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Short-Term Vitamin D3 Supplementation in Children with Neurodisabilities: Comparison of Two Delivery Methods.
Penagini, F, Borsani, B, Maruca, K, Giosia, V, Bova, S, Mastrangelo, M, Zuccotti, GV, Mora, S
Hormone research in paediatrics. 2017;(3-4):281-284
Abstract
BACKGROUND/AIMS: Vitamin D deficiency is common in children with neurodisabilities. Oral vitamin D3 may not be absorbed appropriately due to dysphagia and tube feeding. The aim of this study was to compare efficacy of vitamin D3 buccal spray with that of oral drops. METHODS Twenty-four children with neurodisabilities (5-17 years) and vitamin D deficiency (25(OH)D ≤20 ng/mL) were randomized to receive vitamin D3 buccal spray 800 IU/daily (n = 12) or oral drops 750 IU/daily (n = 12) for 3 months during winter. RESULTS Both groups had a significant increase in 25(OH)D (z = 150; p < 0.0001). The differences between baseline and final parathyroid hormone measurements did not reach significance in both groups. Markers of bone formation and resorption did not change significantly in both groups. The satisfaction with the formulation was significantly higher in the patients using spray. CONCLUSION Vitamin D3 supplementation with buccal spray and oral drops are equally effective in short-term treatment of vitamin D deficiency in children with neurodisabilities. Buccal spray may be more acceptable by the patients.
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Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health.
Hakami, T, O'Brien, TJ, Petty, SJ, Sakellarides, M, Christie, J, Kantor, S, Todaro, M, Gorelik, A, Seibel, MJ, Yerra, R, et al
Calcified tissue international. 2016;(6):556-65
Abstract
Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0 %; p < 0.001 in levetiracetam vs. -9.8 %; p < 0.001 in older AED group), FA (-1.46 %; p < 0.001 vs. -0.96 %; p < 0.001, respectively) and radial trabecular BMD (-1.46 %; p = 0.048 and -2.31 %; p = 0.013, respectively). C-terminal telopeptides of type I collagen (βCTX; bone resorption marker) decreased in both groups (-16.1 %; p = 0.021 vs. -15.2 %; p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (-27.3 %; p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover.
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Favorable change of lipid profile after carbamazepine withdrawal.
Lossius, MI, Nakken, KO, Mowinckel, P, Taubøll, E, Gjerstad, L
Acta neurologica Scandinavica. 2016;(3):219-23
Abstract
OBJECTIVE Patients treated with carbamazepine (CBZ) have increased serum levels of total cholesterol (TC), high-density lipoproteins (HDL), and low-density lipoproteins (LDL). We aimed to investigate whether these changes of serum lipids are reversible after CBZ withdrawal. MATERIAL AND METHODS We used a prospective, randomized double-blinded design. A total of 160 patients who had been seizure free on anti-epileptic drug monotherapy for more than 2 years were included and randomized to withdrawal or not. The intervention was completed by 150 (80 females, 53%) patients. Serum samples from before and 4 months after completed withdrawal or no withdrawal were obtained from 130 patients (63 females, 48%). Of these, 84 were treated with CBZ, 28 with valproate, nine with phenytoin, four with phenobarbital, and five with lamotrigine. Of the patients who had been treated with CBZ, 47 were randomized to the withdrawal group, and 37 were randomized to the non-withdrawal group. RESULTS Among the CBZ-treated patients, a significant decrease in serum levels of TC, LDL, and apolipoprotein B (ApoB) were found in the withdrawal group compared with the non-withdrawal group. Mean differences in change were as follows: TC 0.68 mmol/l (P = 0.005, CL - 1.15 to -0.21); LDL - 0.67 mmol/l (P = 0.001, CL - 1.03 to -0.29); ApoB - 0.13 g/l (P = 0.02, CL - 0.23 to -0.03). No significant changes in HDL, apolipoprotein A, and C-reactive protein were detected. CONCLUSION Our results indicate that CBZ may have unfavorable effects on serum levels of TC, LDL, and ApoB. However, these changes seem to be reversible even after years of treatment.
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Comparative effectiveness of levetiracetam, valproate and carbamazepine among elderly patients with newly diagnosed epilepsy: subgroup analysis of the randomized, unblinded KOMET study.
Pohlmann-Eden, B, Marson, AG, Noack-Rink, M, Ramirez, F, Tofighy, A, Werhahn, KJ, Wild, I, Trinka, E
BMC neurology. 2016;(1):149
Abstract
BACKGROUND Few clinical trials have evaluated the efficacy and tolerability of antiepileptic drugs (AEDs) as initial monotherapy for elderly patients. METHODS This post-hoc subgroup analysis of data from an unblinded, randomized, 52-week superiority study (KOMET) compared the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients aged ≥ 60 years with newly diagnosed epilepsy. The physician chose VPA or CBZ as preferred standard treatment; patients were randomized to standard AEDs or LEV. The primary endpoint was time to treatment withdrawal. Results are exploratory, since KOMET was not powered for a subgroup analysis by age. RESULTS Patients (n = 308) were randomized to LEV (n = 48) or VPA-ER (n = 53) in the VPE-ER stratum or to LEV (n = 104) or CBZ-CR (n = 103) in the CBZ-CR stratum. Mean age was 69.6 years, range 60.2-89.9 years (intention-to-treat population n = 307). Time to treatment withdrawal hazard ratio [HR] (95 % confidence interval [CI]) for LEV vs. standard AEDs was 0.44 (0.28-0.67); LEV vs. VPA-ER: 0.46 (0.16-1.33); LEV vs. CBZ-CR: 0.45 (0.28-0.72). Twelve-month withdrawal rates were: LEV vs. standard AEDs, 20.4 vs. 38.7 %; LEV vs. VPA-ER, 10.4 vs. 23.1 %; LEV vs. CBZ-CR, 25.0 vs. 46.6 %. Time to first seizure was similar between LEV and standard AEDs (HR: 0.92, 95 % CI: 0.63-1.35), LEV and VPA-ER (0.77, 0.38-1.56), and LEV and CBZ-CR (1.02, 0.64-1.63). Adverse events were reported by 76.2, 67.3, and 82.5 % of patients for LEV, VPA-ER, and CBZ-CR, respectively. Discontinuation rates due to AEs were 11.3, 10.2, and 35.0 % for LEV, VPA-ER, and CBZ-CR, respectively. CONCLUSIONS Time to treatment withdrawal was longer with LEV compared with standard AEDs. This finding was driven primarly by the result in the CBZ-CR stratum, which in turn was likely due to the more favorable tolerability profile of LEV. Results of this post-hoc analysis suggest that LEV may be a suitable option for initial monotherapy for patients aged ≥ 60 years with newly diagnosed epilepsy. TRIAL REGISTRATION ClinicalTrials.gov: NCT00175903 ; September 9, 2005.
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Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes.
Kwan, P, Brodie, MJ, Laurenza, A, FitzGibbon, H, Gidal, BE
Epilepsy research. 2015;:117-24
Abstract
AIM: To further explore the impact of concomitant antiepileptic drugs (AEDs) on the efficacy and tolerability of adjunctive perampanel for focal epilepsy. METHODS Data were pooled from three phase III trials of adjunctive perampanel in patients (≥12 years of age) with refractory partial-onset seizures. Concomitant AEDs were categorized according to whether or not they were enzyme-inducing AEDs (EIAEDs; known to reduce perampanel plasma concentrations) or sodium channel blockers (SCBs). Post hoc analyses assessed the impact of co-administration of non-EIAED SCBs and the overall number of concomitant AEDs on changes in seizure frequency, 50% responder rates, rates of treatment-emergent adverse events (TEAEs), and rates of discontinuation due to TEAEs, in patients randomized to receive daily placebo or perampanel 2, 4, 8, or 12mg. RESULTS Amongst 1480 randomized and treated patients, most were receiving two or more concomitant AEDs (n=1273, 86.0%), one or more EIAEDs (n=1083, 73.2%), and/or one or more SCBs (n=1203, 81.3%) at Baseline. The magnitude of seizure reduction appeared unaffected by the presence of non-EIAED SCBs, but lower in the presence of multiple AEDs. Frequency of TEAEs did not appear to be affected by the presence of non-EIAED SCBs or multiple AEDs. CONCLUSION Beyond the known interactions between perampanel and EIAEDs, perampanel efficacy appears to be unaffected by the use of concomitant non-EIAED SCBs, but may be reduced in the presence of multiple concomitant AEDs (possibly indicative of the presence of more refractory epilepsy). Nonetheless, with careful titration to balance efficacy and tolerability, perampanel may be combined with a range of AEDs, facilitating integration into treatment plans.
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A pilot double-blind trial using verapamil as adjuvant therapy for refractory seizures.
Borlot, F, Wither, RG, Ali, A, Wu, N, Verocai, F, Andrade, DM
Epilepsy research. 2014;(9):1642-51
Abstract
RATIONALE Given verapamil's property as a glycoprotein inhibitor, this drug could increase the effective concentration of antiepileptic drugs (AEDs) in the epileptic foci, reducing the number of seizures. This pilot study was designed to evaluate the safety and efficacy of verapamil as adjunct therapy in pharmacoresistant patients with focal onset seizures. METHODS This was a single-centered, randomized, double-blind and placebo-controlled trial evaluating verapamil as an add-on therapy for adult patients with refractory epilepsy. RESULTS Twenty-two patients were randomized, but five of them withdrew and one patient passed away after consent, having no exposure to either verapamil or placebo; four patients withdrew during or after the double-blind phase due to side effects. From these four patients, only one patient was in the verapamil group. Twelve patients (59%) finished the study. Some patients experienced lower seizure frequencies, but none of them reached 50% reduction. In addition, there was no statistically significant decrease in the seizure frequency of patients receiving verapamil. When comparing the verapamil with the placebo at the double-blind or the open label study phases, the average difference in seizure range also failed to show significance (p=0.41 and p=0.98, respectively). No significant cardiovascular effects were observed, and side effects unique to verapamil were skin rashes and feet edema. Throughout the study, carbamazepine, valproic acid and clobazam levels increased following verapamil intake; minor dosage adjustment was required in one patient on carbamazepine. CONCLUSIONS This pilot study has shown mild benefits of verapamil use in comparison to placebo as an add-on therapy for a group of non-selected patients with refractory epilepsy. A partial response in a subset of patients was seen. No significant safety problems happened, but adjustments on AEDs may be required during verapamil use.
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Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial.
Klinkenberg, S, Aalbers, MW, Vles, JS, Cornips, EM, Rijkers, K, Leenen, L, Kessels, FG, Aldenkamp, AP, Majoie, M
Developmental medicine and child neurology. 2012;(9):855-61
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Abstract
AIM: The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety. METHOD In this study, the first randomized active controlled trial of its kind in children, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo-17y 8mo) were included. Thirty-five participants had localization-related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high-output VNS (maximally 1.75mA) and the other half received low-output stimulation (0.25mA). Finally, all participants received high-output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi-structured interviews. RESULTS At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high-output stimulation group and in 21% of the low-output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add-on phase The overall seizure severity also improved (p<0.001). INTERPRETATION VNS is a safe and well-tolerated adjunctive treatment of epilepsy in children. Our results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well-being makes this treatment worth considering in individual children with intractable epilepsy.
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Efficacy of 4:1 (classic) versus 2.5:1 ketogenic ratio diets in refractory epilepsy in young children: a randomized open labeled study.
Raju, KN, Gulati, S, Kabra, M, Agarwala, A, Sharma, S, Pandey, RM, Kalra, V
Epilepsy research. 2011;(1-2):96-100
Abstract
PURPOSE The ketogenic (lipid to non-lipid) ratio may play an important role in the efficacy and tolerability of ketogenic diets (KD). This study was planned to compare the efficacy and tolerability of 2.5:1 versus 4:1 lipid:non-lipid ratio KD in young children with refractory epilepsy. METHODS Children aged 6 months to 5 years with refractory epilepsy were enrolled. They were randomized to receive either a 4:1 or 2.5:1 ketogenic ratio diet, which was introduced using a non-fasting protocol. Seizure frequency, biochemical profile (liver and kidney function tests, fasting lipid profile, and spot urinary calcium-creatinine ratio), and adverse effects were recorded at three months in both groups. RESULTS Thirty eight children were enrolled, 19 in each group. At three months, 11 children (58%) in the 4:1 group and 12 (63%) in the 2.5:1 group had more than 50% reduction in seizures (p=0.78). Five children (26%) in the 4:1 group and four (21%) in 2.5:1 group became seizure free. There was no significant difference in the biochemical parameters between the two groups. CONCLUSION 2.5:1 ratio KD is possibly as effective as 4:1 KD in controlling seizures and has fewer adverse effects.
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Growth failure in children with intractable epilepsy is not due to increased resting energy expenditure.
Bergqvist, AG, Trabulsi, J, Schall, JI, Stallings, VA
Developmental medicine and child neurology. 2008;(6):439-44
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The aim of this study was to evaluate the resting energy expenditure (REE) of children with intractable epilepsy (IE) compared with healthy children, and to determine factors that contribute to the pattern of REE. REE, growth status, and body composition were assessed in 25 prepubertal children with IE (15 males, 10 females; mean age 5y 5mo [SD 2y 2mo] range 2-9y) with and without cerebral palsy (CP) and compared with those in 75 healthy children of similar age, sex, and fat free mass (FFM; 43 males, 32 females; mean age 6y 4mo [SD 1y 8mo], range 2-9y). Of the 25 children with IE, 12 had generalized and 13 partial seizures; 10 children had CP (four hemiplegia, one diplegia, and five tetraplegia); 18 were ambulators. REE (kcal/d), determined by indirect calorimetry, was expressed as a percentage of that predicted using Schofield equations. Energy intake from 3-day weighed food records was assessed for children with IE only and expressed as a percentage of estimated energy requirement. Compared with healthy children, children with IE had significantly lower percentage (Student's t-test, p<0.05) of predicted REE (111 [SD 13] vs 104 [SD 4]), weight z-score, body mass index z-score, and FFM. Using multiple regression, REE adjusted for FFM, fat mass, and sex were significantly lower in children with IE and CP (-110 kcal/d, 95% confidence interval -199 to -21, p=0.016). In children with IE, energy intake was also a statistically significant predictor of REE. CP largely explained the suboptimal growth status and lower REE of children with IE compared with healthy children.
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Sodium valproate versus lamotrigine: a randomised comparison of efficacy, tolerability and effects on circulating androgenic hormones in newly diagnosed epilepsy.
Stephen, LJ, Sills, GJ, Leach, JP, Butler, E, Parker, P, Hitiris, N, Leach, VM, Wilson, EA, Brodie, MJ
Epilepsy research. 2007;(2-3):122-9
Abstract
We have performed a randomised, prospective study to compare the efficacy and tolerability of sodium valproate (VPA) and lamotrigine (LTG) monotherapy, and their effects on circulating androgenic hormones, in newly diagnosed epilepsy. A total of 225 patients (116 male; median age 35 years, range 13-80 years) were followed-up at 6-weekly intervals until they reached an end-point (12 months' seizure freedom; withdrawal due to intolerable side-effects; lack of efficacy despite adequate dosing). Twelve month seizure-free rates were identical (47%) in the VPA (n=111) and LTG (n=114) treatment arms. More patients taking VPA withdrew from the study due to adverse events (26 VPA versus 15 LTG; p=0.046). Eight patients, all taking VPA, dropped out during the first 6 months due to weight gain. There were no changes in mean serum concentrations of testosterone, sex-hormone binding globulin and androstenedione or in the free androgen index after 6 or 12 months' treatment with either drug in 112 patients who fulfilled the criteria for hormone analysis. No difference in efficacy was found between VPA and LTG in our patients with newly diagnosed epilepsy. LTG appeared to be better tolerated. Neither drug appeared to alter the circulating levels of androgenic hormones.