Epilepsy therapy research

Lamotrigine extended-release as adjunctive therapy for partial seizures. Related Articles

Lamotrigine extended-release as adjunctive therapy for partial seizures.

Neurology. 2007 Oct 16;69(16):1610-8

Recent epilepsy therapy research Authors: Naritoku DK, Warnock CR, Messenheimer JA, Borgohain R, Evers S, Guekht AB, Karlov VA, Lee BI, Pohl LR

OBJECTIVE: To evaluate the efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for partial seizures in epilepsy. METHODS: Patients more than 12 years old diagnosed with epilepsy with partial seizures and taking one to two baseline antiepileptic drugs were randomized to adjunctive once-daily lamotrigine XR or placebo in a double-blind, parallel-group trial. The study comprised a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase during which doses of study medication and concomitant antiepileptic drugs were maintained. RESULTS: Of the 243 randomized patients, 239 (118 lamotrigine XR, 121 placebo) entered the escalation phase and received study medication. Lamotrigine XR was more effective than placebo with respect to median percent reduction from baseline in weekly partial seizure frequency (primary endpoint-entire 19-week treatment phase: 46.1% vs 24.2%, p = 0.0004 via Wilcoxon test; escalation phase: 28.0% vs 16.3%, p = 0.028; maintenance phase: 58.0% vs 26.7%, p < 0.0001). The percentage of patients with >or=50% reduction in partial seizure frequency (42.2% vs 24.2%, p = 0.0037) and time to >or=50% reduction in partial seizure frequency (p = 0.0007) also favored lamotrigine XR over placebo. A similar pattern of results was observed for secondarily generalized seizures. The most common adverse events were headache (lamotrigine XR 17%, placebo 15%) and dizziness (lamotrigine XR 18%, placebo 5%). Differences between lamotrigine XR and placebo on health outcomes measures were not significant. CONCLUSIONS: Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation.

Recent epilepsy therapy research PMID: 17938371 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]CNS lupus: a study of 41 patients. Related Articles

CNS lupus: a study of 41 patients.

Neurology. 2007 Aug 14;69(7):644-54

Recent epilepsy therapy research Authors: Joseph FG, Lammie GA, Scolding NJ

BACKGROUND: CNS lupus is a serious but potentially treatable illness, which, though long recognized, may still present very difficult diagnostic challenges. We believed that further detailed study of patients with neuropsychiatric lupus would yield clinical information of practical value in improving both recognition and management of this difficult illness. METHODS: A retrospective case analysis of 41 patients with CNS systemic lupus erythematosus (CNS-SLE) was performed largely in the southwest of England and South Wales, covering the period 1990 to 2002. RESULTS: We found that primary neurologic presentation of SLE was not rare (10/41 patients), and there was an unexpected emergence of movement disorders (particularly parkinsonism and myoclonus) early in the disease course (4/10 patients). These showed a good response to immunosuppressants, but not to standard dopaminergic therapy. Typically, the erythrocyte sedimentation rate (ESR) or plasma viscosity was elevated during neurologic episodes while C-reactive protein levels were normal, and lupus-related serum antibody tests usually supportive. But, significantly, neither a normal ESR nor negative serology excluded CNS lupus. MR brain imaging is more commonly abnormal in patients with focal neurologic deficits and normal or shows wholly nonspecific change with more diffuse manifestations (cognitive decline, epilepsy). Abnormal CSF correlated significantly with poorer outcome. At the end of the period of study, 54% had no more than minor functional disability, the remainder having a severe or fatal outcome. CONCLUSIONS: Our observations, particularly the emergence of non-choreic movement disorders, the blood, serum, and imaging findings, and the prognostic importance of CSF abnormalities, should help improve both the recognition of CNS systemic lupus erythematosus, perhaps particularly in elderly individuals, and its management.

Recent epilepsy therapy research PMID: 17698785 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Response to carbamazepine in children with newly diagnosed partial onset epilepsy. Related Articles

Response to carbamazepine in children with newly diagnosed partial onset epilepsy.

Neurology. 2007 Aug 7;69(6):596-9

Recent epilepsy therapy research Authors: Holland KD, Glauser TA

OBJECTIVE: The purpose of this work is to characterize the effectiveness and therapeutic doses of carbamazepine (CBZ) in children with localization-related epilepsy. METHODS: Treatment to initial CBZ monotherapy and doses associated with 1-year seizure freedom were examined in 100 consecutive children with partial epilepsy. RESULTS: Of the 100 patients studied, 55 became seizure-free on CBZ monotherapy, 10 did not tolerate CBZ within the first 3 months of therapy owing to either hypersensitivity or intolerable side effects, and 35 continued to have seizures. In children age <12, over 95% responded at doses below 17.5 mg/kg/day; in children age >12, over 95% responded at below 15 mg/kg/day. CONCLUSIONS: We suggest that other antiepileptic treatments be considered when seizures continue in children taking carbamazepine doses between 15 and 17.5 mg/kg/day even if side effects are absent.

Recent epilepsy therapy research PMID: 17679679 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Related Articles

A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.

Neurology. 2007 Sep 25;69(13):1342-9

Recent epilepsy therapy research Authors: Shimomura K, Hörster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, Wolf NI, Ashcroft F, Ebinger F

OBJECTIVES: Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome. METHODS: We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant K(ATP) channels heterologously expressed in Xenopus oocytes. RESULTS: We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell K(ATP) currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities. CONCLUSIONS: We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.

Recent epilepsy therapy research PMID: 17652641 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Risk factors for development of subclinical hypothyroidism during valproic acid therapy. Related Articles

Risk factors for development of subclinical hypothyroidism during valproic acid therapy.

J Pediatr. 2007 Aug;151(2):178-81

Recent epilepsy therapy research Authors: Mikati MA, Tarabay H, Khalil A, Rahi AC, El Banna D, Najjar S

OBJECTIVE: To identify risk factors for subclinical hypothyroidism (SCH) (thyroid-stimulating hormone levels >5 mIU/mL) in patients receiving valproate (VPA) therapy. STUDY DESIGN: During a period of 2 years, consecutive patients with epilepsy receiving VPA and a control group of patients with diseases other than epilepsy attending a tertiary care neurology clinic were screened for SCH. The 2 groups were compared. The association between SCH and specific risk factors was investigated with bivariate and multivariate analyses. RESULTS: Thirty-six of 143 patients receiving VPA (25.2%, mean age +/- SD: 8.5 +/- 6.6 years) and none of the 35 control subjects had SCH (P < .001). Predictors of SCH were younger age (OR: 1.15, cutoff age 3.9 years); duration of treatment between 6 and 24 months versus <6 months (OR: 2.98) and >24 months (OR: 2.66); VPA polytherapy with enzyme-inducing agents (OR: 6.08), or polytherapy with non-enzyme-inducing agents (OR: 3.34) compared with VPA monotherapy. Most (88.2%) patients with duration of therapy >2 years were older than 3.9 years. CONCLUSION: Risk factors for SCH were young age, co-medication with antiepileptic drugs, and duration of therapy between 6 and 24 months. Screening patients with these risk factors may be warranted.

Recent epilepsy therapy research PMID: 17643774 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy. Related Articles

An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy.

Neurology. 2007 Jul 17;69(3):250-4

Recent epilepsy therapy research Authors: Striano P, Coppola A, Pezzella M, Ciampa C, Specchio N, Ragona F, Mancardi MM, Gennaro E, Beccaria F, Capovilla G, Rasmini P, Besana D, Coppola GG, Elia M, Granata T, Vecchi M, Vigevano F, Viri M, Gaggero R, Striano S, Zara F

OBJECTIVE: To conduct an open-label, add-on trial on safety and efficacy of levetiracetam in severe myoclonic epilepsy of infancy (SMEI). Patients and METHODS: SMEI patients were recruited from different centers according to the following criteria: age > or =3 years; at least four tonic-clonic seizures/month during the last 8 weeks; previous use of at least two drugs. Levetiracetam was orally administrated at starting dose of approximately 10 mg/kg/day up to 50 to 60 mg/kg/day in two doses. Treatment period included a 5- to 6-week up-titration phase and a 12-week evaluation phase. Efficacy variables were responder rate by seizure type and reduction of the mean number per week of each seizure type. Analysis was performed using Fisher exact and Wilcoxon tests. RESULTS: Twenty-eight patients (mean age: 9.4 +/- 5.6 years) entered the study. Sixteen (57.1%) showed SCN1A mutations. Mean number of concomitant drugs was 2.5. Mean levetiracetam dose achieved was 2,016 mg/day. Twenty-three (82.1%) completed the trial. Responders were 64.2% for tonic-clonic, 60% for myoclonic, 60% for focal, and 44.4% for absence seizures. Number per week of tonic-clonic (median: 3 vs 1; p = 0.0001), myoclonic (median: 21 vs 3; p = 0.002), and focal seizures (median: 7.5 vs 3; p = 0.031) was significantly decreased compared to baseline. Levetiracetam effect was not related to age at onset and duration of epilepsy, genetic status, and concomitant therapy. Levetiracetam was well tolerated by subjects who completed the study. To date, follow-up ranges 6 to 36 months (mean, 16.2 +/- 13.4). CONCLUSION: Levetiracetam add-on is effective and well tolerated in severe myoclonic epilepsy of infancy. Placebo-controlled studies should confirm these findings.

Recent epilepsy therapy research PMID: 17636062 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Related Articles

Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy.

Neurology. 2007 Oct 30;69(18):1751-60

Recent epilepsy therapy research Authors: Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U,

OBJECTIVE: To assess the efficacy and tolerability of adjunctive levetiracetam in patients with uncontrolled generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsies (IGE). METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults and children (4 to 65 years) with IGE experiencing >or=3 GTC seizures during the 8-week baseline period (4-week retrospective and 4-week prospective), despite receiving stable doses of one or two antiepileptic drugs (AEDs). Patients were randomized to levetiracetam (target dose 3,000 mg/day for adults; 60 mg/kg/day for children) or placebo and a 4-week titration period was followed by a 20-week evaluation period. RESULTS: Of 229 patients screened, 164 were randomized (levetiracetam, n = 80; placebo, n = 84). Levetiracetam produced a greater mean reduction in GTC seizure frequency per week over the treatment period (56.5%) than placebo (28.2%; p = 0.004). The percentage of patients who had >or=50% reduction of GTC seizure frequency per week (responders) during the treatment period was 72.2% for levetiracetam and 45.2% for placebo (p < 0.001; OR 3.28; 95% CI 1.68 to 6.38). During the first 2-week treatment 64.6% of patients on levetiracetam and 45.2% on placebo (p = 0.018) were classified as responders. During the evaluation period the percent of patients free of GTC seizures (34.2% vs 10.7%; p < 0.001) and all seizure types (24.1% vs 8.3%; p = 0.009) was greater for levetiracetam than placebo. Levetiracetam was well tolerated with 1.3% of patients discontinuing therapy due to adverse events vs 4.8% on placebo. CONCLUSION: Adjunctive levetiracetam is an effective and well-tolerated antiepileptic drug for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsies.

Recent epilepsy therapy research PMID: 17625106 [PubMed - in process]Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Related Articles

Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants.

Brain. 2007 May;130(Pt 5):1276-88

Recent epilepsy therapy research Authors: Li T, Steinbeck JA, Lusardi T, Koch P, Lan JQ, Wilz A, Segschneider M, Simon RP, Brüstle O, Boison D

Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk-/-), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk(-/-)-NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.

Recent epilepsy therapy research PMID: 17472985 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels. Related Articles

Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels.

Anesth Analg. 2007 May;104(5):1256-64, tables of contents

Recent epilepsy therapy research Authors: Punke MA, Friederich P

BACKGROUND: Kv1.1 and Kv7.2/7.3 channels control excitability of neuronal cells. As hyperexcitability is a sign of neuropathic pain, epilepsy, and anxiety disorders, these channels may be important molecular targets of amitriptyline that cause pharmacological as well as toxicological effects by altering neuronal excitability. Since the molecular mechanisms underlying these effects of amitriptyline have not been fully elucidated, we aimed to characterize the interaction of amitriptyline with human Kv1.1 and Kv7.2/7.3 channels. We also intended to establish the interaction of amitriptyline with the Kv7.2/7.3 channel opener, retigabine. METHODS: Kv1.1 and Kv7.2/7.3 channels were expressed in human embryonic kidney cells and in Chinese hamster ovary cells. The effects of amitriptyline and retigabine were studied with the patch-clamp technique. RESULTS: Amitriptyline inhibited Kv1.1 and Kv7.2/7.3 channels in a concentration-dependent and reversible manner. The IC50-value was 22 +/- 3 microM (n = 33) and 10 +/- 1 microM (n = 40), respectively. Deactivating inward currents of Kv7.2/7.3 channels were inhibited with an IC50-value of 4.2 +/- 0.6 microM (n = 32). Inhibition of Kv7.2/7.3 channels by amitriptyline reversibly depolarized the resting membrane potential. Retigabine reversed both the inhibitory action of amitriptyline on Kv7.2/7.3 channels as well as the depolarization of the membrane potential. CONCLUSIONS: Since amitriptyline inhibited Kv1.1 and Kv7.2/7.3 channels only at toxicologically relevant plasma concentrations, our results suggest a role for these channels in the neuroexcitatory side effects of amitriptyline. As the inhibitory effects of amitriptyline were reversed by retigabine, a combination of amitriptyline and retigabine could be of additional benefit in the therapy of neuropathic pain.

Recent epilepsy therapy research PMID: 17456683 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Targeted therapy for inherited GPI deficiency. Related Articles

Targeted therapy for inherited GPI deficiency.

N Engl J Med. 2007 Apr 19;356(16):1641-7

Recent epilepsy therapy research Authors: Almeida AM, Murakami Y, Baker A, Maeda Y, Roberts IA, Kinoshita T, Layton DM, Karadimitris A

Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase-encoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM. The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency.

Recent epilepsy therapy research PMID: 17442906 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Long-term electrical stimulation-induced inhibition of partial epilepsy. Case report. Related Articles

Long-term electrical stimulation-induced inhibition of partial epilepsy. Case report.

J Neurosurg. 2006 Dec;105(6):894-7

Recent epilepsy therapy research Authors: Elisevich K, Jenrow K, Schuh L, Smith B

The aim of this study was to determine the effects of long-term continuous cerebrocortical electrical stimulation in the treatment of partial epilepsy. The authors review the case of a 44-year-old man with medically intractable postencephalitic localization-related epilepsy with ictal onset in the primary motor cortex. For 5 years he was treated using patterned subthreshold electrical stimulation of the ictal site. This therapy has successfully eliminated the jacksonian march of cortical excitability and secondary generalization and reduced seizure frequency and intensity with an immediate postictal return of motor function. Over time, the seizure frequency subsided by more than 90%, with the patient showing no adverse features resulting from focal stimulation. The results in this case support the hypothesis that effective and safe long-term modulation of focal epilepsy is possible with focal cerebrocortical electrical stimulation.

Recent epilepsy therapy research PMID: 17405261 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]New ABCC8 mutations in relapsing neonatal diabetes and clinical features. Related Articles

New ABCC8 mutations in relapsing neonatal diabetes and clinical features.

Diabetes. 2007 Jun;56(6):1737-41

Recent epilepsy therapy research Authors: Vaxillaire M, Dechaume A, Busiah K, Cavé H, Pereira S, Scharfmann R, de Nanclares GP, Castano L, Froguel P, Polak M,

Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained.

Recent epilepsy therapy research PMID: 17389331 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Second-generation antiepileptic drugs' impact on balance: a meta-analysis. Related Articles

Second-generation antiepileptic drugs' impact on balance: a meta-analysis.

Mayo Clin Proc. 2007 Jan;82(1):40-7

Recent epilepsy therapy research Authors: Sirven JI, Fife TD, Wingerchuk DM, Drazkowski JF

OBJECTIVE: To systematically review available evidence regarding whether second-generation antiepileptic drugs (AEDs) contribute to the risk of balance disorders. METHODS: We systematically evaluated data from randomized controlled trials that compared adjunctive therapy with a second-generation AED (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topIramate, or zonisamide) vs placebo for partial epilepsy and that reported dose-specific rates of ataxia or Imbalance for each group. Random-effects meta-analysis was used to pool ratios (risk ratio [RR]) and associated 95% confidence Intervals to determine whether there was evidence of an overall AED class effect or a dose-response effect and whether there were differences between Individual AEDs. RESULTS: Sixteen studies met inclusion criteria, representing 4279 individuals randomized to a second-generation AED and 1830 patients to placebo. Pooled analyses of all AEDs demonstrated that they Increase imbalance risk at any dose (RR, 2.73; 95% confidence interval, 2.07-3.61) and at lowest dose (RR, 1.76; 95% confidence interval, 1.26-2.46). The highest dose analysis showed heterogeneity; evaluation of individual AEDs revealed that oxcarbamazepine and topiramate increased imbalance risk at all doses, whereas gabapentin and levetiracetam did not increase imbalance risk at any dose. A dose-response effect was observed for most AEDs. CONCLUSION: Second-generation AEDs at standard dosages, except for gabapentin and levetiracetam, increase the imbalance risk, and evidence exists for a dose-response effect. The mechanisms, risk factors, and consequences of this risk for individual AEDs warrant further study.

Recent epilepsy therapy research PMID: 17285784 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. Related Articles

An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes.

Diabetes. 2007 Feb;56(2):328-36

Recent epilepsy therapy research Authors: Masia R, Koster JC, Tumini S, Chiarelli F, Colombo C, Nichols CG, Barbetti F

Mutations in the pancreatic ATP-sensitive K(+) channel (K(ATP) channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the K(ATP) channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of K(ATP) channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg . kg(-1) . day(-1)) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.

Recent epilepsy therapy research PMID: 17259376 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. Related Articles

Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys.

Neurology. 2007 Jan 2;68(1):56-8

Recent epilepsy therapy research Authors: Horvath R, Kley RA, Lochmüller H, Vorgerd M

We describe a patient who presented with parkinsonism associated with the A8344G myoclonus epilepsy, ataxia, and myopathy with ragged red fibers mutation in the tRNA(Lys) gene. In addition, neurogenic changes and mitochondrial myopathy with ragged red fibers were observed. Neither myoclonus epilepsy nor other clinical signs described in association with A8344G were noted. Similar to previously reported patients with parkinsonism and mtDNA deletions, the symptoms of our patient responded favorably to levodopa therapy.

Recent epilepsy therapy research PMID: 17200493 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in women who use oral contraceptives. Related Articles

Optimizing therapy of seizures in women who use oral contraceptives.

Neurology. 2006 Dec 26;67(12 Suppl 4):S56-8

Recent epilepsy therapy research Authors: Harden CL, Leppik I

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

Recent epilepsy therapy research PMID: 17190925 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in children and adolescents with developmental disabilities. Related Articles

Optimizing therapy of seizures in children and adolescents with developmental disabilities.

Neurology. 2006 Dec 26;67(12 Suppl 4):S52-5

Recent epilepsy therapy research Authors: Smith MC

Children and adolescents with intellectual and developmental disabilities and epilepsy are a unique patient population that offers significant challenges. They are more likely to suffer lifelong intractable epilepsy with multiple seizure types than other patients with epilepsy. In addition, these patients often cannot clearly express their complaints about antiepileptic drug (AED) side effects, and the caregiver's role becomes all-important as an advocate for the patient. Finally, behavioral and psychiatric comorbidities are common and need to be considered when choosing an AED in this patient population. Our society will be judged by how we care for the most unfortunate among us.

Recent epilepsy therapy research PMID: 17190924 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in children and adolescents with ADHD. Related Articles

Optimizing therapy of seizures in children and adolescents with ADHD.

Neurology. 2006 Dec 26;67(12 Suppl 4):S49-51

Recent epilepsy therapy research Authors: Aldenkamp AP, Arzimanoglou A, Reijs R, Van Mil S

Attention deficit hyperactivity disorder (ADHD) can coexist with epilepsy and the prevalence of ADHD in epilepsy is three to five times greater than normal. This may be an effect of the epilepsy (particularly as a secondary symptom of subtle seizures) or of the antiepileptic treatment. There is an ongoing debate about the nature of ADHD in epilepsy and especially whether successive comorbidity exists (i.e., the possibility that epilepsy lowers the threshold for developing ADHD). Treatment of comorbid ADHD may be difficult. Methylphenidate is still the treatment of choice for the condition and, although it has been shown that neither methylphenidate nor other psychostimulants provoke seizures, there is still a possibility that seizure frequency may increase in children with active epilepsy.

Recent epilepsy therapy research PMID: 17190923 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in adult patients with psychiatric comorbidity. Related Articles

Optimizing therapy of seizures in adult patients with psychiatric comorbidity.

Neurology. 2006 Dec 26;67(12 Suppl 4):S39-44

Recent epilepsy therapy research Authors: Brodtkorb E, Mula M

This article provides an overview of appropriate antiepileptic treatment in adult patients with chronic epilepsy and concomitant psychiatric disorders. It highlights the influence of various treatment options for epilepsy on psychiatric symptoms. Six specific topics are discussed: psychosocial aspects and treatment compliance; positive and negative psychotropic effects of antiepileptic drugs (AEDs); pharmacokinetic and pharmacodynamic interactions between AEDs and psychoactive drugs; risks and benefits of resective surgery; the effect of vagal nerve stimulation; and recommended strategies for optimizing epilepsy therapy in patients with psychiatric disorders. Given the multitude of epilepsy treatment options with various CNS effects, it is crucial to select treatments according to the clinical profile of each individual patient.

Recent epilepsy therapy research PMID: 17190921 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in stroke patients. Related Articles

Optimizing therapy of seizures in stroke patients.

Neurology. 2006 Dec 26;67(12 Suppl 4):S3-9

Recent epilepsy therapy research Authors: Ryvlin P, Montavont A, Nighoghossian N

Stroke is the leading cause of symptomatic epilepsy in adults, accounting for up to one-third of newly diagnosed seizures among the elderly. About 3% to 5% of stroke patients will suffer a remote seizure, 54% to 66% of whom will develop epilepsy. Thus far, the optimal timing and type of antiepileptic treatment for patients with post-stroke seizure and epilepsy have not been specifically assessed. Although several studies suggest that seizures alter the functional recovery after a stroke, it remains difficult to determine whether or not the occurrence of a second seizure in an untreated stroke patient might hamper the overall outcome. The decision to initiate antiepileptic drug (AED) treatment after a first or a second post-stroke seizure should therefore be individualized, primarily based on the functional impact of the first seizure episode and the patient's preference. Several converging findings suggest that the majority of first-generation AEDs, particularly phenytoin, are not the most appropriate choice in stroke patients because of their potential harmful impact on functional recovery and bone health, their suboptimal pharmacokinetic profile and interaction with anticoagulants or salicylates, their greater likelihood to be poorly tolerated, and the lack of level A evidence regarding their specific use in elderly patients. Among the new-generation AEDs that do not interact with anticoagulants, antiplatelet agents, or bone health, lamotrigine and gabapentine are the only two drugs that proved to be more effective than immediate-release carbamazepine in elderly patients, providing level A evidence for their use in this indication. In addition, gabapentin remains the only drug that has been specifically evaluated in stroke patients, demonstrating a high rate of long-term seizure freedom. At present, low-dose lamotrigine or gabapentin appears to represent the optimal first-line therapy for post-stroke seizure and epilepsy in elderly patients or in younger patients requiring anticoagulants. However, low-dose extended-release carbamazepine might be a reasonable and less expensive option in patients with appropriate bone health who do not requiring anticoagulation.

Recent epilepsy therapy research PMID: 17190919 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Related Articles

Optimizing therapy of seizures in patients with renal or hepatic dysfunction.

Neurology. 2006 Dec 26;67(12 Suppl 4):S28-33

Recent epilepsy therapy research Authors: Lacerda G, Krummel T, Sabourdy C, Ryvlin P, Hirsch E

Patients with epilepsy may suffer from renal or hepatic diseases that interfere with their antiepileptic drug (AED) treatment. Furthermore, such diseases may themselves cause seizures. Reduced renal function and hypoalbuminemia lead to accumulation of renally excreted AEDs, such as gabapentin, vigabatrin, topiramate, levetiracetam, and phenytoin. Valproate, lamotrigine, and benzodiazepines are less affected. Low protein-bound AEDs are extensively removed by hemodialysis and supplemental doses are required for dialysis patients. Uremia and related conditions, including intracranial hemorrhage, glucose and electrolyte imbalances, and concomitant drug use, can cause seizures, as can dialysis encephalopathy, primary cerebral lymphoma, fungal infections, and immunosuppressant toxicity in renal transplant recipients. Hepatic dysfunction reduces enzymatic metabolism of AEDs and causes hypoalbuminemia. Gabapentin, topiramate, and levetiracetam are preferred in these conditions, whereas conversely valproate and felbamate are potentially hepatotoxic and should be avoided. Seizures related to hepatic encephalopathy are controlled by oral lactulose or neomycin. Porphyria sufferers may benefit from gabapentin, oxcarbazepine, or levetiracetam. Seizures in Wilson's disease may derive from d-penicillamine-induced pyridoxine deficiency. Effective treatment of seizures in renal and hepatic diseases requires attention to changes in AED pharmacokinetics and adequate care of the underlying illnesses. Monitoring of free drug concentrations is a valuable aid to therapy.

Recent epilepsy therapy research PMID: 17190918 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in patients with endocrine disorders. Related Articles

Optimizing therapy of seizures in patients with endocrine disorders.

Neurology. 2006 Dec 26;67(12 Suppl 4):S23-7

Recent epilepsy therapy research Authors: Steinhoff BJ

Endocrinologic disorders, such as thyroid dysfunction or diabetes, may be comorbidities in patients with epilepsy. The choice of medication should address such comorbidities wherever possible. Enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine, phenytoin, barbiturates, and oxcarbazepine among the new AEDs, may reduce the levels of free and total thyroxin. However, clinically relevant thyroid dysfunction owing to AED treatment is rare. Nevertheless, there are now better alternative AEDs with similar efficacy to the classic first-line drugs but without their enzyme-inducing properties. Such drugs should be considered in cases of thyroid dysfunction to reduce the likelihood of iatrogenic adverse effects. Sufficient data on some of the new AEDs to support this hypothesis are, however, still lacking and urgently needed. Several reports have pointed out the possible negative impact of valproate on glucose and insulin metabolism and particularly on body weight. The increased risk for development of polycystic ovarian syndrome remains a matter of debate but is certainly another argument for the development of alternative agents. The group of new AEDs offers some potential candidates. Topiramate is the AED that is most likely to lead to weight loss; this may be perceived as a positive side effect in some patients. This review summarizes the data on the possible impact of AEDs in endocrinological disorders, concentrating on thyroid dysfunction, insulin/glucose metabolism, and body weight.

Recent epilepsy therapy research PMID: 17190917 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in patients with HIV and cysticercosis. Related Articles

Optimizing therapy of seizures in patients with HIV and cysticercosis.

Neurology. 2006 Dec 26;67(12 Suppl 4):S19-22

Recent epilepsy therapy research Authors: Bhigjee AI, Rosemberg S

Worldwide, about 40 million people are living with HIV and 50 million people have neurocysticercosis (NCC). About 5% of patients with HIV and the majority of patients with NCC develop recurrent seizures. Mechanisms of seizure production in HIV include mass lesions, meningitis, encephalitis, and ischemia. Seizures in NCC may occur at all stages of cyst development, from the vesicular and colloidal to the calcified stages. Seizures in HIV present special problems with regard to choice of antiepileptic drug (AED) and the potential for drug-drug interactions with antiretroviral (ARV) treatments. Newer AEDs with simpler pharmacokinetic profiles may be the preferred agents, particularly when protease inhibitors form part of ARV regimens. Seizures in NCC are easily controlled with the older AEDs. Although there has been some debate about the value of antiparasitic drugs in NCC, accumulating data suggest that the use of these agents in active disease decreases the risk for development of chronic epilepsy.

Recent epilepsy therapy research PMID: 17190916 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in neurosurgery. Related Articles

Optimizing therapy of seizures in neurosurgery.

Neurology. 2006 Dec 26;67(12 Suppl 4):S14-8

Recent epilepsy therapy research Authors: Michelucci R

The use of antiepileptic drugs (AEDs) in the neurosurgical setting has a number of implications, including their possible role in the prevention of seizures after acute cerebral insults or brain tumors and the potential for toxicity and interactions when these agents are administered in association with radiotherapy or chemotherapy. This review discusses these controversial issues and draws the following conclusions. 1) AEDs should be prescribed on a short-term basis to prevent seizures occurring within the first week after a cerebral insult (trauma, neurosurgical procedure) but are ineffective to avoid true post-traumatic epilepsy or first seizures in patients with primary or secondary cerebral neoplasms. 2) The use of phenytoin and, to a lesser extent, phenobarbital and carbamazepine during cranial irradiation is associated with an increased risk for severe, potentially fatal, mucocutaneous reactions. In this context, new AEDs with a very low potential for allergic cutaneous reactions should be preferred. 3) Enzyme-inducing AEDs, such as phenytoin, phenobarbital, and carbamazepine, may increase the clearance and reduce the clinical efficacy of corticosteroids and anticancer agents that are also metabolized by the cytochrome P450 system. The newly developed AEDs that are devoid of hepatic metabolism, such as levetiracetam and gabapentin, are now recommended because of good results in preliminary studies and because they do not show interactions with anticancer agents.

Recent epilepsy therapy research PMID: 17190915 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Optimizing therapy of seizures in patients with brain tumors. Related Articles

Optimizing therapy of seizures in patients with brain tumors.

Neurology. 2006 Dec 26;67(12 Suppl 4):S10-3

Recent epilepsy therapy research Authors: Vecht CJ, van Breemen M

The mechanism of epilepsy in brain tumor patients is probably multifactorial, and its incidence depends on tumor type and location. Refractory epilepsy is common in patients with structural brain lesions, and a role for multidrug-resistance proteins has been suggested. The medical treatment of epilepsy in brain tumor patients has mainly been studied retrospectively, and the optimal management of seizures with antiepileptic drugs (AEDs) is unclear. Enzyme-inducing anticonvulsants are generally not recommended because they can lead to insufficient serum levels of concomitantly administered chemotherapeutic drugs. Although valproic acid is an enzyme inhibitor and may therefore lead to toxic levels of simultaneously administered chemotherapeutic agents, this does not appear to be a major problem in patients with brain tumors. Preliminary observations of add-on treatment with the AEDs levetiracetam or gabapentin suggest that these non-enzyme-inducing AEDs can be useful for control of seizures in patients with brain tumors. Conversely, prophylactic use of AEDs in brain tumor patients is generally not recommended.

Recent epilepsy therapy research PMID: 17190914 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Clinical implications of status epilepticus in patients with neoplasms. Related Articles

Clinical implications of status epilepticus in patients with neoplasms.

Arch Neurol. 2006 Dec;63(12):1746-9

Recent epilepsy therapy research Authors: Cavaliere R, Farace E, Schiff D

OBJECTIVES: To elucidate factors that contribute to the development of status epilepticus (SE) and determine prognostic factors and the impact on 30-day survival. DESIGN: Retrospective review of medical records. SETTING: University of Virginia Health System. Patients Thirty-five patients with SE secondary to a tumor, either primary or systemic, or its treatment. MAIN OUTCOME MEASURES: Seizure control, 30-day mortality, and overall survival. RESULTS: Status epilepticus most commonly occurred at tumor presentation or progression and was controlled in all cases. Thirty-day mortality was 23%. Patients with systemic cancer were at higher risk of death, although they were older and had more acute comorbidities. Age, tumor type, status of tumor at time of event, history of epilepsy, and status type were not predictive of mortality. Age was associated with a higher rate of nursing home placement and shorter overall survival. Overall survival was determined by underlying tumor. CONCLUSIONS: Status epilepticus in patients with cancer is responsive to therapy. Workup of underlying causes is indicated, even in the presence of subtherapeutic antiepileptic drug levels, because coexistent conditions contributing to the development of SE may be present. In those with known cancer, brain imaging should be performed because SE usually occurs in the setting of tumor progression or new metastases.

Recent epilepsy therapy research PMID: 17172614 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Oxidative stress in children receiving valproic acid. Related Articles

Oxidative stress in children receiving valproic acid.

J Pediatr. 2006 Nov;149(5):692-6

Recent epilepsy therapy research Authors: Michoulas A, Tong V, Teng XW, Chang TK, Abbott FS, Farrell K

OBJECTIVE: To determine whether valproic acid (VPA) influences urinary levels of 15-F2t -isoprostane (15-F2t -IsoP), a marker of oxidative stress, in children. STUDY DESIGN: Morning urine samples were collected from children with epilepsy receiving VPA (n = 25), carbamazepine (n = 16), or clobazam (n = 12) for > or = 4 weeks and from age-matched control subjects (n = 39). Urinary 15-F2t -IsoP levels were determined by enzyme-linked immunosorbent assay. RESULTS: The mean (+/- standard deviation) urine 15-F2t -IsoP levels (nmol/mmol Cr) were: valproic acid (0.36 +/- 0.15); carbamazepine (0.24 +/- 0.10); clobazam (0.23 +/- 0.10); control group (0.20 +/- 0.09). Patients treated with VPA had significantly elevated 15-F2t -IsoP levels when compared with the control, carbamazepine, and clobazam groups (P < .05). Multiple linear regression analysis demonstrated that younger patient age and exposure to second-hand smoke were significant predictors of elevated urine 15-F2t -IsoP levels within the control group (r2 = 0.261, P = .05 and P = .01, respectively). Subjects not exposed to second-hand smoke receiving valproic acid therapy had a significantly elevated mean urine 15-F2t -IsoP level compared to subjects not exposed to second-hand smoke in the carbamazepine, clobazam and control groups (P < .05). CONCLUSIONS: These data demonstrate that treatment of children with VPA is associated with higher urinary levels of 15-F2t -IsoP, a marker of oxidative stress.

Recent epilepsy therapy research PMID: 17095346 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Vagal nerve stimulation: overview and implications for anesthesiologists. Related Articles

Vagal nerve stimulation: overview and implications for anesthesiologists.

Anesth Analg. 2006 Nov;103(5):1241-9

Recent epilepsy therapy research Authors: Hatton KW, McLarney JT, Pittman T, Fahy BG

Vagal nerve stimulation is an important adjunctive therapy for medically refractory epilepsy and major depression. Additionally, it may prove effective in treating obesity, Alzheimer's disease, and some neuropsychiatic disorders. As the number of approved indications increases, more patients are becoming eligible for surgical placement of a commercial vagal nerve stimulator (VNS). Initial VNS placement typically requires general anesthesia, and patients with previously implanted devices may present for other surgical procedures requiring anesthetic management. In this review, we will focus on the indications for vagal nerve stimulation (both approved and experimental), proposed therapeutic mechanisms for vagal nerve stimulation, and potential perioperative complications during initial VNS placement. Anesthetic considerations during initial device placement, as well as anesthetic management issues for patients with a preexisting VNS, are reviewed.

Recent epilepsy therapy research PMID: 17056962 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Ground-glass, polyglucosan-like hepatocellular inclusions: A "new" diagnostic entity. Related Articles

Ground-glass, polyglucosan-like hepatocellular inclusions: A "new" diagnostic entity.

Gastroenterology. 2006 Sep;131(3):713-8

Recent epilepsy therapy research Authors: Lefkowitch JH, Lobritto SJ, Brown RS, Emond JC, Schilsky ML, Rosenthal LA, George DM, Cairo MS

BACKGROUND & AIMS: Ground-glass (GG) inclusions within hepatocytes are an important histopathologic marker of chronic hepatitis B virus (HBV) infection but may also be seen in Lafora's disease (myoclonus epilepsy), cyanamide alcohol aversion therapy, and type IV glycogenosis. We have noted a recent increased incidence of liver biopsy and postmortem specimens with GG inclusions associated with none of these etiologic factors. This study was undertaken to further delineate the clinical and liver pathologic features in such cases and their possible pathogenesis. METHODS: Ten cases with GG inclusions (8 biopsy, 2 postmortem) were examined by light and electron microscopy, and the patients' clinical records were reviewed. RESULTS: Light microscopy demonstrated pale pink, oval to crescentic intracytoplasmic inclusions with a predilection for periportal hepatocytes but sometimes present throughout the lobules. The inclusions were intensely positive on periodic acid-Schiff stain and digested with diastase. Transmission electron microscopy of two cases showed non-membrane-bound cytoplasmic collections of granules with mild-to-moderate electron density, consistent with abnormal glycogen granules. The patients included 7 transplant recipients (liver, hematopoietic stem cell), 3 with type 2 diabetes and a child on chronic parenteral nutrition for short bowel syndrome. Medications included immunosuppressive agents, antibiotics, and insulin. CONCLUSIONS: GG hepatocellular inclusions may be seen in individuals without HBV infection or other recognized etiologies, appear to be composed of abnormal glycogen and closely resemble polyglucosan bodies described in humans, animals, and experimental models. The possible pathogenetic roles of disturbed glycogen metabolism and polypharmacotherapy are stressed.

Recent epilepsy therapy research PMID: 16952540 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy. Related Articles

Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy.

Neurology. 2006 Aug 8;67(3):400-6

Recent epilepsy therapy research Authors: Blum D, Meador K, Biton V, Fakhoury T, Shneker B, Chung S, Mills K, Hammer A, Isojärvi J

OBJECTIVE: To compare the cognitive effects of lamotrigine vs topiramate as adjunctive therapy in adults with epilepsy. METHODS: A multicenter, double-blind, randomized, prospective study was conducted in adults with partial seizures. Lamotrigine or topiramate was introduced as an adjunctive therapy to carbamazepine or phenytoin and titrated over 8 weeks to target doses. These drugs were maintained another 8 weeks (maintenance phase) without dosage changes. The primary endpoint was change from screening to the end of the maintenance phase in a combined analysis of standardized measures of cognition (Controlled Oral Word Association Task [COWA]; Stroop Color-Word Interference; Digit Cancellation; Lafayette Grooved Pegboard, dominant hand; Rey Auditory Verbal Learning Test, delayed recall; and Symbol-Digit Modalities test). RESULTS: For the primary endpoint, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topiramate (415.3 vs 315.1; p < 0.001). On the individual cognitive tests, performance was better with lamotrigine than with topiramate in mean changes from screening on the COWA (p < 0.001), Stroop Color-Word Interference (p = 0.038), and Symbol-Digit Modalities tests (p < 0.001). The treatment effect exceeded the minimum clinically important difference for the COWA and the Symbol-Digit Modalities test. Mean changes from screening in the Performance-On-Line test simulating driving skills reflected better performance with lamotrigine than with topiramate (p = 0.021). The median percentage change from baseline in seizure frequency was lower with lamotrigine than with topiramate during the escalation phase (-80% vs -100%; p = 0.028) but not during the maintenance phase (-75% vs -100%; p = 0.062). The frequencies of cognitive adverse events and of premature withdrawals related to cognitive decline were higher with topiramate than with lamotrigine (6% vs 0%; p = 0.013). CONCLUSION: Lamotrigine had significantly less impact than topiramate on measures of cognition when used as adjunctive therapy for partial seizures.

Recent epilepsy therapy research PMID: 16894098 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures. Related Articles

Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures.

Pediatrics. 2006 Aug;118(2):e371-8

Recent epilepsy therapy research Authors: Trevathan E, Kerls SP, Hammer AE, Vuong A, Messenheimer JA

CONTEXT AND OBJECTIVE: Primary generalized tonic-clonic seizures are relatively more common among children than among adults. Primary generalized tonic-clonic seizures are associated with increased risk of injury and death. Therefore, effective control of primary generalized tonic-clonic seizures is necessary to reduce epilepsy-related morbidity and mortality. Lamotrigine has demonstrated efficacy from published randomized clinical trials for childhood partial seizures, absence seizures, and for the generalized seizures associated with Lennox-Gastaut syndrome. A randomized, blinded, placebo-controlled study was conducted to assess the efficacy and tolerability of adjunctive therapy with lamotrigine in the treatment of primary generalized tonic-clonic seizures among patients > or = 2 years of age; we report the data from children and adolescents 2 to 20 years of age from this randomized clinical trial. This is the first published analysis of data from a randomized, double-blind, controlled clinical trial of primary generalized tonic-clonic seizures focusing on children and adolescents. PATIENTS AND METHODS: We randomly assigned (1:1) 117 patients, aged 2 to 55 years, with primary generalized tonic-clonic seizures inadequately controlled on 1 to 2 current antiepileptic drugs and with evidence of primary generalized tonic-clonic seizures on electroencephalogram and no historical or electroencephalogram evidence of partial seizures to either lamotrigine or placebo in a double-blind parallel group clinical trial from 2001 through 2004. We analyzed the subgroup of children and adolescents, aged 2 to 20 years (n = 45), from this randomized clinical trial. Patients having > or = 3 primary generalized tonic-clonic seizures over an 8-week baseline were randomly assigned (1:1) to receive either lamotrigine or placebo. The treatment period consisted of an escalation phase (12 weeks for patients 2-12 years; 7 weeks for patients > 12 years) and a maintenance phase (12 weeks). The study had 4 phases: screening phase, baseline phase, escalation phase, and maintenance phase. During the screening phase, baseline medical examinations and seizure type and seizure frequency assessments were performed. During the 8-week baseline phase, the number and dosages of concomitant antiepileptic drugs were maintained while seizure frequency was assessed. The assessment of primary generalized tonic-clonic seizure frequency was determined during the 8-week baseline phase. Patients eligible for random assignment experienced > or =3 primary generalized tonic-clonic seizures during the baseline phase and > or = 1 primary generalized tonic-clonic seizure in the 8 weeks before the baseline phase. Lamotrigine was introduced and titrated using a schedule based on the patients' age and concurrent antiepileptic drug regimen. During the escalation phase, the number and doses of concomitant antiepileptic drugs were not changed. The escalation phase was followed by a 12-week maintenance phase during which time the lamotrigine dose was maintained at a specific dose defined by the patients' age and concomitant antiepileptic drugs, whereas the doses of concurrent antiepileptic drugs were maintained at a constant dose. Concurrent antiepileptic drugs could not be discontinued or added during the maintenance phase. The primary efficacy end point measure was the median reduction in the frequency of primary generalized tonic-clonic seizures from baseline; seizure counts were recorded prospectively in standardized daily seizure diaries. Other efficacy end point data for analysis were as follows: the median seizure counts, the median percentage change from the baseline phase in average monthly seizure frequency for other generalized seizure types, and the percentage of patients with a reduction of > or = 25%, > or = 50%, > or = 75%, or 100% in frequencies of primary generalized tonic-clonic seizures and all generalized seizures during the escalation phase and/or maintenance phase relative to the baseline phase. Accurate counts of absence seizure frequency require electroencephalogram-video monitoring; absence seizure frequency was not an outcome measure for this analysis. RESULTS: Forty-five (21 lamotrigine and 24 placebo) patients 2 to 19 years of age were randomly assigned and received study drug. Eight patients (3 lamotrigine and 5 placebo) had a combination of clinical (myoclonus and/or absence seizures) and electroencephalogram findings that were consistent with juvenile myoclonic epilepsy. Among the 45 children randomly assigned, 74% had generalized spike, polyspike, and/or generalized spike and wave discharges on routine electroencephalogram recordings; the remaining 26% of children had no electroencephalogram findings suggestive of partial epilepsy and a clear history consistent with primary generalized tonic-clonic seizures. Electroencephalogram findings were not significantly different between the lamotrigine and the placebo treatment groups. The median percentage decrease from baseline in primary generalized tonic-clonic seizures during the entire treatment period was 77% in the lamotrigine group and 40% in the placebo group (P = .044). The median primary generalized tonic-clonic seizure counts per month were 0.7 in the lamotrigine group and 3.6 in the placebo group during escalation (P = .008), 0.3 in the lamotrigine group and 2.0 in the placebo group during maintenance (P = .005), and 0.4 in the lamotrigine group and 2.5 in the placebo group during the entire treatment period (P = .007). Trends were noted during escalation and maintenance with a median percentage decrease in primary generalized tonic-clonic seizures during escalation of 72% in the lamotrigine group and 30% in the placebo group (P = .059), and 83% in the lamotrigine group and 42% in the placebo group during maintenance (P = .058). During the maintenance phase, 48% of lamotrigine patients were seizure free compared with 17% treated with placebo (P = .051). One patient from each treatment group discontinued from the study because of an adverse event; 1 patient who received lamotrigine experienced "disorientation"; and 1 patient who received placebo had a convulsion with apnea. No rashes occurred among patients taking lamotrigine or placebo. No patient experienced worsening of the intensity or frequency of myoclonus. CONCLUSIONS: Adjunctive lamotrigine therapy seems effective in controlling primary generalized tonic-clonic seizures among patients 2 to 20 years of age.

Recent epilepsy therapy research PMID: 16847080 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Effect of lamotrigine on cognition in children with epilepsy. Related Articles

Effect of lamotrigine on cognition in children with epilepsy.

Neurology. 2006 May 23;66(10):1495-9

Recent epilepsy therapy research Authors: Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO

BACKGROUND: Lamotrigine does not affect cognition in healthy adult volunteers or adult patients with epilepsy, but its effect on cognition in children is uncertain. OBJECTIVE: To compare the effect of lamotrigine and placebo on cognition in children with well-controlled or mild epilepsy. METHOD: In a double-blind, placebo-controlled, crossover study, 61 children with well-controlled or mild epilepsy were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Each treatment phase was 9 weeks, the crossover period 5 weeks. A neuropsychological test battery was performed during EEG monitoring at baseline and at the end of placebo and drug phases. The paired Student' t test was used for statistical analysis for neuropsychological data (two tailed) with a p value of 0.01 considered significant. Carryover and period effect were analyzed with generalized linear modeling (SPSS 10). RESULTS: Forty-eight children completed the study. Seizure frequency was similar during both treatment phases. No significant difference was found in continuous performance, binary choice reaction time, verbal and nonverbal recognition, computerized visual searching task, verbal and spatial delayed recognition, and verbal and nonverbal working memory between placebo and lamotrigine treatment phase. There was no significant carryover and period effect when corrected for randomization. CONCLUSION: Lamotrigine exhibits no clinically significant cognitive effects in adjunctive therapy for children with epilepsy.

Recent epilepsy therapy research PMID: 16717207 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Related Articles

Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients.

Brain. 2006 Jul;129(Pt 7):1907-16

Recent epilepsy therapy research Authors: Fauser S, Huppertz HJ, Bast T, Strobl K, Pantazis G, Altenmueller DM, Feil B, Rona S, Kurth C, Rating D, Korinthenberg R, Steinhoff BJ, Volk B, Schulze-Bonhage A

Focal cortical dysplasias (FCDs) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. However, little is known about the clinical characteristics of epilepsy in these patients. In order to elucidate the clinical characteristics of their epilepsy, 120 pharmacoresistant patients including children and adults with histologically proven FCD were studied retrospectively. Age at seizure onset was analysed in the total group and compared between subgroups with different localization and different histological subtypes of FCD. The role of febrile seizures with respect to dual pathology was investigated. Seizure semiology was analysed focusing on initial seizure type and change of seizure semiology during the course of disease. Finally, transient responsiveness to antiepileptic drug therapy was studied. In the majority of patients, epilepsy began in the first 5 years of life. However, onset of epilepsy could also occur in the second or third decade until the age of 60. Age at epilepsy onset was not significantly different between temporal, extratemporal and multilobar localization of FCD. Patients without cytoarchitectural abnormalities (mild malformations of cortical development, FCD 1a according to Palmini) had significantly later epilepsy onset (P= 0.001) compared with patients with cytoarchitectural abnormalities (FCD 1b, 2a and 2b according to Palmini). In patients with additional hippocampal sclerosis (dual pathology) febrile seizures were significantly more frequently reported (P = 0.02) than in patients without dual pathology. Moreover, patients with dual pathology and febrile seizures significantly more frequently presented with severe hippocampal sclerosis (Wyler Grade 3-4) as compared with patients with dual pathology in the absence of febrile seizures (P = 0.03). First observed seizures were mainly tonic or generalized tonic-clonic. A change of seizure semiology seemed to be age-dependent and occurred between the age of >1 and 14 years. About 15.8% of the patients presented with status epilepticus during the course of disease. About 17% of the patients showed transient responsiveness (> or =1 year seizure freedom) to antiepileptic drug therapy either after initial therapy (50%) or later in the course of epilepsy (50%). Patients with FCD represent a heterogeneous group. Different age at epilepsy onset and transient responsiveness to antiepileptic drugs in approximately 17% of patients may reflect different dynamics in epileptogenicity of the underlying FCD. Dual pathology may be associated with different pathomechanisms in patients with and without febrile seizures.

Recent epilepsy therapy research PMID: 16714316 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Adult epilepsy. Related Articles

Adult epilepsy.

Lancet. 2006 Apr 1;367(9516):1087-100

Recent epilepsy therapy research Authors: Duncan JS, Sander JW, Sisodiya SM, Walker MC

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possible presentations and causes. Although incidence in childhood has fallen over the past three decades in developed countries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. A clinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene can lead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits with environmental effects acting on inherited susceptibility, mediated by common variation in particular genes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome. Brain imaging is making great progress in identifying the structural and functional causes and consequences of the epilepsies. Current antiepileptic drugs suppress seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Pharmacogenetic studies hold the promise of being able to better individualise treatment for each patient, with maximum possibility of benefit and minimum risk of adverse effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changing cure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neural stimulation, and biological grafts.

Recent epilepsy therapy research PMID: 16581409 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Neurologic links between epilepsy and depression in women: is hippocampal neuroplasticity the key? Related Articles

Neurologic links between epilepsy and depression in women: is hippocampal neuroplasticity the key?

Neurology. 2006 Mar 28;66(6 Suppl 3):S13-22

Recent epilepsy therapy research Authors: Hajszan T, MacLusky NJ

Recent advances in our understanding of the actions of sex steroids on the brain and the pathophysiology of depression have provided a hypothetical framework that may functionally connect epilepsy, ovarian hormone levels, and depression. The hippocampus plays a critical role in both seizure activity and mood disorders, which suggests that pathology in this area of the brain might provide a link between epilepsy and depression. Recent findings support the view that neurogenesis is not the only factor that contributes to the pathomechanism of depression and antidepressant responses, which may involve other hippocampal cellular or molecular changes, or both. Specifically, remodeling of the hippocampal spine synapses may play a significant role in the neurobiology of depression and the effects of antidepressant therapy. Because the effects of estrogens on hippocampal synaptogenesis parallel those of antidepressants, loss of estrogen appears to be a critical contributor to the etiology of depressive disorders. The increased incidence of depression observed in women with epilepsy might therefore reflect a hormonal deficiency state because epilepsy is frequently associated with defects in reproductive function. In women with catamenial epilepsy, changes in gonadal steroid production are seen to link seizure frequency with reproductive state, emphasizing the importance of gonadal steroid levels not only in depression but also in seizure activity. Paradoxical features of epilepsy, i.e., seizure-induced increases in hippocampal neurotrophin expression and neurogenesis, suggest that the most important factor in the neurobiology of depression might be the extent to which the hippocampus can adapt appropriately to changes in the environment through alterations in hippocampal synaptic connectivity.

Recent epilepsy therapy research PMID: 16567737 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Effects of intermittent levetiracetam dosing in a patient with refractory daily seizures. Related Articles

Effects of intermittent levetiracetam dosing in a patient with refractory daily seizures.

Neurology. 2006 Feb 28;66(4):590-1

Recent epilepsy therapy research Authors: Friedman D, French JA

Some epilepsy patients quickly develop resistance to antiepileptic drugs (AEDs). We report a case of a patient with refractory epilepsy with daily seizures who initially responded to levetiracetam daily therapy, but then returned to baseline seizure frequency. However, when levetiracetam was given once weekly, the patient had significantly fewer seizures on the day of and after administration. These results suggest a useful treatment strategy for patients with refractory epilepsy who have developed resistance to AEDs.

Recent epilepsy therapy research PMID: 16505320 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Cutaneous burns treated with hydrogel (Burnshield) and a semipermeable adhesive film. Related Articles

Cutaneous burns treated with hydrogel (Burnshield) and a semipermeable adhesive film.

Arch Surg. 2006 Jan;141(1):39-42

Recent epilepsy therapy research Authors: Osti E

HYPOTHESIS: A transparent adhesive film possessing selective permeability combined with a hydrogel (Burnshield) may be effective in burn patients to reduce skin maceration, improve medication, control pain more effectively, and reduce the incidence of late complications (hypertrophic scars). DESIGN: This is a prospective study; the mean follow-up in all patients was 28.4 months (range, 14-35 months). The external part of the film is impermeable to fluid and microorganisms, but allows transpiration of water vapor from the cutis. The permeability to water vapor of a semipermeable film in contact with liquids is measured in grams per meters squared every 24 hours at 37 degrees C, and is defined as the moisture vapor transmission rate. In this study, a film with a moisture vapor transmission rate of 1600 g/m(2) every 24 hours at 37 degrees C was used. PATIENTS: For about 2 years, this type of therapy was used in the first aid treatment of 48 burn patients, 4 of whom were lost during therapy and 4 of whom were unavailable for follow-up. INTERVENTIONS: The patients were treated with hydrogel and a semipermeable film at first medication, and some were treated in this way during subsequent medications. MAIN OUTCOME MEASURES: The mean reepithelialization time of all patients was 17 days (range, 4-60 days); 8 (20%) of 40 patients with complications were treated with a gel (Same Plast Gel). Late complications were observed: hypertrophic scars in 2 patients (5%) and dyschromic lesions in 6 (15%). RESULTS: The most frequent complication, which occurred at various stages during medication, was skin maceration (15 [34%] of 44 patients). Other complications recorded during therapy were infections in 2 patients (5%), vertigo in 1 patient (2%), and abundant fibrin production in 1 patient (2%). In some of the patients, associated diseases and/or conditions were found: hepatic cirrhosis, diabetes mellitus, epilepsy, and pregnancy (33rd week) (each found in 1 patient each). Four patients were sent to the burn unit, 3 with second-degree burns of the hand and 1 with first-/second-degree burns of the abdomen and thigh, with 12% of the total body surface area burned. CONCLUSIONS: In the reepithelialization phase, complications were recorded in 8 of the 40 patients: 7 (18%) had residual inflammation and 1 (2%) had a hypertrophic scar. During the follow-up, late complications were recorded in 2 (5%) of the 40 patients. A gel was used in 8 patients: in 6 of the 7 patients with residual inflammation, the complication resolved, while in 1, despite therapy, the residual inflammation evolved into hypertrophic scarring. Treatment with the gel in the 2 patients with late lesions reduced the thickness and extent of the lesions, with minimal aesthetic and functional damage.

Recent epilepsy therapy research PMID: 16418161 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Serum antibodies in epilepsy and seizure-associated disorders. Related Articles

Serum antibodies in epilepsy and seizure-associated disorders.

Neurology. 2005 Dec 13;65(11):1730-6

Recent epilepsy therapy research Authors: McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, Shoenfeld Y, Vincent A, Palace J, Lang B

OBJECTIVE: To investigate whether autoantibodies to ion channels and other neural antigens are present in the sera of patients with epilepsy and seizure-related diseases. METHODS: Sera were obtained from 139 patients, including 26 with preexisting autoimmune disease, 46 in whom an autoimmune basis was suspected, and 67 with drug-resistant epilepsy. The sera were assayed for antibodies to voltage-gated potassium (VGKC) and calcium (VGCC) channels, glutamic acid decarboxylase (GAD), gangliosides, glutamate receptor type 3, cardiolipins, DNA, and nuclear antigens; the results were compared with results from a large cohort of healthy and disease controls. RESULTS: Increased titers of VGKC antibodies (>100 pM) were detected in 16 of 139 (11%) patients with seizures but only 1 control (0.5%). Eight VGKC-positive patients presented with an acute/subacute illness, and 5 of these had the highest VGKC antibodies; 3 patients improved spontaneously, another 5 patients responded well to immunomodulatory therapy. The other VGKC-positive patients had longer disease duration (>6 years) and intermediate levels of antibodies; immunotherapies have not been tested in this group. Very high levels of GAD antibodies (>1,000 U) were found in an additional 3 patients (2.1%) with long-standing drug-resistant epilepsy. CONCLUSIONS: The presence of autoantibodies to voltage-gated potassium channels and glutamic acid decarboxylase suggests that the immune system may contribute to certain forms of epilepsy or seizure-associated disorders. Further studies are needed to determine whether the antibodies are pathogenic.

Recent epilepsy therapy research PMID: 16344514 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Topiramate in patients with juvenile myoclonic epilepsy. Related Articles

Topiramate in patients with juvenile myoclonic epilepsy.

Arch Neurol. 2005 Nov;62(11):1705-8

Recent epilepsy therapy research Authors: Biton V, Bourgeois BF,

BACKGROUND: Topiramate is a broad-spectrum agent effective against primarily generalized tonic-clonic seizures (PGTCS) as well as partial-onset seizures. Juvenile myoclonic epilepsy is one of the most common idiopathic generalized epilepsies, with most patients experiencing PGTCS. OBJECTIVE: To evaluate topiramate as add-on therapy in patients with juvenile myoclonic epilepsy. DESIGN: Post-hoc analysis of a patient subset from 2 multicenter, double-blind, randomized, placebo-controlled, parallel-group trials. SETTING: Eighteen centers in the United States; 10 centers in Europe; 1 center in Costa Rica (primary trials). PATIENTS: A total of 22 patients with juvenile myoclonic epilepsy participating in placebo-controlled trials assessing topiramate (target dose, 400 mg/d in adults) in inadequately controlled PGTCS. MAIN OUTCOME MEASURE: Reduction of PGTCS. RESULTS: A 50% or more reduction of PGTCS in 8 of 11 topiramate-treated patients (73%) and 2 of 11 placebo-treated patients (18%) (P = .03). Reductions in myoclonic, absence, and total generalized seizures were also observed, although topiramate vs placebo differences did not achieve statistical significance. CONCLUSION: As a broad-spectrum agent, topiramate is an effective option for patients with juvenile myoclonic epilepsy.

Recent epilepsy therapy research PMID: 16286543 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]The primary periodic paralyses: diagnosis, pathogenesis and treatment. Related Articles

The primary periodic paralyses: diagnosis, pathogenesis and treatment.

Brain. 2006 Jan;129(Pt 1):8-17

Recent epilepsy therapy research Authors: Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, Tristani-Firouzi M, Tawil R, Griggs RC,

Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.

Recent epilepsy therapy research PMID: 16195244 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Complementary and alternative therapy for epilepsy: much less than meets the eye. Related Articles

Complementary and alternative therapy for epilepsy: much less than meets the eye.

Arch Neurol. 2005 Sep;62(9):1475-6

Recent epilepsy therapy research Authors: Roach ES

Recent epilepsy therapy research PMID: 16157760 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Effect of antiepileptic drug comedication on lamotrigine clearance. Related Articles

Effect of antiepileptic drug comedication on lamotrigine clearance.

Arch Neurol. 2005 Sep;62(9):1432-6

Recent epilepsy therapy research Authors: Weintraub D, Buchsbaum R, Resor SR, Hirsch LJ

OBJECTIVE: To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL). DESIGN: We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication. RESULTS: Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. CONCLUSION: Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.

Recent epilepsy therapy research PMID: 16157751 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Related Articles

Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.

Diabetes. 2005 Sep;54(9):2503-13

Recent epilepsy therapy research Authors: Hattersley AT, Ashcroft FM

Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic beta-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in approximately 47% of patients diagnosed with permanent diabetes at <6 months of age. There is a striking genotype-phenotype relationship with specific Kir6.2 mutations being associated with transient neonatal diabetes, permanent neonatal diabetes alone, and a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. All mutations appear to cause neonatal diabetes by reducing K(ATP) channel ATP sensitivity and increasing the K(ATP) current, which inhibits beta-cell electrical activity and insulin secretion. The severity of the clinical symptoms is reflected in the ATP sensitivity of heterozygous channels in vitro with wild type > transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated K(ATP) channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) channel.

Recent epilepsy therapy research PMID: 16123337 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Vagus nerve stimulation for epilepsy: randomized comparison of three stimulation paradigms. Related Articles

Vagus nerve stimulation for epilepsy: randomized comparison of three stimulation paradigms.

Neurology. 2005 Jul 26;65(2):317-9

Recent epilepsy therapy research Authors: DeGiorgio C, Heck C, Bunch S, Britton J, Green P, Lancman M, Murphy J, Olejniczak P, Shih J, Arrambide S, Soss J

Vagus nerve stimulation (VNS) is an effective adjunctive treatment for intractable epilepsy. However, the optimal range of device duty-cycles [on/(on + off times)] is poorly understood. The authors performed a multicenter, randomized trial of three unique modes of VNS, which varied primarily by duty-cycle. The results indicate that the three duty-cycles were equally effective. The data support the use of standard duty-cycles as initial therapy.

Recent epilepsy therapy research PMID: 16043810 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Suppression of secondary generalization of limbic seizures by stimulation of subthalamic nucleus in rats. Related Articles

Suppression of secondary generalization of limbic seizures by stimulation of subthalamic nucleus in rats.

J Neurosurg. 2005 Jun;102(6):1122-9

Recent epilepsy therapy research Authors: Usui N, Maesawa S, Kajita Y, Endo O, Takebayashi S, Yoshida J

OBJECT: Deep brain stimulation (DBS) of subcortical nuclei such as the subthalamic nucleus (STN) or the substantia nigra pars reticulata (SNR) may provide an alternative therapy for intractable epilepsy. The authors attempted to evaluate the antiepileptic effects of DBS to these structures in an experimental seizure model. METHODS: Three groups of rats were prepared. In the first two groups, the rats underwent unilateral implantation of stimulation electrodes in the STN (six rats) or the SNR (six rats). A control group received no electrodes (six rats). Kainic acid (KA) was systemically administered to induce limbic seizures, which started with focal seizures and became generalized secondarily. High-frequency electrical stimulation of the STN or SNR was begun immediately after KA administration, and changes on electroencephalography (EEG) and the magnitude of clinical seizures were evaluated. Results showed that STN stimulation significantly reduced the duration of generalized seizures on EEG, although the total duration of seizures (generalized plus focal seizures) was unchanged. The duration of focal seizures on EEG was prolonged by STN DBS, a result possibly due to the suppression of secondary generalization. In addition, STN DBS reduced the severity of clinical seizures. On the other hand, stimulation of the SNR demonstrated no effect. CONCLUSIONS: Unilateral STN DBS showed significant suppression of the secondary generalization of limbic seizures. Note, however, that SNR DBS was less effective, which implies that in addition to the nigral control of the epilepsy system, another antiepileptic mechanism such as antidromic stimulation of the corticosubthalamic pathway should be considered.

Recent epilepsy therapy research PMID: 16028773 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Epilepsy in the oral and maxillofacial patient: current therapy. Related Articles

Epilepsy in the oral and maxillofacial patient: current therapy.

J Oral Maxillofac Surg. 2005 Jul;63(7):996-1005

Recent epilepsy therapy research Authors: Turner MD, Glickman RS

Recent epilepsy therapy research PMID: 16003629 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Current treatments of epilepsy. Related Articles

Current treatments of epilepsy.

Neurology. 2005 Jun 28;64(12 Suppl 3):S2-11

Recent epilepsy therapy research Authors: Nadkarni S, LaJoie J, Devinsky O

Medical therapy is the mainstay for epilepsy, with most patients well controlled on a single antiepileptic drug (AED). In this non-refractory group, many patients have medication side effects and occasional seizures. Approximately 30% of patients with partial epilepsy and 25% of patients with generalized epilepsy are not well controlled on medications. These patients are often receiving multiple AEDs, with disabling seizures and side effects. Although second-generation AEDs are safer and better tolerated than the older AEDs, there are scant data to support significant advantages in efficacy. In VA studies with older AEDS, therapy with two AEDs improved seizure control in 40% of patients but seizure freedom was achieved in only 9%. A meta-analysis of the second-generation AEDs used as adjunctive therapies shows that 12% to 29% of patients had a 50% or greater reduction in seizure frequency. Surgery and the vagus nerve stimulator provide important therapeutic options in patients whose seizures are not controlled by AEDs. Special considerations about epilepsy care must be made in pediatric populations, those with developmental delays, women, and the elderly.

Recent epilepsy therapy research PMID: 15994220 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Related Articles

New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.

Neurology. 2005 Jun 14;64(11):1868-73

Recent epilepsy therapy research Authors: Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, Spitz M, Frederick T, Towne A, Carter GS, Marks W, Felicetta J, Tomyanovich ML,

OBJECTIVE: To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared to carbamazepine (CBZ) in older patients with epilepsy. METHODS: This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. RESULTS: Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 +/- 4.83 microg/mL, LTG 2.87 +/- 1.60 microg/mL, CBZ 6.79 +/- 2.92 microg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% (p = 0.0002). Significant paired comparisons: LTG vs CBZ: p < 0.0001; GBP vs CBZ: p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% (p = 0.001). Significant paired comparisons: LTG vs CBZ: p < 0.0001; LTG vs GBP: p = 0.015. There were no significant differences in seizure free rate at 12 months. CONCLUSIONS: The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.

Recent epilepsy therapy research PMID: 15955935 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Related Articles

Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures.

Brain. 2005 Jun;128(Pt 6):1358-68

Recent epilepsy therapy research Authors: Volk HA, Löscher W

Medical intractability, i.e. the absence of any response to anti-epileptic drug (AED) therapy, is an unresolved problem in many patients with epilepsy. Mechanisms of intractability are not well understood, but may include alterations of pharmacological targets and poor penetration of AEDs into the brain because of increased expression of multiple drug-resistance proteins, such as P-glycoprotein (Pgp; ABCB1), capable of active brain extrusion of various drugs, including AEDs. Increased expression of Pgp has been reported in brain tissue of patients with refractory epilepsy, but there is a lack of adequate controls, i.e. brain tissue from patients with drug-responsive epilepsy. In the present study, we used a rat model of temporal lobe epilepsy to examine whether AED responders differ from non-responders in their expression of Pgp in the brain. In this model, spontaneous recurrent seizures develop after status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video-EEG monitoring before, during and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders (n = 7) and non-responders (n = 4). Pgp expression was studied by immunohistochemistry and showed striking overexpression in non-responders compared with responders in limbic brain regions, including the hippocampus. The Pgp overexpression was confined to brain capillary endothelial cells which form the blood-brain barrier. The present data are the first to demonstrate that rats with drug-resistant spontaneous seizures differ from rats with drug-responsive seizures in their Pgp expression in the brain, thereby substantiating the multidrug transporter hypothesis of intractable epilepsy.

Recent epilepsy therapy research PMID: 15716304 [PubMed - indexed for MEDLINE Recent epilepsy therapy research ]

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