In vivo studies of epilepsy typically use prolonged status epilepticus to generate recurrent seizures. However, reports on variable status duration have found discrete differences in injury after 40–50 min of seizures, suggesting a pathophysiologic sensitivity to seizure duration. In this report we take a multivariate cluster analysis to study a short duration status epilepticus model using in vivo 7T magnetic resonance spectroscopy (MRS) and histologic evaluation.Methods
The Hellier Dudek model was applied with 45 min of status epilepticus after which the animals were imaged twice, at 3 days and 3 weeks post–status epilepticus. Single voxel point resolved spectroscopy (PRESS) MRS was used to acquire data from the dentate gyrus and CA3 region of the hippocampus, assessing metabolite ratios to total creatine (tCr). In a subset of animals after the second imaging study, brains were analyzed histologically by Nissl staining.Results
A hierarchical cluster analysis performed on the 3-day data from 21 kainate-treated animals (dentate gyrus voxel) segregated into two clusters, denoted by KM (more injured, n = 6) and KL (less injured, n = 15). Although there was no difference in kainate dosing or seizure count between them, the metabolic pattern of injury was different. The KM group displayed the largest significant changes in neuronal and glial parameters; the KL group displayed milder but significant changes. At 3 weeks, the KL group returned to normal compared to controls, whereas the KM group persisted with depressed N-acetyl aspartate (NAA)/tCr, glutamate/tCr, and increased inositol/tCr and glutamine/tCr. The classification was also consistent with subsequent histologic patterns at 3 weeks.Significance
Although a short status period might be expected to generate a continuous distribution of metabolic injury, these data show that the short Hellier Dudek model appears to generate two levels of injury. The changes seen in segregated groups persisted into 3 weeks, and can be interpreted according to neuronal and glial biomarkers consistent with histology results.
The properties and structure of tissue can be visualized without labeling or preparation by multiphoton microscopy combining coherent anti-Stokes Raman scattering (CARS), addressing lipid content, second harmonic generation (SHG) showing collagen, and two-photon excited fluorescence (TPEF) of endogenous fluorophores. We compared samples of sclerotic and nonsclerotic human hippocampus to detect pathologic changes in the brain of patients with pharmacoresistant temporomesial epilepsy (n = 15). Multiphoton microscopy of cryosections and bulk tissue revealed hippocampal layering and micromorphologic details in accordance with reference histology: CARS displayed white and gray matter layering and allowed the assessment of axonal myelin. SHG visualized blood vessels based on adventitial collagen. In addition, corpora amylacea (CoA) were found to be SHG-active. Pyramidal cell bodies were characterized by intense cytoplasmic endogenous TPEF. Furthermore, diffuse TPEF around blood vessels was observed that co-localized with positive albumin immunohistochemistry and might indicate degeneration-associated vascular leakage. We present a label-free and fast optical approach that analyzes pathologic aspects of HS. Hippocampal layering, loss of pyramidal cells, and presence of CoA indicative of sclerosis are visualized. Label-free multiphoton microscopy has the potential to extend the histopathologic armamentarium for ex vivo assessment of changes of the hippocampal formation on fresh tissue and prospectively in vivo.
According to a study published in the journal Pharmacoepidemiology and Drug Safety, children exposed to antidepressants in the womb have an increased risk of being diagnosed with epilepsy later on if their mothers are diagnosed with depression during pregnancy*. A child’s risk of epilepsy also appears to increase if its mother takes antidepressants 2-6 months before, but not during, pregnancy.
Interestingly, the findings suggest that if a women takes antidepressants during pregnancy, but does not receive a clinical diagnosis of depression during this time, their child’s risk of epilepsy does not increase.
The study, conducted at Aarhus University Hospital, in Denmark, identified 734,237 Danish children born between 1997 and 2008. The researchers used the Danish National Registers to collect information about their epilepsy diagnoses, and about their mothers’ use of antidepressants and diagnoses of depression.
The results showed that, of the 734,237 children, 12,438 (1.7%) were born to women who took antidepressants between 1 month prior to conception and delivery. Amongst these 12,438, 5829 (0.8%) were diagnosed with epilepsy an average of 6.7 years later.
The researchers calculated that the children exposed to antidepressants before birth had (overall) a 27% higher risk of epilepsy compared with the children who were not exposed to antidepressants.
They then separated the data for cases where the mother took antidepressants during pregnancy and received (1)/ did not receive (2) a clinical diagnosis of depression during pregnancy. They found that for (1) the children had a 71% increased risk of epilepsy compared with unexposed children, but that for (2) there was actually no increase in risk compared with the unexposed group.
Children of women who took antidepressants 2-6 months before pregnancy, but not during pregnancy, were found to have a 36% increased risk of epilepsy compared with unexposed children. However, these women had a number of characteristics that could, themselves, have influenced the baby’s epilepsy risk; e.g. they were more likely to be older, to have a history of epilepsy/psychiatric disorders and to take antiepileptic/antipsychotic drugs.
The authors acknowledge that this study has a number of limitations, and they recommend further research to a) verify their findings and b) differentiate the effects of antidepressant medication from depression itself, upon the risk of epilepsy.
*In this article, reference to the diagnosis of depression ‘during pregnancy’ also extends to a diagnosis in the six months prior to pregnancy.
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Poor versus rich children with epilepsy have the same clinical course and remission rates but a less favorable social outcome: A population-based study with 25 years of follow-up
To explore the influence of several estimates of family socioeconomic status on the long-term clinical course and social outcomes of children with epilepsy.Methods
The Nova Scotia childhood epilepsy cohort is population based and includes all children in this Canadian province who developed epilepsy between 1977 and 1985. Eligible patients had ≥10 years of follow-up. Children with childhood absence epilepsy were excluded. Total family income at seizure onset was assessed at seizure onset and classified as “poor” (first quintile), “adequate” (second to third quintiles), and “well-off” (fourth to fifth quintiles). We also assessed parental education and home ownership. Social outcome was assessed in those with normal intelligence who were ≥18 years of age at the end of follow-up using a semistructured interview that explored eight adverse effects.Results
Of 584 patients, 421 (72%) were included. Average follow-up was 26 ± 5.6 years. Overall 137 families (33%) had “poor” income, 159 (38%) had “adequate income,” and 125 (30%) were “well-off.” Terminal remission of epilepsy occurred in 65% of the poor, 61% of the adequate, and 61% of the well-off (p = ns). Intractable epilepsy, status epilepticus, number of antiepileptic drugs (AEDs) used, and the number of generalized tonic–clonic or focal with secondary generalization seizures through the clinical course was the same in all groups. Home ownership did not predict remission. Neither paternal nor maternal education was associated with remission. Poor children had significantly more adverse social outcomes including failure to graduate from high school, unemployment, personal poverty, inadvertent pregnancy, and psychiatric diagnoses.Significance
In Nova Scotia with universal health care, coming from a poor or more affluent family does not seem to affect the clinical course or long-term seizure outcome of childhood epilepsy. Unfortunately children from poor families are less likely to have a good social outcome.
The behaviour of children with epilepsy could help identify those at a greater risk of severe psychiatric conditions, according to a study published in the journal, Epilepsia.
This finding is important, because it means that children who are identified in this way can be given the necessary care and treatment so that chronic mental health problems (which may negatively influence quality of life and increase the risk of suicide) are not carried into adulthood.
During the study, researchers led by Dr Rochelle Caplan, at the University of California, recruited 328 children with epilepsy and divided them into two groups: a ‘younger’ group (aged 5-12) and an ‘older’ group (aged 13-18). They then asked the parents of the children to complete the Child Behavior Checklist (CBCL) questionnaire, which includes 113 items to assess children’s behaviour.
The team also conducted psychiatric interviews with the children and their parents, to try and identify or diagnose some of the children with a psychiatric disorder (e.g. depression, anxiety and attention deficit and hyperactivity disorder (ADHD)).
The results showed that seven characteristics on the CBCL – clinginess, cruelty/bullying, perfectionism, nervousness, poor schoolwork, inattentiveness and sulkiness – were helpful in identifying/diagnosing children in the younger group with multiple psychiatric conditions, but not those with a single psychiatric condition.
Similarly, amongst the older group of children, three traits on the CBCL – disobedience at school, loner behaviour and lying/cheating – were found to be useful in identifying/diagnosing those with multiple psychiatric conditions (but again, not those with a single condition).
The authors conclude that CBCL is a simple and accurate screening tool, which could easily be used to identify children with epilepsy who are at an increased risk of multiple psychiatric conditions and need to be referred to a psychiatrist.
People with epilepsy have a higher risk of suicide compared with the general population, and the risk significantly increases if one or more psychiatric conditions are also present.
Author: Dr Özge Özkaya
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Antiepileptic drug (AED) treatment failures may occur because there is insufficient drug in the brain or because of a lack of relevant therapeutic response. Until now it has not been possible to measure these factors. It has been recently shown that the combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) can measure the effects of drugs in healthy volunteers. TMS-evoked EEG potentials (TEPs) comprise a series of positive and negative deflections that can be specifically modulated by drugs with a well-known mode of action targeting inhibitory neurotransmission. Therefore, we hypothesized that TMS-EEG can detect effects of two widely used AEDs, lamotrigine and levetiracetam, in healthy volunteers.Methods
Fifteen healthy subjects participated in a pseudo-randomized, placebo-controlled, double-blind, crossover design, using a single oral dose of lamotrigine (300 mg) and levetiracetam (3,000 mg). TEPs were recorded before and 120 min after drug intake, and the effects of drugs on the amplitudes of TEP components were statistically evaluated.Results
A nonparametric cluster-based permutation analysis of TEP amplitudes showed that AEDs both increased the amplitude of the negative potential at 45 msec after stimulation (N45) and suppressed the positive peak at 180 msec (P180). This is the first demonstration of AED-induced modulation of TMS-EEG measures.Significance
Despite the different mechanism of action that lamotrigine and levetiracetam exert at the molecular level, both AEDs impact the TMS-EEG response in a similar way. These TMS-EEG fingerprints observed in healthy subjects are candidate predictive markers of treatment response in patients on monotherapy with lamotrigine and levetiracetam.
Temporal behavior of seizures and interictal bursts in prolonged intracranial recordings from epileptic canines
Epilepsy is a chronic disorder, but seizure recordings are usually obtained in the acute setting. The chronic behavior of seizures and the interictal bursts that sometimes initiate them is unknown. We investigate the variability of these electrographic patterns over an extended period of time using chronic intracranial recordings in canine epilepsy.Methods
Continuous, yearlong intracranial electroencephalography (iEEG) recordings from four dogs with naturally occurring epilepsy were analyzed for seizures and interictal bursts. Following automated detection and clinician verification of interictal bursts and seizures, temporal trends of seizures, burst count, and burst–burst similarities were determined. One dog developed status epilepticus, the recordings of which were also investigated.Results
Multiple seizure types, determined by onset channels, were observed in each dog, with significant temporal variation between types. The first 14 days of invasive recording, analogous to the average duration of clinical invasive recordings in humans, did not capture the entirety of seizure types. Seizures typically occurred in clusters, and isolated seizures were rare. The count and dynamics of interictal bursts form distinct groups and do not stabilize until several weeks after implantation.Significance
There is significant temporal variability in seizures and interictal bursts after electrode implantation that requires several weeks to reach steady state. These findings, comparable to those reported in humans implanted with the NeuroPace Responsive Neurostimulator System (RNS) device, suggest that transient network changes following electrode implantation may need to be taken into account when interpreting or analyzing iEEG during evaluation for epilepsy surgery. Chronic, ambulatory iEEG may be better suited to accurately map epileptic networks in appropriate individuals.
Removing granule cells (types of neuron) at a certain time point after an epilepsy-causing brain injury could have disease-modifying effects, according to a study published the Journal of Neuroscience.
Granule cells that are generated in the weeks before and after an epilepsy-causing brain injury can abnormally integrate into certain areas of the brain, mediating the development of temporal lobe epilepsy.
The authors, based in Cincinnati, write: “These findings support the long-standing hypothesis that newly generated … granule cells are pro-epileptogenic and contribute to the occurrence of seizures.”
For the study, the researchers induced status epilepticus in a rodent model using a chemical. Three days later they removed the granule cells from the animals’ brains that had been generated up to five weeks before the chemical ‘injury’, and they noticed a 50% reduction seizure frequency.
The scientists also noticed a 20% increase in seizure duration, which wasn’t expected. They explain that this paradoxical effect may reflect a disruption of the balancing mechanisms that normally act to reduce seizure duration when seizures occur frequently.
Previous studies had shown that inhibiting granule cell production before an epilepsy-causing brain insult could reduce the development of epilepsy. This new study provides proof-of-concept data demonstrating that granule cell removal therapy applied at a certain time point after injury can have disease-modifying effects in epilepsy.
Author: Dr Özge Özkaya
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Hormone replacement therapy with estrogens may reduce lamotrigine serum concentrations: A matched case–control study
Lamotrigine (LTG) is an antiepileptic drug that is metabolized via glucuronidation. Since the glucuronidizing enzyme is inducible by estrogens, LTG serum concentrations may fall by 50–60% when combined with hormonal contraceptives that contain ethinyl estradiol (EE). Little is known about a possible interaction between estrogens used for hormone replacement therapy (HRT) and LTG, and the few available data are conflicting. Data from serum samples analyzed for LTG were therefore retrieved from a routine therapeutic drug monitoring database. Users of HRT and EE were identified and matched with controls for age and dose. No enzyme-inducing or enzyme-inhibiting comedication was allowed. LTG serum concentration-to-dose ratios (CDRs) were calculated. Case groups and their respective control groups were compared by the Mann-Whitney U test. Seventy-nine HRT users (dose range 1–4 mg/day) and 200 EE users (dose range 20–40 μg/day), as well as 158 and 400 matching controls, respectively, could be included. Both EE users and HRT users had significantly lower mean LTG CDRs than their respective matched controls. These results suggest that HRT with estrogens may reduce serum LTG concentrations.
According to a new study published in the Journal of Patient Preferences and Adherence, patient-reported medication adherence has potential as a quality indicator in the care of people with epilepsy.
To assess whether addressing the side effects caused by antiepileptic drugs (AEDs) at every visit to the neurologist increases patient-reported medication adherence, a team of researchers led by Dr Daniel Hoch, at Harvard Medical School, identified 243 adults with epilepsy who were seen at two academic hospitals. All had had at least two visits to the hospital over a period of three years.
In order determine whether AED side effects were addressed at the visits, the researchers conducted phone interviews with the participants and also analysed their medical records.
A total of 62 subjects (25%) completed the phone interviews. According to their medical records, AED side effects were addressed in 48 (77%) them; however the phone interviews themselves revealed this number to be 51 (82%).
Twenty-eight of the participants (45%) reported complete adherence to medication. Amongst the remaining 34 subjects, the most common reason for incomplete adherence (reported by 31 or 91%) was missing medication due to forgetfulness.
The team found no evidence (based on either the medical records or interview data) that addressing AED side effects increased the likelihood of (self-reported) complete medication adherence. They conclude from this that addressing side effects at every visit doesn’t have a positive impact on(self-reported) adherence, but they make the following recommendation: “Addressing AED side effects remains a neglected part of epilepsy care and should be incorporated in the development of a model that can predict quality of care.”
Author: Dr Özge Özkaya
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Epilepsy Surgery in the Back of the Brain Can Achieve Excellent Results if Performed Early, Study Suggests
Surgery in the back of the brain can attain excellent results if it is conducted early, according to a study published in the scientific journal, Epilepsy and Behavior.
Currently this type of surgery is rarely performed, because it is associated with a high number of failures due to the fact that it is extremely difficult to localise the origin from which the seizures spread in this part of the brain.
A team of researchers led by Dr Stefano Francione, at the Niguarda Ca’ Granda Hospital, in Milan, analysed the outcome of brain surgery in 125 adults and 83 children who had drug- resistant epilepsy, and in whom the focus of the epilepsy was at the back of the brain.
They followed the patients for at least five years after surgery with electroencephalography (EEG), magnetic resonance imaging (MRI) and neurologic and neuropsychological evaluation.
They found that seizure freedom was achieved in 70% of individuals following surgery, whilst a further 10% only had rare disabling seizures following surgery.
Importantly, the earlier the surgery was performed the more likely it was to be successful, with best results being obtained when the operation was carried out in childhood.
“Duration of epilepsy represents a most consistent predictor of surgical outcome, with early surgery being correlated with higher chances of surgical success,” the authors write. “We recommend an early surgical referral in cases of [drug resistant] posterior cortex seizures,” they add.
They also note that surgical failure could be predicted as early as within the first six months following surgery.
Author: Dr Özge Özkaya
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Activations in temporal areas using visual and auditory naming stimuli: A language fMRI study in temporal lobe epilepsy
Researchers at the University of Calgary, in Canada, have developed a neuro chip that enables long-term, high fidelity recordings from brain cells at a resolution 15 times higher than existing setups.
According to Pierre Wijdenes and the co-authors of the study, which is published in the journal, Scientific Reports, this new technology could help better understand brain function and offers great opportunities, not only to test different drug compounds and find the best medication that works for a particular patient, but also to develop new drug discovery devices in the future.
“So we’re actually getting closer to personal medication in a sense,” said Wijdenes in a news release. However, he added that the new chip is a “baby step” towards developing personalised treatments and warned that this kind of approach is likely still decades away.
So far, the scientists have used the chip to take recordings from the neurons of a fresh water snail, Lymnea stagnalis, which provides structurally and functionally well-characterised neurons that are relatively large in size.
They isolated individual neurons from the snails, cultured them in the laboratory and placed them on the chip inside an incubator. They then studied their electrophysiological activity over time.
According to the researchers, whereas most setups can only record neuronal activity for a few minutes, the new neuro chip allows them to take continuous recordings for several weeks. This means that they can evaluate the effects of different drug compounds on neuronal activity over time.
Senior Author Dr Naweed Syed told the Calgary Metro: “We don’t know what goes wrong with conditions like epilepsy. This technology is proof of concept that we can integrate technology with the brain. We are hoping in the future we will be able to use these chips to regain lost brain function.”
Author: Dr Özge Özkaya
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Voluntary exercise can increase the time it takes for the development of status epilepticus following a stimulation, according to experimental research published in the scientific journal, Epilepsy and Behavior.
During the study, researchers led by Dr Ricardo Mario Arida, at Universidade Federal de São Paulo, in Brazil, used female adult rodents to try and establish whether exercise programmes can interfere with seizure susceptibility.
While many studies have investigated the effects of exercise on epilepsy, these have been exclusively performed in male animals by convention.
“However, females are also worthy of investigation because of their cyclical hormonal fluctuations and possible pregnancy,” the authors write.
For the present study, the team divided the female rodents into three groups. They subjected them to controlled, forced and voluntary exercise, and then induced epileptic seizures in them using the drug pilocarpine.
The scientists observed the animals for four hours and recorded: the time that passed until the animals developed status epilepticus; the number of animals that developed status epilepticus; and the intensity of motor signs induced by the drug.
Although they saw no difference among the three groups of animals in the time that passed for first motor signs to appear, or in the number of animals that developed status epilepticus, they found that in animals that were provided with an exercise wheel in their cage (the voluntary exercise group), the time it took for status epilepticus to develop was longer compared to animals in the controlled exercise and forced exercise groups. In other word, in animals that exercised as they wanted status epilepticus developed later.
“Our behavioral results are not enough to explain physiological and molecular pathways, but there are mechanisms described in literature which may allow us to propose possible explanations,” the authors write.
They also note that future studies should address the possible mechanism behind these results, and that gender specific differences should be considered.
Status epilepticus is defined as a continuous seizure lasting more than 30 minutes, or two or more seizures without full recovery of consciousness between them. According to some scientists, any seizures that lasts more than five minutes should to be treated as status epilepticus.
Author: Dr Özge Özkaya