Increased Seizure Activity Research Articles

Hormone Replacement Therapy in Women with Epilepsy: A Randomized, Double‐Blind, Placebo‐Controlled Study

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. 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. Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years; SD, +/-5), 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. CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.

General Anesthetic-induced Seizures Can Be Explained by a Mean-field Model of Cortical Dynamics

General Anesthetic-induced Seizures Can Be Explained by a Mean-field Model of Cortical Dynamics

Gonadal steroids regulate GABA A receptor subunit mRNA expression in NT2-N neurons

Changes in gonadal steroid hormone levels during the menstrual cycle affect seizure frequency in women with catamenial epilepsy. Since GABA A receptors (GABARs) contribute to the prevention and termination of seizures by reducing neuronal excitability, we hypothesized that fluctuating gonadal steroid levels might affect GABAR subunit expression, which could alter inhibitory tone leading to increased seizure activity. To address this question in a simplified environment in vitro, we examined the effects of gonadal steroids on NT2-N neuronal cells. We have previously shown that NT2-N cells express functional GABARs, and that the expression pattern of GABAR subunits is regulated by chronic benzodiazepine exposure and hypoxia. NT2-N neurons were exposed to progesterone (0.1 μM), β-estradiol (3 nM), or vehicle (DMSO) for 2 days or 7 days prior to RNA harvesting. GABAR subunit mRNA levels were assessed by semiquantitative RT-PCR normalized to actin levels. Progesterone exposure for 7 days increased α2 and γ3 and decreased α5 subunit mRNAs, while β-estradiol caused significant increases in α3, β3 and ε expression. Further analysis revealed differential regulation of α4, α5, ε and π subunit expression. Plots of relative PCR density in progesterone-treated cells for α2 vs. α5, α5 vs. γ3 and α2 vs. γ3 showed correlation between samples, suggesting coordinate regulation. Both progesterone and estrogen nuclear receptor mRNAs were detected by RT-PCR, and 2 days but not 7 days estrogen exposure upregulated progesterone receptor mRNA. Gonadal steroid fluctuations regulate GABA A receptor subunit expression in NT2-N cells. Such changes, if observed in vivo, could affect seizure frequency.

Gamma knife radiosurgery of radiation-induced intracranial tumors: Local control, outcomes, and complications

To determine local control (LC) and complication rates for patients who underwent radiosurgery for radiation-induced intracranial tumors. Review of a prospectively maintained database (2,714 patients) identified 16 patients (20 tumors) with radiation-induced tumors treated with radiosurgery between 1990 and 2004. Tumor types included typical meningioma (n=17), atypical meningioma (n=2), and schwannoma (n=1). Median patient age at radiosurgery was 47.5 years (range, 27-70 years). The median tumor margin dose was 16 Gy (range, 12-20 Gy). Median follow-up was 40.2 months (range, 10.8-146.2 months). Time-to-event outcomes were calculated with Kaplan-Meier estimates. Three-year and 5-year LC rates were 100%. Three-year and 5-year overall survival rates were 92% and 80%, respectively. Cause-specific survival rates at 3 and 5 years were 100%. Three patients died: 1 had in-field progression 65.1 months after radiosurgery and later died of the tumor, 1 died of progression of a preexisting brain malignancy, and 1 died of an unrelated cause. One patient had increased seizure activity that correlated with development of edema seen on neuroimaging. LC, survival, and complication rates in our series are comparable to those in previous reports of radiosurgery for intracranial meningiomas. Also, LC rates with radiosurgery are at least comparable to those of surgical series for radiation-induced meningiomas. Radiosurgery is a safe and effective treatment option for radiation-induced intracranial tumors, most of which are typical meningiomas.

Increased susceptibility of glutathione peroxidase-1 transgenic mice to kainic acid-related seizure activity and hippocampal neuronal cell death

Glutathione peroxidase (GSHPx) has been demonstrated in several in vivo studies to reduce both the risk and severity of oxidatively-induced tissue damage. The seizure-inducing neurotoxin kainic acid (KA) has been suggested to elicit its toxic effects in part via generation of oxidative stress. In this study, we report that expression of elevated levels of murine GSHPx-1 in transgenic mice surprisingly results in increased rather than decreased KA susceptibility including increased seizure activity and neuronal hippocampal damage. Isolated transgenic primary hippocampal culture neurons also display increased susceptibility to KA treatment compared with those from wildtype animals. This could be due to alterations in the redox state of the glutathione system resulting in elevated glutathione disulfide (GSSG) levels which, in turn, may directly activate NMDA receptors or enhanced response of the NMDA receptor.

A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice

The voltage-dependent calcium channel gamma4 subunit protein, CACNG4, is closely related to the gamma2 subunit, CACNG2. Both are expressed primarily in the brain and share 53% amino acid identity. The Cacng2 gene is disrupted in the stargazer mouse, with its distinctive phenotype including ataxia, frequent absence seizure episodes, and head elevation. A disruption within Cacng4 was engineered to assess its particular function. The homozygous Cacng4-targeted mutant mouse appeared normal with no ataxic gait or absence seizures, suggesting that other members of the gamma subunit family might functionally compensate for the absence of CACNG4. To test this hypothesis, the targeted Cacng4 mutation was combined with alleles of Cacng2. Absence seizures were observed in combination with the stargazer 3J mutation, which itself does not have seizures, and increased seizure activity was observed in combination with the waggler allele. Furthermore, within the corticothalamic loop, where absence seizures arise, CACNG4 expression is restricted to the thalamus. Our studies show that the CACNG4 protein has seizure suppressing activity, but this effect is revealed only when CACNG2 expression is also compromised, suggesting that CACNG subunits have in vivo overlapping functions.

THE USE OF ACEPROMAZINE IN DOGS WITH A HISTORY OF SEIZURES

Acepromazine (ACE) is a phenothiazine derivative used for its sedative properties. The primary mechanism of action of ACE is through inhibition of dopaminergic‐2 receptors in the brain. It is a common belief that ACE lowers the seizure threshold. The purpose of this clinical study is to retrospectively evaluate the occurrence of seizures in dogs presenting with a history of seizures that were treated with ACE during hospitalization. A retrospective review of records from dogs that had a chronic or acute seizure history and received ACE was done. Factors evaluated included the presenting complaint, historical seizure information, ACE dosage and route of administration, reason for giving and length of hospitalization following ACE, occurrence of seizure activity post‐ACE administration, time interval between ACE and seizure activity, and use of other medications. Thirty‐one dogs qualified for the study, 20 males and 11 females. Age range was 3 months ‐ 14.9 years. Presenting complaint was seizure in 28 patients, bite wound in 1 patient, ruptured cranial cruciate ligament in 1 patient, and hind limb paresis in 1 patient. Twenty‐seven dogs did not seize after ACE administration within an average of 16.4 hours of observation (range: 0.25–66 hours). There was a known history of seizures in 22/31 prior to the day of presentation, and 15/22 were currently on maintenance anti‐epileptic medication. Of the 16 not on anti‐seizure medication at the time of presentation, 13 were started on phenobarbital. One was also started on potassium bromide, and 3 received no anti‐seizure medication during hospitalization. All received at least one dose of ACE while in the hospital (range 1–5). Mean ACE dose was 0.029 mg/kg IV (range: 0.008–0.057 mg/kg; n=46), 0.036 mg/kg IM (range: 0.017–0.059 mg/kg; n=14), 0.53 mg/kg PO (n=2). Twenty‐three received some form of anti‐seizure medication in the hospital prior to being given ACE. Eight seizure episodes occurred 0.3–10 hours after ACE administration in 4. All 4 presented for seizures. The time interval between ACE administration and seizure activity was greater than that expected for measurable effects to be seen in one dog (10 hours). In conclusion, there is no clinical evidence that ACE administration at the listed dosages is associated with increased seizure activity in dogs with seizure disorders. A larger study group is needed to more thoroughly evaluate the safety of short‐term ACE use in dogs with a seizure history.

Cellular and molecular effects of steroid hormones on CNS excitability.

The steroid hormones 17beta-estradiol (estradiol) and progesterone not only regulate the reproductive system but have other central nervous system effects that can directly affect a variety of behaviors. Generally, estradiol has been shown to have activating effects, including the ability to increase seizure activity, while progesterone has been shown to have depressant effects, including anticonvulsant properties. Because levels of these hormones fluctuate across the menstrual cycle, it is important to understand how changes in these hormone levels may influence levels of excitability in the brain, especially in women who have seizure patterns that are related to their menstrual cycle, a phenomenon known as catamenial epilepsy. This paper reviews the effects of estradiol and progesterone on excitatory and inhibitory neurotransmitters, respectively, and the possible cellular and molecular mechanisms underlying the changes in brain excitability mediated by these hormones.

Safety of Diastat, a rectal gel formulation of diazepam for acute seizure treatment.

Diazepam rectal gel (Diastat) is the only medication approved by the US FDA for the management of selected, refractory patients with epilepsy, on stable regimens of antiepilepsy drugs, who require intermittent use of diazepam to control bouts of increased seizure activity. An analysis of the safety of diazepam rectal gel reveals that this formulation has certain advantages over intravenous diazepam administration: most notably a very low incidence of respiratory depression, low potential for abuse and the opportunity for out-of-hospital use by non-professional caregivers. Sedation is the most common adverse effect of rectal diazepam treatment, occurring in approximately one-quarter of patients, although drug-induced somnolence is difficult to distinguish from normal post-ictal sedation. Overdosage of diazepam rectal gel is rarely associated with serious clinical consequences, and overdoses of up to 330% of the maximum recommended dosage have been reported without any respiratory or cardiac depression. Under-administration may be a serious safety issue because of morbidity that may result if seizures are not terminated. Chronic administration may cause tachyphylaxis and should be avoided.

Interleukin‐1 in the Brain

Interleukin-1 (IL-1) exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. Much of this is based on studies using the IL-1 receptor antagonist, which inhibits cell death caused by ischemia, brain injury, or excitotoxins. Our aim is to determine how and where in the brain IL-1 acts to produce these effects. Most of the neurodegenerative effects of IL-1 are thought to be through IL-1 beta. However, we have data implicating IL-1 alpha in excitotoxic cell death. Furthermore mice lacking both IL-1 alpha and IL-1 beta show dramatically reduced ischemic cell death, whereas deletion of IL-1 alpha or IL-1 beta alone fails to modify damage. It has also been demonstrated that IL-1 exacerbates ischemic injury in mice in the absence of the type I IL-1 receptor, suggesting the existence of novel IL-1 receptors in the brain. IL-1 also dramatically exacerbates neuronal loss in response to intrastriatal administration of the excitotoxin AMPA in the rat brain, an effect accompanied by marked increases in cytokine expression in the frontoparietal cortex, which precedes subsequent cell death in this region. Intrastriatal AMPA also results in limbic seizures that are exacerbated by IL-1, and we hypothesize, therefore, that IL-1 exacerbates cell death through increased seizure activity. Therefore, IL-1 appears to induce acute neurodegeneration through a number of mechanisms.

Utility of antiepileptic drug monitoring in the pediatric emergency department.

Convulsive disorders are common in the pediatric age group, and measurement of serum concentration of an antiepileptic drug (AED) is frequently ordered for epileptic patients in the emergency department (ED). The objective of this study was to develop a better understanding of the indications for, and consequences of, monitoring AED serum concentrations in the pediatric ED. Charts of 116 patients who visited the ED and were tested for blood levels of AED were retrospectively reviewed. Main outcome measures were number and percentage of levels outside the therapeutic range, discontinuation of an AED or introduction of a new one, dosage modifications, and admission to hospital. Two pediatricians and a pediatric neurologist aware only of patients' age, weight, diagnosis, history, clinical presentation, and drug details reviewed each case and on the basis of predetermined criteria decided whether measurement of AED was indicated. Mean age (+/- SD) of the study population was 7 +/- 5 years (range, 2 months-17 years). Forty-two patients (36%) were on monotherapy, and 74 (64%) were on polytherapy. Sixty-eight patients (59%) presented with increased seizure frequency, 7 (6%) with status epilepticus, and 13 (11%) with suspected AED toxicity. The remainder of the children presented with problems unrelated to epilepsy. No significant difference was found between patients with AED levels within the therapeutic range and those with levels outside it in the proportion of children needing dosage change, change in medication, or hospital admission (P = 0.5, 0.8, and 0.8, respectively). None of the patients presenting with status epilepticus and only 15% of those with increased seizure activity had subtherapeutic levels. Review of the cases suggested that measuring serum AED level was not indicated in 57 (49.1%) patients. In the pediatric ED, abnormal AED levels do not correlate with clinical management. Before ordering tests, physicians should consider whether their results would alter patient treatment.

Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

Low-dose stereotactic radiosurgery is inadequate for medically intractable mesial temporal lobe epilepsy: a case report

The successful surgical treatment of medically refractory epilepsy is based on one of three different principles: (1) elimination of the epileptic focus, (2) interruption of the pathways of neural propagation, and (3) increasing the seizure threshold through cerebral lesions or electrical stimulation. Temporal lobe epilepsy, being the most common focal epilepsy, may ultimately require temporal lobectomy. This is a case report of a 36-year-old male with drug-resistant right mesial temporal lobe epilepsy who failed to obtain seizure control after stereotactic radiosurgery to the seizure focus. Complex-partial seizures occurred 6–7 times monthly, and consisted of a loss of awareness followed by involuntary movements of the right arm. EEG/CC TV monitoring indicated a right mesial temporal lobe focus, which was corroborated by decreased uptake in the right temporal lobe by FDG-PET and by MRI findings of right hippocampal sclerosis. Stereotactic radiosurgery was performed with a 4MV linac, utilizing three isocenters with collimator sizes of 10, 10, and 7 mm respectively. A dose of 1500 cGy (max dose 2535 cGy) was delivered in a single fraction to the patient’s right amygdala and hippocampus. There were no acute complications. Following radiosurgery the patient’s seizures were improved in both frequency and intensity for approximately 3 months. Antiepileptic medications were continued. Thereafter, seizures increased in both frequency and intensity, occurring 10–20 times monthly. At 1 year post radiosurgery, standard right temporal lobectomy including amygdalohippocampectomy was performed with subsequent resolution of complex-partial seizures. Histopathology of the resected temporal lobe revealed hippocampal cell loss and fibrillary astrocytosis, consistent with hippocampal sclerosis. No radiation-induced histopathologic changes were seen. We conclude that low-dose radiosurgery doses temporarily changed the intensity and character of seizure activity, but actually increased seizure activity long-term. If radiosurgery is to be an effective alternative to temporal lobectomy for medically intractable temporal lobe epilepsy, higher radiosurgery doses will be required. The toxicity and efficacy of higher-dose radiosurgery is currently under investigation.

Long-lasting effects of feline amygdala kindling on monoamines, seizures and sleep

This report describes the relationship between monoamines, sleep and seizures before and 1-month after amygdala kindling in young cats (<1 year old; n=8; six female and two male). Concentrations (fmoles of norepinephrine or NE, dopamine or DA and serotonin or 5-HT) were quantified in consecutive, 5-min microdialysis samples (2 μl/min infusion rate) from amygdala and locus ceruleus complex (LC) during four, 6–8-h polygraphic recordings before ( n=2) and 1 month post-kindling ( n=2); 5-min recording epochs were temporally adjusted to correspond to dialysate samples and differentiated according to dominant sleep or waking state (lasting ≥80% of 5-min epoch) and degree of spontaneous seizure activity (number and duration of focal versus generalized spikes and spike trains and behavioral seizure correlates). Post-kindling records in each cat were divided into two groups ( n=1 record each) based on higher or lower spontaneous EEG and behavioral seizure activity and compared to pre-kindling records. We found: (1) before and after kindling, NE and 5-HT but not DA concentrations were significantly lower in sleep than waking at both sites; (2) after kindling, each cat showed cyclic patterns, as follows: (a) higher NE, 5-HT and DA concentrations accompanied increased seizure activity with delayed sleep onset latency and increased sleep fragmentation (reduced sleep state percentages, number of epochs and/or epoch duration) in one recording versus (b) lower monoaminergic concentrations accompanied reduced seizure activity, rapid sleep onset and reduced sleep disruption in the other recording. The alternating, post-kindling pattern suggested ‘rebound’ effects which could explain some controversies in the literature about chronic effects of kindling on monoamines and sleep–waking state patterns.

Alopecia in three women of southeast asian descent with chronic renal failure: Possible association with erythropoietin use

Recombinant human erythropoietin (Epo) has been used successfully to correct the anemia caused by chronic renal failure in patients undergoing dialysis, as well as the anemia associated with other conditions, including cancer therapy. Despite its benefits, it can be associated with adverse side effects. These include hypertension, headaches, increased seizure activity, clotted vascular access, and occasional thromboembolic events, such as myocardial infarction or stroke. We report a potentially new side effect associated with Epo of a cosmetic nature. Three Southeast Asian women with chronic renal failure developed diffuse, nearly total, hair loss during erythropoietin use. Two cases were strongly associated with Epo use, and a third had other intercurrent illnesses as well. Alopecia may be associated with Epo use in certain ethnic populations.

Management of Acute Repetitive Seizures

Acute repetitive seizures, more commonly known as cluster, crescendo or sequential seizures, are defined as episodes of increased seizure activity occurring in patients with refractory epilepsy who are already receiving stable regimens of anticonvulsants. They lie in the seizure spectrum between isolated seizures and status epilepticus. If acute repetitive seizures are left untreated, they may progress to status epilepticus.

Seizure-induced neuronal death is associated with induction of c-Jun N-terminal kinase and is dependent on genetic background

Previous studies have shown that expression of c-Jun protein, as well as the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein kinases, may play a critical role in the pathogenesis of glutamate neurotoxicity. In order to define the molecular cascade that leads to c-Jun activation following excitotoxic injury and delineate whether induction of protein synthesis is related to cell death signaling cascades or those changes associated with increased seizure activity, we examined the expression of JNK-1, as well as its substrate, c-Jun and N-terminal phosphorylated c-Jun following kainic acid (KA) administration in two strains of mice. In the present study, we assessed the immunohistochemical expression of these proteins at time points between 2 h and 7 days, in excitotoxic cell death-resistant (C57BL/6) and -susceptible (FVB/N) mouse strains that were systemically injected with saline or kainic acid. No strain-related differences in the immunohistochemical expression of any of the proteins were observed in intact control mice. However, following KA administration, the magnitude and period of induction of JNK-1 protein was associated with impending cell death, while increased phosphorylation of c-Jun protein was associated with resistance to cell death. In contrast, expression of c-Jun protein does not appear to be a reliable indicator of impending cell death, as it was expressed in resistant and vulnerable subfields in mice susceptible to kainate injury. These results provide the first evidence that JNK-1 expression may be involved in producing the neuronal cell death response following excitotoxin-induced injury.

Sleep and epilepsy.

Sleep disturbance in patients with epilepsy is frequently overlooked, but may contribute to decreased daytime functioning and increased seizure activity. Although complicated, the relationship between sleep and epilepsy is becoming clearer. Sleep, and particularly deep non-rapid-eye-movement sleep, increase interictal epileptiform activity. Sleep increases certain seizure types and the rate of generalization of partial seizures, however rapid-eye-movement sleep seems to suppress seizures. Sleep disorders, particularly sleep apnea, exacerbate seizures. Seizures, in turn, can disrupt sleep structure, particularly rapid-eye-movement sleep. An understanding of these relationships is important in seizure control and in maximizing the quality of life for patients with epilepsy.

Melatonin was found to increase seizure activity

Melatonin was found to increase seizure activity

Pro-convulsant effects of oral melatonin in neurologically disabled children

seizure activity. All seizure activity returned to pre-treatment levels after discontinuing melatonin. Three subjects were rechallenged with a smaller dose (1 mg). Observed clinical seizure activity increased, returning to baseline after again discontinuing treatment. Because of this increased seizure activity, the study was suspended. Although melatonin had a positive effect on our patients’ sleep disorders, four of six children with severe neurological disabling conditions and seizures had increased seizure activity after treatment. Seizure frequency returned to baseline after melatonin was discontinued and re-challenge resulted in recurrence. Our patients visit the hospital frequently and have had multiple medical procedures, so it is unlikely that the circumstances of the investigation confounded our observations. Melatonin has been shown to be involved in seizure and sleep mechanisms. Suppression of seizure activity has been shown to occur after administration of melatonin and melatonin-treated animals that have had their pineal glands removed have been shown to exhibit fewer seizures than animals without pineal glands not given melatonin. Limited human studies of temporal-lobe epilepsy indicate melatonin may attenuate seizure activity. It is unknown if melatonin has an effect on the normal EEG. Further investigations are needed before recommending melatonin for the treatment of sleep disorders in children with chronic neurologically disabling conditions. In addition, this possible pro-convulsant potential warrants further investigation, particularly in view of the ready availability of melatonin.