Childhood-onset epilepsy could be associated with accelerated brain ageing, according to a new study published in JAMA Neurology. According to the authors, childhood onset epilepsy could therefore be considered a neurobiological predisposition to cognitive disorders in later life.
In order to determine whether adults with a history of childhood-onset epilepsy have an increased risk of accelerated cognitive impairment in later life, researchers led by Dr Matti Sillanpää at the University off Turku in Finland analysed 41 adults with childhood-onset epilepsy who were followed for more than 50 years from the onset of the condition, and 46 matched controls.
They found that people with childhood-onset epilepsy had increased levels of amyloid loads in their brain. Amyloids are protein fragments that accumulate in the brain with age. While in a healthy brain these proteins are broken down and eliminated, in brain disorders such as Alzheimer’s disease, they stick together and form amyloid plaques which are neurotoxic.
Interestingly, the researchers of the presents study found that people who carried a certain type of genetic variant called ε4 in their apolipoprotein E (APOE) gene had a particularly increased risk of having amyloid load in their brain in late middle age, as measured by positron emission tomography (PET) scan.
They concluded that APOE ε4 could be a biomarker indicating accelerated brain ageing in people with epilepsy.
“Childhood-onset epilepsy appears to be associated with increased amyloid accumulation in late middle age, even among individuals in remission without antiepileptic drug therapy for decades,” the authors wrote. “The findings suggest a link between epilepsy, APOE genotype, and amyloid pathology”
They added that these findings prompt more research into brain ageing in people with epilepsy and that further follow-up with frequent amyloid assessments are needed to confirm these results.
Author: Dr Özge Özkaya
A new study published in the leading scientific journal Scientific Reports describes how cellular abnormalities caused by defects in a gene called GRIN2A may lead to epilepsy. Understanding the exact mechanism of how seizures develop at the cellular level could help scientists design better treatments against them in the future.
It was already known that mutations in the GRIN2A gene are associated with different types of childhood epilepsies. However the exact effect of the mutations on brain cells was not well understood.
In the present study, researchers led by Dr Daniel Ursu, at Eli Lilly Research Centre in Windlesham, Surrey showed that mutations in the GRIN2A gene lead to the GRIN2A protein being trapped inside nerve cells. The GRIN2A protein is normally found on the cell surface at the junctions between two nerve cells. There, it functions as a “channel” allowing the passage of electrical signals form one nerve cell to the other.
The researchers think that in the absence of GRIN2A protein, or if the GRIN2A protein does not function properly, the passage of electrical activity is affected, increasing the risk of epilepsy.
Importantly, the team showed that it was possible to restore the activity of the GRIN2A protein using a chemical compound in cells carrying the same mutations in the GRIN2A gene as in people with epilepsy. This is an exciting finding as it suggests that it may also be possible to restore the function of the GRIN2A in patients, offering a potentially treatment against seizures.
“This study is important as it shows that mutations in GRIN2A cause the protein produced to malfunction in different ways, leading to epilepsy,” said the first author of the study, Dr Laura Addis in a press release. “By understanding exactly what is going wrong in children with defects in GRIN2A, we can now try to work out what medicines target the pathways in the nerve cells that aren’t working properly”.
Professor Deb Pal at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London and a co-author of the study added: “Personalised medicine is the future of epilepsy treatment and will involve prescribing treatments based on the specific effects of a patient’s genetic defect”. He said that scientists need to develop methods to screen different medicines to see if they can restore the function of the defective GRIN2A protein. “As the mutations cause the protein to malfunction in different ways, we will need to work out strategies for the different types of effect,” he explained. “Some medicines will need to be able to get the protein to the cell surface, whereas others will need to make the protein work more, or less effectively, depending on the type of mutation.”
Author: Dr Özge Özkaya
The aim of this study was to examine the impact of seizures on persons living with epilepsy in a national, community-based setting.Methods
The data source was the Survey of Living with Neurological Conditions in Canada (SLNCC), a cohort derived from a national population-based survey of noninstitutionalized persons aged 15 or more years. Participants had to be on a seizure drug or to have had a seizure in the past 5 years to meet the definition of active epilepsy. The respondents were further stratified by seizure status: the seizure group experienced ≥1 seizure in the past 5 years versus the no seizure group who were seizure-free in the past ≥5 years regardless of medication status. Weighted overall and stratified prevalence estimates and odds ratios were used to estimate associations.Results
The SLNCC included 713 persons with epilepsy with a mean age of 45.4 (standard deviation 18.0) years. Fewer people in the seizure group (42.7%) reported being much better than a year ago versus those in the no seizure group (70.1%). Of those with seizures, 32.1% (95% confidence interval [95% CI] 18.8–45.3) had symptoms suggestive of major depression (as per the Patient Health Questionnaire-9) compared to 7.7% (95% CI 3.4–11.9) of those without seizures. Driving, educational, and work opportunities were also significantly limited, whereas stigma was significantly greater in those with seizures.Significance
This community-based study emphasizes the need for seizure freedom to improve clinical and psychosocial outcomes in persons with epilepsy. Seizure freedom has an important influence on overall health, as those with at least one seizure over the prior 5 years had an increased risk of mood disorders, worse quality of life, and faced significantly more stigma.
Diffusion magnetic resonance imaging (MRI) studies have demonstrated acute white matter changes following prolonged febrile seizures (PFS), but their longer-term evolution is unknown. We investigated a population-based cohort to determine white matter diffusion properties 8 years after PFS.Methods
We used diffusion tensor imaging (DTI) and applied Tract-Based Spatial Statistics for voxel-wise comparison of white matter microstructure between 26 children with PFS and 27 age-matched healthy controls. Age, gender, handedness, and hippocampal volumes were entered as covariates for voxel-wise analysis.Results
Mean duration between the episode of PFS and follow-up was 8.2 years (range 6.7–9.6). All children were neurologically normal, and had normal conventional neuroimaging. On voxel-wise analysis, compared to controls, the PFS group had (1) increased fractional anisotropy in early maturing central white matter tracts, (2) increased mean and axial diffusivity in several peripheral white matter tracts and late-maturing central white matter tracts, and (3) increased radial diffusivity in peripheral white matter tracts. None of the tracts had reduced fractional anisotropy or diffusivity indices in the PFS group.Significance
In this homogeneous, population-based sample, we found increased fractional anisotropy in early maturing central white matter tracts and increased mean and axial diffusivity with/without increased radial diffusivity in several late-maturing peripheral white matter tracts 8 years post-PFS. We propose disruption in white matter maturation secondary to seizure-induced axonal injury, with subsequent neuroplasticity and microstructural reorganization as a plausible explanation.
Predictors of meaningful improvement in quality of life after temporal lobe epilepsy surgery: A prospective study
To investigate prospectively the independent predictors of a minimum clinically important change (MCIC) in quality of life (QOL) after anterior temporal lobectomy (ATL) for drug-resistant mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) in Brazilian patients.Methods
Multiple binary logistic regression analysis was performed to identify the clinical, demographic, radiologic, and electrophysiologic variables independently associated with MCIC in the Quality of Life in Epilepsy-31 Inventory (QOLIE-31) overall score 1 year after ATL in 77 consecutive patients with unilateral MTLE-HS.Results
The overall QOLIE-31 score and all its subscale scores increased significantly (p < 0.0001) 1 year after ATL. In the final logistic regression model, absence of presurgical diagnosis of depression (adjusted odds ratio [OR] 4.4, 95% confidence interval [CI] 1.1–16.1, p = 0.02) and a complete postoperative seizure control (adjusted OR 4.1, 95% CI 1.2–14.5, p = 0.03) were independently associated with improvement equal to or greater than the MCIC in QOL after ATL. The overall model accuracy for MCIC improvement in the QOL was 85.6%, with a 95.2% of sensitivity and 46.7% of specificity.Significance
These results in Brazilian patients reinforce the external validation of previous findings in Canadian patients showing that presurgical depression and complete seizure control after surgery are independent predictors for meaningful improvement in QOL after ATL, and have implications for the surgical management of MTLE patients.
Intracranial electroencephalography (EEG), performed presurgically in patients with drug-resistant and difficult-to-localize focal epilepsy, samples only a small fraction of brain tissue and thus requires strong hypotheses regarding the possible localization of the epileptogenic zone. EEG/fMRI (functional magnetic resonance imaging), a noninvasive tool resulting in hemodynamic responses, could contribute to the generation of these hypotheses. This study assessed how these responses, despite their interictal origin, predict the seizure-onset zone (SOZ).Methods
We retrospectively studied 37 consecutive patients who underwent stereo-EEG (SEEG) and EEG/fMRI that resulted in significant hemodynamic responses. Hemodynamic response maps were co-registered to postimplantation anatomic imaging, allowing inspection of these responses in relation to SEEG electrode's location. The area containing the most significant t-value (primary cluster) explored with an electrode was assessed for concordance with SEEG-defined SOZ. Discriminant analysis was performed to distinguish the primary clusters having a high probability of localizing the SOZ.Results
Thirty-one patients had at least one study with primary cluster explored with an electrode, and 24 (77%) had at least one study with primary cluster concordant with the SOZ. Each patient could have multiple types of interictal discharge and therefore multiple studies. Among 59 studies from the 37 patients, 44 had a primary cluster explored with an electrode and 30 (68%) were concordant with the SOZ. Discriminant analysis showed that the SOZ is predictable with high confidence (>90%) if the primary cluster is highly significant and if the next significant cluster is much less significant or absent.Significance
The most significant hemodynamic response to interictal discharges delineates the subset of the irritative zone that generates seizures in a high proportion of patients with difficult-to-localize focal epilepsy. EEG/fMRI generates responses that are valuable targets for electrode implantation and may reduce the need for implantation in patients in whom the most significant response satisfies the condition of our discriminant analysis.
A consensus panel of epilepsy specialists, experts in Dravet syndrome, and parents of children with Dravet syndrome came together to develop a set of recommendations for the better diagnosis and management of the condition. The recommendations were published in the journal Pediatric Neurology.
“We were able to identify areas where there was strong consensus that we hope will (1) inform health care providers on optimal diagnosis and management of patients with Dravet syndrome, (2) support reimbursement from insurance companies for genetic testing and Dravet syndrome-specific therapies, and (3) improve quality of life for patients with Dravet syndrome and their families by avoidance of unnecessary testing and provision of an early accurate diagnosis allowing optimal selection of therapeutic strategies,” the authors wrote.
The panel consisted of 13 physicians and five family members who had an enhanced experience and understanding of the condition through the active roles they were playing in Dravet syndrome associations. Three rounds of online questionnaires were conducted to identify areas of consensus and contention about the diagnosis and management of Dravet syndrome.
Strong consensus was reached among panelists in the following areas: typical clinical presentation of Dravet syndrome, range of EEG and MRI findings, need for genetic testing, critical information that should be conveyed to families at the time of diagnosis, priorities for seizure control, factors triggering seizures and recommendations to avoid these, first- and second-line therapies for seizures, requirement and indications for rescue therapy, specific recommendations for screening for other diseases that may co-occur at the same time as Dravet syndrome, and the need for family support.
Consensus was not as strong regarding later therapies, such as vagus nerve stimulation and surgery, and for specific therapies of associated diseases.
Apart from the initial treatment with drugs called benzodiazepines and the use of valproate, no consensus was reached on the best way to manage convulsive status epilepticus in a hospital setting.
Dravet syndrome is a type of childhood epilepsy affecting around one in 40,000 to one in 20.000 children. It is characterised by prolonged seizures that may require emergency intervention. It is usually managed with antiepileptic drugs (AEDs) but these may not be able to suppress seizures completely.
Author: Dr Özge Özkaya
What is Dravet Syndrome?
Link Between Epilepsy and Multiple Sclerosis Uncovered, Could Help Scientists Develop New Treatments for Both Conditions
Researchers at the University of California uncovered a potential new link between epilepsy and multiple sclerosis (MS), an auto-immune disease where the immune system attacks the myelin sheath that covers nerve fibres. This new finding could lead to potential new treatments against epilepsy as well as MS.
The study that was published in the journal Neuroscience, showed that people with MS were three to six times more likely to develop epilepsy than the general population. When nerve cells loose their myelin, they are not able to function properly. When this happens in a subset of nerve cells called parvalbumin interneurons, whose role is to prevent hyperactivity, seizures occur.
To test whether it is really the loss of myelin that cause seizures in MS, researchers led by Dr Seema Tiwari-Woodruff fed mice a compound called cuprizone, which is known to damage the myelin-producing cells in the nervous system. They saw that after nine weeks, the mice started having seizures. “Without myelin, axons are vulnerable,” explained Dr Tiwari-Woodruff in a press release. “In both MS and our mouse model, parvalbumin interneurons are more vulnerable and likely to die. This causes the inhibition to be removed and induce seizures.”
When the researchers stopped feeding cuprizone to the mice, the nerve fibres started becoming myelinated again. However it is not know if this decreases seizures.
“Does remyelination affect seizure activity? Could we accelerate the remyelination with drugs? …We are interested in addressing these questions,” Dr Tiwari-Woodruff said. She added that they now have a mouse model with which they can work to test and suggest some therapeutic cures. Such drugs aimed at reducing neuronal hyperactivity could reduce the incidence of seizures and could help both epilepsy and MS patients.
Author: Dr Özge Özkaya
What is Myelin?
Myelin is a fatty white substance that surrounds the axon of some nerve cells, forming an electrically insulating layer. It is essential for the proper functioning of the nervous system. It is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination or myelinogenesis.
The intravenous formulation of lacosamide (LCM) and its good overall tolerability and safety favor the use in status epilepticus (SE). The aim of this systematic review was to identify and evaluate studies reporting on the use of LCM in SE.Methods
We performed a systematic literature search of electronic databases using a combined search strategy from 2008 until October 2016. Using a standardized assessment form, information on the study design, methodologic framework, data sources, efficacy, and adverse events attributed to LCM were extracted from each publication and systematically reported.Results
In total, 522 SE episodes (51.7% female) in 486 adults and 36 children and adolescents were evaluated with an overall LCM efficacy of 57%. Efficacy was comparable between use in nonconvulsive (57%; 82/145) and generalized-convulsive (61%; 30/49; p = 0.68) SE, whereas overall success rate was better in focal motor SE (92%; 34/39, p = 0.013; p < 0.001). The efficacy with later positioning of LCM decreased from 100% to 20%. The main adverse events during treatment of SE are dizziness, abnormal vision, diplopia, and ataxia. Overall, lacosamide is well tolerated and has no clinically relevant drug–drug interactions.Significance
The available data regarding the use of LCM in SE are promising, with a success rate of 57%. The strength of LCM is the lack of interaction potential and the option for intravenous use in emergency situations requiring rapid uptitration.
Cav1.3 channels play a crucial role in the formation of paroxysmal depolarization shifts in cultured hippocampal neurons
An increase of neuronal Cav1.3 L-type calcium channels (LTCCs) has been observed in various animal models of epilepsy. However, LTCC inhibitors failed in clinical trials of epileptic treatment. There is compelling evidence that paroxysmal depolarization shifts (PDSs) involve Ca2+ influx through LTCCs. PDSs represent a hallmark of epileptiform activity. In recent years, a probable epileptogenic role for PDSs has been proposed. However, the implication of the two neuronal LTCC isoforms, Cav1.2 and Cav1.3, in PDSs remained unknown. Moreover, Ca2+-dependent nonspecific cation (CAN) channels have also been suspected to contribute to PDSs. Nevertheless, direct experimental support of an important role of CAN channel activation in PDS formation is still lacking.Methods
Primary neuronal networks derived from dissociated hippocampal neurons were generated from mice expressing a dihydropyridine-insensitive Cav1.2 mutant (Cav1.2DHP−/− mice) or from Cav1.3−/− knockout mice. To investigate the role of Cav1.2 and Cav1.3, perforated patch-clamp recordings were made of epileptiform activity, which was elicited using either bicuculline or caffeine. LTCC activity was modulated using the dihydropyridines Bay K 8644 (agonist) and isradipine (antagonist).Results
Distinct PDS could be elicited upon LTCC potentiation in Cav1.2DHP−/− neurons but not in Cav1.3−/− neurons. In contrast, when bicuculline led to long-lasting, seizure-like discharge events rather than PDS, these were prolonged in Cav1.3−/− neurons but not in Cav1.2DHP−/− neurons. Because only the Cav1.2 isoform is functionally coupled to CAN channels in primary hippocampal networks, PDS formation does not require CAN channel activity.Significance
Our data suggest that the LTCC requirement of PDS relates primarily to Cav1.3 channels rather than to Cav1.2 channels and CAN channels in hippocampal neurons. Hence, Cav1.3 may represent a new therapeutic target for suppression of PDS development. The proposed epileptogenic role of PDSs may allow for a prophylactic rather than the unsuccessful seizure suppressing application of LTCC inhibitors.
We previously observed that adults with Lennox-Gastaut syndrome (LGS) show abnormal functional connectivity among cognitive networks, suggesting that this may contribute to impaired cognition. Herein we report network reorganization following seizure remission in a child with LGS who underwent functional magnetic resonance imaging (fMRI) before and after resection of a cortical dysplasia. Concurrent electroencephalography (EEG) was acquired during presurgical fMRI. Presurgical and postsurgical functional connectivity were compared using (1) graph theoretical analyses of small-world network organization and node-wise strength; and (2) seed-based analyses of connectivity within and between five functional networks. To explore the specificity of these postsurgical network changes, connectivity was further compared to nine children with LGS who did not undergo surgery. The presurgical EEG-fMRI revealed diffuse activation of association cortex during interictal discharges. Following surgery and seizure control, functional connectivity showed increased small-world organization, stronger connectivity in subcortical structures, and greater within-network integration/between-network segregation. These changes suggest network improvement, and diverged sharply from the comparison group of nonoperated children. Following surgery, this child with LGS achieved seizure control and showed extensive reorganization of networks that underpin cognition. This case illustrates that the epileptic process of LGS can directly contribute to abnormal network organization, and that this network disruption may be reversible.
The ketogenic diet is clinically used to treat drug-resistant epilepsy. The diet treatment markedly increases ketone bodies (acetoacetate and β-hydroxybutyrate), which work as energy metabolites in the brain. Here, we investigated effects of acetoacetate on voltage-dependent Ca2+ channels (VDCCs) in pyramidal cells of the hippocampus. We further explored an acetoacetate analog that inhibited VDCCs in pyramidal cells, reduced excitatory postsynaptic currents (EPSCs), and suppressed seizures in vivo.Methods
The effects of acetoacetate and its analogs on VDCCs and EPSCs were evaluated using patch-clamp recordings from CA1 pyramidal cells of mouse hippocampal slices. The in vivo effects of these reagents were also evaluated using a chronic seizure model induced by intrahippocampal injection of kainate.Results
Acetoacetate inhibited VDCCs in pyramidal cells of hippocampal slices, and reduced EPSCs in slices exhibiting epileptiform activity. More potent EPSC inhibitors were then explored by modifying the chemical structure of acetoacetate, and 2-phenylbutyrate was identified as an acetoacetate analog that inhibited VDCCs and EPSCs more potently. Although acetoacetate is known to inhibit vesicular glutamate transporters (VGLUTs), 2-phenylbutyrate did not inhibit VGLUTs, showing that 2-phenylbutyrate is an acetoacetate analog that preferably inhibits VDCCs. In addition, 2-phenylbutyrate markedly reduced EPSCs in slices exhibiting epileptiform activity, and suppressed hippocampal seizures in vivo in a mouse model of epilepsy. The in vivo antiseizure effects of 2-phenylbutyrate were more potent than those of acetoacetate. Finally, intraperitoneal 2-phenylbutyrate was delivered to the brain, and its brain concentration reached the level enough to reduce EPSCs.Significance
These results demonstrate that 2-phenylbutyrate is an acetoacetate analog that inhibits VDCCs and EPSCs in pyramidal cells, suppresses hippocampal seizures in vivo, and has brain penetration ability. Thus 2-phenylbutyrate provides a useful chemical structure as a lead compound to develop new antiseizure drugs originating from ketone bodies.
The International League Against Epilepsy (ILAE) recently updated the system used to classify different types of epilepsy. It is hoped that the new system will pave the way to better research, diagnosis, and treatments in epilepsy.
In a press release, Professor Ingrid Scheffer, a paediatric nephrologist and professor at The University of Melbourne said: “The new classification will help clinicians to think more deeply about each patient so that they can improve their care with optimised treatment and understanding of their disease. It will also be used for research into the epilepsies and to frame collaborative approaches that will lead to greater insights into this important group of diseases.”
It is important to have a thorough classification system as “applying the right therapy often depends upon knowing the precise type of seizure,” according to Dr Robert Fisher, the director of the Stanford Epilepsy Center. The last classification related to epilepsy was published in the 1980s and failed to capture many types of seizures.
According to Dr Fisher, the new classification system may also help patients and families better understand the name of their seizures. “[F]or example, a ‘focal aware seizure’ is more understandable than is the old term ‘simple partial seizure’,” he said.
The 2017 ILAE seizure classification includes the whole clinical picture of epilepsy underlining the potential causes of the condition. Groupings the different types of seizures in this way could lead to the advancement of research and the development of potential new treatments.
Three research articles outlining the changes in the new classification and providing guidance on how to use it in clinical practice have been published back to back in the scientific journal Epilepsia. They are titled “Operational Classification of Seizure Types by the International League Against Epilepsy”, “ILAE classification of the epilepsies. Position paper of the ILAE Commission for Classification and Terminology”, and “Instruction Manual for the ILAE 2017 Operational Classification of Seizure Types”.
Author: Dr Özge Özkaya
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