Treatment Of Intractable Seizures Research Articles

9. The anticonvulsant effects of cannabidiol examined in animal seizure models

Cannabidiol (CBD), a major nonpsychotropic compound of Cannabis sativa, is emerging as a treatment for intractable seizures and their comorbid cognitive, behavioral and quality of life sequelae. Basic research studies in animals have started to define the anticonvulsant properties of CBD. Studies of CBD in mice and rats using maximal electroshock (MES) and pentylenetetrazol (PTZ) models of generalized clonus or myoclonus reported ED50 values of CBD as early as the 1970s – however chromatographic analysis of CBD purity was often not reported. The ED50 values for CBDs reported previously may be inaccurate for some botanical derived extracts; although historically, the ED50 values reported for MES in rats (10 mg/kg) may be an order of magnitude lower than those reported in mice. We will compare recent data derived from in vivo studies with the published data. Testing of CBD in seizure models will be interpreted in this context – including a study of CBD in ventral subiculum kindling. The latter studies provide a useful comparison with the drug-standardized amygdala kindling model – the model in which we evaluate novel drugs that may be effective against complex-partial seizures of temporal lobe origin. The systematic investigation of CBD efficacy, toxicity and pharmacokinetics may be important in view of the tendency to add CBD to other antiepileptic drug regimens for the treatment of treatment-resistant epilepsy. Better evaluation of the ED50 of CBD in animal models will form the basis for more reliable dosing in human epileptic patients.

Felbamate in intractable pediatric and young adult epilepsy

Felbamate (FBM) use in treatment of pediatric and adult epilepsy has sharply declined since early reports of FBM- associated hematologic and hepatic injury. We retrospectively reviewed the efficacy and safety profile of FBM in children and young adults with intractable epilepsy treated with this antiepileptic drug as adjunctive therapy in our pediatric epilepsy clinic from 2001-2010. We identified 101 patients 2-22 yr (mean 12.8 ± 1.8 yr) with various seizure types and epilepsy syn- dromes. FBM dosing was titrated according to tolerability and seizure control. Mean duration of FBM treatment was 43.7 ± 30.4 mo. Patients had periodic serum drug levels, serum hematologic and metabolic panels and body-mass index measurements during treatment and follow-up. No patient had serious adverse effects, including aplastic anemia or hepatic failure. Using sub- jective seizure counts, FBM also seemed to be effective in seizure control; 22 (22%) patients were reported as seizure-free; 59 (59%) patients were said by parents to have had fewer seizures, and 20 (20%) patients were estimated as having unchanged sei- zure frequency. Weight loss, though typically mild, was the major adverse effect. In children older than 3 yr, 46 (53%) of 86 lost weight during FBM administration and 40 (47%) children gained weight. No patients required discontinuation of FBM due to adverse effects. FBM was well-tolerated and without serious adverse effects in our patients. FBM seemed to be effective in reducing seizure frequency. It should be considered a viable current option for treatment of intractable seizures in children, though weight should be monitored in these patients.

Advances in the neurosurgical management of epilepsy caused by hypothalamic hamartoma

Hypothalamic hamartoma (HH) is an uncommon intrinsically epileptogenic lesion of the hypothalamus that is associated with medically intractable epilepsy. Intractable seizures caused by HH may lead to progressive cognitive delay and are also associated with generation of secondary epileptic foci. Therefore, early referral and surgery for children with HH is critical. Recent advances in minimally invasive neurosurgical techniques, including endoscopy, radiosurgery, magnetic resonance-guided laser interstitial ablation, and deep brain stimulation, have increased both the variety and feasibility of treatment options available for treating the intractable seizures caused by HH. In this manuscript, we review emerging techniques available for treatment of intractable seizures associated with HH.

Efficacy and safety of zonisamide in Thai children and adolescents with intractable seizures.

This retrospective study examined the efficacy and safety of zonisamide for Thai children and adolescents with intractable seizures. The medical records of 24 patients (13 male, 11 female), aged 2 to 18 years (median 11.5, mean 10.4) who received zonisamide were reviewed. The underlying illness, etiology of epilepsy, seizure types, previous and concomitant antiepileptic drugs, dosage, and adverse effects of the drug were collected. Zonisamide's efficacy was evaluated on the basis of seizure reduction rates. At final evaluation, 7 patients were still taking zonisamide from 4.7 to 10.3 mg/kg/d (median 8). One patient became seizure-free and the other 6 experienced favorable seizure control. The median duration of zonisamide therapy was 23.75 months (range 20.5-25 months). Minor adverse effects were reported in 41.6% of patients during the first 3 months of therapy. Zonisamide is an option for the treatment of intractable seizures with favorable seizure control in children and adolescents.

Ketogenic dietary therapy for epilepsy and other disorders: current perspectives

Ketogenic dietary therapy for epilepsy and other disorders: current perspectives Elizabeth G Neal 1Matthew's Friends Clinics, Lingfield, UK, 2UCL Institute of Child Health, London, UK Abstract: The ketogenic diet (KD) is a high-fat, restricted-carbohydrate regime, originally designed to mimic metabolic responses to fasting and has been used since the 1920s as a treatment for epilepsy. Modified variants of the KD include the addition of medium-chain triglyceride and less-restrictive modified Atkins and low glycemic index protocols. Scientifically proven as treatment for intractable seizures in children, these ketone-generating diets are increasingly also being used in adults. They are the treatment of choice in glucose transporter type 1 deficiency syndrome and pyruvate dehydrogenase deficiency. Evidence for the potential of KD therapy to be included within the treatment options for cancer and neurodegenerative disorders is more limited, albeit an exciting area of research with future clinical potential. This review discusses the key aspects of KD therapy, including the efficacy of treatments and clinical implementation. The importance of appropriate initiation, adequate clinical supervision, regular monitoring, and assessment of nutritional needs is highlighted. Keywords: diet, seizures, ketosis

Therapeutic brain hypothermia, its mechanisms of action, and its prospects as a treatment for epilepsy

Cooling the core body temperature to 32-35°C, is almost standard practice for conditions such as cardiac arrest in adults, and perinatal hypoxic ischemic encephalopathy in neonates. Limited clinical data, and more extensive animal experiments, indicate that hypothermia could help control seizures, and could be applied directly to the brain using implantable devices. These data have fostered further research to evaluate whether cooling would be a viable means to treat refractory epilepsy. Although the effect of temperature on cellular physiology has long been recognized, with possibly dual effects on pyramidal cells and interneurons, the exact mechanisms underlying its beneficial effects, in particular in epilepsy, are yet to be discovered. This article reviews currently available clinical and laboratory data with a focus on cellular mechanisms of action and prospects of hypothermia as a treatment for intractable seizures.

Activity-Dependent Human Brain Coding/Noncoding Gene Regulatory Networks

While most gene transcription yields RNA transcripts that code for proteins, a sizable proportion of the genome generates RNA transcripts that do not code for proteins, but may have important regulatory functions. The brain-derived neurotrophic factor (BDNF) gene, a key regulator of neuronal activity, is overlapped by a primate-specific, antisense long noncoding RNA (lncRNA) called BDNFOS. We demonstrate reciprocal patterns of BDNF and BDNFOS transcription in highly active regions of human neocortex removed as a treatment for intractable seizures. A genome-wide analysis of activity-dependent coding and noncoding human transcription using a custom lncRNA microarray identified 1288 differentially expressed lncRNAs, of which 26 had expression profiles that matched activity-dependent coding genes and an additional 8 were adjacent to or overlapping with differentially expressed protein-coding genes. The functions of most of these protein-coding partner genes, such as ARC, include long-term potentiation, synaptic activity, and memory. The nuclear lncRNAs NEAT1, MALAT1, and RPPH1, composing an RNAse P-dependent lncRNA-maturation pathway, were also upregulated. As a means to replicate human neuronal activity, repeated depolarization of SY5Y cells resulted in sustained CREB activation and produced an inverse pattern of BDNF-BDNFOS co-expression that was not achieved with a single depolarization. RNAi-mediated knockdown of BDNFOS in human SY5Y cells increased BDNF expression, suggesting that BDNFOS directly downregulates BDNF. Temporal expression patterns of other lncRNA-messenger RNA pairs validated the effect of chronic neuronal activity on the transcriptome and implied various lncRNA regulatory mechanisms. lncRNAs, some of which are unique to primates, thus appear to have potentially important regulatory roles in activity-dependent human brain plasticity.

Cost-effectiveness of adding-on new antiepileptic drugs to conventional regimens in controlling intractable seizures in children.

Background and purpose of the studyIntractable seizures are a subgroup of epileptic disorders challenging the physicians’ skills to become controlled. Showing resistance towards common pharmacotherapy, they demand newer antiepileptic drugs acquired at higher costs. 0.06% of children around the world are estimated to suffer from epilepsy and its consequences. The aim of the present study has been to evaluate the cost-effectiveness of these drugs in the treatment of intractable seizures in children.MethodsClinical and cost data were collected from medical and cost records preserved at a neurologist office and a referral pharmacy respectively. Based on the new AED which are accessible in Iran, regimens were categorized into eight groups. The first group consisting of conventional AEDs was considered as comparator and the effectiveness of other groups was compared with it. Incremental Cost-effectiveness Ratio (ICER) of adding-on each new antiepileptic drug was calculated in terms of Rials per consequence (Rls/consq) and compared with each other. Furthermore ICER of the regimens was compared with the GDP per capita (Gross Domestic Product) of the year (2010).Resultsthe ICER of the adding-on regimens range from negative values for Gabapentin, Levetiracetam and Zonisamide to low values for Lamotrigine (~ 6.4 million Rials/consequence [mil Rls/consq]) and Oxcarbazepine (~7.7 mil Rls/consq) and followed by high values for Topiramate (~21 mil Rls/consq) and Vigabatrin (~43.7 mil Rls/consq) considering the three months of remaining on regimen. By increasing the limit of remaining time to six months, the previously mentioned regimens persist on negative values. However Oxcarbazepine (~28.7 mil Rls/consq) and Lamotrigine (~13.8 mil Rls/consq) show a steep increase. Topiramate (~23.6 mil Rls/consq) displays a less change. Opposite to other regimens, the ICER value of Vigabatrin (~17.26 mil Rls/consq) has shown an important increase.Major conclusionsAdding-on new antiepileptics to conventional regimens are cost-effective and justified considering the GDP per capita.

Abstract IA3: Regulatory networks in onco-lncRNAomics: Cis-regulation and non-conservation

Abstract IA3: Regulatory networks in onco-lncRNAomics: Cis-regulation and non-conservation

Épilepsie et lésions focales chez l’enfant. Traitement chirurgical

Epilepsy surgery has gained a large role in the treatment of intractable seizures in the last few decades because of the development of operative techniques and better identification of the cerebral anomalies using electrophysiological recordings and neuroimaging. A series of 419 children, aged from five months to 15 years, with epilepsy (medically refractory in 85.5% of them) associated with focal cortical lesions, who underwent surgery between 1986 and 2006 was analyzed to identify the factors that correlated with outcome. Mean follow-up was 5.2 years. According to Engel's classification; 75.8% of the children were seizure-free. When the lesion was well defined, correlations between clinical data, radiological features and electrophysiological features, suggesting a zone of seizure onset around (or even in) the lesion, was the best guarantee of achieving good seizure control by lesionectomy. Nevertheless, seizure outcome was also determined by other factors: the duration of the epilepsy and the surgery. Persistence of seizures was found to be significantly associated with the preoperative duration of epilepsy, the completeness of the lesional resection and de novo brain damage induced by the surgical procedure itself. Early surgery must be considered in children because of the benefits of seizure control on the developing brain and the risk of secondary epileptogenesis.

Poster 238: Rehabilitation of Hemiparesis, Neglect, Mutism, and Dysphagia Following Hemispherectomy for the Treatment of Intractable Seizures: A Case Report

Poster 238: Rehabilitation of Hemiparesis, Neglect, Mutism, and Dysphagia Following Hemispherectomy for the Treatment of Intractable Seizures: A Case Report

Comparison of Continuous Drip of Midazolam or Lidocaine in the Treatment of Intractable Neonatal Seizures

Seizures constitute the most common neurological symptom in the neonatal period. Treatment usually involves the administration of intravenous benzodiazepines followed by either phenobarbital or phenytoin. For nonresponsive cases, continuous intravenous drip of either midazolam or lidocaine has been suggested for seizure control. Some reports suggest that seizures themselves may have a deleterious effect on long-term neurological outcome. Therefore, there is a need to find treatment regimens with better efficacy to provide maximum seizure control. The authors compared the effectiveness of lidocaine and midazolam in the treatment of intractable seizures in newborn infants born at or after 36 weeks of gestation who suffered from hypoxic-ischemic encephalopathy and who had their cerebral activity monitored. Thirty infants were included in the study: 22 received lidocaine, and 8 received midazolam. Seventeen (77%) infants had a good or partial response to lidocaine, and 4 (50%) had a partial response to midazolam. Of 20 infants diagnosed with hypoxic-ischemic encephalopathy grade 2, 18 (90%) responded to second-line treatment (14 [93%] of 15 to lidocaine and 4 [80%] of 5 to midazolam). Among 10 infants with hypoxic-ischemic encephalopathy grade 3, only 3 (30%) responded to second-line treatment (all 3 to lidocaine, none to midazolam). The findings suggest that lidocaine may be more effective than midazolam in reducing or controlling refractory neonatal seizures. The lower response rate to midazolam was more evident in infants with severe hypoxic-ischemic encephalopathy (grade 3).

Safety and Tolerability of the Ketogenic Diet in Pediatric Epilepsy: Effects of Valproate Combination Therapy

To evaluate safety and tolerability of ketogenic diet (KGD) and valproate (VPA) cotherapy in the treatment of intractable seizures. The patient records of children who underwent KGD initiation at the Massachusetts General Hospital for Children from February 2002 to September 2004 were retrospectively assessed. Efficacy was measured by comparing reported seizure frequency at baseline and at 3-month intervals thereafter. Adverse events and reasons for terminating the diet were tabulated. Of 71 patients who underwent KGD initiation, 24 were concomitantly using VPA at the time of initiation. The most serious adverse events were two cases of acute pancreatitis (2.8%), both of which occurred in patients not taking VPA. The most common complications in both groups were acidosis (39.4%), nausea and vomiting (23.9%), hypertriglyceridemia (21.1%), lethargy (18.3%), and behavioral changes and irritability (15.5%). No significant difference in adverse-event profiles was found between the VPA group and the non-VPA group. At 1 year, 32 patients remained on the diet, including 11 in the VPA group. Efficacy was nearly identical in these two groups. KGD and VPA combination therapy is relatively safe and effective in refractory pediatric epilepsy. Adverse-event profiles of patients on KGD and VPA cotherapy are similar to those of patients on the KGD without VPA. In considering possible treatment options for intractable seizures, cotherapy with these two modalities should not be excluded for safety or tolerability concerns. In some patients, this combination may provide optimal seizure control.

Effect of Combined Ketogenic Diet and Valproate Treatment for Intractable Seizures

The safety and tolerability of ketogenic diet (KGD) and valproate (VPA) cotherapy in the treatment of intractable seizures were evaluated retrospectively at the Massachusetts General Hospital, Boston.

Anticonvulsant Therapy in Children: An Update

Over the years, extensive research has led to the development of a new generation of anticonvulsant medications for the treatment of patients with intractable seizure disorders. Currently three new drugs have been approved in the United States since 1993, and many others have entered into the later stages of development. The purpose of this article is to discuss the pharmacology, pharmacokinetics, drug interactions, clinical use, adverse effects, and dosage and administration of felbamate, gabapentin, lamotrigine, and vigabatrin. Felbamate is indicated in children as adjunctive therapy in the treatment of partial and generalized seizures secondary to Lennox-Gastaut syndrome. Because of life-threatening adverse effects, including aplastic anemia and hepatotoxicity, felbamate is reserved for use only when the benefits of treatment outweigh the risks of toxicity. Presently, gabapentin is indicated as adjunctive treatment of partial seizures with or without generalization in patients older than 12 years of age. To date gabapentin has not been studied in patients younger than age 12 years. Even though lamotrigine is not approved by the Food and Drug Administration (FDA) for pediatric use, preliminary clinical trials show promising results in the treatment of partial and absence seizures as well as Lennox-Gastaut syndrome. Many studies have evaluated the use of vigabatrin for the treatment of intractable seizures. Seizure types most effectively treated include partial seizures, Lennox-Gastaut syndrome, and possibly infantile spasms. Lamotrigine and vigabatrin should be used with caution in patients with myoclonic seizures because an increase in seizure frequency may occur. Copyright © 1996 by W.B. Saunders Company

Epileptic EEG Discharges During Burst Suppression*

Barbiturate anaesthesia is used in the treatment of status epilepticus and severe epilepsy of children. EEG is then used as a measure of the depth of anaesthesia, burst suppression being an easily identified EEG pattern. In this case report we describe epileptiform discharges during EEG suppression in two children undergoing barbiturate anaesthesia for treatment of intractable seizures. One of them had focal, rhythmic discharges of negative spikes on the positive suppression level. Bursts were readily produced by visual stimuli with flashes of red light but this did not increase the frequency of focal spike discharges after bursts. The other patient had generalised, high amplitude spike-wave complexes, which were easy to distinguish from the bursts. We emphasise that it is important to make a distinction between electrocerebral silence, or isoelectric EEG as it was previously called, from EEG suppression. It is also important to distinguish epileptiform discharges from bursts, if the intention is to keep the anaesthesia at EEG burst suppression level.

Surgical Management of Intractable Seizure Disorders

The surgical treatment of intractable seizures is still regarded by some as an experimental procedure with questionable rationale. However, in centers where care is taken in the selection process and facilities are available for adequate diagnosis, the procedure has been successful in complete alleviation of seizures in some cases. The decision about surgical interventions for epilepsy is never an easy one. Potential surgical candidates are evaluated by a team of specialists and undergo numerous diagnostic tests and examinations before a decision for surgery is made. It is essential for the neuroscience nurse to have knowledge of the underlying etiology of seizures, diagnostic testing and surgical procedures in order to effectively care for the seizure patient pre- and postoperatively. With this knowledge, nursing management becomes a vital part in the total treatment of the seizure patient.

Vagal Stimulation Reduces the Severity of Maximal Electroshock Seizures in Intact Rats: Use of a Cuff Electrode for Stimulating and Recording

J. Zabara showed that repetitive vagal stimulation (VS) prevents or ameliorates convulsive seizures in dogs. We have studied the effects of VS on maximal electroshock seizures (MES) in intact rats: (1) A 5 wire cuff electrode was developed for stimulating and recording from the vagus. Compound action potentials (AP) were recorded and strength-duration curves obtained for A and C fibers. There is a monotonic relationship with a negative slope between heart rate (HR) and AP amplitude. C fibers remain excitable for 25 days after cuff implant. (2) The anticonvulsant efficacy of VS is directly related to the fraction of vagal C fibers stimulated and the frequency of stimulation. (3) The anticonvulsant efficacy of VS has been established using two rat models of human epilepsy. VS abolishes the extensor component of the tonic phase of a MES and shortens or prevents tonic seizures induced by pentylenetetrazol (PTZ). (4) VS appears to act via release of large quantities of the inhibitory mediators GABA and glycine throughout large volumes of the brain. (5) It is rational to test VS in man as a treatment for intractable seizures.

Treatment of intractable seizures with intravenous immunoglobulins: Stanley A. Schwartz, Kevin E. Gordon, Michael V. Johnston, and Gary W. Goldstein, The University of Michigan, Ann Arbor, Michigan

Treatment of intractable seizures with intravenous immunoglobulins: Stanley A. Schwartz, Kevin E. Gordon, Michael V. Johnston, and Gary W. Goldstein, The University of Michigan, Ann Arbor, Michigan

High-dose monotherapy in treatment of intractable seizures.

We evaluated the therapeutic efficacy and toxicity of high-dose monotherapy, using carbamazepine or phenytoin, in patients with previously uncontrolled seizures. Treatment with a single drug was equal to or better than polypharmacy, but only a few patients became free of seizures. Toxicity was mild and associated with higher total plasma levels after polypharmacy. Free fractions ranged from 0.14 to 0.30 for carbamazepine and from 0.60 to 0.13 for phenytoin. Toxicity was associated with free phenytoin levels above 3 micrograms/ml; there was no clear relationship between free carbamazepine level and toxicity.