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Epilepsy in young Tsc1+/− mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex

Epilepsia - Sat, 02/13/2016 - 03:16
Summary Objective

To describe the epileptic phenotype of Tsc1+/− mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC).

Methods

Tsc1+/− and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8–24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin.

Results

Spontaneous seizures were disclosed in 55% of Tsc1+/− mice at P9–18. Three ictal patterns were identified: from P9 to P12 “spike clusters” consisted of recurring large spikes without clinical correlate; “spasm-like” discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2–10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a “tonic–clonic like” pattern comprised rhythmic spikes of increasing amplitude with tonic–clonic movements. Early onset “spike clusters” were mainly unilateral, whereas “spasm-like” and “tonic–clonic like” patterns were bilateral. Interhemispheric propagation was significantly faster for “tonic–clonic like” than for “spasm-like” events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases.

Significance

Tsc1+/− mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.

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New study confirms different generics have equal efficacy when treating epilepsy

Science Daily - Fri, 02/12/2016 - 09:16
A new study tested two generic lamotrigine (prescription antiepileptic) products and found no detectable difference in clinical effects among patients in the trial.
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New study confirms different generics have equal efficacy when treating epilepsy

Science Daily - Fri, 02/12/2016 - 09:16
A new study tested two generic lamotrigine (prescription antiepileptic) products and found no detectable difference in clinical effects among patients in the trial.
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Resective focal epilepsy surgery – has selection of candidates changed? A systematic review

Epilepsy Research Journal - Fri, 02/12/2016 - 00:00
No standard, widely accepted criteria exist to determine who should be referred for an epilepsy surgical evaluation. As a result, indications for epilepsy surgery evaluation vary significantly between centers.
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Epilepsy at the molecular level

Medical News Today - Thu, 02/11/2016 - 07:00
Researchers study the link between malformations of the cerebral cortex and the occurrence of the neurological disease.
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Ictal motor sequences: Lateralization and localization values

Epilepsia - Thu, 02/11/2016 - 05:55
Summary Objective

To determine the lateralization and localization values of ictal motor sequences in the setting of focal epilepsy ending with a secondarily generalized motor seizure.

Methods

Retrospectively, the ictal motor sequences were analyzed in patients with focal epilepsy ending with a secondarily generalized motor seizure by three readers blinded to all clinical and electrographic data. One representative seizure per patient was selected. Prevalence, positive predictive value (PPV), and Fleiss Kappa for the following motor signs were calculated: version, unilateral limb tonic posturing, unilateral limb clonic seizure, figure-of-4, M2e, hand dystonia, clonic asymmetric ending, and Todd's paralysis. Sequences of signs with a PPV ≥ 80% were then analyzed to determine their lateralization and localization values.

Results

A total of 47 seizures were studied. The “reliable” motor signs with a robust lateralizing value (PPV > 80%) were version, unilateral tonic posturing, M2e, unilateral clonic seizure, asymmetric clonic ending, and Todd's paralysis. Figure-of-4 and hand dystonia had a relatively low PPV, and therefore were not included in the following sequence analysis, which included only 38 patients with two or more motor signs of high PPV. Multiple combinations of temporal progression of motor signs were seen in these 38 patients, with version being the most common initial motor sign (29 of 38 patients) usually followed by M2e (15 of 29 patients), and/or a focal tonic seizure (7 of 29 patients). Accurate lateralization of the epileptogenic zone (EZ) with a PPV of 100% can be predicted when two or more reliable motor signs point to the same side. However, the various sequences of reliable motor signs did not differentiate between temporal and extratemporal epilepsy.

Significance

The presence of reliable ictal motor signs in focal epilepsy is extremely valuable in lateralizing the EZ, but not in determining the localization of the EZ. This is especially useful when epilepsy surgery is indicated.

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Patients' expectations and experiences of epilepsy surgery—A population-based long-term qualitative study

Epilepsia - Thu, 02/11/2016 - 03:57
Summary Objective

The aim of this prospective and population-based longitudinal study was to explore patients' expectations before surgery and their experiences both short and long term after epilepsy surgery.

Methods

A national sample of adult patients answered open-ended questions preoperatively, 2 years after surgery and at a cross-sectional long-term follow-up (mean 13 years, standard deviation [SD] 1.85). The answers were analyzed by qualitative content analysis.

Results

Eighty patients participated in the study. Before surgery, patients experienced a belief in a “normal” life; they hoped for reduction of seizures and medication, a richer social life, and more self-confidence. However, they also experienced anxiety of the unknown. They were afraid of the operation, of continued seizures, and of complications. At both postoperative follow-ups patients experienced increased independence. They had symptom reduction, felt relief from worries and fears, and felt that they had a new life. However, some patients experienced that the operation had changed their life to the worse due to both psychological and neurologic adverse effects, regardless of whether they had obtained seizure freedom or improvement.

Significance

Positive experiences of epilepsy surgery dominated, both in the short and long term. However, attention must be paid to negative expectations before and negative experiences after surgery in order to provide individual support and information. This should increase the possibility for patients to have realistic hopes before surgery and to find coping strategies in the new life situation after surgery.

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Progression of gray matter atrophy in seizure-free patients with temporal lobe epilepsy

Epilepsia - Thu, 02/11/2016 - 02:26
Summary Objectives

To investigate the presence and progression of gray matter (GM) reduction in seizure-free patients with temporal lobe epilepsy (TLE).

Methods

We enrolled 39 consecutive TLE patients, seizure-free for at least 2 years—20 with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 19 with normal MRI (TLE-NL), and 74 healthy controls. For longitudinal analysis, we included individuals who had a second MRI with minimum interval of 18 months: 21 patients (10 TLE-HS, 11 TLE-NL) and 11 controls. Three-dimensional (3D) T1-weighted images acquired in 3 Tesla MRI were analyzed with voxel-based morphometry (VBM). The images of patients with right-sided interictal epileptogenic zone (EZ) were right–left flipped, as well as a comparable proportion of controls. Cross-sectional analysis: The patients' images from each group were compared to controls to investigate differences in GM volumes. Longitudinal analysis: The first and second images were compared in each group to look for decreased GM volume.

Results

Cross-sectional analysis: Patients with TLE-HS had diffuse GM atrophy, including hippocampus and parahippocampal gyrus, insula, frontal, and occipital lobes ipsilateral to EZ, bilateral thalamus and contralateral orbitofrontal gyrus, and caudate. In contrast, TLE-NL group did not present significant differences compared to controls. Longitudinal analysis: TLE-HS presented progressive GM reduction in ipsilateral insula and occipital lobe, contralateral motor area, and bilateral temporal and frontal lobes. TLE-NL had GM progression in ipsilateral hypothalamus and parietal lobe, contralateral cerebellum, and bilateral temporal lobe. Controls did not show changes in GM volume between MRIs.

Significance

Diffuse extrahippocampal GM atrophy is present in seizure-free patients with TLE-HS. In addition, there is progressive GM atrophy in patients with and without HS. These results demonstrate that not only ongoing seizures are involved in the progression of GM atrophy. An underlying pathologic mechanism could be responsible for progressive brain volume loss in TLE patients even in seizure-free periods.

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Parental anxiety in childhood epilepsy: A systematic review

Epilepsia - Thu, 02/11/2016 - 00:17
Summary

The aim was to systematically review studies that have focused on symptoms of anxiety reported by parents of children (0–18 years) with epilepsy. PubMed was used to identify relevant studies. Selected studies were reviewed with respect to prevalence of above threshold scores and comparisons with controls on standardized measures of anxiety. Studies are also reported with respect to factors associated with parental anxiety, impact on child outcomes, and comparisons with studies that have included equivalent measures of symptoms of depression. Fifteen studies that met inclusion criteria were identified. None of the studies were population based. The percentage of parents scoring above cutoffs on standardized measures of anxiety was 9–58%. In comparison with parents of healthy controls, parents of children with epilepsy had higher mean scores in two of three studies where this was measured. Possible correlates of parental anxiety in childhood epilepsy that were considered varied widely across studies. Factors such as seizure frequency and use of antiepileptic drugs (AEDs) have been associated with parental anxiety in some but not all studies. With respect to child outcome, increased parental anxiety has been associated with lower quality of life and lower scores on adaptive behavior domains. Symptoms of anxiety are common among parents of children with epilepsy. There is a need for more systematic, representative studies to identify the prevalence of clinically significant anxiety and track the course of symptoms. Such studies will help to identify more clearly factors associated with parental anxiety and impact of symptoms on child and parent outcomes. Intervention studies are needed to evaluate approaches that target a reduction in symptoms and the potential impact on parental and child functioning. Furthermore, there is a need to evaluate the impact of antiepileptic therapies and interventions that focus on child neurobehavioral comorbidities on parental anxiety

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Profile of retigabine-induced neuronal apoptosis in the developing rat brain

Epilepsia - Wed, 02/10/2016 - 23:42
Summary Objective

Acute neonatal exposure to some, but not all, anticonvulsant drugs induces a profound increase in neuronal apoptosis in rats. Phenobarbital and phenytoin induce apoptosis at a therapeutically relevant dose range, lamotrigine and carbamazepine do so only at supratherapeutic doses or in polytherapy, and valproate does so even at subtherapeutic doses. Levetiracetam is devoid of pro-apoptotic effects. Retigabine, a new-generation drug, acts uniquely by enhancing the M-type potassium current. Because its safety profile in developing animals is unstudied, we sought to determine if retigabine would induce apoptosis.

Methods

Postnatal day (P) 7 rat pups were treated with retigabine (5–30 mg/kg), vehicle (saline), or comparator drugs (phenobarbital, lamotrigine, levetiracetam, or carbamazepine). Cell death was assessed using amino-cupric-silver staining. A separate group of animals was treated repeatedly (three times over 24 h) with retigabine (15 mg/kg) or vehicle. To establish a pharmacokinetic profile for retigabine, we measured plasma and brain levels after drug treatment.

Results

Consistent with prior studies from our group and others, we found phenobarbital-induced cell death throughout thalamus, nucleus accumbens, and several neocortical areas. By contrast, levetiracetam, lamotrigine, and carbamazepine were found to have no appreciable apoptotic effect on the aforementioned structures. Acute (single) exposure to retigabine, even at doses of 30 mg/kg, was also without effect on apoptosis. However, repeated (three times) exposure to retigabine triggered apoptosis in a subset of brain areas. The half-life of retigabine in plasma was 2.5 h, with appreciable concentrations reached in the brain within 1 h of administration.

Significance

These data demonstrate that retigabine, like many other anticonvulsant drugs, is capable of triggering neuronal apoptosis in the developing rat brain. Unlike other drugs, repeated dosing of retigabine was necessary to induce this effect. This may be due to its shorter half-life as compared to other drugs, such as phenobarbital.

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New guideline for treatment of prolonged seizures in children and adults

Medical News Today - Wed, 02/10/2016 - 09:00
Status epilepticus - continuous or rapid sequential seizure activity for 30 minutes or more - is a medical emergency with a high mortality rate in both children and adults.
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Involvement of TRPV1 channels in the activity of the cannabinoid WIN 55,212-2 in an acute rat model of temporal lobe epilepsy

Epilepsy Research Journal - Wed, 02/10/2016 - 00:00
Epilepsy is broadly recognized as a multi-factorial neurologic disorder (Stafstrom and Carmant, 2015; Roseti et al., 2013), predominantly rooted on imbalanced excitability phenomena (Morelli et al., 2014). In this regard, endocannabinoids stand out for their major role in regulating synaptic function through various mechanisms (Di Marzo and De Petrocellis, 2012). Although cannabinoid (CB) transmission is principally known to act via a retrograde signaling pathway, novel evidence support the compelling importance of post-synaptic activation by cannabinoids of a particular class of ionotropic receptors, namely transient receptor potential vanilloid type 1 (TRPV1) (Castillo et al., 2012; Di Marzo and De Petrocellis, 2012; Yang et al., 2013; Wang et al., 2012).
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Response to Placebo in Clinical Epilepsy Trials - Old Ideas and New Insights

Epilepsy Research Journal - Wed, 02/10/2016 - 00:00
Epilepsy affects at least 2.2 million Americans, costs $9.5-$12.5 billion annually, and has a 10-fold increased risk of sudden death compared to the general public (Institute of Medicine (U.S.) et al., 2012). Approximately 30% of patients remain uncontrolled by anti-seizure drugs(Kwan and Brodie, 2000). Surgery for uncontrolled patients results in 13.5-92.5% seizure-freedom(West et al., 2015), but only 44-45% achieve long-term seizure-freedom(Englot et al., 2012; Schmidt and Stavem, 2009)(Englot et al., 2012; Schmidt and Stavem, 2009).
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Major and minor complications in extraoperative electrocorticography: A review of a national database

Epilepsy Research Journal - Wed, 02/10/2016 - 00:00
Extraoperative electrocorticography (ECoG) is a means of obtaining high quality electroencephalographic data that can then be used to localize otherwise occult seizure foci (Lee et al., 2000; Rolston et al., 2015; Vale et al., 2013; Van Gompel et al., 2008). Without the critical information ECoG provides, many patients would not be candidates for surgery, since no definitive seizure onset zone would be recognized. Yet all surgeries carry risk. Reported case series of ECoG procedures are typically from high-volume academic centers, and often fail to report minor complications like urinary tract infections (UTIs), deep venous thromboses (DVTs), and pneumonias.
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Single dose efficacy evaluation of two partial benzodiazepine receptor agonists in photosensitive epilepsy patients: a placebo-controlled pilot study

Epilepsy Research Journal - Wed, 02/10/2016 - 00:00
Benzodiazepines (BZDs) are widely used for difficult-to-treat seizures and as rescue therapy (acute repetitive seizures, status epilepticus) (Prasad et al., 2014, McKee and Abou-Khalil, 2015). Their prophylactic and therapeutic use is, however, limited due to adverse effects such as sedation, motor incoordination, alcohol potentiation, impairment of cognitive function and withdrawal seizures (Riss et al., 2008). Furthermore, long-term treatment is associated with loss of efficacy (tolerance) and development of physical and psychological dependence and addiction, so that BZDs such as diazepam and clonazepam are only of limited use in the long-term treatment of epilepsy (Löscher and Schmidt, 2006).
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New guideline for treatment of prolonged seizures in children and adults

Science Daily - Tue, 02/09/2016 - 14:07
Status epilepticus -- continuous or rapid sequential seizure activity for 30 minutes or more -- is a medical emergency with a high mortality rate in both children and adults. Prompt and effective treatment is key; therefore the American Epilepsy Society (AES) has released a new guideline to help physicians, hospitals, and health systems treat patients effectively.
Categories: What's Current?

New guideline for treatment of prolonged seizures in children and adults

Science Daily - Tue, 02/09/2016 - 14:07
Status epilepticus -- continuous or rapid sequential seizure activity for 30 minutes or more -- is a medical emergency with a high mortality rate in both children and adults. Prompt and effective treatment is key; therefore the American Epilepsy Society (AES) has released a new guideline to help physicians, hospitals, and health systems treat patients effectively.
Categories: What's Current?

Epilepsy at the molecular level

Science Daily - Tue, 02/09/2016 - 12:18
Researchers study the link between malformations of the cerebral cortex and the occurrence of the neurological disease. Why does a structural irregularity in the temporal lobe make humans more susceptible to epileptic seizures? Experts have been searching for the answer to this question for a long time. A group of scientists has published a study involving a comparison of nearly 30,000 genes.
Categories: What's Current?

Epilepsy at the molecular level

Science Daily - Tue, 02/09/2016 - 12:18
Researchers study the link between malformations of the cerebral cortex and the occurrence of the neurological disease. Why does a structural irregularity in the temporal lobe make humans more susceptible to epileptic seizures? Experts have been searching for the answer to this question for a long time. A group of scientists has published a study involving a comparison of nearly 30,000 genes.
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Where are they now? Psychosocial, educational, and vocational outcomes after epilepsy surgery in childhood

Epilepsia - Tue, 02/09/2016 - 03:48
Summary Objective

To evaluate the social, educational, and vocational outcomes of young adults who underwent resective epilepsy surgery in childhood (4–11 years earlier), and in a comparison group of nonsurgical patients with intractable epilepsy.

Methods

Participants were 78 patients (mean age 22.37, standard deviation [SD] 2.47 years) with childhood onset intractable epilepsy, of whom 51 underwent surgery. At follow-up, participants were at least 18 years of age. Patients' current education, employment, income, and various social factors, including living arrangements, relationship status, and involvement with friends and community organizations were recorded. In addition, parents of patients completed the Adult Behaviour Checklist (ABCL). Employment status, education, and income were compared with provincial census data.

Results

There was no statistically significant difference in the proportion of surgical and nonsurgical patients who were seizure-free in the 12 months preceding the study: 53% and 33%, respectively (p = 0.10). Among all patients, 60% were enrolled in, or had completed, postsecondary education and 82% were employed or a student; similar to the general population. However, compared with population data, fewer patients with epilepsy (20%) had an annual income of $10,000 or greater (p < 0.001). Compared to normative data, a greater proportion of patients scored in the abnormal range in some ABCL scales (p < 0.028). Patients with IQs > 85 had significantly better educational, vocational, and psychosocial outcomes compared to patients with IQs ≤ 85. Surgical and nonsurgical patients did not differ on any outcome variable. Compared to patients with seizures, more seizure-free patients were living independently (p = 0.03), and had a driver's licence (p < 0.001). Other outcomes were similar among patients with and without seizures.

Significance

Overall, patients with intractable epilepsy in childhood attained educational and vocational outcomes similar to that of the general population, but earned a significantly lower income. Seizure freedom, attained through surgery or medication management, was associated with better outcomes in limited psychosocial measures.

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