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Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy

Epilepsia - 9 hours 21 min ago
Summary Objective

Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices.

Methods

The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala kindling model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis.

Results

When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose–effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism.

Significance

The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison.

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Epilepsia - Fri, 02/05/2016 - 06:40
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Epilepsia - Fri, 02/05/2016 - 06:39
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Mortality in people with epilepsy: a statewide retrospective cohort study

Epilepsy Research Journal - Fri, 02/05/2016 - 00:00
The quality of and access to health care has been the focus of rural health research; however, health disparities can involve a complex interaction of factors including race/ethnicity, age, sex, educational level, income level, insurance status and place of residence. (Burneo et al., 2009; Hartley, 2004; Johnson et al., 2008; Marmot, 2005; Scott and Wilson, 2011; Smedley et al., 2001; Szaflarski, 2014) Healthy People 2020 lists geographic region (rural/urban residence) as an important social determinant of health (Healthy People 2020, 2015) Rural/urban residence may affect health through individual (use of self-care, no routine source of care, lifestyle and behavior) or environmental (poverty, income inequality, access to care, health care shortages) factors.
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Brain formation pattern shows why early trauma may leave no clues

Medical News Today - Thu, 02/04/2016 - 05:00
Some of the earliest nerve cells to develop in the womb shape brain circuits that process sights and sounds, but then give way to mature networks that convert this sensory information into thoughts.
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International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue: A consensus Task Force report from the ILAE Commission on Diagnostic Methods

Epilepsia - Wed, 02/03/2016 - 06:35
Summary

Epilepsy surgery is an effective treatment in many patients with drug-resistant focal epilepsies. An early decision for surgical therapy is facilitated by a magnetic resonance imaging (MRI––visible brain lesion congruent with the electrophysiologically abnormal brain region. Recent advances in the pathologic diagnosis and classification of epileptogenic brain lesions are helpful for clinical correlation, outcome stratification, and patient management. However, application of international consensus classification systems to common epileptic pathologies (e.g., focal cortical dysplasia [FCD] and hippocampal sclerosis [HS]) necessitates standardized protocols for neuropathologic workup of epilepsy surgery specimens. To this end, the Task Force of Neuropathology from the International League Against Epilepsy (ILAE) Commission on Diagnostic Methods developed a consensus standard operational procedure for tissue inspection, distribution, and processing. The aims are to provide a systematic framework for histopathologic workup, meeting minimal standards and maximizing current and future opportunities for morphofunctional correlations and molecular studies for both clinical care and research. Whenever feasible, anatomically intact surgical specimens are desirable to enable systematic analysis in selective hippocampectomies, temporal lobe resections, and lesional or nonlesional neocortical samples. Correct orientation of sample and the sample's relation to neurophysiologically aberrant sites requires good communication between pathology and neurosurgical teams. Systematic tissue sampling of 5-mm slabs along a defined anatomic axis and application of a limited immunohistochemical panel will ensure a reliable differential diagnosis of main pathologies encountered in epilepsy surgery.

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Treatment non-adherence in pseudo-refractory epilepsy

Epilepsy Research Journal - Wed, 02/03/2016 - 00:00
Poor adherence to prescribed treatment is considered one of the most serious obstacles to the management of epilepsy (Faught, 2012; Samsonsen et al., 2014). It is of major importance to acknowledge that uncontrolled epilepsy does not necessarily reflect drug-resistant epilepsy. Recently, the International League Against Epilepsy defined drug-resistant epilepsy as uncontrolled seizures in spite of adequate trials of at least two tolerated, appropriately chosen and appropriately used antiepileptic drug (AED) schedules (Kwan et al., 2010).
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Genetics of reflex seizures and epilepsies in humans and animals

Epilepsy Research Journal - Mon, 02/01/2016 - 00:00
Reflex seizures are epileptic events triggered by specific motor, sensory or cognitive stimulation. Frequently, reflex seizures occur in association with spontaneous seizures, and are considered as “seizure types” (Engel, 2001). The term of reflex epilepsy is traditionally applied to rare conditions in which all, or almost all seizures are provoked by one specific stimulus (Wolf & Koepp, 2012). Currently, only Idiopathic Photosensitive Occipital Lobe Epilepsy, Primary Reading Epilepsy (PRE), Startle Epilepsy and other Visual Sensitive Epilepsies are recognized as specific reflex epileptic syndromes (Engel, 2001).
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Graphene shown to safely interact with neurons in the brain

Medical News Today - Fri, 01/29/2016 - 10:00
Researchers have successfully demonstrated how it is possible to interface graphene - a two-dimensional form of carbon - with neurons, or nerve cells, while maintaining the integrity of these vital...
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Penn researchers use network science to help pinpoint source of seizures

Medical News Today - Fri, 01/29/2016 - 09:00
For the third of all epilepsy patients who don't respond to medication, an alternative is to locate the small cluster of neurons that act as the seed of a seizure's aberrant electrical activity and...
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The sensitivity and significance of lateralized interictal slow activity on magnetoencephalography in focal epilepsy

Epilepsy Research Journal - Fri, 01/29/2016 - 00:00
Drug resistant focal epilepsy results in significant morbidity, but many patients can become free of seizures with surgical resection or ablation, although epilepsy surgery remains under-utilized (Cascino, 2008; Englot, 2015; Englot et al., 2012). Successful epilepsy surgery depends critically on accurate delineation of the epileptogenic zone (EZ), resulting in seizure freedom in approximately two-thirds of patients with temporal lobe epilepsy (TLE) and one-half of individuals with extra-temporal lobe epilepsy (ETLE) (Englot et al., 2013; Englot et al., 2014; Spencer and Huh, 2008).
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Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy

Epilepsia - Wed, 01/27/2016 - 04:06
Summary Objective

Examine therapeutic potential of a selective serotonin reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor (NERI) in an animal model of comorbidity between epilepsy, depression-like, and impulsive-like impairments.

Methods

Epilepsy was induced in male Wistar rats by LiCl and pilocarpine. An SSRI fluoxetine (FLX), and an NERI reboxetine (RBX) were administered either alone or as a combination over 1 week. Depressive-like and impulsive-like behaviors were examined using the forced swim test. Fast scan cyclic voltammetry was used to analyze serotonergic transmission in the raphe nucleus (RN)–prefrontal cortex (PFC) pathway, and noradrenergic transmission in locus coeruleus (LC)-PFC, and LC-RN projections. Monoamine levels in PFC were measured using high-performance liquid chromatography (HPLC). Functional capacities of 5-HT1A receptors and α2A adrenoreceptors in PFC were analyzed by autoradiography.

Results

Epileptic rats showed behavioral signs of depression and hyperimpulsivity, suppressed serotonergic and noradrenergic tones, decreased levels of serotonin (5-HT), and norepinephrine (NE); 5-HT1A receptor and α2A adrenoreceptors functions remained intact. FLX failed to improve behavioral deficits, but effectively raised 5-HT level and marginally improved RN-PFC serotonergic transmission. RBX reversed impulsive-like behavior, normalized content of NE and noradrenergic tone in LC-PFC and LC-RN. FLX-RBX combination fully reversed depressive-like behavior, and normalized RN-PFC serotonergic transmission. None of the treatment modified the function of 5-HT and NE receptors.

Significance

Depressive- and impulsive-like behaviors in the pilocarpine model of epilepsy stem respectively from dysfunctions of serotonergic and noradrenergic ascending pathways. At the same time, epilepsy-associated depression is SSRI resistant. The finding that an SSRI-NERI combination exerts antidepressant effect, along with RBX-induced improvement of LC-RN noradrenergic transmission point toward the involvement of LC-RN noradrenergic input in enabling therapeutic potential of FLX. Medications that improve serotonergic and noradrenergic transmission, such as serotonin–norepinephrine reuptake inhibitors may be effective in treating epilepsy-associated SSRI-resistant depression, as well as concurrent depression and attention-deficit/hyperactivity disorder (ADHD).

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Seizures as presenting and prominent symptom in chorea-acanthocytosis with c.2343del VPS13A gene mutation

Epilepsia - Wed, 01/27/2016 - 04:00
Abstract Objective

The aim of the study was to characterize the clinical features of nine patients in three families with chorea-acanthocytosis (ChAc) sharing the same rare c.2343del mutation in the VPS13A gene.

Methods

Genetic test results, clinical description, magnetic resonance imaging (MRI), and electroencephalography (EEG), as well as laboratory results are summarized.

Results

ChAc is a rare genetic disorder characterized by hyperkinetic movements, seizures, cognitive decline, neuropsychiatric symptoms, and acanthocytes on peripheral blood smear. This unique cohort of nine patients is characterized by seizures as a first and prominent symptom. In our patients, other features of ChAc appeared later, including tics, other movement disorders, dysarthria, and mild to moderate cognitive decline.

Significance

Patients with chorea-acanthocytosis carrying the described rare mutation can present with focal, treatment-resistant seizures.

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Heart rate variability in untreated newly diagnosed temporal lobe epilepsy: Evidence for ictal sympathetic dysregulation

Epilepsia - Wed, 01/27/2016 - 03:53
Summary Objective

To compare heart rate variability (HRV) parameters in newly diagnosed and untreated temporal lobe epilepsy (TLE) between the interictal, preictal, ictal, and postictal states.

Methods

HRV parameters were extracted from single-lead electrocardiography data collected during video–electroencephalography (EEG) recordings from 14 patients with newly diagnosed TLE in a resting, awake, and supine state. HRV parameters in the time and frequency domains included low frequency (LF), high frequency (HF), standard deviation of all consecutive R wave intervals (SDNN), and square root of the mean of the sum of the squares of differences between adjacent R wave intervals (RMSSD). Cardiovagal index (CVI), cardiosympathetic index (CSI), and approximate entropy (ApEn) were also studied.

Results

Frequency domain analysis showed significantly higher preictal, ictal, and postictal LF/HF ratio compared to the interictal state. Similarly, the LF component increased progressively and was significantly higher during the ictal state compared to interictal and preictal states. RR interval values were lower in the ictal state compared to basal and preictal states and in the postictal state compared to the preictal state. Interictal RMSSD was significantly higher compared to all other states, and ictal SDNN was significantly higher compared to all other states. Ictal CSI was significantly higher compared to preictal and interictal states, whereas preictal CVI was lower than in basal and ictal states. In addition, ictal ApEn was significantly lower than interictal and preictal ApEn. Interictal CVI was lower in left TLE compared to right TLE. In addition, in left TLE, ictal CVI was higher than interictal CVI, whereas in right TLE, CVI was lower in the preictal state compared to all other states.

Significance

Our data suggest an ictal sympathetic overdrive with partial recovery in the postictal state. Higher sympathetic tone and vagal tone imbalance may induce early autonomic dysfunction and increase cardiovascular risk in patients affected by TLE.

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Seizure Facilitating Activity of the Oral Contraceptive Ethinyl Estradiol

Epilepsy Research Journal - Wed, 01/27/2016 - 00:00
Contraceptive management in women with epilepsy is critical owing to the potential maternal and fetal risks if contraception or seizure management fails. A wide range of hormonal contraceptive methods are available for women, including injectable progestogens and oral contraceptive (OC) pills. The combination OC pills are composed of low-dose synthetic estrogen and progestogen and are usually taken for 21 days with a 7 day gap. Ethinyl estradiol (EE) is a major estrogen constituent in OCs including monophasic, biphasic, triphasic and extended-cycle regimens (Reddy, 2010).
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The anticonvulsant action of the galanin receptor agonist NAX-5055 involves modulation of both excitatory- and inhibitory neurotransmission

Epilepsy Research Journal - Wed, 01/27/2016 - 00:00
The most abundant excitatory and inhibitory neurotransmitters in the mammalian brain are glutamate and γ-aminobutyric acid (GABA), respectively. Under physiological conditions the ratio between glutamatergic and GABAergic synapses is about 9 (Attwell and Laughlin, 2001) and an imbalance in this relationship appears to be involved in a number of neurological disorders such as Alzheimer's disease, schizophrenia and epilepsy (Sonnewald and Kondziella, 2003; Barker-Haliski et al., 2014; Schousboe et al.
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Lesion guided stereotactic radiofrequency thermocoagulation for palliative, in selected cases curative epilepsy surgery

Epilepsy Research Journal - Wed, 01/27/2016 - 00:00
Resective epilepsy surgery is an established treatment option for patients with pharmacoresistant focal epilepsy resulting in significantly better seizure free outcomes than continued medical treatment alone (Jobst and Cascino, 2015). Yet, not every patient who enters a formal presurgical work-up can finally be recommended resective epilepsy surgery. Some patients suffer from multifocal epilepsy or have vast, badly demarcated, or complex organized epileptogenic zones with only a low chance for seizure freedom.
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Proton magnetic resonance spectroscopy in juvenile myoclonic epilepsy: a systematic review and meta-analysis

Epilepsy Research Journal - Wed, 01/27/2016 - 00:00
Juvenile myoclonic epilepsy (JME), as an idiopathic generalized epilepsy syndrome, has three primary clinical seizure types, including myoclonia, generalized tonic–clonic seizures (GTCS), and few absences (Panayiotopoulos et al., 1994). JME patients have no structural alterations in the conventional magnetic resonance imaging (MRI) and computed tomography; however, structural and functional neuroimaging provides us with visible structural and functional alterations in the brains of patients with epilepsy, which has promoted a transformation in the conceptualization of epileptogenesis from ‘locality’ to ‘networks’ in recent years (Koepp, 2005; van Diessen et al., 2013).
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