Reduced Seizure Activity Research Articles

Effect of myo-inositol on convulsions induced by pentylenetetrazole and kainic acid in rats

We studied the effect of myo-inositol on pentylenetetrazole and kainic acid-induced seizures in rats. Myo-inositol significantly reduced seizure activity.

Toward the Substitution of Invasive Electroencephalography in Epilepsy Surgery

The authors compared the localization accuracy of interictal magnetoencephalography (MEG) with ictal and interictal invasive video electroencephalography (VEEG) in identifying the epileptogenic zone in epilepsy surgery candidates. Forty-one patients, 29 with temporal lobe epilepsy (TLE) and 12 with extratemporal lobe epilepsy (ETLE), participated. Only patients with interictal changes during the MEG recordings were included. A comparison of the accuracy of invasive VEEG and MEG seizure zone identification was based on the degree of overlap between the location of the actual surgical resection and the zone identified by each method, and the success of surgery in reducing seizure activity. No statistical differences were observed between the accuracy of invasive VEEG and MEG in determining the location of the seizure zone across TLE and ETLE cases. Invasive VEEG and MEG localization judgments were correct in 54% and 56% of the cases, respectively. Separate group analyses suggested that MEG may be less beneficial relative to invasive VEEG in ETLE than TLE cases. MEG is of statistically equivalent accuracy to invasive VEEG, despite the fact that its use has not reached optimal conditions. The authors predict the replacement of the more invasive procedure with MEG in the near future for TLE cases, subsequent to the optimization of the conditions under which preoperative MEG is performed.

Progestins in the Hippocampus of Female Rats Have Antiseizure Effects in a Pentylenetetrazole Seizure Model

Progestins can have profound effects on seizure processes. However, the effects and mechanisms of progestins to modulate seizures have not been systematically investigated. The present studies were designed to characterize the effects of progestins to modulate pentylenetetrazole (PTZ)-induced seizures in female rats. In Experiment 1, ictal activity and plasma and hippocampal progesterone (P) and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) levels of proestrous rats were compared with those of diestrous and ovariectomized (ovx) rats. Experiments 2 and 3 examined effects of ovx and replacement with vehicle, P, or 3alpha,5alpha-THP, systemically (Experiment 2) or to the hippocampus (Experiment 3) on seizures and plasma and hippocampal P and 3alpha,5alpha-THP concentrations. Proestrous rats had reduced ictal activity and increased levels of P and 3alpha,5alpha-THP in plasma and hippocampus compared with diestrous or ovx rats (Experiment 1). Rats administered systemic P or 3alpha,5alpha-THP had significantly reduced ictal activity and increased plasma and hippocampal P and 3alpha,5alpha-THP levels compared with vehicle-administered rats (Experiment 2). Administration of P or 3alpha,5alpha-THP to the hippocampus of ovx rats significantly reduced seizure activity and increased hippocampal, but not plasma, levels of P and 3alpha,5alpha-THP compared with vehicle administration (Experiment 3). Together, these data suggest that P can have antiseizure effects, and these effects may be due in part to actions of its metabolite, 3alpha,5alpha-THP, in the hippocampus.

Aminoglutethimide but not spironolactone enhances the anticonvulsant effect of some antiepileptics against amygdala-kindled seizures in rats

Aminoglutethimide (AGLD, an inhibitor of adrenal steroid synthesis) up to 5 mg/kg and spironolactone (SPIR, a mineralocorticosteroid antagonist and a weak antiandrogen) up to 50 mg/kg did not affect any seizure parameter in amygdala-kindled rats. AGLD (10 mg/kg) significantly reduced seizure activity in rats of both gender. The combination of AGLD (5 mg/kg) with phenobarbital (PB, applied at its subeffective dose of 15 mg/kg) significantly shortened motor seizure and afterdischarge duration in amygdala-kindled seizures. The combined treatment of AGLD (5 mg/kg) and clonazepam (CLO) at its subeffective dose of 0.01 mg/kg caused significant reduction of the seizure severity, seizure duration and afterdischarge duration. Finally, AGLD (5 mg/kg) proved ineffective upon the action of valproate (VPA) in this model of epilepsy. In contrast to AGLD, SPIR (50 mg/kg) did not affect the action of PB, CLO or VPA against kindled seizures in rats. AGLD did not alter the free plasma levels and brain concentration of PB or CLO, so a pharmacokinetic interaction does not seem probable. Among a variety of chemoconvulsants, bicuculline and N-methyl-D-aspartic acid reversed the effects of AGLD/PB and AGLD/CLO combinations. Aminophylline, kainic acid, strychnine and the glucocorticosteroid (hydrocortisone) were ineffective in this respect. Our data confirm the hypothesis that AGLD-mediated events may play a role in seizure activity and can affect the anticonvulsant activity of some conventional antiepileptic drugs against kindled seizures. Moreover, extrapolation of obtained results to clinical practice may indicate that patients with complex partial seizures may be safely co-medicated with AGLD or SPIR without the risk of worsening of seizure control.

Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy.

Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open-label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data. We report an open-label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range, 24-47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline. Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters. Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.

The enhanced expression of c-Jun immunoreactivity in the adrenalectomized gerbil hippocampus.

Recent in vitro and in vivo studies have shown that glucocorticoids have a profound influence on the survival of hippocampal neurones, and that the depletion of glucocorticoids as a result of adrenalectomy (ADX) reduces nerve growth factor levels in the hippocampus. It is also believed that ADX is associated with the seizure susceptibility of the Mongolian gerbil. In the present study, the choronological changes of c-jun immunoreactivity were investigated after ADX in the hippocampal formations in the seizure-prone gerbil model. In the sham hippocampus, c-jun immunoreactivity was not observed in the neurones of the hippocampus proper and dentate gyrus. C-jun immunoreactive neurones appeared 3 h after ADX in the neurones of the CA1 area and dentate gyrus, and these immunoreactivities peaked 24 h after ADX and then gradually decreased. These results suggest that, in the adrenalectomized gerbil, c-jun may be expressed in the neurones of the hippocampus in compensation for glucocorticoid deficit. The result of enhanced c-jun expression of the hippocampal formation provides anatomical support for the hypothesis that c-jun may play a role in the reduction of seizure activity.

3P-0701 A novel PPAR agonist, MCC-555, ameliorates endothelial cell dysfunction in vitro

To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ETB receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats.Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV + SB202190, LEV + BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2 h of recording per day at the same time of day. We also performed western blot after EEG analysis.Compared to control animals, PGP, ETB receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ETB receptor expression was enhanced in the hippocampus of non-responders.To the best of our knowledge, these findings are the first indications of the role of ETB receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ETB receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.

3P-0700 Antiatherosclerotic effect of novel PPAR agonist, MCC-555 in macrophages and foamed macrophages

To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ETB receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats.Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV + SB202190, LEV + BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2 h of recording per day at the same time of day. We also performed western blot after EEG analysis.Compared to control animals, PGP, ETB receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ETB receptor expression was enhanced in the hippocampus of non-responders.To the best of our knowledge, these findings are the first indications of the role of ETB receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ETB receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.

Effectiveness of muscimol-containing microparticles against pilocarpine-induced focal seizures.

To investigate the efficacy of in situ lipid-protein-sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in rats. LPSPs with and without muscimol were produced by spray-drying, sized by Coulter counter, and muscimol content determined by high-pressure liquid chromatography (HLPC). Particles, free muscimol or saline, were injected into the hippocampi of Sprague-Dawley rats before 40 mM pilocarpine, and seizure activity was scored. The trajectories of behavioral scores between groups were compared with two-way repeated measures analysis of variance. Animals were killed after 2 weeks. Brain sections were stained (Timm and thionin) and scored. LPSPs were 4 to 5 microm in diameter, and contained 0 or 2% (wt/wt) muscimol. In vitro, muscimol was released over a 5-day period. Intrahippocampal injections of normal saline and blank LPSPs did not deter seizure activity from pilocarpine. The rise of the trajectory in behavior scores in animals given LPSPs containing 5 microg muscimol was significantly slower than in those receiving saline, blank particles, or 5 microg of unencapsulated muscimol. There was less apparent neuronal injury and CA3 and supragranular mossy fiber sprouting in hippocampi of animals receiving muscimol-containing particles than in animals that did not receive muscimol. Hippocampi of animals that received 5 microg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 microg of unencapsulated muscimol, but showed no difference in cell loss or CA3 sprouting. Focally delivered biodegradable microparticles loaded with muscimol are effective in reducing seizure activity from pilocarpine in animals and mitigate the histologic effects.

Cognitive and behavioral effects of antiepileptic drugs

Multiple factors contribute to the increased risk of cognitive and emotional deficits experienced by patients with epilepsy, including both the underlying disease state from which they suffer and the psychosocial disruption in their lifestyles that their seizures can produce. While antiepileptic drugs (AEDs) have the potential to reduce such risks by reducing seizure activity, they can also compound problems by dampening neuronal excitability throughout the brain and altering underlying neurochemical systems that impact thinking and mood. Therefore, for optimal treatment of epilepsy, one must achieve a balance between adequate seizure control and minimizing the potential side effects of the employed AEDs. This requires knowledge of the specific cognitive and behavioral effects of both established newer AEDs and an understanding of the general principles governing their delivery.

The intracerebral administration of phenytoin using controlled-release polymers reduces experimental seizures in rats

Purpose: An alternative strategy for the treatment of intractable seizures may be to administer anticonvulsants directly into the brain near the site of a seizure focus using controlled-release polymers. We describe the pharmacokinetics of a phenytoin–ethylene-vinyl acetate (EVAc) controlled-release polymer and report the reduction of seizures in a cobalt-induced rat model of epilepsy with the intracerebral delivery of phenytoin using surgically implanted polymers. Methods: In the pharmacokinetics study, the drug release rate of 50%-loaded phenytoin–EVAc polymers ( n=3) was determined in vitro over 15 weeks initially and then several months later (over a 2-week period after 1 year of in vivo release). In the efficacy study, 85 rats underwent implantation of skull-mounted cortical electrodes for electrocorticography (ECoG) and then underwent application of cobalt chloride to the cerebral cortex for the induction of seizures. Rats in the treatment group ( n=9) underwent surgical implantation of phenytoin–EVAc polymers and rats in the control group ( n=10) underwent implantation of empty EVAc polymers. In the morbidity study, the potential histologic pathology of the intracerebral delivery of increasing doses of phenytoin from the polymer (10, 20, 30, and 50% loading) was assessed. Results: Phenytoin was released in vitro from EVAc polymers in a controlled fashion with an initial release of 0.20% of the total loaded dose per week and a continued release of 0.70% of the total loaded dose per week after 365 days of implantation in the brain. The intracerebral controlled-release of phenytoin resulted in a statistically significant reduction in seizure activity in the treatment group as evidenced by lower Racine scores. The four groups of rats ( n=5 per group) that underwent intracerebral implantation of 10, 20, 30, or 50%-loaded phenytoin–EVAc polymers displayed expected average weight gain and normal behavior over 365 days. One rat in the 50% group, however, died 354 days after polymer implantation for undetermined reasons. Conclusions: The intracerebral delivery of phenytoin using an EVAc polymer, which will release this drug for a calculated period of 3.5 years, resulted in a significant reduction in seizures in a rat model of cobalt-induced epilepsy by both behavioral and ECoG criteria. In rats, the long-term interstitial delivery of phenytoin in the brain was not associated with any deleterious effects.

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.

Reduction of Pentylenetetrazole-Induced Seizure Activity in Awake Rats by Seizure-Triggered Trigeminal Nerve Stimulation

Stimulation of the vagus nerve has become an effective method for desynchronizing the highly coherent neural activity typically associated with epileptic seizures. This technique has been used in several animal models of seizures as well as in humans suffering from epilepsy. However, application of this technique has been limited to unilateral stimulation of the vagus nerve, typically delivered according to a fixed duty cycle, independently of whether ongoing seizure activity is present. Here, we report that stimulation of another cranial nerve, the trigeminal nerve, can also cause cortical and thalamic desynchronization, resulting in a reduction of seizure activity in awake rats. Furthermore, we demonstrate that providing this stimulation only when seizure activity begins results in more effective and safer seizure reduction per second of stimulation than with previous methods. Seizure activity induced by intraperitoneal injection of pentylenetetrazole was recorded from microwire electrodes in the thalamus and cortex of awake rats while the infraorbital branch of the trigeminal nerve was stimulated via a chronically implanted nerve cuff electrode. Continuous unilateral stimulation of the trigeminal nerve reduced electrographic seizure activity by up to 78%, and bilateral trigeminal stimulation was even more effective. Using a device that automatically detects seizure activity in real time on the basis of multichannel field potential signals, we demonstrated that seizure-triggered stimulation was more effective than the stimulation protocol involving a fixed duty cycle, in terms of the percent seizure reduction per second of stimulation. In contrast to vagus nerve stimulation studies, no substantial cardiovascular side effects were observed by unilateral or bilateral stimulation of the trigeminal nerve. These findings suggest that trigeminal nerve stimulation is safe in awake rats and should be evaluated as a therapy for human seizures. Furthermore, the results demonstrate that seizure-triggered trigeminal nerve stimulation is technically feasible and could be further developed, in conjunction with real-time seizure-predicting paradigms, to prevent seizures and reduce exposure to nerve stimulation.

Oxidative abnormalities in Menkes disease.

Menkes disease (MD; McKusick 309400) is an X-linked neurodegenerative disorder secondary to extrahepatic copper accumulation, caused by mutations of the gene encoding for the intracellular copper transporter ATPase alpha polypeptide (ATP7A). The clinical picture is characterized by severe psychomotor retardation, seizures, skin hypopigmentation and abnormal hair. Biochemically, MD patients have reduced serum levels of copper and ceruloplasmin. In some cases, early supplementation with parenteral copper histidinate reduced seizure activity and improved muscle tone and motor activity (Kreuder et al 1993). Some of the clinical findings of MD have been proposed to be secondary to reduced activities of copper-dependent enzymes (i.e. cytochrome-c-oxidase, lysyl oxidase and dopamine β-hydroxylase) (Kaler 1994). To study oxidative status and effects of copper histidinate therapy, we serially evaluated urinary organic acids in MD patients. We also evaluated respiratory chain enzymes activities in muscle and/or fibroblasts.

The ketogenic diet in refractory epilepsy: the experience of Children's Hospital of Pittsburgh.

The ketogenic diet appears to be effective in reducing seizure frequency in patients with epilepsy refractory to antiepileptic drug therapy. Reported seizure frequencies before and after the diet was initiated were obtained for 48 patients started on the ketogenic diet between December 1994 and January 1998 at Children's Hospital of Pittsburgh. The majority of patients (71%) were able to achieve > or = 50% reduction in seizure activity. Of these, more than half (53%) had > 90% reduction in seizures after 45 days of diet therapy. Complications included gastrointestinal complaints and infrequent lipid abnormalities. The ketogenic diet appears to be an effective method of treatment for children with epilepsy refractory to drug therapy.

Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene.

Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.

GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid.

The hormone progesterone is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) in the brains of males and females. In the brain, 3alpha,5alpha-THP acts like a sedative, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid), the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety and seizure susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3alpha,5alpha-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines and ethanol can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3alpha,5alpha-THP which enhance transcription of the gene encoding the alpha4 subunit of the GABA(A) receptor. We also find that increased susceptibility to seizure after progesferone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the alpha4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal.

Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene.

Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system. Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented. Although application of kainic acid imposed the same level of noxious stress, the phosphorylation of c-Jun and the transcriptional activity of the AP-1 transcription factor complex were markedly reduced in the mutant mice. These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity.

Effectiveness of Ketone Level on Seizure Control

LEARNING OUTCOME: Determine the effect of the level of ketosis on seizure control The ketogenic diet is one of the oldest forms of treatment for seizure control. The diet is designed to maintain ketosis which helps to reduce seizure activity and has improved seizure control in 50–70% of children in past research studies. Limited research has been conducted to determine if the level of ketosis has any effect on seizure control. A retrospective study involving 51 patients (29 male, 22 female) was conducted to determine what effect urine and serum ketone levels have on seizure control and if there is a correlation between urine and serum ketone levels. Age of participants ranged from 2–18 years (median age: 6 years). In this study, 82% (42) of the individuals maintained ketone levels between 80–160 mg/dl; 43% (18) were seizure free, 50% (21) had reduced seizures and 7% (3) showed no change in seizure control. For the 16% (8) of the study participants who maintained ketone levels of 40–80 mg/dL; one was seizure free, 5 had reduced seizures and 2 showed no change in seizure control. Two percent (1) maintained only trace amounts of ketones, however the seizures were decreased. B-hydroxybutyrate (BHB) was available for 31% (16) of the individuals in this study. BHB is one of three serum ketone bodies. Because of its greater concentration and stability relative to acetoacetate and acetone, BHB may become a more reliable guide in monitoring the effect of the diet. BHB > 1.0 resulted in a urine ketone level > 40 mg/dL. A rise in BHB values did not reflect a direct correlation with a rise in urine ketone levels. Trace ketone levels were seen when BHB was between 0–1. The results of this study indicate that high ketone levels will benefit patients on the ketogenic diet through eliminating or reducing seizures when a trained registered dietitian supervises this diet to ensure optimal ketone levels. Further studies are necessary to identify the appropriate urine and BHB levels needed for maximum success on the ketogenic diet as well as to determine what correlation exists between urine and blood ketone levels.

P-10-38 - Anxiety-depressive disorders after subarachnoid hemorrhage (SAH): Association with fatiguability

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100 mg/kg) or vehicle 60 min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1 mg/kg), a 5HT1A antagonist, or saline vehicle injection 80 min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3 mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80 min prior to seizure testing. 85 mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30 min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.