What's Current?

Development and pharmacologic characterization of the rat 6 Hz model of partial seizures

Epilepsia - Thu, 04/27/2017 - 13:41
Summary Objective

The mouse 6 Hz model of psychomotor seizures is a well-established and commonly used preclinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with seizure behaviors similar to those observed in mice including head nod, jaw clonus, and forelimb clonus.

Methods

A convulsive current that elicits these seizure behaviors in 97% of rats (CC97) was determined using a Probit analysis. Numerous prototype ASDs were evaluated in this model using stimulus intensities of 1.5× and 2× the CC97, which is comparable to the approach used in the mouse 6 Hz seizure model (e.g., 32 and 44 mA stimulus intensities). The ASDs evaluated include carbamazepine, clobazam, clonazepam, eslicarbazepine, ethosuximide, ezogabine, gabapentin, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, rufinamide, tiagabine, topiramate, and sodium valproate. Median effective dose (ED50) and median toxic (motor impairment) dose (TD50) values were obtained for each compound.

Results

Compounds that were effective at the 1.5 × CC97 stimulus intensity at protective index (PI) values >1 included clobazam, ethosuximide, ezogabine, levetiracetam, phenobarbital, and sodium valproate. Compounds that were effective at the 2 × CC97 stimulus intensity at PI values >1 included ezogabine, phenobarbital, and sodium valproate.

Significance

In a manner similar to the use of the mouse 6 Hz model, development of a rat 6 Hz test will aid in the differentiation of ASDs, as well as in study design and dose selection for chronic rat models of pharmacoresistant epilepsy. The limited number of established ASDs with demonstrable efficacy at the higher stimulus intensity suggests that, like the mouse 6 Hz 44 mA model, the rat 6 Hz seizure model may be a useful screening tool for pharmacoresistant seizures.

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Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury

Epilepsia - Thu, 04/27/2017 - 11:45
Summary Objective

Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury.

Methods

Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE.

Results

Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE.

Significance

Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

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New analysis of brain network activity offers unique insight into epileptic seizures

Science Daily - Thu, 04/27/2017 - 11:22
Little is known about which specific areas of the brain contribute to a patient's epileptic network or the roles these different areas play. As a group of researchers now reports one way to get closer to the complex wiring of the human brain is by merging concepts from a timed-based synchronization theory and space-based network theory to construct functional brain networks.
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22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy

Epilepsia - Thu, 04/27/2017 - 11:11
Summary Objective

Previous studies examining seizures in patients with 22q11.2 deletion syndrome (22q11.2DS) have focused primarily on children and adolescents. In this study we investigated the prevalence and characteristics of seizures and epilepsy in an adult 22q11.2DS population.

Methods

The medical records of 202 adult patients with 22q11.2DS were retrospectively reviewed for documentation of seizures, electroencephalography (EEG) reports, and magnetic resonance imaging (MRI) findings. Epilepsy status was assigned in accordance with 2010 International League Against Epilepsy Classification.

Results

Of 202 patients, 32 (15.8%) had a documented history of seizure. Of these 32, 23 (71.8%) had acute symptomatic seizures, usually associated with hypocalcemia and/or antipsychotic or antidepressant use. Nine patients (9/32, 28%; 9/202, 4%) met diagnostic criteria for epilepsy. Two patients had genetic generalized epilepsy; two patients had focal seizures of unknown etiology; two had epilepsy due to malformations of cortical development; in two the epilepsy was due to acquired structural changes; and in one patient the epilepsy could not be further classified.

Significance

Similarly to children, the prevalence of epilepsy and acute symptomatic seizures in adults with 22q11.2DS is higher than in the general population. Hypocalcemia continues to be a risk factor for adults, but differently from kids, the main cause of seizures in adults with 22q11.2DS is exposure to antipsychotics and antidepressants. Further prospective studies are warranted to investigate how 22q11.2 microdeletion leads to an overall decreased seizure threshold.

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Magnetic resonance imaging connectivity for the prediction of seizure outcome in temporal lobe epilepsy

Epilepsia - Thu, 04/27/2017 - 10:56
Summary Objective

Currently, approximately 60–70% of patients with unilateral temporal lobe epilepsy (TLE) remain seizure-free 3 years after surgery. The goal of this work was to develop a presurgical connectivity-based biomarker to identify those patients who will have an unfavorable seizure outcome 1-year postsurgery.

Methods

Resting-state functional and diffusion-weighted 3T magnetic resonance imaging (MRI) was acquired from 22 unilateral (15 right, 7 left) patients with TLE and 35 healthy controls. A seizure propagation network was identified including ipsilateral (to seizure focus) and contralateral hippocampus, thalamus, and insula, with bilateral midcingulate and precuneus. Between each pair of regions, functional connectivity based on correlations of low frequency functional MRI signals, and structural connectivity based on streamline density of diffusion MRI data were computed and transformed to metrics related to healthy controls of the same age.

Results

A consistent connectivity pattern representing the network expected in patients with seizure-free outcome was identified using eight patients who were seizure-free at 1-year postsurgery. The hypothesis that increased similarity to the model would be associated with better seizure outcome was tested in 14 other patients (Engel class IA, seizure-free: n = 5; Engel class IB-II, favorable: n = 4; Engel class III–IV, unfavorable: n = 5) using two similarity metrics: Pearson correlation and Euclidean distance. The seizure-free connectivity model successfully separated all the patients with unfavorable outcome from the seizure-free and favorable outcome patients (p = 0.0005, two-tailed Fisher's exact test) through the combination of the two similarity metrics with 100% accuracy. No other clinical and demographic predictors were successful in this regard.

Significance

This work introduces a methodologic framework to assess individual patients, and demonstrates the ability to use network connectivity as a potential clinical tool for epilepsy surgery outcome prediction after more comprehensive validation.

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New US Guidelines on sudden unexpected death in epilepsy (SUDEP)

Epilepsy Research - Wed, 04/26/2017 - 05:43

New guidelines from the American Academy of Neurology and the American Epilepsy Society, titled “Practice guideline: Sudden unexpected death in epilepsy incidence rates and risk factors” were presented at the 2017 American Academy of Neurology Annual Meeting currently being held in Boston, Massachusetts.  At the same time they were published in the journal Neurology.

Guidelines author Dr Cynthia Harden said “Our guideline bring clarity to the discussion, giving health care providers practical information they can use to help people with epilepsy reduce their risk.”  She added that it was critical for health care professionals to communicate the occurrence rate and specific risk factors for SUDEP to persons and families affected by epilepsy

After systematically reviewing all available evidence, the guideline authors concluded that every year, in the USA,  SUDEP affects 1 in 4500 children; this number increases to 1 in 1000 people in adulthood.

Furthermore, the authors found that the major risk factor for SUDEP was generalized tonic-clonic seizures (GTCS). Specifically, results indicated that individuals who have 3 or more GTCS per year were 15 times more likely to experience SUDEP than individuals who did not experience GTCS 3 or more times per year.

In light of these findings, the guideline authors recommend health care professionals treating patients with epilepsy inform them about the small risk for SUDEP (Level B), and that controlling seizures, particularly GTCS, may reduce the risk for SUDEP (Level B).

In addition, the authors recommend that for patients with epilepsy who continue to experience GTCS, “Clinicians should continue to actively manage epilepsy therapies to reduce seizure occurrences and the risk of SUDEP while incorporating patient preferences and weighing the risks and benefits of any new approach (Level B),” the guideline authors wrote.

Dr Harden noted that educating health professionals and people with epilepsy about SUDEP is an important first step. “This guideline makes the conversation much easier with information that may motivate people to take their medications on time, to never skip taking their medications, and to learn and manage their seizure triggers so they can work toward reducing seizures,” she said in the release. “People who follow their medication schedule or pursue other treatments such as surgery may be more likely to become seizure-free.”

Going forward, Dr Harden said more research is necessary to identify other preventable risk factors so that future studies can focus on finding ways to reduce the occurrence of SUDEP.

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The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients

Epilepsia - Tue, 04/25/2017 - 09:18
Summary Objective

This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1.

Methods

We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure.

Results

Thirty-one individuals were studied, aged 2–35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma.

Significance

The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence.

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Heart-rate variability indices as predictors of the response to vagus nerve stimulation in patients with drug-resistant epilepsy

Epilepsia - Tue, 04/25/2017 - 09:11
Summary Objective

To assess heart-rate variability (HRV) measures of interictal electrocardiography (ECG) for drug-resistant epilepsy and to relate the findings to the outcome of vagus nerve stimulation (VNS) treatment.

Methods

Time-domain, frequency-domain, and nonlinear analyses were used to analyze preoperative HRV measures in 32 patients with drug-resistant epilepsy who had received VNS implants at the same hospital and 32 healthy age- and sex-matched control subjects. HRV measurements based on ambulatory 24 h ECG recordings were analyzed to identify seizure reduction 1 year after VNS treatment. Responders were defined as having at least 50% seizure reduction 1 year after treatment.

Results

Patients with drug-resistant epilepsy had significantly lower time domain (SDNN, RMSSD, pNN50), frequency domain (VLF, LF, HF, TP), and nonlinear (SD1, SD2) HRV measurements than matched healthy controls. None of the analyzed HRV measures of the responders differed significantly from their controls, whereas those of the nonresponders had significantly lower RMSSD, pNN50, HF, and SD1 than the responders.

Significance

The preoperative HRV indices demonstrate that nonresponders have more pronounced impairment of their cardiac autonomic function than the responders. Presurgical HRV measurements representing parasympathetic cardiac control or vagal tone were significantly associated with the responsiveness to VNS. Thus the measurements show promise for predicting the reduction of seizure frequency after VNS treatment.

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Young adults with uncomplicated epilepsy fare as well as their siblings

Science Daily - Mon, 04/24/2017 - 17:21
A 15-year follow-up study of young adults with epilepsy found that those with uncomplicated epilepsy who were seizure-free for five years or more did as well as their siblings without epilepsy in measures of education, employment, family arrangements and driving status. Youth with complicated epilepsy had worse social outcomes and were less likely to drive, even if living without seizures.
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London Marathon 2017

Epilepsy Research - Mon, 04/24/2017 - 09:33

Yesterday was my first London Marathon cheering on runners for Epilepsy Research UK as CEO of the charity. The whole event was inspirational and the effort that all of the runners made was fantastic. Until you have stood and watched people running at the 24 mile mark, you do not appreciate the effort involved. I was and still am stunned. The blood, sweat, tears and strain that clearly goes into running a marathon just leaves you awestruck. Thank you all. And thanks to our supporters who came along to cheer.

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Brighton Marathon 2017

Epilepsy Research - Mon, 04/24/2017 - 07:48

Our runners and supporters provide us with a non-stop feeling of inspiration. The effort to run a marathon is immense and we thank all of our runners and the people who turn up to support them. If you could not be there, here is some video of Brighton 2017.

Categories: What's Current?

Maximal/Exhaustive Treadmill Test Features in Patients with Temporal Lobe Epilepsy: Search for Sudden Unexpected Death Biomarkers

Epilepsy Research Journal - Mon, 04/24/2017 - 00:00
Epilepsy is one of the most important neurological diseases in clinical practice, being the second most common neurological disease in primary care. All over the world, around 65 million individuals suffer from epilepsy (Thurman et al., 2011) and patients with epilepsy (PWE) have a 20 to 40-fold increased risk for sudden death (Ficker et al., 1998; Mohanraj et al., 2006). In fact, Sudden Unexpected Death in Epilepsy (SUDEP) is responsible for 17 to 38% of deaths in PWE. SUDEP has been defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in PWE, with or without evidence for a seizure, with exclusion of documented status epilepticus, and when post-mortem examination does not reveal a structural or toxicological cause for death (Nashef, 2012, 1997).
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A Survey of Medical Examiner Death Certification of Vignettes on Death in Epilepsy: Gaps in Identifying SUDEP

Epilepsy Research Journal - Fri, 04/21/2017 - 00:00
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in individuals with chronic, uncontrolled epilepsy (Tomson et al., 2005, 2008). These poorly understood deaths can occur in anyone with epilepsy of any kind, and both high and low risk groups have been identified (So, 2006; Tomson et al., 2005). The specific mechanism of death is unknown for SUDEP cases and likely multifactorial, with evidence suggesting brainstem dysfunction and cardiorespiratory dysregulation as a final common pathway associated with sudden death in these individuals (de la Grandmaison, 2006; Partemi et al., 2015; So, 2008; Tu et al., 2011).
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Length of stay for patients undergoing invasive electrode monitoring with stereoelectroencephalography and subdural grids correlates positively with increased institutional profitability

Epilepsia - Thu, 04/20/2017 - 08:31
Summary Objective

Lowering the length of stay (LOS) is thought to potentially decrease hospital costs and is a metric commonly used to manage capacity. Patients with epilepsy undergoing intracranial electrode monitoring may have longer LOS because the time to seizure is difficult to predict or control. This study investigates the effect of economic implications of increased LOS in patients undergoing invasive electrode monitoring for epilepsy.

Methods

We retrospectively collected and analyzed patient data for 76 patients who underwent invasive monitoring with either subdural grid (SDG) implantation or stereoelectroencephalography (SEEG) over 2 years at our institution. Data points collected included invasive electrode type, LOS, profit margin, contribution margins, insurance type, and complication rates.

Results

LOS correlated positively with both profit and contribution margins, meaning that as LOS increased, both the profit and contribution margins rose, and there was a low rate of complications in this patient group. This relationship was seen across a variety of insurance providers.

Significance

These data suggest that LOS may not be the best metric to assess invasive monitoring patients (i.e., SEEG or SDG), and increased LOS does not necessarily equate with lower or negative institutional financial gain. Further research into LOS should focus on specific specialties, as each may differ in terms of financial implications.

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Stress associated with an increased risk of recurrent seizures in adults.

Epilepsy Research - Thu, 04/20/2017 - 05:56

Researchers at Columbia University in New York have conducted research which shows an association between stress and an increase in recurrent seizures in adults.  Recognising that there is a limited amount of research on the relationship between epilepsy and stressors, depression and anxiety disorders the researchers wanted to see if such a link existed.

The researchers recruited patients from a low income community in New York who had either newly diagnosed epilepsy or a single unprovoked seizure.  The researchers then collected information about a number of measures of stress including environmental stress, stressful life events, psychiatric disorders and the cumulative effect of adapting to stress.

The 81 patients were then monitored for 2 years.  Almost 40% of those patients who had had an unprovoked seizure (52 patients in this group) had a further recurrence.  In the newly diagnosed epilepsy patients (29 patients in this group) almost 70% had a recurrence.

In all patients, the risk of recurrence was increased 3 fold for those with lifetime generalised anxiety disorder and 2 fold for those with lifetime mood disorder.

While a small study the researchers state that in addition to other treatment, the use of low cost stress reducing interventions such as mindfulness may be a useful addition for individuals with recognised stress disorders.

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