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Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature.
Schubert-Bast, S, Wolff, M, Wiemer-Kruel, A, von Spiczak, S, Trollmann, R, Reif, PS, Pritchard, C, Polster, T, Neubauer, BA, Mayer, T, et al
Epilepsy & behavior : E&B. 2019;(Pt A):88-95
Abstract
OBJECTIVE The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. METHODS Patient use of routine AEDs and emergency medications over 3-6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. RESULTS The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. SIGNIFICANCE This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
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2.
Valproate decreases vitamin D levels in pediatric patients with epilepsy.
Xu, Z, Jing, X, Li, G, Sun, J, Guo, H, Hu, Y, Sun, F, Wen, X, Chen, F, Wang, T, et al
Seizure. 2019;:60-65
Abstract
PURPOSE To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls. METHODS A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed. RESULTS Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses. CONCLUSION This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient.
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3.
Effectiveness of eslicarbazepine acetate in dependency of baseline anticonvulsant therapy: Results from a German prospective multicenter clinical practice study.
Weissinger, F, Losch, F, Winter, Y, Brecht, S, Lendemans, D, Kockelmann, E
Epilepsy & behavior : E&B. 2019;(Pt A):106574
Abstract
Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug (AED) approved as monotherapy for partial-onset seizures in adults and as adjunctive therapy in patients aged above 6 years in the European Union (EU). The prospective observational Zebinix Effects in DEpendency of BAseline Conditions (ZEDEBAC) study aimed at investigating the effectiveness of ESL in clinical practice, with ESL being administered as monotherapy (mono group), as only add-on to a current monotherapy (1+ group), or as add-on to ≥2 baseline AEDs (≥2+ group). In total, 237 patients were included, 35 in the mono group, 114 in the 1+, and 88 in the ≥2+ group. Six-month retention rates were 93.9%, 78.0%, and 75.3% in the mono, 1+, and ≥2+ group. There were 90.5%, 77.6%, and 48.3% of patients in the mono, 1+, and ≥2+ groups who were responders (patients with a ≥50% reduction in seizure frequency at follow-up vs. baseline). Seizure freedom rates were 81.5%, 47.9%, and 23.4%, respectively. Adverse drug reactions (ADRs) occurred in 11.4% of patients of the mono, 19.3% of the 1+, and 28.4% of patients of the ≥2+ group. Hyponatremia was reported as ADR in 3.4% of all patients. Although baseline variables differed considerably, with most elderly patients with tumor-related and vascular etiologies in the mono group and most patients with refractory epilepsies with pronounced use of concomitant sodium channel blockers (SCBs) in the ≥2+ group, retention as a measure of real-life effectiveness turned out not to be substantially different and favorable in all groups.
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Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): A prospective randomized controlled pilot study.
Nene, D, Mundlamuri, RC, Satishchandra, P, Prathyusha, PV, Nagappa, M, Bindu, PS, Raghavendra, K, Saini, J, Bharath, RD, Thennarasu, K, et al
Seizure. 2019;:111-117
Abstract
PURPOSE This randomized control study was conducted to compare the efficacy of sodium valproate (SVP) and levetiracetam (LEV) following initial intravenous lorazepam in elderly patients (age: >60years) with generalized convulsive status epilepticus (GCSE) and to identify predictors of poor seizure control. METHODS A total of 118 patients (mean age: 67.5 ± 7.5 years, M:F = 1.6:1), who had presented with GCSE were randomized into the SVP or LEV treatment arms. All patients received initial intravenous lorazepam (0.1 mg/kg) followed by one of the two antiepileptic drugs (AEDs), parenteral SVP (20-25 mg/kg) or LEV (20-25 mg/kg). Those who failed to achieve control with the initial AED, were crossed over to receive the other AED. One-hundred patients (SVP = 50; LEV = 50) completed the study. RESULTS SE could be controlled with lorazepam and one of the AEDs (SVP or LEV) in 71.18% (84/118). Intention-to-treat analysis showed that the two groups did not differ significantly in terms of seizure control [SVP: 41/60 (68.3%); LEV: 43/58 (74.1%), p = 0.486]. Of 100 patients who completed the study, seizure control was achieved in 38/50(76%) in the SVP and 43/50(86%) in the LEV group (p = 0.202). After crossing over to the second AED, SE could be controlled in an additional in 50% (6/12) in SVP (+LEV) group and in 14.3% (1/7) in LEV (+SVP) group. Overall, after the second AED, seizure control was achieved in 77.1% (91/118). Higher STESS was associated with poor therapeutic response (p = 0.049). CONCLUSIONS The efficacy of SVP and LEV following initial lorazepam in controlling GCSE in elderly population was comparable, hence the choice of AED could be individualized.
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5.
Pharmacotherapies for co-occurring substance use and bipolar disorders: A systematic review.
Coles, AS, Sasiadek, J, George, TP
Bipolar disorders. 2019;(7):595-610
Abstract
OBJECTIVES Substance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co-occurring SUDs in bipolar illness have not been well-developed and may be an important practical reason for the reduced effectiveness of these medications in community practice. METHODS We conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N = 29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co-occurring bipolar disorders and SUDs. RESULTS Our findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co-occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open-label designs and of modest sample sizes. CONCLUSIONS Thus, given the gaps in our knowledge, recommendations for treatment of this common and important co-morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co-morbidity is clearly needed.
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Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: a randomized controlled trial.
de Greef, BTA, Hoeijmakers, JGJ, Geerts, M, Oakes, M, Church, TJE, Waxman, SG, Dib-Hajj, SD, Faber, CG, Merkies, ISJ
Brain : a journal of neurology. 2019;(2):263-275
Abstract
Symptomatic treatment of neuropathic pain in small fibre neuropathy is often disappointing. The finding of voltage-gated sodium channel mutations in small fibre neuropathy (with mutations in SCN9A, encoding for Nav1.7) being most frequently reported suggest a specific target for therapy. The anticonvulsant lacosamide acts on Nav1.3, Nav1.7, and Nav1.8. The aim of this study was to evaluate the efficacy, safety, and tolerability of lacosamide as a potential treatment for pain in Nav1.7-related small fibre neuropathy. The Lacosamide-Efficacy-'N'-Safety in SFN (LENSS) was a randomized, placebo-controlled, double-blind, crossover-design study. Subjects were recruited in the Netherlands between November 2014 and July 2016. Patients with Nav1.7-related small fibre neuropathy were randomized to start with lacosamide followed by placebo or vice versa. In both 8-week treatment phases, patients received 200 mg two times a day (BID), preceded by a titration period, and ended by a tapering period. The primary outcome was efficacy, defined as the proportion of patients with 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. The trial is registered with ClinicalTrials.gov, number NCT01911975. Twenty-four subjects received lacosamide, and 23 received placebo. In 58.3% of patients receiving lacosamide, mean average pain decreased by at least 1 point, compared to 21.7% in the placebo group [sensitivity analyses, odds ratio 5.65 (95% confidence interval: 1.83-17.41); P = 0.0045]. In the lacosamide group, 33.3% reported that their general condition improved versus 4.3% in the placebo group (P-value = 0.0156). Additionally, a significant decrease in daily sleep interference, and in surface pain intensity was demonstrated. No significant changes in quality of life or autonomic symptoms were found. Lacosamide was well tolerated and safe in use. This study shows that lacosamide has a significant effect on pain, general wellbeing, and sleep quality. Lacosamide was well tolerated and safe, suggesting that it can be used for pain treatment in Nav1.7-related small fibre neuropathy.
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Comparison of the relapse rates in seizure-free patients in whom antiepileptic therapy was discontinued and those in whom the therapy was continued: A meta-analysis.
Wang, J, Huang, P, Song, Z
Epilepsy & behavior : E&B. 2019;(Pt A):106577
Abstract
About 70% of patients with epilepsy can be seizure-free with an appropriate treatment. When the seizures are under control, discontinuation of the antiepileptic drugs (AEDs) can help avoid their side effects; however, it may increase the risk of relapse. Some studies have compared the relapse rates between patients in whom AEDs have been continued and those in whom AEDs have been discontinued. However, it is not clear whether AED discontinuation causes a higher seizure recurrence rate. This meta-analysis aimed mainly to determine whether the seizure recurrence rate was different between seizure-free patients in whom AEDs were continued and those in whom AEDs were discontinued. The I2 value was used for assessing the heterogeneity; the Mantel-Haenszel test was used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs). Seven cohort studies and randomized controlled trials (RCTs) met the inclusion criteria. The study quality evaluation was performed respectively using the Newcastle-Ottawa Scale and the Jadad scale. A total of 1253 patients were included. The relapse rate was higher in patients in whom AEDs were discontinued than in those in whom the AED treatment was continued. Furthermore, we also compared the epilepsy recurrence rates after AED discontinuation between seizure-free patients who were on monotherapy with different AEDs (carbamazepine, phenytoin, sodium valproate, and phenobarbitone/primidone). Four studies and 625 patients were included in this analysis. The epilepsy recurrence rates did not significantly differ between the patients on different AED treatment.
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Effects of antiepileptic drugs on cortical excitability in humans: A TMS-EMG and TMS-EEG study.
Darmani, G, Bergmann, TO, Zipser, C, Baur, D, Müller-Dahlhaus, F, Ziemann, U
Human brain mapping. 2019;(4):1276-1289
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Abstract
Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double-blinded randomized placebo-controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco-physiological characterization of TEPs will facilitate utilization of TMS-EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.
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Hyponatremia-Inducing Drugs.
Liamis, G, Megapanou, E, Elisaf, M, Milionis, H
Frontiers of hormone research. 2019;:167-177
Abstract
In clinical practice, several medications such as diuretics, psychotropic drugs, and anticonvulsants have been reported to be a frequent cause of hyponatremia. Drugs may cause hyponatremia either by affecting the homeostasis of sodium and water (e.g., diuretics) or by altering the water homeostasis as a consequence of the syndrome of inappropriate secretion of antidiuretic hormone. On the contrary, drugs commonly prescribed in everyday clinical practice, including proton pump inhibitors, antibiotics, angiotensin-converting enzyme inhibitors, hypoglycemic agents and, amiodarone, have been infrequently 'incriminated' as causes of hyponatremia. Therefore, in the diagnostic approach of patients with low serum [Na+] levels, meticulous history taking and recording of pharmacotherapy is warranted to identify potentially culprit medications. Taking into account the adverse outcomes associated with even mild hyponatremia (i.e., impaired cognition, falls and fractures, mortality), recognition of drug-induced hyponatremia is of vital importance, while responsible agents should be discontinued and "re-challenge" should be avoided by informing the patient and involved caregivers.
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Antiepileptic Drug Treatment of Epilepsy in Children.
Moosa, ANV
Continuum (Minneapolis, Minn.). 2019;(2):381-407
Abstract
PURPOSE OF REVIEW The treatment of epilepsy in children is highly individualized at each and every major step in the management. This review examines various factors that modify the treatment from the point of initiation of therapy to the decision to stop an antiepileptic drug (AED). RECENT FINDINGS AED therapy leads to seizure freedom in about 70% of all children with epilepsy. AED initiation could be delayed until a second seizure in most children and may be avoided altogether in many children with self-limited childhood focal epilepsies. Three key factors influence the choice of AED: seizure type(s), efficacy of the drug for the seizure type, and the side effect profile of the drug(s). For epileptic spasms, steroids and vigabatrin are the most effective treatment options. For absence seizures, ethosuximide and valproic acid are superior to lamotrigine. For focal seizures, many newer AEDs have favorable side effect profiles with efficacy comparable to older-generation drugs. For generalized epilepsies, valproic acid remains the most effective drug for a broad range of seizure types. Genetic and metabolic etiologies may guide unique treatment choices in some children. After 2 years or more of seizure freedom, if the recurrence risk after AED withdrawal is acceptable, slow weaning of AEDs should be done over the span of 6 weeks or longer. After discontinuation, about 70% of patients remain seizure free, and of those with recurrence, the majority achieve seizure control with restarting an AED. When treatment with two or more AEDs fails, other treatment opportunities for drug-resistant epilepsy, including epilepsy surgery, vagal nerve stimulation, and dietary therapies should be considered. SUMMARY Carefully selected medical therapy guided by seizure type and AED characteristics is effective in more than two-thirds of children with epilepsy.