Increased Seizure Activity Research Articles

Antifibrinolytics in cardiac surgery

Cardiac surgery exerts a significant strain on the blood bank services and is a model example in which a multi-modal blood-conservation strategy is recommended. Significant bleeding during cardiac surgery, enough to cause re-exploration and/or blood transfusion, increases morbidity and mortality. Hyper-fibrinolysis is one of the important contributors to increased bleeding. This knowledge has led to the use of anti-fibrinolytic agents especially in procedures performed under cardiopulmonary bypass. Nothing has been more controversial in recent times than the aprotinin controversy. Since the withdrawal of aprotinin from the world market, the choice of antifibrinolytic agents has been limited to lysine analogues either tranexamic acid (TA) or epsilon amino caproic acid (EACA). While proponents of aprotinin still argue against its non-availability. Health Canada has approved its use, albeit under very strict regulations. Antifibrinolytic agents are not without side effects and act like double-edged swords, the stronger the anti-fibrinolytic activity, the more serious the side effects. Aprotinin is the strongest in reducing blood loss, blood transfusion, and possibly, return to the operating room after cardiac surgery. EACA is the least effective, while TA is somewhere in between. Additionally, aprotinin has been implicated in increased mortality and maximum side effects. TA has been shown to increase seizure activity, whereas, EACA seems to have the least side effects. Apparently, these agents do not differentiate between pathological and physiological fibrinolysis and prevent all forms of fibrinolysis leading to possible thrombotic side effects. It would seem prudent to select the right agent knowing its risk-benefit profile for a given patient, under the given circumstances.

Evaluating the concerns of pregnant women with epilepsy: A focus group approach

RationaleSome women with epilepsy stop or decrease their antiepileptic drug (AED) therapy during pregnancy because they fear fetal effects of the therapy. This places the patient and her fetus at risk for potential adverse outcomes due to increased seizure activity. The rationale of this behavior is not completely understood and is underexplored. The aim of this qualitative project was to determine the concerns of pregnant women with epilepsy via small focus groups. MethodsPregnant women with epilepsy were recruited to participate in small group sessions involving direct interviews which were analyzed by thematic content analysis. ResultsTen focus groups were conducted with a total of 21 second or third trimester pregnant women with epilepsy. Twelve women reported changes to their AED regimen during pregnancy, with six having made changes requested by their prescriber and six (29% of all study participants) self-altering their AED regimen. In contrast to the former group, the alterations made by the latter group were either dose-lowering or stopping AEDs altogether. Via content analysis, four pregnancy specific patient-related concerns arose: 1) the safety of drug therapy during pregnancy, 2) potential neonatal complications, 3) labor and delivery issues and 4) neonatal and post-partum management. An unanticipated benefit was the fostering of patient comfort and an opportunity for patient-to-patient collaboration. ConclusionsOur study adds insight into the concerns of pregnant women with epilepsy. By identifying these concerns, we may be able to provide more effective patient education, and we hope to ultimately improve outcomes in women with epilepsy.

Case Report

Case Report

049 The association between seizure activity and neural injury following endotoxin exposure and hypoxic-ischaemic insults in a preterm ovine model

IntroductionNeonatal seizures following hypoxic-ischaemic insults at birth are common. Additional exposure to endotoxins (LPS) prior to ischaemia has been shown to be able to increase or decrease neural injury, though...

Athletes With Seizure Disorders

Individuals with seizure disorders have long been restricted from participation in certain sporting activities. Those with seizure disorders are more likely than their peers to have a sedentary lifestyle and to develop obesity. Regular participation in physical activity can improve both physical and psychosocial outcomes for persons with seizure disorders. Seizure activity often is reduced among those patients who regularly engage in aerobic activity. Recent literature indicates that the diagnosis of seizure disorders remains highly stigmatizing in the adolescent population. Persons with seizure disorders may be more accepted by peer groups if they are allowed to participate in sports and recreational activities. Persons with seizure disorders are encouraged to participate in regular aerobic activities. They may participate in team sports and contact or collision activities provided that they utilize appropriate protective equipment. There seems to be no increased risk of injury or increasing seizure activity as the result of such participation. Persons with seizure disorders still are discouraged from participating in scuba diving and skydiving. The benefits of participation in regular sporting activity far outweigh any risk to the athlete with a seizure disorder who chooses to participate in sports.

Spontaneously Resolving Seronegative Autoimmune Limbic Encephalitis

We describe a patient with seronegative autoimmune limbic encephalitis (SNALE) masquerading as glioma. Brain magnetic resonance imaging (MRI) abnormalities, distinctive pathological findings, and spontaneous remission are highlighted. There are 15 previously reported SNALE cases, 1 with pathology. A 66-year-old man presented with prominent amnestic syndrome, progressive cognitive decline, and refractory complex partial seizures. Initial brain MRI suggested herpes limbic encephalitis. A 3-week course of intravenous acyclovir was ineffective. Cerebrospinal fluid analysis revealed no pleocytosis. Repeat brain MRI showed a left uncal-hippocampal, contrast-enhancing lesion with mass effect, which was resected. Pathology revealed perivascular and parenchymal mixed lymphocytic inflammatory infiltrates, microglial nodules, neuronophagia, microglial activation, astrocytosis, and lymphocyte emperipolesis within neurons. Thorough searches for infectious pathogens and autoantibodies were negative. Six weeks later, a new enhancing right mesial temporal lesion appeared, with increased seizure activity and further cognitive impairment. Although immune therapy was declined, spontaneous resolution of the new enhancing lesion, with full seizure control and significant cognitive improvement, occurred. SNALE may masquerade as glioma. Pathologic changes in our case of SNALE are distinctive. Spontaneous resolution of a focal SNALE lesion may potentially occur without immune therapy.

P14.10 Levetiracetam and Lamotrigin May Increase Seizure Activity in Idiopathic or Cryptogenic Paediatric Epilepsies

P14.10 Levetiracetam and Lamotrigin May Increase Seizure Activity in Idiopathic or Cryptogenic Paediatric Epilepsies

Generic Substitution of Levetiracetam Resulting in Increased Incidence of Breakthrough Seizures

We report on 4 patients having an increased incidence of seizures when treatment was switched from brand name levetiracetam (Keppra) to generic levetiracetam formulations. Patients reported an increase in seizure activity to their neurologists after treatment was switched from Keppra to generic levetiracetam formulations. To confirm the timeline of increased seizure activity with use of the generic drug and report these adverse events to MedWatch, we made a telephone call to each patient's pharmacy to collect information on dispensing dates and the generic formulations' manufacturers. Subsequent to the increase in seizure frequency with generic levetiracetam, treatment in all 4 patients was switched back to Keppra. Seizure frequency in all patients returned to baseline when Keppra was reinstituted. The Food and Drug Administration (FDA) considers generic medications to be therapeutically equivalent to their corresponding brand name formulation when the generic meets bioequivalence criteria. Considering the linear pharmacokinetic profile of levetiracetam, loss of seizure control or fluctuations of serum concentrations are unexpected if the patient remains on a consistent dose. However, there is growing evidence to support the concept that brand name antiepileptic drugs (AEDs) are not clinically equivalent to their generic counterparts. Because the FDA relies on voluntary reporting of adverse events from health-care professionals and consumers to their MedWatch program, underreporting makes it difficult to quantify the significance of brand to generic switches, and, equally important, generic to generic switches. Until the use of generic AEDs can be evaluated in a large randomized blinded controlled study, clinicians must be vigilant in their efforts to report to MedWatch adverse events resulting from the switch from an AED brand to generic formulation of an AED.

Myelin‐associated glycoprotein protects neurons from excitotoxicity

In addition to supporting rapid nerve conduction, myelination nurtures and stabilizes axons and protects them from acute toxic insults. One myelin molecule that protects and sustains axons is myelin-associated glycoprotein (MAG). MAG is expressed on the innermost wrap of myelin, apposed to the axon surface, where it interacts with axonal receptors that reside in lateral membrane domains including gangliosides, the glycosylphosphatidylinositol-anchored Nogo receptors, and β1-integrin. We report here that MAG protection extends beyond the axon to the neurons from which those axons emanate, protecting them from excitotoxicity. Compared to wild type mice, Mag-null mice displayed markedly increased seizure activity in response to intraperitoneal injection of kainic acid, an excitotoxic glutamate receptor agonist. Mag-null mice also had larger lesion volumes in response to intrastriatal injection of the excitotoxin NMDA. Prior injection of a soluble form of MAG partially protected Mag-null mice from NMDA-induced lesions. Hippocampal neurons plated on proteins extracted from wild-type rat or mouse myelin were resistant to kainic acid-induced excitotoxicity, whereas neurons plated on proteins from Mag-null myelin were not. Protection was reversed by anti-MAG antibody and replicated by addition of soluble MAG. MAG-mediated protection from excitotoxicity was dependent on Nogo receptors and β1-integrin. We conclude that MAG engages membrane-domain resident neuronal receptors to protect neurons from excitotoxicity, and that soluble MAG mitigates excitotoxic damage in vivo.

The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats

Deficits in memory function have been observed in pentylentetrazole (PTZ)-kindled rats. In the present study we examined the effects of atorvastatin ((3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor) on PTZ kindling and related memory deficits in rats trained with the passive avoidance test. Subconvulsive PTZ doses rendered a gradual increase in seizure activity. PTZ kindling caused long-term memory to deteriorate. Atorvastatin per se and in PTZ-kindled rats improved learning and memory functions. It also prolonged latency (time to appearance of spike potentials) and diminished the amplitude and frequency of spike potentials, which indicate epileptic discharges. These novel findings suggest that the favorable effect of the atorvastatin on memory deficits provoked by PTZ kindling might be of clinical utility.

Seizure tests distinguish intermittent fasting from the ketogenic diet

Calorie restriction can be anticonvulsant in animal models. The ketogenic diet was designed to mimic calorie restriction and has been assumed to work by the same mechanisms. We challenged this assumption by profiling the effects of these dietary regimens in mice subjected to a battery of acute seizure tests. Juvenile male NIH Swiss mice received ketogenic diet or a normal diet fed in restricted quantities (continuously or intermittently) for ∼12 days, starting at 3-4 weeks of age. Seizures were induced by the 6 Hz test, kainic acid, maximal electroshock, or pentylenetetrazol. The ketogenic and calorie-restricted diets often had opposite effects depending on the seizure test. The ketogenic diet protected from 6 Hz-induced seizures, whereas calorie restriction (daily and intermittent) increased seizure activity. Conversely, calorie restriction protected juvenile mice against seizures induced by kainic acid, whereas the ketogenic diet failed to protect. Intermittent caloric restriction worsened seizures induced by maximal electroshock but had no effect on those induced by pentylenetetrazol. In contrast to a longstanding hypothesis, calorie restriction and the ketogenic diet differ in their acute seizure test profiles, suggesting that they have different underlying anticonvulsant mechanisms. These findings highlight the importance of the 6 Hz test and its ability to reflect the benefits of ketosis and fat consumption.

Treatment of Epilepsy in Postmenopausal Women

Menopausal women represent a rapidly growing proportion of the population. Epidemiologic evidence for the increased incidence of epilepsy in elderly patients suggests that with global aging of the population, there is likely to be a growing need for healthcare workers to manage seizures in older women. Unfortunately, there has been relatively little scientific investigation into the unique concerns of postmenopausal woman with epilepsy. There is some evidence that women may experience increased seizure activity during the menopausal transition owing to the effects of estrogen and progesterone on neuronal excitability. During perimenopause and menopause, use of hormone-replacement therapy can also worsen seizure control. Menopausal women are particularly vulnerable to osteoporosis and fragility fractures, both of which demonstrate increased risk following exposure to antiepileptic drugs. Optimization of epilepsy therapy to avoid both seizures and falls caused by antiepileptic drug-induced imbalance is crucial in order to minimize fracture risk in this group of women. Elderly patients are more susceptible to adverse medication side effects owing to drug interactions and the physiologic changes of aging that result in altered drug pharmacokinetics.

Genotype–phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations

PurposePitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. MethodsWe screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. ResultsWe identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. ConclusionsOn the basis of an analysis of published cases, we propose a genotype–phenotype correlation of increased seizure activity with missense TCF4 mutations.

Women and epilepsy.

Women with epilepsy face additional challenges when compared to their peers. Hormonal influences may increase seizure activity, alter endocrine function, and affect fertility. In this population, antiepileptic drugs (AEDs) reduce the efficacy of contraception methods and increase the risk of fetal malformations. Other pertinent issues to women with epilepsy include breastfeeding as well as bone mineral health. This article summarizes our current, collective knowledge of these issues and makes specific recommendations with respect to management.

The safety and tolerability of galantamine in patients with epilepsy and memory difficulties

Individuals with epilepsy commonly experience memory loss. We investigated the safety and tolerability of galantamine in treatment of memory loss in a pilot study of 28 patients with epilepsy, randomly assigned to galantamine ( n = 13) or placebo ( n = 15) and followed for a total of 12 weeks. Participants underwent blinded memory assessment at baseline and 12 weeks (Selective Reminding Test, 7/24 Spatial Recall). One participant in the galantamine group had a suspected recurrence of brain neoplasm and increased seizures; all other participants receiving galantamine showed no increase in seizure activity during the trial. Patients in both groups reported mild, tolerable side effects (headache, appetite suppression), with no difference between groups. No significant differences were observed on the memory measures when both groups were retested at Week 12. Galantamine appears to be safe and tolerable in patients with epilepsy. Further studies with larger samples and comparison with other cholinesterase inhibitors should be considered.

Increased expression of SOX2 in Ammon's Horn Sclerosis: Further evidence for neurogenesis in epilepsy

Neurogenesis persists throughout adult human life in the dentate gyrus and subventricular zone. Recent evidence points to increased neurogenesis in the hippocampus of epileptic animal models. The abnormal migration of new neurons to ectopic locations in the dentate gyrus, in conjunction with aberrant integration of new neurons into the granule cell layer, has been hypothesized to contribute to increased seizure activity. Many studies have also shown an increase in neurogenesis secondary to CNS insults such as stroke and trauma. We therefore hypothesized that we would see increased expression of SOX2, a neural stem cell marker, in hippocampal sclerosis. Using immunohistochemical analysis, we examined the hippocampus from nine patients for SOX2 expression. Seven were from patients with a known history of temporal lobe epilepsy and histologically confirmed Ammon's horn sclerosis and two were from normal autopsy controls. We found many immunoreactive cells throughout the hippocampous, including the subventricular zone, in all seven seizure cases, and no expression of sox2 in the autopsy controls. These results provide further evidence in support of active neurogenesis in epilepsy and suggest that SOX2 plays a role in neurogenesis in hippocampal sclerosis.This research was funded and supported by Barrow Neurological Institute.

More is Not Better: Hormones for Menopausal Women with Epilepsy?

Hormone Replacement Therapy in Women with Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Study. Harden CL, Herzog AG, Nikolov BG, Koppel BS, Christos PJ, Fowler K, Labar DR, Hauser WA. Epilepsia 2006;47(9):1447–1451. PURPOSE: Previous reports have suggested that hormone replacement therapy (HRT) could increase seizure activity in women with epilepsy. We sought to determine whether adding HRT to the medication regimen of postmenopausal women with epilepsy was associated with an increase in seizure frequency. METHODS: This was a randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy, taking stable doses of antiepileptic drugs (AEDs), and within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period. RESULTS: Twenty-one subjects were randomized after completing baseline. The subjects’ ages ranged from 45 to 62 years (mean, 53 years; SD, μ5), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25–30% while taking CEE/MPA. CONCLUSIONS: CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.

A Protracted Case of Psychosis, Motor Abnormalities, and Agitation

A Protracted Case of Psychosis, Motor Abnormalities, and Agitation

Optimizing therapy of seizures in women who use oral contraceptives

There is no evidence that oral contraceptives (OCs) increase seizure activity, and OC use in the setting of antiepileptic drug (AED) treatment provides pregnancy prevention at among the highest rates of any available contraceptive method. One concern, however, is the increased risk for OC failure with the use of cytochrome P450 3A4 enzyme-inducing AEDs, such as phenobarbital, carbamazepine, phenytoin, felbamate, topiramate, and oxcarbazepine. Felbamate induces metabolism of only the progestogenic component, whereas topiramate induces metabolism of only the estrogenic component. There is preliminary evidence that lamotrigine induces the metabolism of a progestin, levonorgestrel. It is unclear whether the estrogenic or the progestogenic component is more clinically important in preventing pregnancy. To ensure maximal pregnancy prevention, it is therefore recommended that women taking enzyme-inducing AEDs should receive OCs containing at least 50 mug of ethinyl estradiol and that low-dose formulations in general should not be used. AEDs that do not induce cytochrome P450 3A4 enzymes, including valproic acid, gabapentin, levetiracetam, tiagabine, vigabatrin, zonisamide, and pregabalin, do not interact with OCs. There are no concerns regarding the treatment of seizures or increased pregnancy risk with the use of OCs and these non-enzyme-inducing AEDs. Lamotrigine levels, however, are reduced by 50% in the setting of OC use. Therefore, women with epilepsy taking lamotrigine need to be monitored carefully for seizures when OCs are started and for toxicity when OCs are discontinued. Dose adjustment to maintain clinical stability may be necessary in these settings. The placebo or pill-free week of the OC regimen may also be a period when clinical toxicity can occur. Even with the considerations discussed in this review, OCs are a reasonable contraceptive option for women with epilepsy taking AEDs.

Serotonin and epilepsy

In recent years, there has been increasing evidence that serotonergic neurotransmission modulates a wide variety of experimentally induced seizures. Generally, agents that elevate extracellular serotonin (5-HT) levels, such as 5-hydroxytryptophan and serotonin reuptake blockers, inhibit both focal and generalized seizures, although exceptions have been described, too. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsions. Furthermore, it has been shown that several anti-epileptic drugs increase endogenous extracellular 5-HT concentration. 5-HT receptors are expressed in almost all networks involved in epilepsies. Currently, the role of at least 5-HT(1A), 5-HT(2C), 5-HT(3) and 5-HT(7) receptor subtypes in epileptogenesis and/or propagation has been described. Mutant mice lacking 5-HT(1A) or 5-HT(2C) receptors show increased seizure activity and/or lower threshold. In general, hyperpolarization of glutamatergic neurons by 5-HT(1A) receptors and depolarization of GABAergic neurons by 5-HT(2C) receptors as well as antagonists of 5-HT(3) and 5-HT(7) receptors decrease the excitability in most, but not all, networks involved in epilepsies. Imaging data and analysis of resected tissue of epileptic patients, and studies in animal models all provide evidence that endogenous 5-HT, the activity of its receptors, and pharmaceuticals with serotonin agonist and/or antagonist properties play a significant role in the pathogenesis of epilepsies.