Showing papers in "Epilepsy Currents in 2009"

New Developments in Antiepileptic Drug Resistance: An Integrative View:

Abstract: Current theories on drug resistance in epilepsy include the drug transporter hypothesis, the drug target hypothesis, and a novel approach called the inherent severity model of epilepsy, which posits that the severity of the disease determines its relative response to medication. Valuable as each of these hypotheses is, none is currently a stand-alone theory that is able to convincingly explain drug resistance in human epilepsy. As a consequence, it may be of interest to update and integrate the various hypotheses of drug resistance and to explore possible links to the severity of epilepsy. The observation that a high frequency of seizures prior to onset of treatment is a prognostic signal of increased severity and future drug failure suggests that common neurobiological factors may underlie both disease severity and pharmacoresistance. Such a link has been proposed for depression; however, the evidence for a direct mechanistic link, genetic or otherwise, between drug response and disease severity of human epilepsy is still elusive. Although emerging data from experimental studies suggest that alterations in GABAA receptors may present one example of a mechanistic link, clearly more work is needed to explore whether common neurobiological factors may underlie both epilepsy severity and drug failure.

Origins of Epilepsy in Fragile X Syndrome

Abstract: Fragile X syndrome is the leading heritable form of cognitive impairment and the leading known monogenic disorder associated with autism. Roughly one-quarter of children with this disorder have seizures, most of which are relatively benign and are resolved beyond childhood. Because of the prevalence of fragile X syndrome, numerous animal models have been developed and electrophysiological studies have taken place to investigate its pathogenesis. The investigations have yielded a wealth of information regarding the synaptic dysfunction that underlies the hyperexcitability and epileptiform features associated with this disorder.

Cardiac Effects of Seizures

Abstract: Seizures frequently affect the heart rate and rhythm. In most cases, seizure-related cardiac changes are transient and do not appear to cause clinically significant abnormalities for the patient. Great interest in this area of research has been generated because of a possible connection with sudden unexpected death in epilepsy (SUDEP). While there are clear, but rare complications from seizure-related cardiac arrhythmias, such as ictal asystole that causes syncope, the overall risk of seizures on cardiac status and any potential connection between seizures and SUDEP still remain uncertain.

Driving Issues in Epilepsy: Past, Present, and Future

Abstract: Driving restrictions for people with seizure disorders are intended to ensure the public's safety, but driving is of such great importance in the United States that the imposed restrictions also may unduly harm the welfare of these individuals. Because driving restrictions historically have been based more on expert opinion than sound scientific evidence, the appropriateness and application of standards for licensing drivers with seizures continue to raise questions and concerns, as does the role physicians should have in the process. Driving is an important and complex practical concern for physicians who care for people with epilepsy or who may serve as consultants to regulatory authorities, requiring them to be well informed about the relevant issues to properly manage their patients and to protect themselves against lawsuits.

Infantile Spasms: A Critical Review of Emerging Animal Models

Abstract: Infantile spasms is a developmental epilepsy syndrome with unique clinical and EEG features, a specific pattern of pharmacological responsiveness, and poor outcome in terms of cognition and epilepsy. Despite the devastating nature of infantile spasms, little is known about its pathogenesis. Until recently, there has been no animal model available to investigate the pathophysiology of the syndrome or to generate and test novel therapies. Now, several promising animal models have emerged, spanning the etiological spectrum from genetic causes (e.g., Down syndrome or Aristaless-related homeobox [ARX] mutation) to acquired causes (e.g., endogenous and exogenous toxins or stress hormones with convulsant activity or blockade of neural activity). These new models are discussed in this review, with emphasis on the insights each can provide for understanding, treating, and preventing infantile spasms.

Extended‐Release Formulations of Antiepileptic Drugs: Rationale and Comparative Value

Abstract: Extended-release products are designed to prolong the absorption of drugs with short half-lives, thereby allowing longer dosing intervals while minimizing fluctuations in serum drug levels. The relationship between serum drug concentration and clinical effects of antiepileptic drugs (AEDs) can be complex and reducing fluctuations in serum drug levels is not equally advantageous for all AEDs. Extended-release formulations have been shown to be particularly valuable for carbamazepine, whereas for other AEDs advantages, other than prolongation of the dosing interval, have not been clearly demonstrated. Differences in bioavailability may exist between extended-release and immediate-release formulations and among different brands of extended-release products. Therefore, when switching from one formulation to another, careful monitoring of clinical response and attention to the need for dose adjustment are warranted.

Clinical perspectives on lacosamide.

Abstract: Despite the advent of new antiepileptic drugs (AEDs) over the past 15 years, the treatment of uncontrolled partial-onset seizures remains a dilemma for clinicians. The most recent AEDs offer new mechanisms of action and more favorable safety profiles than the first generation of AEDs. Lacosamide (LCM) is the latest AED awaiting approval by the FDA for adjunctive use in partial-onset seizures. It differs from all other approved AEDs in that it has two novel mechanisms of action and favorable pharmacokinetic and safety profiles. The purposes of this article are to present the significant parameters for its use in clinical practice, by summarizing the preliminary results of phase II and III clinical trials, and to compare its efficacy data with other second-generation AEDs.

Molecular Pathology of Genetic Epilepsies Associated with GABAA Receptor Subunit Mutations

Abstract: Mutations in ligand-gated ion channel genes associated with idiopathic generalized epilepsies have been reported in excitatory acetylcholine receptor α4 and β2 subunit genes linked to autosomal dominant nocturnal frontal lobe epilepsy and in inhibitory GABAA receptor α1, β3, γ2, and δ subunit genes associated with childhood absence epilepsy, juvenile myoclonic epilepsy, pure febrile seizures, generalized epilepsy with febrile seizures plus, and generalized epilepsy with tonic–clonic seizures. Recent studies suggest that these mutations alter receptor function or biogenesis, including impaired receptor subunit messenger RNA stability, receptor subunit protein folding and stability, receptor assembly, and receptor trafficking.

Suicidality and Epilepsy: A Complex Relationship That Remains Misunderstood and Underestimated

Abstract: Suicidality in people with epilepsy is significantly more frequent than in the general population. The relation between suicidality and epilepsy is multifactorial and bidirectional. The purpose of this review is to highlight the most important psychiatric, pharmacologic, and epilepsy-related variables linked to the increased suicidal risk among these patients.

Pilocarpine-induced seizures revisited: what does the model mimic?

Abstract: Antagonism of Peripheral Inflammation Reduces the Severity of Status Epilepticus. Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, Batra A, Carlton E, Najm I, Granata T, Janigro D. Neurobio...

Epilepsy and the plastic mind.

Abstract: Seizures are linked to many neuroplastic changes within hippocampal circuits, including alterations in neurogenesis and dendritic growth in the dentate gyrus. How do brief seizures cause the long-term plastic changes in the hippocampus that are associated with recurrent epilepsy? Recent experiments by Ma and colleagues provide insights. They demonstrate an epigenetic mechanism for long-lasting neuroplastic changes that is both activity-dependent and brain region-specific. Focusing on Gadd45b, a DNA excision repair gene, they show it is up-regulated after electroconvulsive seizures or glutamate dependent activation of NMDA receptors. Gadd45b demethylates DNA regulatory elements in promoters of genes encoding fibroblast growth factor 1 and brain-derived neurotrophic factor, increasing the expression of these genes within granule neurons of the dentate gyrus. These changes in growth factor expression promote neurogenesis in the subgranular zone and dendritic growth in the granule cell layer of the dentate gyrus. Further regional and temporal differences in the proliferation of astrocytes and microglia after seizures were demonstrated by two additional studies. Together this work highlights how activity-dependent epigenetic modifications to DNA can alter gene expression with remarkable regional and cell type specificity.

A pregnant pause to consider teratogenicity of topiramate.

Abstract: OBJECTIVES: Topiramate (Topamax®) is licensed to be used, either in monotherapy or as adjunctive treatment, for generalized tonic-clonic seizures or partial seizures with or without secondary generalization and for prevention of migraine. The safety of topiramate in human pregnancy is largely unknown. Here we report on our experience of pregnancies exposed to topiramate. METHODS: This study is part of a prospective, observational registration and follow-up study. Suitable cases are women with epilepsy who become pregnant while taking topiramate either singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate. Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, and gestational age at delivery. RESULTS: Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth; 16 had an MCM (9.0%; 95% CI 5.6–14.1%). Three MCMs were observed in 70 monotherapy exposures (4.8%; 95% CI 1.7–13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7–18.2%). Four of the MCMs were oral clefts (2.2%; 95% CI 0.9–5.6%). Four cases of hypospadias were reported (5.1%; 95% CI 0.2–10.1%) among 78 known live male births, of which two were classified as major malformations. CONCLUSIONS: The number of outcomes of human pregnancies exposed to topiramate is low, but the MCM rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

Evaluating Risks for Vigabatrin Treatment

Abstract: Approximately 30 to 40 percent of adults with epilepsy treated chronically with vigabatrin develop concentric visual field constrictions. These deficits are generally mild and asymptomatic, but are usually irreversible, so risks and benefits for vigabatrin treatment must be carefully reviewed. Infantile spasms, a particularly severe form of epilepsy, may respond to vigabatrin; however, some infants treated with the drug develop MRI evidence of possible intramyelinic edema in subcortical structures. This article reviews the benefits of vigabatrin treatment, the risks it poses to the retina and the developing brain, as well as possible subgroups of adults and infants with severe epilepsy for whom treatment may, nevertheless, be warranted.

Should Levetiracetam Replace Phenytoin for Seizure Prophylaxis after Neurosurgery

Abstract: Efficacy and Tolerability of Levetiracetam versus Phenytoin after Supratentorial Neurosurgery. Milligan TA, Hurwitz S, Bromfield EB. Neurology 2008;71(9):665–669. BACKGROUND: Antiepileptic drugs are routinely given after craniotomy. Though phenytoin (PHT) is still the most commonly used agent, levetiracetam (LEV) is increasingly administered for this purpose. This retrospective study compared the use of LEV and PHT as monotherapy prophylaxis following supratentorial neurosurgery. METHODS: Patients receiving LEV monotherapy after supratentorial craniotomy were reviewed and compared to a control group of patients receiving PHT monotherapy. RESULTS: One of 105 patients taking LEV and 9/210 patients taking PHT had seizures within 7 days of surgery (p = 0.17). Adverse drug reactions requiring change in therapy during hospitalization occurred in 1/105 patients taking LEV and 38/210 patients taking PHT (p < 0.001). Among patients followed for at least 12 months, 11/42 (26%) treated with LEV vs 42/117 (36%) treat...

Epileptogenesis: A New Twist on the Balance of Excitation and Inhibition

Abstract: Rapid Plasticity at Inhibitory and Excitatory Synapses in the Hippocampus Induced by Ictal Epileptiform Discharges. Lopantsev V, Both M, Draguhn A. Eur J Neurosci 2009;29(6):1153–1164. Epileptic se...

Lacosamide: What Can Be Expected from the Next New Antiepileptic Drug?

Abstract: Adjunctive Lacosamide for Partial-Onset Seizures: Efficacy and Safety Results from a Randomized Controlled Trial. Halasz P, Kalviainen R, Mazurkiewicz-Beldzinska M, Rosenow F, Doty P, Hebert D, Sul...

Leukocyte–Endothelial Adhesion Mechanisms in Epilepsy: Cheers and Jeers

Abstract: The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood1,2,3. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins 41 and L2. Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.

Pharmacokinetics of Phenytoin: Reminders and Discoveries

Abstract: BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients’ sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2–3 weeks.

Adopting an orphan drug: rufinamide for Lennox-Gastaut syndrome.

Abstract: BACKGROUND: Lennox–Gastaut syndrome is a catastrophic pediatric epilepsy syndrome characterized by multiple types of treatment-resistant seizures and high rates of seizure-related injury. Current available treatments are inadequate, leaving patients with few treatment options and opportunities. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of the antiepileptic drug rufinamide in patients with Lennox–Gastaut syndrome. Eligible patients between 4 and 30 years of age had multiple types of seizures (including tonic–atonic and atypical absence seizures) with a minimum of 90 seizures in the month before baseline and a recent history of a slow spike-and-wave pattern on EEG. RESULTS: After a 28-day baseline period, 139 eligible patients were randomized; 138 patients received either rufinamide (n = 74) or placebo (n = 64) in addition to their other antiepileptic drugs. The median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7% vs 11.7%, p= 0.0015). There was a difference (p < 0.0001) in tonic–atonic (“drop attack”) seizure frequency with rufinamide (42.5% median percentage reduction) vs placebo (1.4% increase). The rufinamide group had a greater improvement in seizure severity (p= 0.0041) and a higher 50% responder rate compared with placebo for total seizures (p= 0.0045) and tonic–atonic seizures (p= 0.002). The common adverse events (reported by 10% of patients receiving rufinamide) were somnolence (24.3% with rufinamide vs 12.5% with placebo) and vomiting (21.6% vs 6.3%). CONCLUSIONS: Rufinamide was an effective and well-tolerated treatment for seizures associated with Lennox–Gastaut syndrome.

First Do No Harm: Safety in the Epilepsy Monitoring Unit

Abstract: Safety of Long-Term Video-Electroencephalographic Monitoring for Evaluation of Epilepsy. Noe KH, Drazkowski JF. Mayo Clin Proc 2009;84(6):495–500. OBJECTIVE: To determine the rate of medical compli...

Rat kainic acid model provides unexpected insight into an emerging epilepsy syndrome in sea lions.

Abstract: Novel Symptomatology and Changing Epidemiology of Domoic Acid Toxicosis in California Sea Lions (Zalophus californianus): An Increasing Risk to Marine Mammal Health. Goldstein T, Mazet JAK, Zabka TS, Langlois G, Colegrove KM, Silver M, Bargu S, Van Dolah F, Leighfield T, Conrad PA, Barakos J, Williams DC, Dennison S, Haulena M, Gulland FMD. Proc Biol Sci 2008;275(1632):267–276. Harmful algal blooms are increasing worldwide, including those of Pseudo-nitzschia spp. producing domoic acid off the California coast. This neurotoxin was first shown to cause mortality of marine mammals in 1998. A decade of monitoring California sea lion (Zalophus californianus) health since then has indicated that changes in the symptomatology and epidemiology of domoic acid toxicosis in this species are associated with the increase in toxigenic blooms. Two separate clinical syndromes now exist: acute domoic acid toxicosis as has been previously documented, and a second novel neurological syndrome characterized by epilepsy descr...

Does a history of postictal psychosis predict a poor postsurgical seizure outcome

Abstract: Postictal Psychosis in Partial Epilepsy: A Case-Control Study. Alper K, Kuzniecky R, Carlson C, Barr WB, Vorkas CK, Patel JG, Carrelli AL, Starner K, Flom PL, Devinsky O. Ann Neurol 2008;63(5):602–610. OBJECTIVE: Divergent findings among prior studies on correlates of risk for postictal psychosis (PIP) suggest the value of a controlled study involving a relatively large number of patients. METHODS: The study population consisted of a consecutive series of 59 patients with partial epilepsy and a history of PIP, and 94 control patients with partial epilepsy and no history of PIP evaluated as inpatients with video-electroencephalography. The groups did not differ significantly regarding demographic features. Exact tests yielded a subset of variables and a tentative interpretation that were evaluated further utilizing principal components analysis and logistic regression. RESULTS: PIP was associated with extratemporal versus temporal (p = 0.036) or undetermined (p = 0.001) localization of seizure onset, bilat...

Seizures in patients undergoing resection of low-grade gliomas.

Abstract: OBJECT: Seizures play an important role in the clinical presentation and postoperative quality of life of patients who undergo surgical resection of low-grade gliomas (LGGs). The aim of this study was to identify factors that influenced perioperative seizure characteristics and postoperative seizure control. METHODS: The authors performed a retrospective chart review of all cases involving adult patients who underwent initial surgery for LGGs at the University of California, San Francisco between 1997 and 2003. RESULTS: Three hundred and thirty-two cases were included for analysis; 269 (81%) of the 332 patients presented with ≥1 seizures (generalized alone, 33%; complex partial alone, 16%; simple partial alone, 22%; and combination, 29%). Cortical location and oligodendroglioma and oligoastrocytoma subtypes were significantly more likely to be associated with seizures compared with deeper midline locations and astrocytoma, respectively ( p= 0.017 and 0.001, respectively; multivariate analysis). Of the 269 patients with seizures, 132 (49%) had pharmacoresistant seizures before surgery. In these patients, seizures were more likely to be simple partial and to involve the temporal lobe, and the period from seizure onset to surgery was likely to have been longer ( p= 0.0005, 0.0089, and 0.006, respectively; multivariate analysis). For the cohort of patients that presented with seizures, 12-month outcome after surgery (Engel class) was as follows: seizure free (I), 67%; rare seizures (II), 17%; meaningful seizure improvement (III), 8%; and no improvement or worsening (IV), 9%. Poor seizure control was more common in patients with longer seizure history ( p 90% of these patients are seizure free or have meaningful improvement. A shorter history of seizures and gross-total resection appear to be associated with a favorable prognosis for seizure control.

Low Fertility in Men with Epilepsy: Unhappy, Uninterested, Unable:

Abstract: OBJECTIVE: To ascertain the effects on sexual function of men with epilepsy (MWE) of testosterone levels and indices of anxiety and depression. METHODS: Sixty MWE taking one antiepileptic drug only (AED), with no comedication, were compared with 60 control men. Total testosterone (TT), free testosterone (FT), bioactive testosterone (BAT), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and sex hormone–binding globulin (SHBG) were measured. Each man also completed validated questionnaires exploring sexual desire (Sexual Desire Inventory [SDI]), sexual response (Sexual Response Inventory [SRI]), erectile function (Sexual Self-Efficacy Scale [SSES]), and anxiety and depression (Hospital Anxiety and Depression Scale). RESULTS: MWE reported lower levels of sexual desire and lower erectile function compared with controls. They had significantly higher levels of anxiety, depression, and psychological distress. MWE had significantly higher SHBG levels and significantly lower DHEAS. There were no significant differences between the groups’ TT, FT, or BAT levels. BAT levels were significantly lower in men taking enzyme-inducing AEDs than in those taking non–enzyme-inducing AEDs. Visual inspection of TT and BAT levels showed that the majority of MWE and controls had TT and BAT levels above the “androgen threshold” levels of 12 nmol/L TT or 3.8 nmol/L BAT considered necessary for normal sexual function. There was a significant correlation (Spearman rank and simple linear regression) between sexual function and indices of anxiety and depression. There was no significant relationship between SDI and SSES and TT, FT, or BAT (Spearman rank correlation). CONCLUSIONS: Concentrating on hormone levels alone as an explanation of sexual dysfunction in epilepsy represents an overly simplistic approach to the problem. Future studies should include measures of quality of life, anxiety, and depression.

The window of epileptogenesis: looking beyond the latent period.

Abstract: Acquired epilepsy (i.e., after an insult to the brain) is often considered to be a progressive disorder, and the nature of this hypothetical progression remains controversial. Antiepileptic drug treatment necessarily confounds analyses of progressive changes in human patients with acquired epilepsy. Here, we describe experiments testing the hypothesis that development of acquired epilepsy begins as a continuous process of increased seizure frequency (i.e., proportional to probability of a spontaneous seizure) that ultimately plateaus. Using nearly continuous surface cortical and bilateral hippocampal recordings with radiotelemetry and semiautomated seizure detection, the frequency of electrographically recorded seizures (both convulsive and nonconvulsive) was analyzed quantitatively for 100 d after kainate-induced status epilepticus in adult rats. The frequency of spontaneous recurrent seizures was not a step function of time (as implied by the “latent period”); rather, seizure frequency increased as a sigmoid function of time. The distribution of interseizure intervals was nonrandom, suggesting that seizure clusters (i.e., short interseizure intervals) obscured the early stages of progression, and may have contributed to the increase in seizure frequency. These data suggest that (1) the latent period is the first of many long interseizure intervals and a poor measure of the time frame of epileptogenesis, (2) epileptogenesis is a continuous process that extends much beyond the first spontaneous recurrent seizure, (3) uneven seizure clustering contributes to the variability in occurrence of epileptic seizures, and (4) the window for antiepileptogenic therapies aimed at suppressing acquired epilepsy probably extends well past the first clinical seizure.

Microseizures in human neocortex: a role for ultra-small seizures?

Abstract: SUMMARY: The authors report the use of dense two-dimensional microelectrode array recordings to characterize fine resolution electrocortical activity (“μEEG”) in epileptogenic human cortex. A 16-mm2 96 microelectrode array with 400-μm interelectrode spacing was implanted in five patients undergoing invasive EEG monitoring for medically refractory epilepsy. High spatial resolution data from the array were analyzed in conjunction with simultaneously acquired data from standard intracranial electrode grids and strips. μEEG recorded from within the epileptogenic zone demonstrates discharges resembling both interictal epileptiform activity (“microdischarges”) and electrographic seizures (“microseizures”) but confined to cortical regions as small as 200 μm2. In two patients, this activity appeared to be involved in the initiation or propagation of electrographic seizures. The authors hypothesize that microdischarges and microseizures are generated by small cortical domains that form the substrate of epileptogenic cortex and play important roles in seizure initiation and propagation.

Thalamic reticular neurons are unexcited by new stargazer seizure mechanism.

Abstract: Stargazer mice are characterized by ataxia and seizures, which resemble the human disorder absence epilepsy. Stargazin, the protein mutated in stargazer mice, promotes the expression and function of neuronal AMPA receptors (AMPARs). However, it is unclear how decreased expression of excitatory AMPARs generates stargazer seizures, given that seizures often result from increased neuronal excitability. Additionally, although stargazer ataxia has been attributed to loss of AMPARs from cerebellar granule cells, other cerebellar neurons have not been examined. To examine the role of AMPAR dysfunction in these behavioral phenotypes, electrophysiological recordings were used to probe AMPAR regulation in relevant brain regions. We found that both cerebellar Purkinje cells and inhibitory thalamic reticular nucleus neurons have strongly reduced synaptic AMPAR function in stargazer mice. Together, our data suggest that impaired AMPAR regulation in multiple neuron populations may contribute to the behavioral phenotypes of absence seizures and ataxia seen in stargazer mice and imply that an understanding of human genetic disorders will require knowledge of both the genes that are mutated as well as their precise cellular expression pattern.

Screening Bone Mineral Density in Epilepsy: A Call to Action, But What Action?

Abstract: Value of Routine Screening for Bone Demineralization in an Urban Population of Patients with Epilepsy. Lado F, Spiegel R, Masur JH, Boro A and Haut SR. Epilepsy Research 2008;78(2–3):155–160.Backgr...

To Comply with AED Therapy … What Patients Are Not Told!

Abstract: OBJECTIVES: The primary objective was to investigate whether nonadherence to antiepileptic drugs (AEDs) is associated with increased mortality and the secondary objective to examine whether nonadherence increases the risk of serious clinical events, including emergency department (ED) visits, hospitalizations, motor vehicle accident (MVA) injuries, fractures, and head injuries. METHODS: A retrospective open-cohort design was employed using Medicaid claims data from Florida, Iowa, and New Jersey from January 1997 through June 2006. Patients aged 18 years with 1 diagnosis of epilepsy by a neurologist and 2 AED pharmacy dispensings were selected. Medication possession ratio (MPR) was used to evaluate AED adherence on a quarterly basis with MPR 0.80 considered adherent and <0.80 nonadherent. The association of nonadherence with mortality was assessed using a time-varying Cox regression model adjusting for demographic and clinical confounders. Incidence rates for serious clinical events were compared between adherent and nonadherent quarters using incidence rate ratios (IRRs) with 95% CIs calculated based on the Poisson distribution. RESULTS: The 33,658 study patients contributed 388,564 AED-treated quarters (26% nonadherent). Nonadherence was associated with an over threefold increased risk of mortality compared to adherence (hazard ratio = 3.32, 95% CI = 3.11–3.54) after multivariate adjustments. Time periods of nonadherence were also associated with a significantly higher incidence of ED visits (IRR = 1.50, 95% CI = 1.49–1.52), hospital admissions (IRR = 1.86, 95% CI = 1.84–1.88), MVA injuries (IRR = 2.08, 95% CI = 1.81–2.39), and fractures (IRR = 1.21, 95% CI = 1.18–1.23) than periods of adherence. CONCLUSION: These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.

Not all first seizures are created equally.

Abstract: Is a First Acute Symptomatic Seizure Epilepsy? Mortality and Risk for Recurrent Seizure. Hesdorffer DC, Benn EK, Cascino GD, Hauser WA. Epilepsia 2009;50(5):1102–1108. PURPOSE: To compare mortality...