thalamic Cacna1h splice variants, either with or without exon 25. gcm introduced into the splice variants acts “epistatically,” requiring the presence of exon 25 to produce significantly faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This gain-of-function mutation, the first reported in the GAERS polygenic animal model, has a novel mechanism of action, being dependent on exonic splicing for its functional consequences to be expressed.
Publisher: Wiley
Date: 04-1999
DOI: 10.1002/1531-8249(199904)45:4<526::AID-ANA17>3.0.CO;2-N
Publisher: BMJ
Date: 10-2022
DOI: 10.1136/BMJOPEN-2022-065440
Abstract: A substantial proportion of patients who undergo surgery for drug resistant focal epilepsy do not become seizure free. While some factors, such as the detection of hippoc al sclerosis or a resectable lesion on MRI and electroencephalogram-MRI concordance, can predict favourable outcomes in epilepsy surgery, the prognostic value of the detection of focal hypometabolism with 18 F-fluorodeoxyglucose positive emission tomography ( 18 F-FDG-PET) hypometabolism is uncertain. We propose a protocol for a systematic review and meta-analysis to examine whether localisation with 18 F-FDG-PET hypometabolism predicts favourable outcomes in epilepsy surgery. A systematic literature search of Medline, Embase and Web of Science will be undertaken. Publications which include evaluation with 18 F-FDG-PET prior to surgery for drug resistant focal epilepsy, and which report ≥12 months of postoperative surgical outcome data will be included. Non-human, non-English language publications, publications with fewer than 10 participants and unpublished data will be excluded. Screening and full-text review of publications for inclusion will be undertaken by two independent investigators, with discrepancies resolved by consensus or a third investigator. Data will be extracted and pooled using random effects meta-analysis, with heterogeneity quantified using the I 2 analysis. Ethics approval is not required. Once complete, the systematic review will be published in a peer-reviewed journal. CRD42022324823.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2000
DOI: 10.1097/00006231-200006000-00008
Abstract: Subtraction ictal SPET co-registered to MRI (SISCOM) has been shown to aid epileptogenic localization and improve surgical outcome in partial epilepsy patients. This paper reports a method of identifying significant areas of epileptogenic activation in the SISCOM subtraction image, taking into account normal variation between sequential 99Tcm-ethyl cysteinate diethylester SPET scans of single in iduals, and attempts to assess the clinical value of statistical mapping in subtraction SPET. Non-linear inter-subject registration is used to combine a group of subtraction images into a common anatomical framework. A map of the pixel intensity standard deviation values in the subtraction images is created, and this map is non-linearly registered to a patient's SISCOM subtraction image. Pixels in the patient subtraction image were then evaluated based upon the statistical characteristics of corresponding pixels in the atlas. SISCOM images created with the voxel variance method were rated higher in quality than the conventional image variance method in 15 patients. No difference in localization rate was observed between the voxel variance mapping and image variance methods. The voxel significance mapping method was shown to improve the quality of clinical SISCOM images.
Publisher: Wiley
Date: 07-04-2022
DOI: 10.1002/JPEN.2373
Abstract: Induction of ketosis by manipulation of nutrition intake has been proposed as an adjunctive treatment for super‐refractory status epilepticus (SRSE). However, the classical 4:1 ketogenic ratio may not meet the nutrition needs, specifically protein for critically ill adults. The aim of this study was to analyze the outcomes of adults with SRSE who received a lower ketogenic ratio of 2:1 grams of fat to non‐fat grams, including 20%–30% of energy from medium chain triglycerides. We reviewed patients aged ≥18 years with SRSE treated with ketogenic therapy between July 2015 and December 2020 at two quaternary teaching hospitals in Melbourne, Australia. Data collected from medical records included patient demographics, nutrition prescription, clinical outcomes, and ketogenic therapy‐related complications. The primary outcome of the study was to assess tolerability of ketogenic therapy. Twelve patients (female = 7) were treated with ketogenic therapy for SRSE. Patients received between 4 and 8 antiseizure medications and 1–5 anesthetic agents prior to commencement of ketogenic therapy. Blood beta‐hydroxybutyrate concentrations were variable (median = 0.5 mmol/L, range: 0.0–6.1 mmol/L). SRSE resolved in 10 cases (83%) after a median of 9 days (range: 2–21 days) following commencement of ketogenic therapy. Ketogenic therapy–associated complications were reported in five patients, leading to cessation in two patients. Despite the challenge in maintaining ketosis during critical illness, low ratio 2:1 ketogenic therapy incorporating medium chain triglycerides is tolerable for adults with SRSE. Further studies are required to determine the optimal timing, nutrition prescription and duration of ketogenic therapy for SRSE treatment.
Publisher: Public Library of Science (PLoS)
Date: 02-10-2013
Publisher: Oxford University Press
Date: 23-11-2010
Publisher: Elsevier BV
Date: 04-2020
Publisher: Frontiers Media SA
Date: 30-09-2020
Publisher: Wiley
Date: 27-06-2012
DOI: 10.1111/J.1528-1167.2012.03569.X
Abstract: A lifetime psychiatric history has been reported to be associated with poorer seizure outcome following temporal lobectomy for drug-resistant focal epilepsy, but it remains unclear whether this is confounded by the nature of the epileptogenic pathology. Here we examined this association in a pathologically homogeneous group of patients with mesial temporal sclerosis (MTS). The study population included 72 consecutive patients who underwent a temporal lobectomy for drug resistant temporal lobe epilepsy (TLE) and had histopathologically proven MTS. All patients were assessed preoperatively by a neuropsychiatrist. Chi-square analysis was undertaken to look for demographic, clinical, psychiatric, or neurologic factors associated with seizure outcome at 1 year. The relationship between having a psychiatric disorder and seizure outcome was examined by generating Kaplan-Meier curves and comparing between groups the log rank test as well as generating Cox regression models to estimate hazard ratios. There were no significant associations between postsurgery seizure outcome and a current or lifetime history of any psychiatric disorder. A history of psychiatric disorder, in particular depression and psychosis, is not associated with a poorer surgical outcome in patients with MTS. These findings have implications for the clinical management of patients under consideration for temporal lobectomy.
Publisher: Frontiers Media SA
Date: 10-09-2019
Publisher: Wiley
Date: 15-04-2020
DOI: 10.1002/ANA.25724
Publisher: Wiley
Date: 16-04-2015
DOI: 10.1111/EPI.12993
Abstract: People with Alzheimer's disease (AD) are up to 10 times more likely to develop epilepsy than the age-matched general population. However, given that only a proportion of patients with AD develop epilepsy, it is likely that additional factors may be required for the epilepsy to emerge. This study aimed to better understand the relationship between AD pathology and seizure susceptibility. It also aimed to investigate a "two-hit" hypothesis for seizure susceptibility through amygdala kindling of rodent AD models. Aged AD mice (Tg2576 model) and wild-type (WT) mice underwent electrical amygdala kindling. Compared with WT mice, Tg2576 mice had significantly lower afterdischarge threshold. Significantly fewer stimulations were required for the Tg2576 mice to reach the first class V seizure. Higher death rate was observed with Tg2576 mice in the kindling group. Both sham and kindled Tg2576 animals had increased levels of sprouting in the supragranular layer of the dentate gyrus compared with the WT counterparts. These findings support the "two-hit" hypothesis and represent a potentially novel research model to help better understand the relationship between AD pathology and epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2017
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.YEBEH.2019.106530
Abstract: Psychopathology is common in patients undergoing investigation for seizure-related disorders. Psychometric examination using self-report instruments, such as the Symptom Checklist 90 - Revised (SCL-90-R), can assist diagnosis. The SCL-90-R, however, is a lengthy instrument and might not be tolerated by all patients. We assessed several abbreviated forms of the SCL-90-R in patients undergoing video encephalographic monitoring (VEM). Six hundred eighty-seven patients completed the SCL-90-R, and scores were computed for the full SCL-90-R and five abbreviated forms. Correlations and mean differences were computed between different forms. Classification accuracy was assessed via receiver operating characteristic (ROC) curves, and measurements models were examined using confirmatory factor analysis (CFA). All abbreviated forms were strongly correlated with the SCL-90-R for general psychopathology (r = 0.93-0.99), depression (r = 0.89-0.95), anxiety (r = 0.97-0.98), psychosis (r = 0.95-0.99), and obsessive-compulsive symptoms (r = 0.97). Classification performance was similar across forms for depression and anxiety, with high negative predictive values (0.90-0.94) and lower positive predictive values (0.34-0.38). Classification performance for psychotic and obsessive-compulsive disorders was poor. Differences were observed between the full SCL-90-R and its abbreviated forms across most domains (d = 0.00-0.65). The published measurement model was most strongly validated for the SCL-27, SCL-14, and the SCL-K-9. These five SCL-90-R abbreviated forms show high convergent validity with the full version. In patients undergoing investigation for seizure-related disorders, the Brief Symptom Inventory full form (BSI) or short form (BSI-18) is most appropriate where screening for both depression and anxiety is required. The SCL-K-9 is appropriate when only a single measure of global psychological distress is required. None of the instruments were able to detect psychotic or obsessive-compulsive symptoms with great accuracy. Caution should be exercised when making direct comparisons across the different forms.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.YEBEH.2019.05.032
Abstract: The objective of the study were to investigate patterns of multiunit cluster firing in the piriform cortex (PC) and mediodorsal thalamus (MDT) in a rat model of genetic generalized epilepsy (GGE) with absence seizures and to assess whether these regions contribute to the initiation or spread of generalized epileptiform discharges. Multiunit clusters and their corresponding local field potentials (LFPs) were recorded from microelectrode arrays implanted in the PC and MDT in urethane anesthetized Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and nonepileptic control (NEC) rats. Peristimulus time histograms (PSTHs) and cross-correlograms were used to observe transient changes in both the rate of firing and synchrony over time. The phase locking of multiunit clusters to LFP signals (spike-LFP phase locking) was calculated for frequency bands associated with olfactory communication between the two brain regions. There were significant increases in both rate of firing and synchronous activity at the onset of generalized epileptiform discharges in both PC and MDT. Prior to and following these increases in synchronous activity, there were periods of suppression. Significant increases in spike-LFP phase locking were observed within the PC prior to the onset of epileptiform discharges across all spectral bands. There were also significant increases in spike-LFP phase locking within the theta band of the MDT prior to onset. Between the two brain regions, there was a significant decrease in spike-LFP phase locking -0.5 s prior to onset in the theta band which coincided with a significant elevation in spike-LFP phase locking in the gamma band. Both the PC and MDT are engaged in the absence epilepsy network. Early spike-LFP phase locking between these two brain regions suggests potential involvement in the initiation of seizure activity.
Publisher: Wiley
Date: 18-03-2020
DOI: 10.1111/EPI.13847
Abstract: The biologic processes underlying epileptogenesis following a brain insult are not fully understood, but several lines of evidence suggest that hyperphosphorylation of tau may be an important factor in these processes. To provide further insight into the causal relationship between tau and epileptogenesis, this study applied amygdala kindling to rTg4510 mice that, concurrent with other pathologies, overexpress phosphorylated tau, tau knockout mice, or their respective wild-type controls. Mice were electrically stimulated twice daily, 5 days per week for 3 weeks. Electroencephalography was recorded to measure the primary afterdischarge duration, and the behavioral progression of kindling-induced seizures was assessed. rTg4510 mice (n = 10) had increased primary afterdischarge durations (p < 0.001), and significantly more rapid progression of kindling (p < 0.001), compared with wild-type mice (n = 10). Tau knockout mice (n = 7), however, did not differ from their wild-type counterparts (n = 8) on any of the seizure outcomes. These results suggest that Tg4510 mice are more vulnerable to epileptogenesis, but that the presence of tau itself is not necessary for kindling epileptogenesis to occur.
Publisher: Elsevier
Date: 2012
Publisher: Elsevier BV
Date: 03-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-07-2012
Publisher: Hindawi Limited
Date: 31-08-2017
DOI: 10.1111/ANE.12816
Abstract: To clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death. Analysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy. The relative risk (6.46 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure. Intrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy.
Publisher: Oxford University Press (OUP)
Date: 19-06-2021
Abstract: Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.
Publisher: Wiley
Date: 07-1999
DOI: 10.1111/J.1528-1157.1999.TB00796.X
Abstract: Despite accurate localization of the seizure focus, not all patients are seizure free after temporal lobectomy. This study determined risk factors for seizure recurrence in patients with proven hippoc al sclerosis. The outcome from surgery was assessed in 56 consecutive patients with proven hippoc al sclerosis. The age at surgery, duration of epilepsy, history and age of febrile seizures, age of onset of epilepsy, sex ratio, laterality of seizure focus, and seizure frequency were compared between patients seizure free and those not seizure free, and those seizure and aura free and those with seizure recurrence including auras. During a mean follow-up of 38 months, 48 (86%) of 56 are seizure free. The mean age at surgery (37 vs. 36 years), duration of epilepsy (26 vs. 22 years), age (1.6 vs. 1.1 years), and occurrence (58 vs. 75%) of febrile seizures, age of onset of epilepsy (11 vs. 14 years), sex ratio (50 vs. 75% female), laterality of seizure focus (42 vs. 50% left), greater than weekly seizures (40 vs. 38%), and a history of (69 vs. 75%) and frequency of (2.10 vs. 2.38 per year) secondarily generalized seizures did not differ significantly between the two groups. Similarly there was no significant difference between patients seizure and aura free and those with seizure recurrence including auras. Clinical factors such as seizure frequency and duration of epilepsy are not risk factors for postoperative seizure recurrence.
Publisher: Wiley
Date: 30-12-2019
DOI: 10.1002/CNE.24589
Abstract: Accumulating research suggests that children may be more vulnerable to poor long-term outcomes after traumatic brain injury (TBI) compared to adults. The neuroinflammatory response, known to contribute to neuropathology after TBI, appears to differ depending upon age-at-insult, although this response has not been well-characterized. Elevated levels of a key initiator of inflammation, high-mobility group box protein 1 (HMGB1), have been associated with worsened outcomes after TBI in young patients. This study therefore aimed to characterize the acute time course of key mediators of the inflammatory cascade, including HMGB1, after pediatric and adult TBI. Male C57Bl/6 mice were subjected to severe controlled cortical impact or a sham control surgery, at either early adulthood (8-10 weeks) or a pediatric age (3 weeks). Cortical tissue was collected for Western blot detection of astrocyte and microglial activation (GFAP and CD68) and HMGB1 at 2 hr, 6 hr, 24 hr, 3 days, and 7 days postinjury, and serum was collected for enzyme-linked immunoassays to quantify peripheral HMGB1. An additional cohort of brains was harvested at 3 day postinjury for immunofluorescence staining. Results demonstrated a temporal profile of CD68, GFAP, and HMGB1 after TBI relative to sham, which differed between the adult and pediatric cohorts. An increase in peripheral HMGB1 was found in serum from pediatric TBI mice, which was not evident in adult serum. Together, these findings demonstrate that HMGB1 and the downstream cellular inflammatory response are influenced by age-at-insult, which may be an important consideration for treatment strategies aiming to ameliorate this response after TBI.
Publisher: Mary Ann Liebert Inc
Date: 09-2015
Abstract: Traumatic brain injury (TBI) is a leading cause of death worldwide. In recent studies, we have shown that experimental TBI caused an immediate (24-h post) suppression of neuronal processing, especially in supragranular cortical layers. We now examine the long-term effects of experimental TBI on the sensory cortex and how these changes may contribute to a range of TBI morbidities. Adult male Sprague-Dawley rats received either a moderate lateral fluid percussion injury (n=14) or a sham surgery (n=12) and 12 weeks of recovery before behavioral assessment, magnetic resonance imaging, and electrophysiological recordings from the barrel cortex. TBI rats demonstrated sensorimotor deficits, cognitive impairments, and anxiety-like behavior, and this was associated with significant atrophy of the barrel cortex and other brain structures. Extracellular recordings from ipsilateral barrel cortex revealed normal neuronal responsiveness and diffusion tensor MRI showed increased fractional anisotropy, axial diffusivity, and tract density within this region. These findings suggest that long-term recovery of neuronal responsiveness is owing to structural reorganization within this region. Therefore, it is likely that long-term structural and functional changes within sensory cortex post-TBI may allow for recovery of neuronal responsiveness, but that this recovery does not remediate all behavioral deficits.
Publisher: Wiley
Date: 28-07-2018
DOI: 10.1111/BCP.13653
Publisher: Elsevier BV
Date: 03-2023
Publisher: Informa UK Limited
Date: 09-1999
Publisher: Wiley
Date: 22-04-2014
DOI: 10.1111/BCP.12205
Publisher: SAGE Publications
Date: 21-09-2011
Abstract: Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2008
Publisher: SAGE Publications
Date: 08-04-2015
Abstract: Multitrauma is a common medical problem worldwide, and often involves concurrent traumatic brain injury (TBI) and bone fracture. Despite the high incidence of combined TBI and fracture, preclinical TBI research commonly employs independent injury models that fail to incorporate the pathophysiologic interactions occurring in multitrauma. Here, we developed a novel mouse model of multitrauma, and investigated whether bone fracture worsened TBI outcomes. Male mice were assigned into four groups: sham-TBI +sham-fracture (SHAM) sham-TBI+fracture (FX) TBI+sham-fracture (TBI) and TBI+fracture (MULTI). The injury methods included a closed-skull weight-drop TBI model and a closed tibial fracture. After a 35-day recovery, mice underwent behavioral testing and magnetic resonance imaging (MRI). MULTI mice displayed abnormal behaviors in the open-field compared with all other groups. On MRI, MULTI mice had enlarged ventricles and diffusion abnormalities compared with all other groups. These changes occurred in the presence of heightened neuroinflammation in MULTI mice at 24 hours and 35 days after injury, and elevated edema and blood–brain barrier disruption at 24 hours after injury. Together, these findings indicate that tibial fracture worsens TBI outcomes, and that exacerbated neuroinflammation may be an important factor that contributes to these effects, which warrants further investigation.
Publisher: Wiley
Date: 13-05-2018
Abstract: The arterial to end-tidal carbon dioxide tension difference (CO Patients presenting to tertiary Australian ED with suspected sepsis (n = 215) underwent near-simultaneous end-tidal carbon dioxide and partial pressure of carbon dioxide measurements. We investigated the correlation of CO Among patients included in the analysis (n = 165), the CO In this pilot study of patients with suspected sepsis from non-respiratory causes, an increased CO
Publisher: Oxford University Press (OUP)
Date: 13-03-2015
DOI: 10.1093/BRAIN/AWV053
Publisher: Mary Ann Liebert Inc
Date: 15-05-2020
Abstract: It is increasingly reported that a history of concussion may be associated with chronic deleterious consequences. While the pathophysiology that contributes to these consequences is not well understood, neuroinflammation is postulated to be critical. Activation of multi-protein complexes termed inflammasomes, a key component of this inflammatory response, has been reported in more severe TBIs however, it has not been investigated in milder TBIs, such as concussion. This study investigated serum levels of interleukin (IL)-1β and IL-18 (key proteins activated downstream of these inflammasomes) at acute, sub-acute, and chronic time-points post-concussion. We recruited 105 Australian footballers (65 male, 40 female) during the pre-season, then prospectively followed these players for the occurrence of concussion during the season. At baseline, 58 footballers reported a previous concussion history, and 47 reported no previous concussion history. Additionally, 25 players sustained a mid-season concussion and were s led at 2, 6, and 13 days post-concussion. Serum levels of IL-1β and IL-18 were quantified using highly sensitive Simoa HD-X Analyzer assays. At baseline, IL-1β levels were higher in male, but not female, footballers with a previous concussion history compared with footballers with no concussion history. There was also a positive correlation between years of collision sport participation and IL-18 levels in males. No evidence was found in males or females to indicate that IL-1β or IL-18 levels differed at 2, 6, or 13 days post-concussion. These findings provide novel insights into potential sex-specific physiological consequences of concussion, and suggest that neuroinflammation may be persistent chronically following concussion in male athletes.
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0967-5868(98)90040-6
Abstract: Previous reports have shown that McArdle's disease may occasionally present in older patients (i.e. greater than 40 years of age) as a progressive myopathy that is clinically and sometimes electrophysiologically indistinguishable from idiopathic polymyositis. We report two such patients who in addition had muscle biopsies showing inflammatory infiltrates compatible with polymyositis. However, subsequent enzyme histochemistry demonstrated complete myophosphorylase deficiency and, in the absence of an alternative explanation, may be the reason for the inflammatory changes seen. These cases highlight the importance of a thorough evaluation of patients with an 'inflammatory myopathy' and the occasional diagnostic confusion that may arise in differentiating metabolic myopathies from idiopathic polymyositis. Diagnostic clarification is important to avoid the use of incorrect and potentially toxic treatment.
Publisher: Future Medicine Ltd
Date: 11-2019
Abstract: The airways of persons with cystic fibrosis are prone to infection by a erse and dynamic polymicrobial consortium. Currently, no models exist that permit recapitulation of this consortium within the laboratory. Such microbial ecosystems likely have a network of interspecies interactions, serving to modulate metabolic pathways and impact upon disease severity. The contribution of less abundant/fastidious microbial species on this cross-talk has often been neglected due to lack of experimental tractability. Here, we critically assess the existing models for studying polymicrobial infections. Particular attention is paid to 3Rs-compliant in vitro and in silico infection models, offering significant advantages over mammalian infection models. We outline why these models will likely become the ‘go to’ approaches when recapitulating polymicrobial cystic fibrosis infection.
Publisher: Frontiers Media SA
Date: 20-10-2022
DOI: 10.3389/FNINS.2022.1003522
Abstract: Behavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain’s glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD. Serial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., “non-progressors”). Overall, PVS cluster number (ß = −3.27, CI [−7.80 – 1.27], p = 0.267) and PVS volume (ß = −36.8, CI [−84.9 – 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = −0.802e –3 , CI [9.45e – 3 – −6.60e – 3 , p ≤ 0.001 PVS volume ß = −1.30e – 3 , CI [−1.55e – 3 – −1.05e – 3 ], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e – 3 , CI [1.33e – 3 – 7.40e – 3 ], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 – 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 – 2.16], p & 0.001) and PVS volume (ß = 13.8, CI [6.37 – 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 – 2.52], p = 0.045) over time. Within the “non-progressor” group ( n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 – 2.34], p = 0.014 PVS volume ß = 14.6, CI [3.86 – 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 – 0.361], p ≤ 0.001 PVS volume ß = 3.67, CI [2.42 – 4.92], p = 0.002). Analysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies.
Publisher: Massachusetts Medical Society
Date: 18-04-2019
DOI: 10.1056/NEJMC1805100
Publisher: Elsevier BV
Date: 2018
Publisher: Elsevier BV
Date: 07-2021
Publisher: Oxford University Press (OUP)
Date: 27-08-2016
Abstract: Traumatic brain injury (TBI) has been suggested to increase the risk of amyotrophic lateral sclerosis (ALS). However, this link remains controversial and as such, here we performed experimental moderate TBI in rats and assessed for the presence of ALS-like pathological and functional abnormalities at both 1 and 12 weeks post-injury. Serial in-vivo magnetic resonance imaging (MRI) demonstrated that rats given a TBI had progressive atrophy of the motor cortices and degeneration of the corticospinal tracts compared with sham-injured rats. Immunofluorescence analyses revealed a progressive reduction in neurons, as well as increased phosphorylated transactive response DNA-binding protein 43 (TDP-43) and cytoplasmic TDP-43, in the motor cortex of rats given a TBI. Rats given a TBI also had fewer spinal cord motor neurons, increased expression of muscle atrophy markers, and altered muscle fiber contractile properties compared with sham-injured rats at 12 weeks, but not 1 week, post-injury. All of these changes occurred in the presence of persisting motor deficits. These findings resemble some of the pathological and functional abnormalities common in ALS and support the notion that TBI can result in a progressive neurodegenerative disease process pathologically bearing similarities to a motor neuron disease.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.JOCN.2011.08.003
Abstract: Data on the use in pregnancy of the new antiepileptic drugs (AED) are limited. We analysed data collected by the Australian Pregnancy Register to provide information on their relative teratogenicity. The database containing pregnancy outcomes from 1317 women with epilepsy (WWE) was examined for three widely used new AED in monotherapy in the first trimester--lamotrigine, levetiracetam and topiramate. This was compared with outcomes of pregnant WWE on monotherapy with three traditional AED, and with untreated women. The incidence of malformations associated with lamotrigine monotherapy was 12/231 (5.2%), with topiramate 1/31 (3.2%) and with levetiracetam 0/22 (0%). This compares with rates of 1/35 (2.9%) for phenytoin, 35/215 (16.3%) for valproate (VPA), 19/301 (6.3%) for carbamazepine and 6/116 (5.2%) for untreated women. There was no evidence of dose-dependent risks of foetal malformation, except with VPA monotherapy. We conclude that the new AED appear no more teratogenic than traditional drugs in monotherapy.
Publisher: Wiley
Date: 22-02-2019
DOI: 10.1002/EPI4.12308
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.NBD.2017.05.012
Abstract: The Aristaless-related homeobox gene (ARX) is a known intellectual disability (ID) gene that frequently presents with X-linked infantile spasm syndrome as a comorbidity. ID with epilepsy in children is a chronic and devastating disorder that has poor treatment options and disease outcomes. To gain a better understanding of the role that mutations in ARX play in ID and epilepsy, we investigate ARX patient mutations modelled in mice. Over half of all ARX mutations result from expansions of the first two polyalanine (PA1 and PA2 respectively) tracts. However, phenotypic data for the mouse modelling the more frequent ARX PA2 dup24 mutation in patients has not been reported and constitutes a barrier to understanding the molecular mechanisms involved. Here we report the first comprehensive analysis of postnatal outcomes for mice modelling disease-causing expansions to both PA1 and PA2 tracts. Both strains were found to have impaired learning and memory, reduced activity, increased anxiety and reduced sociability with PA1 mice generally displaying greater behavioural deficits in keeping with the more severe phenotype reported in patients. In agreement with previous reports, 70% of PA1 males exhibit myoclonic seizures by two months of age, with the first observed at P18. In this report, we show 80% of PA2 males also display myoclonic seizures, with the first observed at P19. Consistent with patient phenotypes, we observe large variations in seizure progression and severity for both PA1 and PA2 in idual mice. The generation of this comprehensive baseline data is a necessary step on the path to the development of therapies to improve patient outcomes.
Publisher: BMJ
Date: 08-2020
DOI: 10.1136/BMJNO-2020-000069
Abstract: Gliomas are the most common central nervous system malignancies and present with significant morbidity and mortality. Treatment modalities are currently limited to surgical resection, chemotherapy and radiotherapy. Increases in survival rate over the previous decades are negligible, further pinpointing an unmet clinical need in this field. There is a continual struggle with the development of effective glioma diagnostics and therapeutics, largely due to a multitude of factors, including the presence of the blood–brain barrier and significant intertumoural and intratumoural heterogeneity. Importantly, there is a lack of reliable biomarkers for glioma, particularly in aiding tumour subtyping and measuring response to therapy. There is a need for biomarkers that would both overcome the complexity of the disease and allow for a minimally invasive means of detection and analysis. This is a comprehensive review evaluating the potential of current cellular, proteomic and molecular biomarker candidates for glioma. Significant hurdles faced in glioma diagnostics and therapy are also discussed here.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.EPLEPSYRES.2014.08.022
Abstract: A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly-diagnosed epilepsy cohort using a k-nearest neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n=281 SANAD, n=491). A "leave-one-out" cross-validation was also employed, with training sets derived internally from the UK datasets. The multigenic classifier using the Australian cohort as the training set was unable to predict treatment response in either UK cohort. In the "leave-one-out" analysis, the five SNPs collectively predicted treatment response in both Glasgow and SANAD patients prescribed either carbamazepine or valproate (Glasgow OR=3.1, 95% CI=1.4-6.6, p=0.018 SANAD OR=2.8, 95% CI=1.3-6.1, p=0.048), but not those receiving lamotrigine (Glasgow OR=1.3, 95% CI=0.6-2.8, p=1.0 SANAD OR=2.2, 95% CI=0.9-5.4, p=0.36) or other AEDs (Glasgow OR=0.6, 95% CI=0.2-2.0, p=1.0 SANAD OR=1.9, 95% CI=0.9-4.2, p=0.36). The Australian-based multigenic kNN model is not predictive of initial treatment response in UK cohorts of newly-diagnosed epilepsy. However, the five SNPs identified in the original Australian study appear to collectively have a predictive influence in UK patients prescribed either carbamazepine or valproate.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.BBR.2009.10.002
Abstract: Rats with a bilateral neonatal ventral hippoc us lesion (NVHL) are used as models of neurobiological aspects of schizophrenia. In view of their decreased number of GABAergic interneurons, we hypothesized that they would show increased reactivity to acoustic stimuli. We systematically characterized the acoustic reactivity of NVHL rats and sham operated controls. They were behaviourally observed during a loud white noise. A first cohort of 7 months' old rats was studied. Then the observations were reproduced in a second cohort of the same age after characterizing the reactivity of the same rats to dopaminergic drugs. A third cohort of rats was studied at 2, 3, 4, 5 and 6 months. In subsets of lesioned and control rats, inferior colliculus auditory evoked potentials were recorded. A significant proportion of rats (50-62%) showed aberrant audiogenic responses with explosive wild running resembling the initial phase of audiogenic seizures. This was not correlated with their well-known enhanced reactivity to dopaminergic drugs. The proportion of rats showing this strong reaction increased with rats' age. After the cessation of the noise, NVHL rats showed a long freezing period that did neither depend on the size of the lesion nor on the rats' age. The initial negative deflection of the auditory evoked potential was enhanced in the inferior colliculus of only NVHL rats that displayed wild running. Complementary anatomical investigations using X-ray scans in the living animal, and alizarin red staining of brain slices, revealed a thin layer of calcium deposit close to the medial geniculate nuclei in post-NVHL rats, raising the possibility that this may contribute to the hyper-reactivity to sounds seen in these animals. The findings of this study provide complementary information with potential relevance for the hyper-reactivity noted in patients with schizophrenia, and therefore a tool to investigate the underlying biology of this endophenotype.
Publisher: Wiley
Date: 14-08-2014
DOI: 10.1111/EPI.12745
Abstract: 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. 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%. 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 er year of VPA, p = 0.03) VPA treatment duration and dose were not significantly associated with AFat%. 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.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-11-2020
Abstract: Brain atrophy in human epilepsy syndromes is explainable by network architecture and strongest in hub regions.
Publisher: Hindawi Limited
Date: 22-10-2019
DOI: 10.1111/ANE.13170
Abstract: To assess (a) the incidence of seizures in the first year of life in infants born to mothers with epilepsy and (b) factors that might contribute to the seizure incidence. Analysis of data collected in the Australian Register of Antiepileptic Drugs in Pregnancy during and at the end of the year after pregnancy. By the end of a year following pregnancy, seizures had occurred in the progeny of 47 pregnancies (2.40%), including febrile seizures in 18 (0.92%), the latter rate being higher than the 0.40% and 0.59% rates for the same situation in the general population reported in the recent literature. Seizures in infancy were more likely in the offspring of mothers with generalized as compared with focal epilepsies (3.65% vs 1.56% RR = 2.332 P < .05) and within the generalized epilepsy mothers in those who were not seizure free during pregnancy (4.83% vs 2.89%). Seizures were also more likely in infants with foetal malformations, especially ones not discovered until after the first post-natal month. These findings may help in advising mothers with epilepsy regarding the chance of their offspring experiencing seizures in the first year of life they also suggest the desirability of achieving maternal seizure control throughout pregnancy.
Publisher: Wiley
Date: 16-07-2023
DOI: 10.1002/EPI4.12790
Abstract: Cortical stimulation is an important component of stereoelectroencephalography (SEEG). Despite this, there is currently no standardized approach and significant heterogeneity in the literature regarding cortical stimulation practices. Via an international survey of SEEG clinicians, we sought to examine the spectrum of cortical stimulation practices to reveal areas of consensus and variability. A 68‐item questionnaire was developed to understand cortical stimulation practices including neurostimulation parameters, interpretation of epileptogenicity, functional and cognitive assessment and subsequent surgical decisions. Multiple recruitment pathways were pursued, with the questionnaire distributed directly to 183 clinicians. Responses were received from 56 clinicians across 17 countries with experience ranging from 2 to 60 years ( M = 10.73, SD = 9.44). Neurostimulation parameters varied considerably, with maximum current ranging from 3 to 10 mA ( M = 5.33, SD = 2.29) for 1 Hz and from 2 to 15 mA ( M = 6.54, SD = 3.68) for 50 Hz stimulation. Charge density ranged from 8 to 200 μC/cm 2 , with up to 43% of responders utilizing charge densities higher than recommended upper safety limits, i.e. 55 μC/cm 2 . North American responders reported statistically significant higher maximum current ( P 0.001) for 1 Hz stimulation and lower pulse width for 1 and 50 Hz stimulation ( P = 0.008, P 0.001, respectively) compared to European responders. All clinicians evaluated language, speech, and motor function during cortical stimulation in contrast, 42% assessed visuospatial or visual function, 29% memory, and 13% executive function. Striking differences were reported in approaches to assessment, classification of positive sites, and surgical decisions guided by cortical stimulation. Patterns of consistency were observed for interpretation of the localizing capacity of stimulated electroclinical seizures and auras, with habitual electroclinical seizures induced by 1 Hz stimulation considered the most localizing. SEEG cortical stimulation practices differed vastly across clinicians internationally, highlighting the need for consensus‐based clinical guidelines. In particular, an internationally standardized approach to assessment, classification, and functional prognostication will provide a common clinical and research framework for optimizing outcomes for people with drug‐resistant epilepsy.
Publisher: Wiley
Date: 14-12-2020
DOI: 10.1111/EVJ.13387
Abstract: There is little consensus on factors associated with survival in foals with septic arthritis and limited data on long‐term racing performance of Thoroughbred foals treated for septic arthritis. A more thorough understanding of short‐ and long‐term outcome is necessary to help inform owners, and subsequently guide treatment. To investigate factors associated with survival, and to analyse racing performance of foals with septic arthritis compared with their maternal siblings. Retrospective cohort and a case‐control study. Veterinary clinical records of Thoroughbred foals ≤180 days old that underwent arthroscopic, cannulae or through‐and‐through needle lavage for the treatment of septic arthritis between 2009 and 2015 were reviewed. Data included signalment, and clinicopathological information. The dam's foaling records were reviewed and the lifetime racing records were obtained for affected foals and two of their maternal siblings. Logistic regression analysis was used to determine factors associated with survival to discharge or racing. Comparisons between treated foals and their maternal siblings were made. Ninety (78%) of 115 foals diagnosed with septic arthritis were discharged alive. Foals days old at the time of admission were five times less likely ( P = .003) and foals with concurrent multisystemic disease were six times less likely ( P = .02) to be discharged alive. Sixty (67%) foals discharged alive started in ≥1 race, and there was no difference in the proportion of foals that started in a race or racing performance between foals treated for septic arthritis and their maternal siblings. Retrospective study design, limited number of foals with multiple joint involvement and failure to accurately record duration of clinical signs. Foals treated for septic arthritis at the Scone Equine Hospital, New South Wales, Australia had a good prognosis for survival, and for this cohort, foals that survived to discharge had a similar ability to race as their maternal siblings.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2007
Publisher: Elsevier BV
Date: 03-2019
Publisher: Wiley
Date: 19-07-2023
DOI: 10.1002/EPI4.12795
Abstract: To determine predictors of successful ictal Single Photon Emission Computed Tomography (SPECT) injections during Epilepsy Monitoring Unit (EMU) admissions for patients undergoing presurgical evaluation for drug resistant focal epilepsy. In this retrospective study, consecutive EMU admissions were analysed at a single centre between 2019‐2021. All seizures that occurred during the admission were reviewed. ‘Injectable seizures’ occurred during hours when the radiotracer was available. EMU‐level data were analysed to identify factors predictive of an EMU admission with a successful SPECT injection (successful admission). Seizure‐level data were analysed to identify factors predictive of an ‘injectable seizure’ receiving a SPECT injection during the ictal phase (successful injection). A multivariate generalised linear model was used to identify predictive variables. 125 EMU admissions involving 103 patients (median 37 years, IQR27.0‐45.5) were analysed. 38.8% of seizures that were eligible for SPECT (n=134) were successfully injected this represented 17.4% of all seizures (n=298) that occurred during admission. Unsuccessful admissions were most commonly due to a lack of seizures during EMU‐SPECT (19.3%) or no 'injectable seizures’ (62.3%). Successful EMU‐SPECT was associated with baseline seizure frequency per week (95%CI 2.1‐3.0, p .001) and focal PET hypometabolism (95%CI 2.0‐3.7, p .001). On multivariate analysis, the only factor associated with successful injection was patients being able to indicate they were having a seizure to staff (95%CI 1.0‐4.4, p=0.038). Completing a successful ictal SPECT study remains challenging. Baseline seizure frequency of per‐week, a PET hypometabolic focus and a patient's ability to indicate seizure onset were identified as predictors of success. These findings may assist EMUs in optimising their SPECT protocols, patient selection, and resource allocation.
Publisher: JMIR Publications Inc.
Date: 10-08-2023
DOI: 10.2196/43612
Abstract: China is facing a rapidly expanding aging population. Insights into the health status of older adults are of great significance for health resource allocation and health care provision to this population. With the goal of providing a comprehensive understanding of the health status of older adults and to inform potential interventions, we investigated the level of disability and identified risk factors associated with disability among the older population (aged ≥60 years) living in China. A total of 8467 older adults living in the Chinese city of Shenzhen were enrolled in this cross-sectional study. We used a multidimensional ability assessment survey, which assessed their activities of daily living (ADL including eating, bathing, grooming, dressing, defecation control, urination control, using a toilet unaided, transfer, flat-ground walking, stair activity), mental status (including cognitive function, aggressive behavior, depression symptoms), sensory and communication (including consciousness level, vision, hearing, communication), and social participation (including living, working, time/space orientation, distinguish persons, social communication) abilities. The impact of demographic risk factors on ability levels was analyzed using ordinal logistic regression. The correlations between the four dimensions of ability mentioned above were analyzed using Spearman correlation analysis. A total of 7766 participants were effectively assessed. The participants’ average age was 70.64 (SD 8.46) years comprising 56.53% females. The overall ability level was classified as mildly, moderately, and severely impaired for 27.57% (n=2141), 2.83% (n=220), and 4.28% (n=332) of the 7766 participants, respectively. With increasing age, the proportion of impaired participants increased from 17.62% (365/2071) in the age group 60-64 years to 91.3% (253/277) in the age group above 90 years (P .001), corresponding to an approximate 10% rise for every 5-year age increment. The odds of having more severe overall ability impairment in females was 1.15 times that in males (odds ratio [OR] 1.15, 95% CI 1.04-1.28). Participants who were orced or widowed had a higher risk of more severe overall ability impairment than those currently married (OR 1.98, 95% CI 1.68-2.33). Participants living with nonrelatives had an increased risk of more severe overall ability impairment than those living alone (OR 2.38, 95% CI 1.46-3.91). Higher education level was a protective factor of overall ability impairment (college degree or above: OR 0.32, 95% CI 0.24-0.42). The four dimensions of ability assessed were significantly correlated a low score for ADL was significantly correlated with poorer mental status, sensory and communication, and social participation (all P .001). The proportion of disability among Chinese older adults increases with age, being female, having lower education levels, being orced or widowed, and living with nonrelatives. Impairment in ADL ability is significantly correlated with poor mental status, social participation, and sensory and communication abilities. A holistic approach to improving the health of the older population is recommended in China.
Publisher: Wiley
Date: 21-11-2007
DOI: 10.1111/J.1528-1167.2007.01412.X
Abstract: This brief report covers an analysis of 7 years outcome data from the Australian Register of Antiepileptic Drugs in Pregnancy. In studying the control of antiepileptic drug-treated epileptic seizures during pregnancy, it was found that pregnancy had little influence on antiepileptic drug-treated epileptic seizure disorders. Seizures during pregnancy occurred in 49.7% of 841 antiepileptic drug (AED) treated pregnancies in women with epilepsy. Epilepsies that were active in the year before pregnancy tended to increase the risk of intrapartum and postpartum seizures. The risk of seizures during pregnancy was 50-70% less if the prepregnancy year was seizure free, and decreased relatively little more with longer periods of prepregnancy seizure control. Once there had been 1 year's freedom from seizures there seemed relatively little further advantage in deferring pregnancy to avoid seizures returning while pregnant.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.EXPNEUROL.2007.09.026
Abstract: The explanation for the increased prevalence of neuropsychiatric disorders in epilepsy patients is uncertain, with both biological and psychosocial factors proposed. Increasing evidence supports the idea of shared neurobiological processes leading both to seizures and to behavioral, emotional and cognitive disturbance. This study addresses this using Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of human generalized epilepsy. We subjected GAERS (n=47) and Non-Epileptic Control rats (NEC n=73) to behavioral measures of depression and anxiety at 7 and 13 weeks of age, ages prior to and after seizure onset. We employed the Sucrose-Preference Test (SPT), the Elevated Plus Maze (EPM), and the Open Field Arena (OFA). GAERS exhibited significantly greater levels of both depression- and anxiety-like behaviors on all measures, including reduced consumption of sucrose solution in the SPT lower percentage of time in the open arms of the EPM and reduced exploratory activity and less time spent in the inner area of the OFA. These differences were evident at both 7 and 13 weeks of age, before and after the onset of epilepsy. Increased anxiety- and depressive-like behaviors are observed in GAERS. These behavioral differences exist before the onset of seizures indicating that they are not secondary consequences of seizures, and suggest shared factors in the biological diathesis underlying the two kinds of disorder. Studying affective disturbance in animal models of epilepsy may illuminate the pathogenesis of affective disorder more generally, as well as modeling psychiatric comorbidities common in epilepsy patients.
Publisher: Wiley
Date: 08-02-2021
DOI: 10.1111/JON.12837
Publisher: Springer Science and Business Media LLC
Date: 09-12-2200
DOI: 10.1038/S41413-020-00119-9
Abstract: Neurological heterotopic ossification (NHO) is a debilitating condition where bone forms in soft tissue, such as muscle surrounding the hip and knee, following an injury to the brain or spinal cord. This abnormal formation of bone can result in nerve impingement, pain, contractures and impaired movement. Patients are often diagnosed with NHO after the bone tissue has completely mineralised, leaving invasive surgical resection the only remaining treatment option. Surgical resection of NHO creates potential for added complications, particularly in patients with concomitant injury to the central nervous system (CNS). Although recent work has begun to shed light on the physiological mechanisms involved in NHO, there remains a significant knowledge gap related to the prognostic biomarkers and prophylactic treatments which are necessary to prevent NHO and optimise patient outcomes. This article reviews the current understanding pertaining to NHO epidemiology, pathobiology, biomarkers and treatment options. In particular, we focus on how concomitant CNS injury may drive ectopic bone formation and discuss considerations for treating polytrauma patients with NHO. We conclude that understanding of the pathogenesis of NHO is rapidly advancing, and as such, there is the strong potential for future research to unearth methods capable of identifying patients likely to develop NHO, and targeted treatments to prevent its manifestation.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2017
DOI: 10.1007/S11064-017-2305-X
Abstract: Epilepsy is a common neurological condition characterised by spontaneous recurrent seizures. Current anti-epileptic drugs are only effective and tolerated in ~70% of patients, leaving a substantial proportion of patients untreated. As such, there is a pressing need to develop new therapies. We assessed the anti-seizure activity of Neural Regeneration Peptide 2945 (NRP 2945) in the GAERS model of absence epilepsy. Drug effects on seizures were assessed using two study designs. Male adult GAERS were implanted with EEG electrodes to measure seizure frequency. The first study compared the effects of acute sc injection of vehicle, NRP 10 µg/kg, NRP 20 µg/kg, and controlled against the active comparator Valproaic acid (200 mg/kg). In the second study, animals received one of four treatments for 4 weeks: vehicle, NRP 60 µg/kg/day, NRP 120 µg/kg/day (delivered by continuous infusion) or NRP 20 µg/kg sc injected every second day (e.s.d). In the acute study, we found significant (p < 0.01) anti-seizure effects in animals treated with NRP2945 (20 µg/kg) and VPA, with NRP2945 slightly more efficacious, despite the 70,000 times lower molar dosage. In the chronic study, animals receiving 120 µg/kg/day and NRP 20 µg/kg e.s.d had significantly fewer seizures (p < 0.001), compared with vehicle. These effects were sustained for at least 10 days after drug treatment had ceased, indicative of disease-modifying activity. We demonstrate sustained anti-seizure effects of NRP2945, a potent small molecule peptide which enters the brain and is devoid of adverse effects. Early stage first-in-man trials have been initiated for subcutaneously delivered NRP2945 which is a promising step to providing therapeutic benefits for refractory epilepsy patients.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.JOCN.2004.05.003
Abstract: To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different anti-epileptic drugs (AED) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study. A voluntary, Australia-wide, telephone-interview-based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy with epilepsy not taking AEDs taking AEDs for a non-epileptic indication. Four hundred and fifty eligible women were enrolled over 40 months. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes. 354 (87.8%) pregnancy outcomes resulted in a healthy live birth, 26 (6.5%) had a FM, 4 (1%) a death in utero, 1 (0.2%) a premature labour with stillbirth, 14 (3.5%) a spontaneous abortion and 4 lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (16.0%) compared with those exposed to all other AEDs (16.0% vs. 2.4%, P < 0.01) or no AEDs (16.0% vs. 3.1%, [Formula: see text] ). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (1,975 vs. 1,128 mg, P or= 1,100 mg was 30.2% vs. 3.2% with doses <1,100 mg (P <0.01). There is a dose-effect relationship for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy.
Publisher: Frontiers Media SA
Date: 14-01-2021
DOI: 10.3389/FIMMU.2020.597858
Abstract: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients’ NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients’ follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed. During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS ≤2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03–1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome. NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE.
Publisher: Wiley
Date: 11-2017
DOI: 10.1111/EPI.13921
Publisher: Wiley
Date: 03-07-2014
DOI: 10.1111/EPI.12711
Abstract: To assess the effectiveness of the newer antiepileptic drugs (AEDs)-in particular lamotrigine, topiramate, and levetiracetam-in controlling epileptic seizures in pregnant women. Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy concerning seizure control in 1,534 pregnancies in women with AED-treated epilepsies. In AED monotherapy (1,111 pregnancies), use of levetiracetam in pregnancies in the Australian Register was associated with levels of seizure control similar to those that applied for the major older AEDs carbamazepine and valproate, but with levels of seizure control superior to those associated with use of lamotrigine and topiramate. Levetiracetam shows promise as a satisfactory drug for controlling seizures in pregnancy.
Publisher: Elsevier BV
Date: 02-2019
Publisher: Wiley
Date: 12-06-2012
DOI: 10.1111/J.1528-1167.2012.03525.X
Abstract: Temporal hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) is a common finding in patients with drug-resistant temporal lobe epilepsy (TLE). The pathophysiology underlying the hypometabolism, including whether it reflects a primary epileptogenic process, or whether it occurs later as result of limbic atrophy or as a result of chronic seizures, remains unknown. This study aimed to investigate the ontologic relationship among limbic atrophy, histological changes, and hypometabolism in rats. Serial in vivo imaging with FDG-PET and volumetric magnetic resonance imaging (MRI) was acquired before and during the process of limbic epileptogenesis resulting from kainic acid-induced status epilepticus in the rat. The imaging data were correlated with histologic measures of cell loss, and markers of astrogliosis (glial fibrillary acid protein [GFAP]), synaptogenesis (synaptophysin), glucose transporter 1 (Glut1) and energy metabolism (cytochrome oxidase C), on brains of the animals following the final imaging point. Hippoc al hypometabolism on FDG-PET was found to be present 24 h following status epilepticus, tending to lessen by 1 week and then become more marked again following the onset of spontaneous seizures. Atrophy of limbic structures was evident from 7 days post-SE, becoming progressively more marked on serial MRI over subsequent weeks. No relationship was observed between the severity of MRI-detected atrophy or CA1 pyramidal cell loss and the degree of the hypometabolism on FDG-PET. However, an inverse relationship was observed between hypometabolism and increased expression of the Glut1 and synaptophysin in the hippoc us. These findings demonstrate that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow. The hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis in addition to any effects of the subsequent recurrent spontaneous seizures.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.NEUROSCIENCE.2017.06.039
Abstract: The NMDA receptor (NMDAr) hypofunction theory of schizophrenia suggests that aberrant signaling through NMDAr underlies the pathophysiology of this disease. This is commonly modeled in rodents via treatment with NMDAr antagonists, which causes a range of behavioral effects that represent endophenotypes related to schizophrenia. These drugs also disrupt high-frequency neural oscillations within the brain, also potentially relevant to disease. We studied the effect of localized NMDAr hypofunction on the generation of neural oscillations occurring both locally and in distant brain regions, and on behaviors routinely used as endophenotypes to model psychosis in rodents. Wistar rats were implanted with local field potential recording electrodes in the prefrontal cortex, dorsal hippoc us and nucleus accumbens, as well as cannulae in these regions to facilitate drug infusion. Rats received bilateral infusions of MK801 (0, 5μg, 20μg, 50μg) into one of the three target regions and their behavior measured in an open field. We also assessed the effects of systemic MK801 injection (0.16mg/kg sc). Electrophysiological signals were recorded continuously, allowing assessment of gamma oscillations (30-80Hz) and high-frequency oscillations (HFO: 130-180Hz) occurring as a result of infusions. Regardless of MK801 infusion location, gamma oscillations and HFOs significantly and consistently increased in all three regions studied, similar to that observed following systemic injection. Locomotor activity, stereotypies and ataxia were also observed following infusion into all regions. We conclude that localized regions exhibiting NMDAr hypofunction are sufficient to disrupt local as well as diffuse neural circuits and global brain function, and concomitantly cause psychosis-related behavioral effects.
Publisher: Wiley
Date: 22-09-2022
DOI: 10.1002/EPI4.12643
Abstract: The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various aspects of preclinical epilepsy research studies, which could help improve the standardization of experimental designs. In this article, we discuss CDEs for neuroimaging data that are collected in rodent models of epilepsy, with a focus on adult rats and mice. We provide detailed CDE tables and case report forms (CRFs), and with this companion manuscript, we discuss the methodologies for several imaging modalities and the parameters that can be collected.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.NBD.2007.12.010
Abstract: Protease-activated receptor-2 (PAR(2)), primarily involved in inflammation, is highly expressed in limbic regions of the brain such as the hippoc us. Although extracellular proteolysis is involved in normal and stress-related neuronal plasticity associated with learning, memory and inflammatory disease states, little is known about the role of PAR(2) and its physiological agonist, trypsin, in the brain. We show immunohistochemically that trypsin co-localises with tissue plasminogen activator within granular-like structures in PAR(2)-positive pyramidal neurons of the rat hippoc us. Central administration of the PAR(2) peptide agonist, SLIGRL, inhibited electrical amygdala kindling-induced epileptogenesis and abolished kindling-induced over-expression of trypsin in the hippoc us. SLIGRL similarly attenuated kindling when administered subcutaneously. Non-enzymatic activation of neuronal PAR(2) using SLIGRL may thus activate feedback mechanisms to inhibit the over-production of trypsin and possibly other proteases during brain insults and thereby attenuate pathogenesis. Prophylactic systemic administration of non-proteolytic PAR(2) agonists may therefore represent a novel approach to protect against epileptogenic brain insults.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.SEIZURE.2019.10.011
Abstract: Psychogenic non-epileptic seizures (PNES) and epileptic seizures (ES) are often difficult to differentiate, leading to incorrect or delayed diagnosis. The aim of the study was to determine whether patients of these two diagnostic groups possess different personality profiles, and whether they could be used to efficiently screen for PNES in clinical settings. Collection of data was conducted on 305 patients who completed the NEO-Five Factor Inventory questionnaire during a Video EEG Monitoring admission to the Royal Melbourne Hospital between 2002-2017. Personality differences were investigated using Bayesian linear mixed effects models, with receiver operating characteristic curve analysis computed to evaluate diagnostic accuracy. The 'openness to experience' domain (BF While openness and aesthetic interests differ greatly between PNES and ES groups, low sensitivity and specificity suggests their use is limited in a clinical setting. Nevertheless, these findings open up new avenues of research using modern personality models to further understand patients with epilepsy and related presentations.
Publisher: Wiley
Date: 30-07-2015
DOI: 10.1002/JMRI.25017
Abstract: To investigate whether there are any white matter changes in a 6-month follow-up of mild-moderate Alzheimer's patients using diffusion tensor imaging (DTI). We recruited 18 mild-moderate Alzheimer's disease patients and they underwent magnetic resonance imaging (MRI) at recruitment and at 6-month follow-up. Diffusion MRI images were processed using DTI-ToolKit to create a population-based tensor template. This template was integrated with a voxel-wise and atlas-based analysis in FSL to determine the magnitude and location of change in diffusion metrics over the 6-month follow-up period. There were significant widespread changes in diffusion metrics across the entire white matter skeleton (P < 0.001), 95% confidence interval (CI) difference in fractional anisotropy: -0.007 (-0.011, -0.002), mean diffusivity: 0.040 (0.023, 0.058), axial diffusivity: 0.015 (0.008, 0.022), radial diffusivity: 0.012 (0.006, 0.019), as well as regions of interest in the splenium and superior longitudinal fasciculus. Our findings show that diffusion metrics are altered in a 6-month follow-up period of mild-moderate Alzheimer's patients, supporting the potential of DTI metrics to act as sensitive biomarkers for disease progression even over a relatively short time interval, and the potential utility to be applied to clinical trials of putative disease-modifying therapies.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2013
DOI: 10.1038/NATURE12439
Publisher: Korean Stroke Society
Date: 31-05-2021
Publisher: Wiley
Date: 06-1998
DOI: 10.1111/J.1528-1157.1998.TB01433.X
Abstract: To determine the frequency and patterns of periictal cerebellar hyperperfusion, whether it is associated with increased cerebellar atrophy, and whether cerebellar hyperperfusion and cerebellar atrophy are associated with predisposing clinical factors or with the outcome of epilepsy surgery. Periictal and interictal SPECT scans and volumetric brain magnetic resonance imaging (MRI) were quantitatively analyzed in 54 consecutive patients with medically refractory partial epilepsy. Their histories were reviewed and their postsurgical outcomes assessed. Significant periictal cerebellar hyperperfusion was found in 26 (48.1%) patients, of whom 18 had CCH, two had homolateral cerebellar hyperperfusion (HCH), and six had symmetrical bilateral hyperperfusion (BCH). No relation found between the site of the SPECT seizure localization and the presence or type of cerebellar hyperperfusion. CCH was more common when the injected seizure involved unilateral clonic motor activity (p < 0.05). A smaller MRI relative cerebellar volume (cerebellar volume/cerebral volume) was correlated with a greater seizure frequency (Rs = -0.30 p 0.05). However, patients without a focal structural MRI lesion had significantly smaller cerebellar volumes (p < 0.05). In patients who underwent epilepsy surgery (n = 31), there was a trend for those without excellent outcomes to have smaller relative cerebellar volumes than did those with excellent outcome (10.6 vs. 11.8% p = 0.08). Periictal changes in cerebellar perfusion, particularly CCH, are common in patients with intractable partial epilepsy. However, periictal hyperperfusion does not appear to be a major contributor to the development of cerebellar atrophy.
Publisher: Akademiai Kiado Zrt.
Date: 26-08-2019
Abstract: The broadcast of wagering advertisements during televised sports matches has been associated with various adverse outcomes. In order to counter these effects, legislative bodies require wagering operators to include responsible gambling messages in their advertisements however, the effectiveness of these messages is unclear. This study sought to examine the extent to which responsible gambling messages are looked at, in the wider context of gambling advertisements. Forty-nine regular sports bettors and 10 non-gamblers viewed a series of sports betting advertisements, while an eye-tracker recorded the number of fixations placed on responsible gambling messages, as well as other text-based wagering content. Responsible gambling messages were, generally, presented in a non-conspicuous manner. Eye-tracking data revealed that significantly fewer fixations were placed on responsible gambling messages, compared to wagering information ( p .001) however, this effect did not differ according to level of gambling risk ( p = .169). The number of fixations placed on the different types of responsible gambling messages was found to vary, based on gambling risk ( p = .006), as well as, what appears to be, the physical characteristics of these messages. Very few fixations were placed on, or near, responsible gambling messages, compared to other wagering information, meaning that, in their current form, they are unlikely to be effective in protecting against gambling harm. Preliminary evidence shows that presenting messages on a high-contrast/block-color background increases the number of fixations on these. Further research is needed to identify ways of increasing the effectiveness of responsible gambling initiatives in the sports betting context.
Publisher: Wiley
Date: 03-2007
DOI: 10.1111/J.1528-1167.2006.00956.X
Abstract: The Liverpool Adverse Events Profile (LAEP) is used as a systematic measure of adverse effects from antiepileptic drugs (AEDs). This study evaluated LAEP in newly diagnosed seizure patients, and examined the relation between LAEP, anxiety, and depression. Seizure patients seen in the two First Seizure Clinics were categorized into group A (AEDs commenced after assessment), group B (AEDs commenced before assessment), and group C (no AEDs). LAEP and the Hospital Anxiety and Depression Scale (HADS) were completed at baseline (n=164) and 3 months (n=103). Each LAEP symptom was assessed for baseline frequency, 3-month frequency, and frequency change over a 3-month period. Global scores for LAEP and HADS were analysed at baseline and 3 months. Symptom-reporting patterns were similar between groups. However, increased frequency over a 3-month period occurred for 12 symptoms in group A, 10 in group B, and one in group C. Global LAEP and HADS showed no significant group differences at baseline or changes over a 3-month period. Multiple regression revealed that HADS scores predicted LAEP global scores better than did AED status. Multivariate analyses of variance demonstrated that increased reporting of 16 of 19 LAEP symptoms was significantly related to higher anxiety and depression rates. In a First Seizure Clinic, LAEP detects changes in specific symptom frequencies when used as a repeated, symptom-by-symptom measure. Increased symptom frequency is associated with diagnostic category/AED treatment, anxiety, and depression. Global LAEP scores do not illustrate differences in symptom reporting between patients.
Publisher: Wiley
Date: 07-09-2012
DOI: 10.1111/J.1528-1167.2012.03635.X
Abstract: Tissue plasminogen activator (t-PA), a proven therapy for acute ischemic stroke, is an endogenous serine protease associated with neuronal activity and synaptic plasticity in the brain. Its expression is enhanced after seizures, and is involved in seizure propagation throughout the brain. Therefore, the increased use of t-PA to treat stroke may have important implications for the development of poststroke epilepsy. Using experimental and clinical approaches, we investigated the role of t-PA in the development of epilepsy. Mice deficient in t-PA (t-PA(-/-) ) or mice transgenically modified to overexpress neuronal t-PA (T4) underwent amygdala kindling, and seizure threshold and rates of kindling were compared to those in wild-type mice. For the clinical study, we recruited acute ischemic stroke patients who either received intravenous t-PA treatment on admission to hospital (n = 177 cases) or did not (n = 158 controls). We then assessed the incidence of early and late onset seizures and epilepsy in these patients. T4 mice were more seizure-prone than wild-type mice, exhibiting lower seizure thresholds (p = 0.002), but there were no significant differences observed in the rate of kindling development when comparing either T4 mice, or t-PA(-/-) mice, to their wild-type controls. Furthermore, we found no significant differences between the proportion of poststroke patients experiencing early or late seizures, or developing epilepsy, between those who received t-PA and those who did not. Overexpression of endogenous t-PA lowers seizure threshold but does not influence kindling epileptogenesis. Moreover, the therapeutic administration of t-PA in humans does not influence the development of acquired poststroke epilepsy.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EPLEPSYRES.2017.02.001
Abstract: Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The 'real-world' clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis. We performed WES, followed by targeted analysis of 64 epilepsy genes, on 40 consecutive children and adults enrolled prospectively from routine clinical practice who had MRI-negative focal epilepsy and a family history of febrile seizures or any type of epilepsy in at least one first- or second-degree relative. Exclusion criteria were previous genetic testing, severe intellectual disability and benign focal epilepsies of childhood. 5/40 (12.5%) patients had a pathogenic or likely pathogenic variant, detected in SCN1A, DEPDC5, PCDH19, GABRG2 or NPRL2. Identifying a pathogenic SCN1A variant in a patient with drug-resistant epilepsy prompted to halt presurgical investigations due to concern of unfavorable post-surgical outcome. It also led in the same patient to discontinue long-standing carbamazepine therapy (a potentially aggravating drug in epilepsies due to SCN1A mutations), resulting in complete seizure control. Patients with pathogenic or likely pathogenic variants had a younger median age of seizure onset (range) compared to those without [18 months (8 months-18 years) vs 18 years (18 months-70 years), p=0.02]. Our data demonstrate that WES with targeted gene analysis is an effective diagnostic tool for patients with common focal epilepsies in whom a genetic etiology is suspected. It can also influence clinical decision-making, including antiepileptic drug selection and consideration of epilepsy surgery, hence supporting its incorporation in the routine clinical care of this patient group.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 07-2006
DOI: 10.3171/JNS.2006.105.1.71
Abstract: The aim of this study was to determine whether ictal single-photon emission computed tomography (SPECT) is useful in localizing the site of seizure onset in patients in whom surgery for intractable epilepsy failed and who are being considered for repeated surgery. Subtraction ictal SPECT coregistered to magnetic resonance imaging (SISCOM) studies were retrospectively analyzed in 58 patients who were being evaluated for possible repeated resection for intractable partial epilepsy between January 1, 1996, and October 31, 1999. All patients had persistent seizures subsequent to an initial resection and underwent another excision. The SISCOM-demonstrated abnormalities were classified as concordant, discordant, or indeterminate, compared with the localization of the epileptogenic zone revealed on video electroencephalography monitoring. The ability of SISCOM to predict operative outcome was also determined in patients who had undergone repeated surgical procedures. The SISCOM studies revealed a localized hyperperfused alteration in 46 (79%) of 58 patients. Forty-one (89%) of these 46 patients had a SISCOM-demonstrated alteration in the hemisphere of the previous epilepsy surgery. Imaging changes in 33 (72%) of the 46 patients were at the site of the previous focal cortical resection. Eight (17%) of the 46 had SISCOM-demonstrated abnormalities remote from the lobe in which surgery had been performed but in the ipsilateral hemisphere. The hyperperfusion focus was in the contralateral hemisphere in the remaining five patients (11%). The site of the epileptogenic zone was concordant with the SISCOM focus in 32 (70%) of 46 patients. Twenty-six patients underwent repeated resection and were followed up for a mean of 44 months thereafter 11 of these patients (42%) had a significant reduction in seizure tendency. Only five patients (19%) were seizure free. Ten (50%) of 20 patients with a concordant SISCOM focus compared with none (0%) of three patients with a discordant focus had a favorable surgical outcome (p = 0.23). The SISCOM method might be useful in the evaluation of, and the surgical planning for, patients with intractable partial epilepsy in whom previous resective treatment has failed and who are being considered for reoperation.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Mary Ann Liebert Inc
Date: 15-11-2014
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.YEBEH.2012.09.002
Abstract: Psychiatric complaints afflict many patients with epilepsy, and these contribute significantly to the impaired quality of life experienced by sufferers of this common group of neurological conditions. Psychiatric disorders in epilepsy patients are under-diagnosed and under-treated. Moreover, evidence suggests that the psychiatric disorders may act as risk factors for some types of epilepsy and exacerbate disease progression in established cases, promoting the case for a bidirectional relationship between epilepsy and psychopathology. While cause and effect relationships can be difficult to establish in human studies, appropriate animal models provide valuable tools with which to study the interactions between epilepsy and stress-related disorders. Indeed, many epilepsy models exhibit behavioral phenotypes which are reflective of psychiatric disorders, and, conversely, stressful environments appear to promote a vulnerability to developing epilepsy. This review summarizes this research area, exploring the behavioral phenotypes in animal models of epilepsy and then examining the influence of stressful environments on susceptibility to seizures and epilepsy. The ultimate goal of this line of research is to be able to translate these findings to humans. Understanding the relationships between epilepsy and associated psychiatric disorders will facilitate effective treatment of mood disorders in epilepsy, inform about the pathophysiology of each in idually, and potentially open up novel therapeutic disease-modifying strategies for patients with epilepsy.
Publisher: Public Library of Science (PLoS)
Date: 18-06-2013
Publisher: IEEE
Date: 07-2017
Publisher: Oxford University Press (OUP)
Date: 09-06-2011
Publisher: Wiley
Date: 06-11-2014
DOI: 10.1111/EPI.12840
Abstract: Originally derived from a Wistar rat strain, a proportion of which displayed spontaneous absence-type seizures, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent the most widely utilized animal model of genetic generalized epilepsy. Here we compare the seizure, behavioral, and brain morphometric characteristics of four main GAERS colonies that are being actively studied internationally: two from Melbourne (MELB and STRAS-MELB), one from Grenoble (GREN), and one from Istanbul (ISTAN). Electroencephalography (EEG) recordings, behavioral examinations, and structural magnetic resonance imaging (MRI) studies were conducted on GAERS and Non-Epileptic Control (NEC) rats to assess and compare the following: (1) characteristics of spike-and-wave discharges, (2) anxiety-like and depressive-like behaviors, and (3) MRI brain morphology of regions of interest. Seizure characteristics varied between the colonies, with MELB GAERS exhibiting the least severe epilepsy phenotype with respect to seizure frequency, and GREN GAERS exhibiting four times more seizures than MELB. MELB and STRAS-MELB colonies both displayed consistent anxiety and depressive-like behaviors relative to NEC. MELB and GREN GAERS showed similar changes in brain morphology, including increased whole brain volume and increased somatosensory cortical width. A previously identified mutation in the Cacna1h gene controlling the CaV 3.2 T-type calcium channel (R1584P) was present in all four GAERS colonies, but absent in all NEC rats. This study demonstrates differences in epilepsy severity between GAERS colonies that were derived from the same original colony in Strasbourg. This multi-institute study highlights the potential impact of environmental conditions and/or genetic drift on the severity of epileptic and behavioral phenotypes in rodent models of epilepsy.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Wiley
Date: 12-06-2023
DOI: 10.1002/EPI4.12772
Abstract: This study evaluated sleep and respiratory abnormalities, and their relationship with seizures, in adults with developmental and epileptic encephalopathies (DEEs). We studied consecutive adults with DEEs undergoing inpatient video‐EEG monitoring and concurrent polysomnography between December 2011 and July 2022. Thirteen patients with DEEs were included (median age: 31 years, range: 20–50 69.2% female): Lennox–Gastaut syndrome ( n = 6), Lennox–Gastaut syndrome‐like phenotype ( n = 2), Landau–Kleffner syndrome ( n = 1), epilepsy with myoclonic‐atonic seizures ( n = 1), and unclassified DEEs ( n = 3). Sleep architecture was often fragmented by epileptiform discharges and seizures resulting in arousals (median arousal index: 29.0 per h, range: 5.1–65.3). Moderate‐to‐severe obstructive sleep apnea (OSA) was observed in seven patients (53.8%). Three patients (23.1%) had tonic seizures that frequently occurred with central apnea one met criteria for mild central sleep apnea. Of the patients with tonic seizures, two had other identifiable seizure manifestations, but in one patient, central apnea was commonly the only discernable seizure manifestation. Polysomnography during video‐EEG is an effective diagnostic tool in detecting sleep and seizure‐related respiratory abnormalities. Clinically significant OSA may increase the risk of comorbid cardiovascular disease and premature mortality. Treatment of epilepsy may improve sleep quality, and conversely, improved sleep, may decrease seizure burden.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2018
DOI: 10.1038/S41598-018-26457-7
Abstract: Recent work has demonstrated the feasibility of minimally-invasive implantation of electrodes into a cortical blood vessel. However, the effect of the dura and blood vessel on recording signal quality is not understood and may be a critical factor impacting implementation of a closed-loop endovascular neuromodulation system. The present work compares the performance and recording signal quality of a minimally-invasive endovascular neural interface with conventional subdural and epidural interfaces. We compared bandwidth, signal-to-noise ratio, and spatial resolution of recorded cortical signals using subdural, epidural and endovascular arrays four weeks after implantation in sheep. We show that the quality of the signals (bandwidth and signal-to-noise ratio) of the endovascular neural interface is not significantly different from conventional neural sensors. However, the spatial resolution depends on the array location and the frequency of recording. We also show that there is a direct correlation between the signal-noise-ratio and classification accuracy, and that decoding accuracy is comparable between electrode arrays. These results support the consideration for use of an endovascular neural interface in a clinical trial of a novel closed-loop neuromodulation technology.
Publisher: S. Karger AG
Date: 2008
DOI: 10.1159/000112859
Abstract: i Background/Aims: /i Centralized prescription databases may provide an efficient mechanism for recruitment of community-treated disease. i Methods: /i The Australian federal government agency, the Health Insurance Commission (HIC), invited patients to participate in the Tasmanian Epilepsy Register (TER). Eligible patients included those who received at least one anticonvulsant above a ‘reportable’ price threshold between July 1, 2001 and June 30, 2002. Patients were asked to disclose their medical indication for anticonvulsant treatment with additional demographic and prescription information obtained from the HIC. i Results: /i 7,541 were eligible for recruitment. After two mail invitations over 6 months, 3,375 (46.6%) had responded, but TER enrollment amongst those indicating treatment for epilepsy was 1,180 (78.3%). TER participants were more likely to obtain their prescriptions exclusively from their general practitioner (70.9%) or from combined sources (19.1%) rather than from pediatrician (4.2%), neurologist (1.4%) or general physician (1.0%) sources. Patients were more likely to respond with increasing age (linear trend p 0.001), when from a higher socioeconomic area (linear trend p 0.001), or if their prescription was obtained from a neurologist (p 0.001). i Conclusion: /i The national Australian prescription database represents community-treated epilepsy and provides an effective and efficient method for patient recruitment for clinical epidemiological research.
Publisher: Elsevier BV
Date: 10-1995
DOI: 10.1016/0967-5868(95)90052-7
Abstract: Anti-Yo is an anti-Purkiney cell cytoplasmic antibody found in approximately 50% of patients with parancoplastic cerebellar degeneration (PCD). We report three patients with anti-Yo positive PCD (one ovarian carcinoma and two poorly differentiated adenocarcinomas consistent with breast origin). Two were treated with chemotherapy and plasmapheresis but died within months of the diagnosis from progressive neurological disease. The other was given gamma-globulin and has remained table at 6 months follow up. Anti-Yo antibodies are highly specific with almost all patients having breast or gynaecological malignanies. Commonly the tumour is of small volume and asymptomatic. Attempts at treatment are usually unsuccessful but there are a number of reports of stabilisation or improvement when treatment is begun before the development of severe neurological disability. The detection of anti-Yo antibodies is very useful for the diagnosis of PCD allowing early tumour detection and prompt institution of treatment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2009
Publisher: Mary Ann Liebert Inc
Date: 12-2019
Abstract: Initial studies have found some evidence for transactive response DNA-binding protein 43 (TDP-43) abnormalities after traumatic brain injury (TBI), and the presence of protein inclusions consisting of TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis (ALS), a condition associated with TBI. However, no study has characterized changes in TDP-43 phosphorylation, mislocalization, and fragmentation (i.e., abnormalities linked to hallmark TDP-43 pathology) after TBI, and how these relate to functional outcomes. Further, how TBI affects an in idual with a known predisposition to TDP-43 pathology is unknown. Therefore, this study examined the effects of TBI on TDP-43 post-translational processing, localization, and behavioral outcomes in wild-type (WT) mice and mutant TDP-43
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.JOCN.2015.07.011
Abstract: The foetal outcomes of 2,635 pregnancies recorded in the Australian Pregnancy Register were studied. In at least the initial 4months of 515 pregnancies, there had been no intrauterine exposure to antiepileptic drugs, though the women involved in 264 of these pregnancies took antiepileptic drugs in later pregnancies. Compared with these 515 drug-unexposed pregnancies, foetal malformations risks were increased more than five-fold in association with valproate monotherapy, and more than doubled in association with carbamazepine monotherapy (p<0.05). There were no statistically significant increases in malformation rates associated with other more commonly used antiepileptic drugs, while the malformation risk in relation to levetiracetam exposure was lower than that in the drug-unexposed pregnancies. The published literature has rather consistently shown raised malformation rates associated with carbamazepine monotherapy, though only once was it statistically significant. There now appears to be enough evidence to make it likely that carbamazepine possesses some teratogenic capacity. This makes it unwise to employ the malformation rate associated with carbamazepine monotherapy as a comparator when assessing the foetal hazards from exposure to newer antiepileptic drugs. Levetiracetam may prove a better comparator if adequate untreated control material is unobtainable.
Publisher: Cambridge University Press
Date: 26-03-2015
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.NBD.2010.02.001
Abstract: The incidence of psychosis is increased in people with epilepsy, including idiopathic generalized epilepsies. To study the biological basis for this co-morbidity, we compared GAERS, a genetic rat model of absence epilepsy, to non-epileptic control rats (NEC). Mature, 14-week old GAERS showed enhanced hetamine-induced locomotor hyperactivity - a feature also present in young (6-week old) GAERS prior to epilepsy onset. Prepulse inhibition and its disruption by psychotropic drugs did not differ between strains, although GAERS displayed elevated startle responses at both epileptic and pre-epileptic ages. The frontoparietal cortex of GAERS displayed a twofold increase in the power of gamma (30-80 Hz) oscillations, a proposed neurophysiological correlate of psychosis. Radioligand binding autoradiography demonstrated reduced densities of dopamine transporters in the caudate nucleus and nucleus accumbens core and of dopamine D2 receptors in the caudate nucleus. GAERS provide an opportunity to study the neurodevelopmental, genetic and therapeutic aspects of psychiatric comorbidities associated with epilepsy.
Publisher: AMPCo
Date: 07-2011
Publisher: IOP Publishing
Date: 05-07-2016
DOI: 10.1088/1741-2560/13/4/046020
Abstract: Recently, we reported a minimally invasive stent-electrode array capable of recording neural signals from within a blood vessel. We now investigate the use of electrochemical impedance spectroscopy (EIS) measurements to infer changes occurring to the electrode-tissue interface from devices implanted in a cohort of sheep for up to 190 days. In a cohort of 15 sheep, endovascular stent-electrode arrays were implanted in the superior sagittal sinus overlying the motor cortex for up to 190 days. EIS was performed routinely to quantify viable electrodes for up to 91 days. An equivalent circuit model (ECM) was developed from the in vivo measurements to characterize the electrode-tissue interface changes occurring to the electrodes chronically implanted within a blood vessel. Post-mortem histological assessment of stent and electrode incorporation into the wall of the cortical vessels was compared to the electrical impedance measurements. EIS could be used to infer electrode viability and was consistent with x-ray analysis performed in vivo, and post-mortem evaluation. Viable electrodes exhibited consistent 1 kHz impedances across the 91 day measurement period, with the peak resistance frequency for the acquired data also stable over time. There was a significant change in 100 Hz phase angles, increasing from -67.8° ± 8.8° at day 0 to -43.8° ± 0.8° at day 91, which was observed to stabilize after eight days. ECM's modeled to the data suggested this change was due to an increase in the capacitance of the electrode-tissue interface. This was supported by histological assessment with >85% of the implanted stent struts covered with neointima and incorporated into the blood vessel within two weeks. This work demonstrated that EIS could be used to determine the viability of electrode implanted chronically within a blood vessel. Impedance measurements alone were not observed to be a useful predictor of alterations occurring at the electrode tissue interface. However, measurement of 100 Hz phase angles was in good agreement with the capacitive changes predicted by the ECM and consistent with suggestions that this represents protein absorption on the electrode surface. 100 Hz phase angles stabilized after 8 days, consistent with histologically assessed s les. These findings demonstrate the potential application of this technology for use as a chronic neural recording system and indicate the importance of conducting EIS as a measure to identify viable electrodes and changes occurring at the electrode-tissue interface.
Publisher: S. Karger AG
Date: 27-11-2016
DOI: 10.1159/000438924
Abstract: b i Background: /i /b Alzheimer's disease (AD) is characterized by two cardinal pathologies, which have different topological distributions. The differential anatomical distributions of these pathologies raise the possibility that they exert differential effects on brain networks. b i Objectives: /i /b To investigate whether cerebrospinal fluid (CSF) biomarkers of the cardinal pathologies have differential relationships with functional connectivity networks in patients with dementia of the Alzheimer's type (DAT). b i Methods: /i /b Thirty-nine participants underwent CSF s ling and resting-state functional magnetic resonance imaging. Functional connectivity networks were computed for each participant. CSF biomarker levels of p-tau and amyloid-β (Aβ) were regressed onto these networks to identify subnetworks associated with each biomarker. b i Results: /i /b A subnetwork associated with tau-related pathology was identified with its hub in the right anterior entorhinal cortex. A separate subnetwork associated with Aβ with its hub in the right dorsal anterior cingulate cortex was identified. b i Conclusion: /i /b These results demonstrate the differential effects of AD biomarkers on functional connectivity networks, supporting a possible ision of labour between the cardinal pathologies.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JOCN.2015.07.012
Abstract: There is growing interest in the neurobiological substrate of general intelligence. Psychometric estimates of general intelligence are reduced in a range of neurological disorders, leading to practical application as sensitive, but non-specific, markers of cerebral disorder. This study examined estimates of general intelligence in neurotypical adults using diffusion tensor imaging and resting-state functional connectivity analysis. General intelligence was related to white matter organisation across multiple brain regions, confirming previous work in older healthy adults. We also found that variation in general intelligence was related to a large functional sub-network involving all cortical lobes of the brain. These findings confirm that in idual variance in general intelligence is related to diffusely represented brain networks.
Publisher: Wiley
Date: 04-09-2022
DOI: 10.1111/EPI.17398
Abstract: Posttraumatic epilepsy (PTE) is a well‐known chronic complication following traumatic brain injury (TBI). Despite some evidence that age at the time of injury may influence the likelihood of PTE, the incidence of PTE in pediatric populations remains unclear. We therefore conducted a systematic review to determine the overall reported incidence of PTE, and explore potential risk factors associated with PTE after pediatric TBI. A comprehensive literature search of the PubMed, Embase, and Web of Science databases was conducted, including randomized controlled trials and cohort studies assessing the incidence of PTE in TBI pediatric patients. We excluded studies with a s le size of patients and those in which a pediatric cohort was not clearly discernable. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines. We found that the overall incidence of PTE following pediatric TBI was 10% (95% confidence interval [CI] = 5.9%–15%). Subgroup analysis of a small number of studies demonstrated that the occurrence of early seizures (cumulative incidence ratio [CIR] = 7.28, 95% CI = 1.09–48.4, p = .040), severe TBI (CIR = 1.81, 95% CI = 1.23–2.67, p .001), and intracranial hemorrhage (CIR = 1.60, 95% CI = 1.06–2.40, p = .024) increased the risk of PTE in this population. Other factors, including male sex and neurosurgical intervention, were nonsignificantly associated with a higher incidence of PTE. In conclusion, PTE is a significant chronic complication following childhood TBI, similar to in the adult population. Further standardized investigation into clinical risk factors and management guidelines is warranted. PROSPERO ID# CRD42021245802.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2023
Publisher: Wiley
Date: 19-03-2004
Publisher: Springer Science and Business Media LLC
Date: 23-01-2015
DOI: 10.1038/NCOMMS7031
Publisher: Wiley
Date: 13-01-2021
DOI: 10.1002/EPI4.12460
Abstract: ‘First seizure’ clinics (FSCs) aim to achieve early expert assessment for in iduals with possible new‐onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research. We reviewed investigation findings over 11 years (2000‐2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new‐onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol‐driven interviews and investigations had been recorded prospectively and were extracted from medical records for study. Median patient age was 37 (IQR 26‐52, range 18‐94) years (AH 34 vs RMH 42 years P .001). Eighty‐six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days P .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy‐six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12% P .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion ( %) at each clinic. At both sites, epilepsy type could be determined in 60% of patients RMH had more focal and AH more generalized epilepsy diagnoses. Differences between the clinics’ administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.
Publisher: Wiley
Date: 07-2015
DOI: 10.1002/ANA.24457
Publisher: Oxford University Press (OUP)
Date: 08-2020
Abstract: The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre s le of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippoc al sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P & 0.001). Across ‘all epilepsies’ lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippoc al sclerosis in the ipsilateral parahippoc al cingulum and external capsule, with smaller effects across most other tracts. In iduals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippoc al sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippoc al sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.
Publisher: eLife Sciences Publications, Ltd
Date: 09-03-2023
DOI: 10.7554/ELIFE.78877
Abstract: There are no pharmacological disease-modifying treatments with an enduring effect to mitigate the seizures and comorbidities of established chronic temporal lobe epilepsy (TLE). This study aimed to evaluate for disease modifying effects of sodium selenate treatment in the chronically epileptic rat post-status epilepticus (SE) model of drug-resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, animals received sodium selenate, levetiracetam, or vehicle subcutaneousinfusion continuously for 4 weeks. To evaluate the effects of the treatments, one week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of epilepsy disease severity in our current study. The results showed that sodium selenate treatment was associated with mitigation of measures of disease severity at 8 weeks post-treatment cessation reducing the number of spontaneous seizures (p 0.05), cognitive dysfunction (p 0.05), and sensorimotor deficits (p 0.01). Moreover, selenate treatment was associated with increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening (p 0.05). Network medicine integration of multi-omics re-clinical outcomes identified protein-metabolite modules positively correlated with TLE. Our results provide evidence that treatment with sodium selenate results in a sustained disease-modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.NBD.2014.09.004
Abstract: Epilepsy is a common brain disorder which is characterised by recurring seizures. In addition to suffering from the constant stress of living with this neurological condition, patients also frequently experience comorbid psychiatric and cognitive disorders which significantly impact their quality of life. There is growing appreciation that stress, in particular occurring in early life, can negatively impact brain development, creating an enduring vulnerability to develop epilepsy. This aligns with the solid connections between early life environments and the development of psychiatric conditions, promoting the possibility that adverse early life events could represent a common risk factor for the later development of both epilepsy and comorbid psychiatric disorders. The influence of sex has been little studied, but recent research points to potential important interactions, particularly with regard to effects mediated by HPA axis programming. Understanding these interactions, and the underlying molecular mechanisms, will provide important new insights into the causation of both epilepsy and of psychiatric disorders, and potentially open up novel avenues for treatment.
Publisher: Wiley
Date: 04-07-2019
DOI: 10.1002/EPI4.12349
Publisher: eLife Sciences Publications, Ltd
Date: 08-11-2022
Publisher: Springer Science and Business Media LLC
Date: 15-06-2023
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.EPLEPSYRES.2010.09.006
Abstract: A subgroup of patients with non-lesional temporal lobe epilepsy (NLTLE) have no evidence of hippoc al sclerosis (HS) on MRI or on histopathology. It is controversial whether this represents a different clinicopathological syndrome from NLTLE with HS, or whether both subgroups represent different ends of the spectrum of mesial TLE. Here the EEG source localization dipoles were compared between NLTLE patients with HS (HS+) and without HS (HS-), and the relationship with post-surgical outcome was investigated. EEG dipole source localization of interictal epileptiform spikes recorded during prolonged video-EEG monitoring was performed from 22 consecutive HS+ and 12 HS- NLTLE patients. EEG was acquired using 29 scalp electrodes, including an inferior temporal row. Up to 13 spikes per patient were averaged and sources localized using a boundary element model based on the patients volumetric MRI. 21/34 patients (62%) had dipoles for the interictal spikes localized to the epileptogenic temporal lobe. The site of the intratemporal localization did not differ significantly between the HS+ and HS- patients, with the dipoles localizing to the mesial temporal region in 27% of HS+ and 25% of HS- patients. There was no significant relationship between the localization and orientation of the dipoles and the surgical outcome. The dipoles for interictal spikes do not differ between HS+ and HS- patients, suggesting that these subgroups of NLTLE patients do not have distinct cerebral generators.
Publisher: Wiley
Date: 22-03-2018
DOI: 10.1002/EPI4.12109
Publisher: Elsevier BV
Date: 11-2007
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NEUROPHARM.2016.05.001
Abstract: Mild traumatic brain injuries may result in cumulative brain damage and neurodegenerative disease. To date, there is no pharmaceutical intervention known to prevent these consequences. Hyperphosphorylated tau has been associated in this process, and protein phosphatase 2A 55 kDa regulatory B subunit (PP2A/PR55) - the major tau phosphatase - is decreased after a brain insult. Sodium selenate up-regulates PP2A/PR55 and dephosphorylates tau, and may hold promise as a treatment in the mild brain injury setting. Here we investigated sodium selenate treatment in rats given repeated mild traumatic brain injuries. Rats were given three mild fluid percussion injuries or three sham-injuries, and treated with sodium selenate (1 mg/kg/day) or saline-vehicle for three months before undergoing behavioral testing, MRI, and post-mortem analysis of brain tissue. Repeated mild traumatic brain injuries increased the phosphorylation of tau and decreased PP2A/PR55, whilst inducing brain atrophy and cognitive and sensorimotor deficits. Sodium selenate treatment increased PP2A/PR55, and decreased tau phosphorylation, brain damage, and cognitive and motor impairments in rats given repeated mild traumatic brain injuries. Our findings implicate PP2A/PR55 and tau as important mechanisms in the pathophysiological aftermath of repeated mild brain traumas, and support sodium selenate as a novel and translatable treatment for these common injuries.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2020
DOI: 10.1038/S41598-020-71887-X
Abstract: Glioblastoma is the most aggressive form of primary brain cancer, with a median survival of 12–15 months. The P2X receptor 7 (P2X7R) is upregulated in glioblastoma and is associated with increased tumor cell proliferation. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is also upregulated in glioblastoma and has been shown to have both pro- and anti-tumor functions. This study investigates the potential mechanism linking P2X7R and GM-CSF in the U251 glioblastoma cell line and the therapeutic potential of P2X7R antagonism in this setting. P2X7R protein and mRNA was demonstrated to be expressed in the U251 cell line as assessed by immunocytochemistry and qPCR. Its channel function was intact as demonstrated by live cell confocal imaging using a calcium indicator Fluo-4 AM. Inhibition of P2X7R using antagonist AZ10606120, decreased both GM-CSF mRNA (P 0.05) and protein (P 0.01) measured by qPCR and ELISA respectively. Neutralization of GM-CSF with an anti-GM-CSF antibody did not alter U251 cell proliferation, however, P2X7R antagonism with AZ10606120 significantly reduced U251 glioblastoma cell numbers (P 0.01). This study describes a novel link between P2X7R activity and GM-CSF expression in a human glioblastoma cell line and highlights the potential therapeutic benefit of P2X7R inhibition with AZ10606120 in glioblastoma.
Publisher: Wiley
Date: 07-1996
DOI: 10.1111/J.1528-1157.1996.TB00636.X
Abstract: Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We report a patient with an unusual form of reflex epilepsy in whom seizures are induced by tooth brushing. Magnetic resonance imaging (MRI) demonstrated a right posterior frontal low-grade tumor predominantly involving the precentral gyrus. Video-telemetry demonstrated right-sided epileptiform activity during a typical induced complex partial seizure. An ictal single photon emission computed tomography (SPECT) scan showed an area of hyperfusion that corresponded to the MRI lesion on coregistration with a surface-matching technique. A subsequent coregistered interictal SPECT scan demonstrated hypoperfusion in the same region. Ours is the first report to demonstrate a structural focus in this unusual form of reflex epilepsy. Possible mechanisms to explain the induction of the seizures are discussed.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 09-06-2023
DOI: 10.1038/S41467-023-39040-0
Abstract: Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine in iduals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY in iduals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome ( I ntellectual disability, N eurodevelopmental defects and D evelopmental delay with 46,X Y GON adal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for in iduals born with this condition.
Publisher: Wiley
Date: 17-06-2019
DOI: 10.1111/EPI.16076
Abstract: Recent data indicate that amygdala kindling leads to significant changes in interictal neuronal firing patterns of thalamic reticular nucleus (TRN) neurons by decreasing the spontaneous firing rate and increasing burst firing in nonepileptic control (NEC) rats. Genetic Absence Epilepsy Rats From Strasbourg (GAERS) were resistant to these kindling-induced firing changes in TRN neurons, and are also resistant to the progression of kindling. We investigated whether a homozygous, missense, single nucleotide mutation (R1584P) in the Ca Double-crossed (GAERS vs NEC F2) rats that were homozygous for the Ca We found that the R1584P mutation did not affect kindling progression in F2 crosses (P = 0.78). However, it influenced kindling-induced neuronal firing of TRN neurons. After 30 stimulations, RR rats exhibited a lower firing rate and a higher percentage of burst firing compared to PP rats. The decrease in firing frequency was correlated with the increase in the amount of burst firing in RR rats (R Our findings suggest that mutation in Ca
Publisher: Cold Spring Harbor Laboratory
Date: 30-04-2021
DOI: 10.1101/2021.04.30.442117
Abstract: Temporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippoc al pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked ergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across in idual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.
Publisher: Springer Science and Business Media LLC
Date: 08-2001
DOI: 10.1007/S11910-001-0091-X
Abstract: Contemporary neuroimaging studies using structural and functional techniques are critical in the evaluation of patients with localization-related epilepsy. Imaging procedures may be used to localize the epileptic brain tissue or determine the likely pathologic findings underlying the epileptogenic zone, or both. The diagnostic yield of magnetic resonance imaging (MRI) has been demonstrated in patients with partial epilepsy. The identification of an MRI epileptogenic lesion is almost invariably a reliable indicator of the site of seizure onset. Peri-ictal single photon emission computed tomography (SPECT) may be of particular benefit in patients with normal MRI studies. The use of neuroimaging in the care and management of patients with partial epilepsy is discussed here.
Publisher: Public Library of Science (PLoS)
Date: 19-05-2015
Publisher: Wiley
Date: 06-11-2007
Publisher: Wiley
Date: 06-2006
DOI: 10.1111/J.1468-1331.2006.01359.X
Abstract: The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P 1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2017
DOI: 10.1007/S00198-017-4098-9
Abstract: Changes in areal bone mineral density (aBMD) and other predictors of bone loss were evaluated in 48 same-sex twin/age-matched sibling pairs discordant for antiepileptic drug (AED) use. AED users had reduced BMD at the hip regions. Prolonged AED users had greater aBMD loss, predicting a higher risk of bone fragility. To investigate the longitudinal associations of bone mineral measures with antiepileptic drug (AED) use, including enzyme-inducing (EIAED) and non-enzyme-inducing (NEIAED) types, and other predictors of bone loss in a study of 48 same-sex twin/age-matched sibling pairs (40 female, 8 male) discordant for AED use. Using dual-energy X-ray absorptiometry (DXA), areal bone mineral density (aBMD) and content (BMC) at the hip regions, forearm, lumbar spine, and whole body were measured twice, at least 2 years apart. The mean within-pair difference (MWPD), MWPD%, and mean annual rate of aBMD change were adjusted for age, weight, and height. Predictors of bone loss were evaluated. AED users, compared to non-users, at baseline and follow-up, respectively, had reduced aBMD at the total hip (MWPD% 3.8, 4.4%), femoral neck (4.7, 4.5%), and trochanter regions (4.1, 4.6%) (p 0.05) regions did not differ within pairs. Nevertheless, EIAED users had greater aBMD loss than non-users (n = 20 pairs) at the total hip (1.7 vs. 0.3%, p = 0.013) and whole body regions (0.7% loss vs. 0.1% BMD gain, p = 0.019), which was not found in NEIAED-discordant pairs (n = 16). AED use >20 years predicted higher aBMD loss at the forearm (p = 0.028), whole body (p = 0.010), and whole body BMC (p = 0.031). AED users had reduced aBMD at the hip regions. Prolonged users and EIAED users had greater aBMD loss, predicting a higher risk of bone fragility. Further prospective studies of AED effects on bone microarchitecture are needed.
Publisher: Wiley
Date: 16-01-2014
Abstract: This pictorial essay highlights the role of the radiologist as a member of the adult epilepsy multidisciplinary team, and gives an overview of MRI-evident epileptogenic lesions.
Publisher: SAGE Publications
Date: 2022
DOI: 10.1177/11772719221081318
Abstract: Sports-related concussion (SRC) is a common form of brain injury that lacks reliable methods to guide clinical decisions. MicroRNAs (miRNAs) can influence biological processes involved in SRC, and measurement of miRNAs in biological fluids may provide objective diagnostic and return to play/recovery biomarkers. Therefore, this prospective study investigated the temporal profile of circulating miRNA levels in concussed male and female athletes. Pre-season baseline blood s les were collected from amateur Australian rules football players (82 males, 45 females). Of these, 20 males and 8 females sustained an SRC during the subsequent season and underwent blood s ling at 2-, 6- and 13-days post-injury. A miRNA discovery Open Array was conducted on plasma to assess the expression of 754 known/validated miRNAs. miRNA target identified were further investigated with quantitative real-time PCR (qRT-PCR) in a validation study. Data pertaining to SRC symptoms, demographics, sporting history, education history and concussion history were also collected. Discovery analysis identified 18 candidate miRNA. The consequent validation study found that plasma miR-221-3p levels were decreased at 6d and 13d, and that miR-27a-3p levels were decreased at 6d, when compared to baseline. Moreover, miR-27a and miR-221-3p levels were inversely correlated with SRC symptom severity. Circulating levels of miR-27a-3p and miR-221-3p were decreased in the sub-acute stages after SRC, and were inversely correlated with SRC symptom severity. Although further studies are required, these analyses have identified miRNA biomarker candidates of SRC severity and recovery that may one day assist in its clinical management.
Publisher: Wiley
Date: 06-08-2012
DOI: 10.1111/J.1528-1167.2012.03625.X
Abstract: Considerable information is now available concerning the risk of teratogenesis in the in idual pregnancy exposed to antiepileptic drugs (AEDs). However, there is comparatively little information available concerning the risk in the subsequent pregnancies of women who continue to take the AED associated with a fetal malformation in a previous pregnancy. This article addresses this matter. Analysis of data concerning fetal abnormalities in 1,243 women who had 2,637 pregnancies between mid-1999 and 2010 recorded in the Australian Register of Antiepileptic Drugs in Pregnancy. Of the 2,637 pregnancies, 1,114 had been completed before initial enrolment in the Register. Women taking any AED who had given birth to a malformed baby in their first enrolled pregnancy and who continue taking the same drug were at increased risk of having a malformed offspring in their next pregnancy (35.7% vs. 3.1% odds ratio [OR] 17.6 95% confidence interval [95% CI] 4.5-68.7). Among these women, those taking valproate (VPA) were more likely to have malformed fetuses in their next pregnancies than those who had taken VPA without fetal abnormalities (57.2% vs. 7.0%, OR 17.8 95% CI 2.7, 119.1). There were similar although not statistically significant trends in those who had taken AEDs other than VPA. Similar, although again not statistically significant, trends were found, when considering the pairings of the most recent preenrollment pregnancy and the following one. If a woman had two or more pregnancies that resulted in AED-associated fetal malformation, the types of malformation were often different. Women whose last pregnancy resulted in a fetal malformation have a substantially increased risk of having further malformed fetuses if they become pregnant again while taking the same AED, particularly VPA. This suggests that maternal factors, perhaps genomic, predispose to at least VPA-associated malformations. This knowledge, together with information about the outcome of any previous pregnancy, should help in advising women with AED-treated epilepsy who plan further pregnancies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1998
Abstract: Objective: To determine the incidence, risk factors, and long-term sequelae of the purple glove syndrome (PGS) in hospital patients receiving IV phenytoin. Background: PGS is a poorly understood, potentially serious local complication of IV phenytoin administration characterized by progressive distal limb edema, discoloration, and pain. Methods: The pharmacologic records of the Mayo Foundation hospitals were reviewed to identify 179 consecutive patients who had IV phenytoin ordered during a 3-month period. Their hospital records were then reviewed to confirm IV phenytoin treatment, the frequency of PGS (defined as the progressive development of edema, discoloration, and pain in the limb after administration of IV phenytoin), and the outcome of PGS. Results: A total of 152 patients received IV phenytoin, and nine (5.9%) developed PGS. PGS patients received a greater median initial dose of phenytoin, total 24-hour dose, and total number of doses (all p 0.05). In addition, the median age of the PGS patients was older, their infusion was more often given for acute seizures, it was less likely to be administered in the operating room, and the length of their hospital stay was longer (all p 0.05). One patient required surgical therapy, and all other patients resolved within 3 weeks with conservative management. Conclusions: PGS is not rare and elderly patients and in iduals receiving large, multiple doses are particularly at risk. This iatrogenic complication may be preventable by substituting fosphenytoin for IV phenytoin.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JNEUROIM.2019.03.004
Abstract: Multiple sclerosis (MS) is characterized by neuroinflammatory infiltrates and central nervous system demyelination. In the neuroinflammatory foci of MS there is increased expression of a purinergic receptor, P2X7R. Although implicated in the neuroinflammation, the exact role of P2X7R in the context of MS is unclear and forms the basis of this review. In this review, we also introduce the immunopathologies and inflammatory processes in MS, with a focus on P2X7R and the possible immunomodulatory role of vitamin D deficiency in this setting.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-12-2017
DOI: 10.1212/WNL.0000000000004853
Abstract: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. We report an association between a rare variant in the complement factor H–related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10 –11 odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.
Publisher: Hindawi Limited
Date: 29-09-2010
DOI: 10.1111/J.1600-0404.2010.01429.X
Abstract: In studies investigating foetal malformations associated with antiepileptic drug exposure during pregnancy, the common practice has been to assess the incidence and nature of the malformations at, or soon after, birth. The adequacy of this approach to determine the true incidence of the malformations has received little attention. To compare the incidence and natures of the foetal malformations recognized by, or soon after, birth with similar data for malformations recognized in the first post-natal year. Analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy. Up to 25% of the malformations recognized by the end of the first post-natal year had not been detected by, or soon after, birth. There was a tendency for the late-recognized malformations to differ from the early-recognized ones in relation to the body parts involved. Early assessment and delayed assessment of infants for the presence of foetal malformations are complementary, with the latter resulting in finding a higher incidence of malformations. However, omission of an early post-natal assessment may result in biases because of loss of subjects to follow-up.
Publisher: No publisher found
Date: 2020
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.BBR.2014.10.050
Abstract: Autism is a complex neurodevelopmental disorder that is characterized by social abnormalities. Genetic, dietary and gut-related factors are implicated in autism, however the causal properties of these factors and how they may interact are unclear. Propionic acid (PPA) is a product of gut microbiota and a food preservative. PPA has been linked to autism, and PPA administration to rats is an animal model of the condition. Seizure-prone (FAST) and seizure-resistant (SLOW) rats were initially developed to investigate differential vulnerability to developing epilepsy. However, FAST rats also display autistic-like features, and have been proposed as a genetic model of autism. Here we examined the effects of PPA on social behavior in FAST and SLOW rats. A single intracerebroventricular injection of PPA, or phosphate-buffered saline (PBS), was administered to young-adult male FAST and SLOW rats. Immediately after treatment, rats were placed in same-treatment and same-strain pairs, and underwent social behavior testing. PPA induced social abnormalities in both FAST and SLOW rat strains. While there was no evidence of social impairment in FAST rats that were not treated with PPA, these rats were hyperactive relative to SLOW rats. Post-mortem immunofluorescence analysis of brain tissue indicated that PPA treatment resulted in increased astrogliosis in the corpus callosum and cortex compared to PBS treatment. FAST rats had increased astrogliosis in the cortex compared to SLOW rats. Together these findings support the use of PPA as a rat model of autism, but indicate there are no interactive effects between the PPA and FAST models.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2009
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.JOCN.2010.07.112
Abstract: We report a patient with an unusual presentation of a temporal low-grade glioma with visual symptoms of formed, coloured meaningful images without coexistent psychiatric symptoms or epileptiform activity consistent with a diagnosis of visual hallucinosis. The location and extent of the lesion on the MRI differs from the lesions commonly associated with this diagnosis.
Publisher: Springer Science and Business Media LLC
Date: 1998
Abstract: Scalp-recorded EEG is a noninvasive and widely available tool for studying normal and dysfunctional human neurophysiology with unsurpassed temporal resolution. However, scalp-recorded EEG data is difficult to correlate with anatomy, and most current display and neural source estimation algorithms are based on unrealistic spherical or elliptical models of the head. It is possible to measure the positions of electrodes on the patient's scalp, and to register those electrode positions into the space of a high-resolution MRI volume, and to then use the patient-specific anatomy as the basis for display and estimation of neural sources. We use a surface matching algorithm to register digitized electrode and scalp surface coordinates to a three-dimensional MRI volume. This study uses fiducial markers in phantom and volunteer studies to quantitatively estimate the accuracy of the electrode registration method. Our electrode registration procedure is accurate to 2.21 mm for a realistic head phantom and accurate to 4.16 mm on average for five volunteers. This level of accuracy is considered within acceptable limits for clinical applications.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.EJPHAR.2008.09.014
Abstract: Approximately one-third of patients with epilepsy display an inherent resistance to pharmacological therapy, manifest as continuing seizures despite maximal tolerated doses of anti-epileptic drugs. One hypothesis for the underlying mechanism of anti-epileptic drug pharmacoresistance is lower drug entry to the epileptic neurones due to the activity of multidrug efflux pumps from the ATP Binding Cassette (ABC) superfamily at the blood-brain barrier. There has been a steady accumulation of animal and human data supporting this theory, particularly for ABC(B1) (P-glycoprotein). However, much of this evidence is indirect. In the present study, several anti-epileptic drugs (carbamazepine, valproic acid, phenytoin, lamotrigine and primidone) were examined for their ability to interact with three ABC transporters that have been implicated pharmacoresistance of anti-epileptic drugs - ABC(B1), ABC(C1) and ABC(G2). Interaction of anti-epileptic drugs with the transporters was assessed by determining whether they could reverse the ability of multidrug ABC transporters to confer a drug resistance phenotype on cancer cell lines. None of these compounds was able to affect the phenotype, suggesting an absence of any interaction with the multidrug transporters. This finding was further investigated by examination of transporter activity namely the ability to reduce steady-state intracellular [(3)H]-radiolabelled drug accumulation. None of the anti-epileptic drugs affected labelled drug accumulation by any of the triumvirate of multidrug transporters examined, indicating that they are unlikely to be substrates. The lack of direct modulation by anti-epileptic drugs of ABC transporter function suggests that these proteins do not contribute significantly to resistance in epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-10-2001
Abstract: The authors prospectively examined the occurrence of subacute local cutaneous reactions (LCR) in patients receiving IV phenytoin over a 12-month period at a general hospital. LCR were detected in 29 of 115 patients (25.2% 22 mild and seven moderate). All resolved within 3 weeks. Patients with LCR were older (median 68 versus 54.5 years, p = 0.004), were more likely to be in a general ward (86% versus 66%, p = 0.04), and had larger catheters (median 16 G versus 18 G, p = 0.05). The authors conclude that LCR are common in routine hospital practice, but are generally mild and benign.
Publisher: Wiley
Date: 13-05-2019
DOI: 10.1002/EPI4.12327
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.61
Publisher: Springer Science and Business Media LLC
Date: 10-01-2021
DOI: 10.1186/S40364-020-00256-7
Abstract: Biomarkers that can objectively guide the diagnosis of sports-related concussion, and consequent return-to-play decisions, are urgently needed. In this study, we aimed to determine the temporal profile and diagnostic ability of serum levels of neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP), and tau in concussed male and female Australian footballers. Blood was collected from 28 Australian rules footballers (20 males, 8 females) at 2-, 6-, and 13-days after a diagnosed concussion for comparison to their levels at baseline (i.e. pre-season), and with 27 control players (19 males, 8 females) without a diagnosis of concussion. Serum concentrations of protein markers associated with damage to neurons (UCHL1), axons (NfL, tau), and astrocytes (GFAP) were quantified using a Simoa HD-X Analyzer. Biomarker levels for concussed players were compared over time and between sex using generalised linear mixed effect models, and diagnostic performance was assessed using area under the receiver operating characteristic curve (AUROC) analysis. Serum NfL was increased from baseline in male footballers at 6- and 13-days post-concussion. GFAP and tau were increased in male footballers with concussion at 2- and 13-days respectively. NfL concentrations discriminated between concussed and non-concussed male footballers at all time-points (AUROC: 2d = 0.73, 6d = 0.85, 13d = 0.79), with tau also demonstrating utility at 13d (AUROC = 0.72). No biomarker differences were observed in female footballers after concussion. Serum NfL may be a useful biomarker for the acute and sub-acute diagnosis of concussion in males, and could inform neurobiological recovery and return-to-play decisions. Future adequately powered studies are still needed to investigate biomarker changes in concussed females.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2021
DOI: 10.1007/S11682-020-00433-0
Abstract: Pediatric traumatic brain injury (pTBI) is a major community health concern. Due to ongoing maturation, injury to the brain at a young age can have devastating consequences in later life. However, how pTBI affects brain development, including white matter maturation, is still poorly understood. Here, we used advanced diffusion weighted imaging (DWI) to assess chronic white matter changes after experimental pTBI. Mice at post-natal day 21 sustained a TBI using the controlled cortical impact model and magnetic resonance imaging (MRI) was performed at 6 months post-injury using a 4.7 T Bruker scanner. Four diffusion shells with 81 directions and b-values of 1000, 3000, 5000, and 7000s/mm
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 06-1997
DOI: 10.1111/J.1528-1157.1997.TB01236.X
Abstract: Because focal encephalomalacia is an important cause of medically intractable partial epilepsy and few studies have evaluated the efficacy and the safety of resecting focal-encephalomalacias to improve seizure control, we studied a cohort of 17 consecutive patients who underwent resection of encephalomalacias in the frontal lobes as a treatment of their intractable epilepsy. We evaluated several factors for their value in predicting postsurgical seizure control. Pre- and postsurgical magnetic resonance imaging (MRI) scans were reviewed independently by 2 blinded investigators. At a median of 3 years of follow-up (range 0.6-7.5 years), 12 patients (70%) were seizure-free or had only rare seizures. The presence of a focal fast frequency discharge (focal ictal beta pattern) at the beginning of seizures on scalp EEG was predictive of seizure-free outcome (p = 0.017), even among patients who had complete resection of their encephalomalacias (p = 0.016). There was no significant differences in outcome with regard to age at the time of the injury that caused encephalomalacia, interval between injury and onset of seizures, duration of presurgical seizure history, presurgical seizure frequency, age at surgery, or the completeness of encephalomalacia resection. The analysis regarding completeness of encephalomalacia resection almost reached significance, suggesting that it may also be an important predictive factor (p = 0.051). We conclude that surgery is a very effective treatment for intractable frontal lobe epilepsy (FLE) secondary to encephalomalacias. Patients are more likely to become seizure-free if they have a focal ictal beta discharge on their scalp EEG. Complete resection of the encephalomalacia should be attempted, since our results suggest that this may be a favorable predictive factor. Moreover, the operative strategy for our patients entailed, whenever possible, complete resection of the encephalomalacias and of the adjacent electrophysiologically abnormal tissues.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-01-2002
DOI: 10.1212/WNL.58.1.104
Abstract: The occurrence of meningitis or encephalitis in early childhood, i.e., < or =4 years of age, may be associated with both the development of medial temporal lobe epilepsy (MTLE) and an excellent operative outcome following an anterior temporal lobectomy (ATL). However, whether the predictive value of this risk factor for partial epilepsy is independent of the finding of mesial temporal sclerosis (MTS) on MRI is not known. Consecutive patients (n = 39) with a remote history of meningitis or encephalitis who underwent an ATL were compared with 78 sex- and age-matched control subjects who had not experienced a CNS infection before ATL. All patients in both groups had nonlesional temporal lobe epilepsy and were followed up for at least 12 months postoperatively. There was a trend for the patients with a history of meningitis or encephalitis to have a lower frequency of class I postoperative outcome (61.5% vs 73.1%, p = 0.21). In the meningitis or encephalitis group, a class I outcome was more frequent in those with a history of meningitis or encephalitis at a young age (<4 years) (19/23 vs 5/16, p = 0.002), those with MTS detected on a preoperative MRI (22/31 vs 2/8, p = 0.04), and those with a history of meningitis (16/21 vs 8/18, p = 0.05). Multivariate logistic regression analysis found that a history of meningitis or encephalitis at a young age (b = 2.0, O.R. = 7.5, p = 0.048) was predictive of a class I outcome independent of the presence of MRI-identified MTS (b = 2.0, O.R. = 7.3, p = 0.07). The age of occurrence of a remote history of meningitis or encephalitis, but not the type of infection, is predictive of outcome after an ATL independent of the finding of MTS on the preoperative MRI.
Publisher: John Libbey Eurotext
Date: 2009
Publisher: Centro Internacional de Agricultura Tropical
Date: 05-07-2019
Abstract: Two perennial ryegrass (Lolium perenne) varieties and 5 festulolium hybrids (L. perenne × Festuca spp.) were evaluated on-farm for their performance over one growing season on clay loam soils at Ol-joro-Orok in the central highlands of Kenya at about 2,600‒2,800 masl. Seed was sown in May 2015 and fertilizer (90 kg N + 90 kg P/ha) was applied at planting. The study continued for 8 months with harvests after 113, 99 and 32 days (3 growth cycles). Growth attributes assessed included dry matter yield (DMY) and plant height, while forage nutritive value was measured in terms of crude protein (CP), acid detergent fiber (ADF) and neutral detergent fiber (NDF) concentrations. At the end of the first growth cycle, 61 local dairy farmers rated the grasses on criteria they nominated as being important, including DMY, growth rate, height, frost tolerance, disease tolerance and leafiness. Total herbage yields for the whole study period (8 months) ranged from 14.6 to 18.0 t DM/ha for perennial ryegrass and 14.3 to 20.9 t DM/ha for festulolium with very poor growth in the third growth cycle. All perennial ryegrass and festulolium lines contained similar (P .05) concentrations of CP (163–190 g/kg DM), ADF (264–281 g/kg DM) and NDF (448–493 g/kg DM). For perennial ryegrass, farmers gave a minimum weighted score of 6.7 and for festulolium, 7.9. Based on herbage production, forage nutritive value and farmers’ assessments, we conclude that all perennial ryegrass and festulolium lines tested have the potential to contribute to improving the forage resource base in this and other similar areas, especially for farmers whose land sizes allow grazing instead of stall-based feeding only. Further studies with N applications after each harvest would determine whether yields can be maintained at high levels for longer than in this study, while grazing and feeding studies would determine how well the pastures support weight gains and milk yields. Studies over a number of years are needed to assess how persistent these varieties/hybrids are in this and other environments.
Publisher: Oxford University Press (OUP)
Date: 27-10-2022
Abstract: Identifying when recovery from a sports-related concussion (SRC) has occurred remains a challenge in clinical practice. This study investigated the utility of ocular motor (OM) assessment to monitor recovery post-SRC between sexes and compared to common clinical measures. From 139 preseason baseline assessments (i.e. before they sustained an SRC), 18 (12 males, 6 females) consequent SRCs were sustained and the longitudinal follow-ups were collected at 2, 6, and 13 days post-SRC. Participants completed visually guided, antisaccade (AS), and memory-guided saccade tasks requiring a saccade toward, away from, and to a remembered target, respectively. Changes in latency (processing speed), visual–spatial accuracy, and errors were measured. Clinical measures included The Sports Concussion Assessment Tool, King-Devick test, Stroop task, and Digit span. AS latency was significantly longer at 2 days and returned to baseline by 13-days post-SRC in females only (P & 0.001). Symptom numbers recovered from 2 to 6 days and 13 days (P & 0.05). Persistently poorer AS visual–spatial accuracy was identified at 2, 6 and 13 days post-SRC (P & 0.05) in both males and females but with differing trajectories. Clinical measures demonstrated consistent improvement reminiscent of practice effects. OM saccade assessment may have improved utility in tracking recovery compared to conventional measures and between sexes.
Publisher: Frontiers Media SA
Date: 24-10-2014
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.YEBEH.2015.04.010
Abstract: The treatment of refractory and super refractory status epilepticus is a "terra incognita" from the point of view of evidence-based medicine. As randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available, we carried out an online multinational audit (registry) in which neurologists or intensivists caring for patients with status epilepticus may prospectively enter patients who required general anesthesia to control the status epilepticus (SE). To date, 488 cases from 44 different countries have been collected. Most of the patients had no history of epilepsy and had a cryptogenic etiology. First-line treatment was delayed and not in line with current guidelines. The most widely used anesthetic of first choice was midazolam (59%), followed by propofol and barbiturates. Ketamine was used in most severe cases. Other therapies were administered in 35% of the cases, mainly steroids and immunotherapy. Seizure control was achieved in 74% of the patients. Twenty-two percent of patients died during treatment, and four percent had treatment actively withdrawn because of an anticipated poor outcome. The neurological outcome was good in 36% and poor in 39.3% of cases, while 25% died during hospitalization. Factors that positively influenced outcome were younger age, history of epilepsy, and low number of different anesthetics tried. This article is part of a Special Issue entitled "Status Epilepticus".
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 08-03-2018
DOI: 10.1002/HBM.24029
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BBR.2009.04.023
Abstract: The incidence of psychiatric disturbances is elevated in temporal lobe epilepsy (TLE) patients. Early life stressful events are believed to have a major impact on mental health later in life, and increasing evidence suggests that such stresses may also promote a vulnerability to TLE. This study investigated whether subjecting rats to early life stress exacerbated mood and cognitive disturbances associated with the development of epilepsy. On postnatal days 2-14, rat pups were separated from their dams for either 180 min/day (handling and maternal separation--HMS180, modelling early life stress) or 15 min/day (control handling and maternal separation--HMS15). At 7 weeks, rats were implanted with a bipolar electrode into the left amygdala. Following recovery, one group of rats from each litter underwent rapid amygdala kindling (RAK) epileptogenesis, while another underwent sham kindling. One week following this, rats were subjected to behavioural tests assessing anxiety and cognition. HMS180-exposed rats kindled faster than HMS15 rats (p<0.0001). RAK induced a potent anxiolytic effect as evidenced by increased % time spent in the open arms of the elevated plus maze, compared with sham kindled rats (p<0.0001). This anxiolytic effect was also observed in the open field task, as evidenced by increased time spent in the inner area (p=0.010). Neither RAK nor maternal separation had any effect on cognitive function in the Morris water maze. We conclude that maternal separation stress accelerates limbic epileptogenesis in adult rats, and that RAK induces potent anxiolytic effects that are not influenced by such early life stressful events.
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1002/EPI4.12693
Abstract: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti‐seizure medication (NaM‐ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. This retrospective, nested case–control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM‐ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Proportions of cases and controls prescribed lamotrigine ( P = 0.166), one NaM‐ASM ( P = 0.80), or ≥2NaM‐ASMs ( P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56 P = 0.054), one NaM‐ASM (aHR = 0.8 P = 0.588) or ≥2 NaM‐ASMs (aHR = 0.49 P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic–clonic seizures at EMU admission associated with ‐fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24 P = 0.031) or NaM‐ASM use (aHR = 2.25 P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow‐up suggest undetected changes to ASM use are unlikely to alter our results. This study provides additional evidence that lamotrigine and other NaM‐ASMs are unlikely to be associated with an increased long‐term risk of SUDEP, up to 16 years post‐EMU admission.
Publisher: BMJ
Date: 05-2021
DOI: 10.1136/BMJOPEN-2020-043488
Abstract: Stroke is a common cause of epilepsy that may be mediated via glutamate dysregulation. There is currently no evidence to support the use of antiseizure medications as primary prevention against poststroke epilepsy. Per anel has a unique antiglutamatergic mechanism of action and may have antiepileptogenic properties. This study aims to evaluate the efficacy and safety of per anel as an antiepileptogenic treatment in patients at high risk of poststroke epilepsy. Up to 328 patients with cortical ischaemic stroke or lobar haemorrhage will be enrolled, and receive their first treatment within 7 days of stroke onset. Patients will be randomised (1:1) to receive per anel (titrated to 6 mg daily over 4 weeks) or matching placebo, stratified by stroke subtype (ischaemic or haemorrhagic). Treatment will be continued for 12 weeks after titration. 7T MRI will be performed at baseline for quantification of cerebral glutamate by magnetic resonance spectroscopy and glutamate chemical exchange saturation transfer imaging. Blood will be collected for measurement of plasma glutamate levels. Participants will be followed up for 52 weeks after randomisation. The primary study outcome will be the proportion of participants in each group free of late (more than 7 days after stroke onset) poststroke seizures by the end of the 12-month study period, analysed by Fisher’s exact test. Secondary outcomes will include time to first seizure, time to treatment withdrawal and 3-month modified Rankin Scale score. Quality of life, cognitive function, mood and adverse events will be assessed by standardised questionnaires. Exploratory outcomes will include correlation between cerebral and plasma glutamate concentration and stroke and seizure outcomes. This study was approved by the Alfred Health Human Research Ethics Committee (HREC No 44366, Reference 287/18). ACTRN12618001984280 Pre-results.
Publisher: Wiley
Date: 21-07-2004
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 03-2002
DOI: 10.1046/J.1528-1157.2002.37501.X
Abstract: To determine whether a focal beta-frequency discharge at seizure onset on scalp EEG predicts outcome of frontal lobe epilepsy (FLE) surgery. We identified 54 consecutive patients with intractable FLE who underwent epilepsy surgery between December 1987 and December 1996. A blind review of EEGs and magnetic resonance images (MRIs) was performed. Lesional epilepsy is defined as presence of an underlying structural abnormality on MRI. Overall, 28 (52%) patients were seizure free, with a mean follow-up of 46.5 months. Presence of a focal beta-frequency discharge at seizure onset on scalp EEG predicted seizure-free outcome in lesional (p = 0.02) and non-lesional (p = 0.01) epilepsy patients. At least 90% of patients who had either lesional or non-lesional epilepsy were seizure free if scalp EEG revealed a focal beta discharge at ictal onset. Moreover, logistic regression analysis showed that focal ictal beta pattern and completeness of lesion resection were independently predictive of seizure-free outcome. Ictal onset with lateralized EEG activity of any kind and postresection electrocorticographic spikes did not predict surgical outcome (p > 0.05). Only about 25% of FLE surgical patients have a focal beta-frequency discharge at seizure onset on scalp EEG. However, its presence is highly predictive of excellent postsurgical seizure control in either lesional or non-lesional FLE surgical patients.
Publisher: Wiley
Date: 31-01-2023
DOI: 10.1002/EPI4.12692
Abstract: Epilepsy is associated with an increased risk of cardiovascular disease and mortality. Whether cardiac structure and function are altered in epilepsy remains unclear. To address this, we conducted a systematic review and meta‐analysis of studies evaluating cardiac structure and function in patients with epilepsy. We searched the electronic databases MEDLINE, PubMed, COCHRANE, and Web of Science from inception to 31 December 2021. Primary outcomes of interest included left ventricular ejection fraction (LVEF) for studies reporting echocardiogram findings and cardiac weight and fibrosis for postmortem investigations. Study quality was assessed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tools. Among the 10 case‐control studies with epilepsy patients (n = 515) and healthy controls (n = 445), LVEF was significantly decreased in epilepsy group compared with controls (MD: −1.80 95% confidence interval [CI]: −3.56 to −0.04 P = 0.045), whereas A‐wave velocity (MD: 4.73 95% CI: 1.87‐7.60 P = 0.001), E/e' ratio (MD: 0.39 95% CI: 0.06‐0.71 P = 0.019), and isovolumic relaxation time (MD: 10.18 95% CI: 2.05‐18.32 P = 0.014) were increased in epilepsy, compared with controls. A pooled analysis was performed in sudden unexpected death in epilepsy (SUDEP) cases with autopsy data (n = 714). Among SUDEP cases, the prevalence of cardiac hypertrophy was 16% (95% CI: 9%–23%) cardiac fibrosis was 20% (95% CI: 15%–26%). We found no marked differences in cardiac hypertrophy, heart weight, or cardiac fibrosis between SUDEP cases and epilepsy controls. Our findings suggest that epilepsy is associated with altered diastolic and systolic echocardiogram parameters compared with healthy controls. Notably, SUDEP does not appear to be associated with a higher incidence of structural cardiac abnormalities, compared with non‐SUDEP epilepsy controls. Longitudinal studies are needed to understand the prognostic significance of such changes. Echocardiography may be a useful noninvasive diagnostic test in epilepsy population.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-06-2023
Publisher: Springer Science and Business Media LLC
Date: 08-12-2022
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.BONE.2017.05.015
Abstract: Neurological heterotopic ossification (NHO) involves the formation of bone in soft tissue following a neurological condition, of which the most common are brain and spinal cord injuries. NHO often forms around the hip, knee and shoulder joints, causing severe pain and joint deformation which is associated with significant morbidity and reduced quality of life. The cellular and molecular events that initiate NHO have been the focus of an increasing number of human and animal studies over the past decade, with this work largely driven by the need to unearth potential therapeutic interventions to prevent the formation of NHO. This review provides an overview of the present understanding of NHO pathogenesis and pathobiology, current treatments, novel therapeutic targets, potential biomarkers and future directions.
Start Date: 2012
End Date: 2015
Funder: Canadian Institutes of Health Research
View Funded ActivityStart Date: 2011
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2010
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 12-2019
Amount: $898,450.00
Funder: Australian Research Council
View Funded Activity