Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--antiepileptic drug and osteoporosis prevention trial. AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies. Systematic screening allows reduction of adverse antiepileptic drug effects Early predisposition to osteomalacia in Indian adults on phenytoin or valproate monotherapy and effective prophylaxis by simultaneous supplementation with calcium and 25-hydroxy vitamin D at recommended daily allowance dosage: a prospective study. Quantifying the response to antiepileptic drugs Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment.
PURPOSE To evaluate whether use of a bisphosphonate ( risedronate ) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs ( AEDs ) long term can prevent the loss of bone mass ( BMD , bone mineral density ) associated with AED use compared to patients who were treated with a placebo plus calcium and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral fractures . METHODS Antiepileptic drug and osteoporosis prevention trial ( ADOPT ) was design ed as a prospect i ve 2-year double-blind , r and omized placebo controlled study involving 80 male veterans with epilepsy who were being treated with AEDs such as phenytoin , phenobarbital , sodium valproate , or carbamazepine for a minimum of 2 years . All enrolled participants received calcium and vitamin D supplementation , and were r and omized to risedronate or matching placebo .  Total body , bilateral proximal femora , and anteroposterior ( AP ) lumbar spine BMDs in addition to morphometric lateral vertebral assessment s ( LVAs ) were evaluated by a dual energy x-ray absorptiometry ( DXA ) instrument . Comparisons of BMDs were made between baseline , 1 year , and after 2 years of enrollment in the study . The incidence of new vertebral and nonvertebral fractures was secondary end point . KEY FINDINGS Of the 80 patients initially enrolled in the study , 53 patients completed the study . Baseline characteristics of the two groups were similar . At the end of the study , in the placebo plus calcium and vitamin D group , we observed a significant improvement in BMD at any of the evaluated sites when compared to their baseline scans in 69 % ( 18/26 ) of the participants . In the risedronate plus calcium and vitamin D group , we observed significant improvement of BMDs in 70 % ( 19/27 ) of the participants . At the end of the study , the risedronate group experienced a significant increase of BMD at the lumbar spine L1 - 4 ( 1.267 - 1.332 g/cm(2 ) ) , which was significantly larger than that seen in the placebo group ) ( 1.229 g/cm(2 ) vs. 1.245 g/cm(2 ) ; p = 0.0066).There were nonsignificant differences between the two groups regarding changes of total body BMD or at the proximal bilateral femora . Five new vertebral fractures and one nonvertebral fracture were observed only in the placebo group . SIGNIFICANCE Calcium and vitamin D supplementation or calcium and vitamin D supplementation in addition to risedronate improved BMD in more than 69 % of male veterans with epilepsy who were taking AEDs . In the group receiving risedronate plus calcium and vitamin D there was a significant improvement of BMD at the lumbar spine as compared to the placebo group , which also received calcium and vitamin D. The use of risedronate plus calcium and vitamin D prevented the incidence of new vertebral fractures and one nonvertebral fracture in this cohort BACKGROUND Pregnant women with epilepsy on antiepileptic drugs ( AEDs ) may experience a reduction in serum AED levels . This has the potential to worsen seizure control . OBJECTIVE To determine if , in pregnant women with epilepsy on AEDs , additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels . DESIGN A double-blind , r and omised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken . Stratified block r and omisation with a 1 : 1 allocation method was carried out . SETTING Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK . PARTICIPANTS Pregnant women with epilepsy on one or more of the following AEDs : lamotrigine , carbamazepine , phenytoin or levetiracetam .  Women with a ≥ 25 % decrease in serum AED level from baseline were r and omised to therapeutic drug monitoring or clinical features monitoring strategies . INTERVENTIONS In the therapeutic drug monitoring group , clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control . In the clinical features monitoring group , AED dosage adjustment was based only on clinical features . MAIN OUTCOME MEASURES Primary outcome - seizure deterioration , defined as time to first seizure and to all seizures after r and omisation per woman until 6 weeks post partum . Secondary outcomes - pregnancy complications in mother and offspring , maternal quality of life , seizure rates in cohorts with stable serum AED level , AED dose exposure and adverse events related to AEDs . ANALYSIS Analysis of time to first and to all seizures after r and omisation was performed using a Cox proportional hazards model , and multivariate failure time analysis by the And ersen-Gill model . The effects were reported as hazard ratios ( HRs ) with 95 % confidence intervals ( CIs ) . Secondary outcomes were reported as mean differences ( MDs ) or odds ratios . RESULTS A total of 130 women were r and omised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group ; 294 women did not have a reduction in serum AED level . A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group ( 98 % of complete data ) were included in the primary analysis . There were no significant differences in the time to first seizure ( HR 0.82 , 95 % CI 0.55 to 1.2 ) or timing of all seizures after r and omisation ( HR 1.3 , 95 % CI 0.7 to 2.5 ) between both trial groups . In comparison with the group with stable serum AED levels , there were no significant increases in seizures in the clinical features monitoring ( odds ratio 0.93 , 95 % CI 0.56 to 1.5 ) or therapeutic drug monitoring group ( odds ratio 0.93 , 95 % CI 0.56 to 1.5 ) associated with a reduction in serum AED levels . Maternal and neonatal outcomes were similar in both groups , except for higher cord blood levels of lamotrigine ( MD 0.55 mg/l , 95 % CI 0.11 to 1 mg/l ) or levetiracetam ( MD 7.8 mg/l , 95 % CI 0.86 to 14.8 mg/l ) in the therapeutic drug monitoring group than in the clinical features monitoring group . There were no differences between the groups on daily AED exposure or quality of life . An increase in exposure to lamotrigine , levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs , but not maternal or fetal complications . Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs . LIMITATIONS Fewer women than the original target were recruited . CONCLUSION There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes . FUTURE WORK RECOMMENDATIONS Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both r and omised groups is needed . An individualised prediction model will help to identify those women who need close monitoring in pregnancy . TRIAL REGISTRATION Current Controlled Trials IS RCT N01253916 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 22 , No. 23 . See the NIHR Journals Library website for further project information Objective : To determine the effectiveness of systematic screening with a brief 19-item self-report instrument , the Adverse Events Profile ( AEP ) , to reduce adverse effects of antiepileptic drugs ( AEDs ) and improve subjective health status . Methods : The authors performed a prospect i ve r and omized trial comparing the use of the AEP with usual care without the AEP .  Sixty-two patients with an AEP score of ≥45 were enrolled from a consecutive group of 200 consenting adults with epilepsy . Results : The mean percent improvement in AEP scores was greater in the patient group for which clinicians received the AEP compared with the usual care group ( 25 % vs 5 % ; p < 0.01 ) . Mean change in Quality of Life in Epilepsy Inventory (QOLIE)-89 total scores was not different between groups , but for the entire sample QOLIE-89 change was greater for patients having a 15-point improvement in AEP scores than for those with a 0- to 15-point improvement or a worsened score ( 24 vs 12 vs 3 ; analysis of variance , p < 0.008 ) . More patients in the AEP group had a > 15-point improvement in QOLIE-89 score ( p < 0.03 ) . Use of the AEP was associated with a 2.8-fold increase ( 95 % CI , 1.7 to 4.8 ) in AED modifications . No difference in seizure rates was observed . Conclusions : Systematic screening for antiepileptic drug side effects may increase identification of toxicity and guide medication changes to reduce adverse effects and possibly improve subjective health status BACKGROUND Long-term therapy with antiepileptic drugs ( AED ) may be associated with increased total serum alkaline phosphatase ( ALP ) levels and reduced serum calcium , inorganic phosphorous , and vitamin D levels . These adverse biochemical alterations have an adverse effect on bone health . OBJECTIVE To determine ( a ) onset of derangements in serum total ALP and its isoenzymes ( liver , bone ) , calcium and 25-hydroxy vitamin D ( 25-OHD ) concentrations after initiation of treatment with phenytoin or valproic acid monotherapy  and ( b ) the effect of simultaneous supplementation with calcium and 25-OHD at recommended daily allowance ( RDA ) dosage , on these biochemical parameters . MATERIAL S AND METHODS Study was a prospect i ve , case-controlled study in adults . Serum biochemical parameters were estimated at baseline , 30 , 60 , and 90 days of starting AED treatment in the study subjects : Groups -- A ( only calcium supplementation ) and Group B ( both calcium and 25-OHD supplementation ) . STATISTICAL ANALYSIS Mean+/-SD , and students ' paired t test ( between groups A and B ) unpaired students ' t test ( drug-wise ) . RESULTS At 60 days of AED therapy Group A showed a significant increase in serum total ALP ( 78.83+/-11.04 to 101.75 + /- 9.56 IU/l ) ( P < 0.001 ) , ALP-liver isoenzyme , ( 41.97+/- 10.81 to 68.83 + /-7.81 IU/L ) ( P < 0.001 ) , significant decrease in calcium ( 9.30 + /- 0.36 to 8.80 + /- 0.38 mg% ) ( P < 0.001 ) , ALP-bone isoenyzme ( 36.84 + /- 5.01 to 32.92 + /- 6.46 IU/L ) ( P < 0.001 ) , and a significant decrease in 25-OHD ( 25.19 + /- 5.98 to 19.76 + /- 5.35 ng/ml ) ( P < 0.001 ) at 90 days . In contrast Group B , at 60 days , showed a significant decrease in serum total ALP ( 81.92 + /- 19.63 to 54.77 . + /- 11.53 IU/L ) ( P < 0.0001 ) , ALP-liver isoenzyme ( 48.01 . + /- 13.53 to 28.12 . + /- 5.88 IU/L ) ( P < 0.0001 ) , significant increase in calcium ( ( 9.24 + /- 0.31 to 9.93 + /- 0.26 mg% ) ( P < 0.001 ) and ALP-bone isoenzyme levels ( 33.93 + /- 12.2 to 26.25 + /- 8.23 IU/L ) . In Group B , 25-OHD levels showed a significant increase at 90 days ( 24.36 + /- 3.42 to 31.53 + /- 327 ng/ml ) ( P < 0.0001 ) . CONCLUSION Biochemical derangements in calcium metabolism involving the bone are seen by 60 days after starting AED monotherapy , indicating predisposition to development of osteomalacia in these patients . This is preventable by simultaneous oral supplementation with calcium and 25-OHD Objective : To quantify the response to treatment with antiepileptic drugs ( AEDs ) as a function of the past treatment history and identify additional prognostic factors for predicting the response to newly administered AED treatments . Methods : A cohort of 478 consecutive patients who received newly administered AED treatments between January 1999 and December 2004 and were followed prospect ively for 1.5 to 7.5 years in a single epilepsy clinic . Results : The response to newly administered AED treatments was highly dependent on the past treatment history . The seizure-free rates decreased from 61.8 % for the first AED to 41.7 % , 16.6 % , and 0 % after one , two to five , and six to seven past AEDs proved inefficient . This response curve corresponded to a mono-exponential function with a maximal response of 61.8 % and half-decay constant of 1.5 AEDs . Likewise the response curve describing a greater than 50 % reduction in seizure frequency corresponded to a mono-exponential function with a maximal response of 85.3 % and half-decay constant of two AEDs . Three additional independent prognostic factors for predicting the response to AEDs were identified : type of epilepsy , duration of epilepsy , and number of seizures in the 3 months prior to AED initiation . Conclusion : Drug resistance is a grade d process that follows a mono-exponential course with a half-decay constant of 1.5 to two antiepileptic drugs ( AEDs ) . Although relative drug-resistant epilepsy can be diagnosed after failure of two past AEDs , absolute drug resistance requires failure of six AEDs , as a significant minority of patients ( 16.6 % ) is rendered seizure-free by addition of newly administered AEDs even after failure of two to five past antiepileptic drugs . GLOSSARY : AED = antiepileptic drug ; CBZ = carbamazepine ; GBP = gabapentin ; LTG = lamotrigine ; TPM = topiramate ; VA = valproic acid Infants born to epileptic women treated with antiepileptic drugs ( AEDs )  have an increased risk of major congenital malformations ( MCMs ) . In order to determine the role of maternal epilepsy we conducted a prospect i ve cohort study on three cohorts of pregnant women : ( i ) 385 epileptic women treated with AEDs , ( ii ) 310 non-epileptic women treated with AEDs , ( iii ) 867 healthy women not exposed to AEDs ( control group ) . The rate of MCMs in the epileptic group ( 7.7 % ) was not statistically higher than in the non-epileptic one ( 3.9 % ) ( p=0.068 ) . The rate in the first group was higher compared to the control group ( p=0.001 ) , while the rate in the second one was not ( p=0.534 ) . Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women ; however a teratogenic role of the maternal epilepsy itself can not be excluded
All 6 studies that investigated bone mineralization had significant findings ; however , due to varying method ologies , the impact of vitamin D on bone mineralization was inconclusive .
SIGNIFICANCE Vitamin D does appear to have some benefit to bone health in adults with epilepsy , and therefore supplementation could potentially be a requisite to using some AEDs .
OBJECTIVE Several antiepileptic drugs ( AEDs ) have been associated with a detrimental effect on bone health through a reduction in serum vitamin D. Subsequently , several studies have investigated the effect of vitamin D supplementation in persons with epilepsy being treated with AEDs .
The present systematic review of published literature was conducted to determine the effect of vitamin D intervention on bone health in adults with epilepsy .