Interictal EEG prediction of response to antiepileptic drug monotherapy

Forty-eight patients had sleep-deprived EEGs prior to antiepileptic drug monotherapy. The majority were seizure-free after one year, or had more than 50% reduction in seizure frequency. Among those with normal EEGs 50% were seizure-free, while 75% with diffuse slowing, 44% with focal abnormality, and 83% with generalized epileptiform discharges were fully controlled. Freedom from seizures was achieved in 13% taking phenobarbital, 50% taking phenytoin, 63% taking carbamazepine, and 100% taking valproate. The sleep-deprived interictal EEG should be an integral part of initial assessment and drug selection in patients with clinical histories of convulsive seizure.     

Bone mineral status in pediatric outpatients on antiepileptic drug monotherapy

Drug-induced osteopenia has been reported in institutionalized children on chronic antiepileptic drug therapy. The aim of this study was to assess longitudinally bone mineral status in pediatric outpatients on antiepileptic drug monotherapy. The study group consisted of 30 ambulatory children on a normal diet: 15 on valproic acid, 11 on carbamazepine, and 4 on phenobarbital monotherapy. Bone mineral density, serum active vitamin D (1,25-dihydroxyvitamin D), and certain biochemical markers of bone formation (calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, osteocalcin, calcitonin, and urinary calcium to serum creatinine and urinary phosphorus to serum creatinine ratios) were studied at the beginning of antiepileptic drug monotherapy and at the end of 2 years of treatment. Age- and sex-specific Z-scores of bone mineral density were measured at anterior-posterior L2-L4 by dual-energy x-ray absorptiometry. Drug-induced osteopenia was defined in only two patients (one on carbamazepine and the other on phenobarbital monotherapy), with Z-scores of bone mineral density less than -1.5. Serum levels of active vitamin D and biochemical markers were not significantly correlated with the Z-scores of bone mineral density. We detected a frequency of antiepileptic drug-induced osteopenia of 6.7% in pediatric outpatients after 2 years of monotherapy. However, osteopenia was not attributed to a defect in serum active vitamin D production owing to hyperparathyroidism in children on antiepileptic drug monotherapy.     

抗癫痫药物四种对中青年绝经前女性骨代谢的影响

目的研究不同的常用抗癫痫药物对中青年女性骨代谢的影响。方法通过测量各组受试者的血清钙、25-羟基维生素D、碱性磷酸酶、甲状旁腺激素、胰岛素生长因子-1、胰岛素结合蛋白-3、骨密度等,分析长期单药服用不同抗癫痫药物如苯妥英钠(PHT)、卡马西平(CBZ)、丙戊酸钠(VPA)、左乙拉西坦(LEV)等对受试者骨代谢的影响。结果服用CBZ、PHT和VPA的受试者血清钙浓度低于服用LEV的受试者(P=0.002);服用PHT的受试者的ALP浓度显著高于服用CBZ、LEV和VPA的受试者(P=0.000);与LEV组相比,PHT组血清IGF-1水平降低(P=0.03);与LEV组相比,PHT组血清的IGFBP-3浓度显著降低(P=0.000)。结论抗癫痫药物会影响骨代谢,导致患者血清钙下降、骨量减低。LEV较其他抗癫痫药物对骨代谢的影响较小,但仍能造成患者碱性磷酸酶含量下降等。抗癫痫药物对中青年女性的骨代谢会产生一定影响,在临床用药过程中需监测相关指标。     

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

Purpose: Long‐term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long‐term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. Methods: One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme‐inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme‐inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B‐mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C‐reactive protein (hs‐CRP), or thiobarbituric acid reactive substances (TBARS). Key Findings: Long‐term monotherapy with older‐generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme‐inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs‐CRP. On the other hand, patients on enzyme‐inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long‐term LTG monotherapy. Significance: Patients with epilepsy who were receiving long‐term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long‐term AED therapy, particularly in aged and high‐risk individuals.     

Efficacy and limitations of antiepileptic drug monotherapy for temporal lobe epilepsy]

To evaluate the efficacy of antiepileptic drug (AED) monotherapy, we studied 147 patients with temporal lobe epilepsy (TLE) aged 15 or older who had been undergoing treatment at our hospital for at least five consecutive years. We divided the treatment time into Period I which included one year beginning six months after the initial diagnosis, and Period II which was the two years from January, 1987 to December, 1989. The efficacy of therapy was evaluated for the two periods based on the following standards: effective, if seizures had been controlled, and ineffective, if at least one seizure had occurred during each period. Patients in whom monotherapy was effective increased by a factor of 1.7 over the period of observation, from 38 cases (28%) in Period I to 65 cases (44%) in Period II. The total number of effectively treated cases (including those on polytherapy) also rose from 58 cases (40%) in Period I to 79 cases (54%) in Period II. The average number of AEDs used was reduced from 3.0 +/- 1.3 at the time of initial diagnosis to 1.8 +/- 0.8 in Period I and 1.6 +/- 0.8 in Period II. When compared with the 68 ineffectively treated cases, significant background factors for the 65 effectively treated cases on monotherapy included: higher age at ictal onset, fewer histories of any previous treatment at initial diagnosis, or of encephalitis or febrile seizures, fewer psychological impairments such as cognitive degeneration or personality disorders, lower frequency of seizures, fewer histories of secondary generalization or automatism, and a higher rate of normal findings of background EEG and cerebral CT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy

PURPOSE: Women with epilepsy (WWE) tend to have hormonal and metabolic abnormalities, raising concerns about an increased risk of cardiovascular disorders. This study was performed to determine whether epilepsy itself and/or antiepileptic drug (AED) medication cause metabolic abnormalities. METHODS: WWE in premenopausal state aged 18 to 45 years old, currently on AED monotherapy for more than six months, were recruited for this study. The subjects checked their oral temperature each morning, and tested serum levels for lipid profiles, insulin, glucose, and leptin. A HOMA-index was used as a marker for insulin resistance. RESULTS: Of the 54 total patients, 18 women were diagnosed with primary generalized epilepsy (PGE) and the other 36 were diagnosed with localization-related epilepsy (LRE). Among the subjects, 19 women were on carbamazepine (CBZ), 12 on valproate (VPA), 12 on lamotrigine (LTG), and 11 on topiramate (TPM). Body mass index increased and HDL-cholesterol decreased in patients on VPA monotherapy compared with CBZ, LTG, or TPM (p=0.046 and 0.002). Metabolic syndrome was more frequently associated with VPA-treated patients (41.7%) than CBZ (5.3%), LTG (0%), or TPM group (0%) (p=0.005). There were no differences in hormonal and metabolic indices between PGE and LRE groups. CONCLUSIONS: WWE on VPA monotherapy are more obese and more frequently suffer from metabolic syndrome. LTG or TPM may be safer when prescribed to the patients with high risk of cardiovascular disease.     

Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy

Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.     

Topiramate monotherapy as broad-spectrum antiepileptic drug in a naturalistic clinical setting.

Topiramate was assessed in an open-label trial as broad-spectrum antiepileptic monotherapy, independently from the epilepsy type or syndrome. Adults and children aged 2 years and older, who were diagnosed with epilepsy within the last 5 years, treatment-naive or failing prior treatment with one antiepileptic drug (AED), received individually adjusted doses of topiramate, after escalation to 100mg/day over 4 weeks (maximum 400mg/day) or 3mg/kg/day over 6 weeks (maximum 9 mg/kg/day), respectively. Patients were followed for >or=7 months and optionally up to a maximum of 13 months. Data were analysed for all patients (n=692), as well as for focal (n=421) and generalized epilepsies (n=148). The median topiramate dose used was 125 mg/day in adults and 3.3mg/kg/day in children (or=50% reduction in mean monthly seizure frequency. Patients with focal and generalized epilepsies alike responded to treatment (73.9 and 83.8% with at least 50% seizure reduction): 39.4% of patients with focal epilepsy and 61.5% of those with generalized epilepsy were seizure-free. The mean monthly seizure frequency was significantly reduced versus baseline at all visits (p<0.001). Similar response rates were obtained from the 237 patients completing the 1-year observation period. During the mandatory 7-month period of study, 8.8% of patients reported insufficient tolerability as a reason for dropout. The most frequent adverse event was paraesthesia. Our results support findings that emerge from controlled studies that topiramate is effective and well tolerated when used as initial or second monotherapy. They also suggest that in a naturalistic setting, overall good retention on treatment and seizure freedom are observed at low doses in a broad spectrum of epilepsies.     

Effect of antiepileptic drug monotherapy on urinary pH in children and young adults

Objects Since alkaline urine is a risk factor for urolithiasis, the relationship between antiepileptic drugs and urinary pH was retrospectively studied in epilepsy patients treated with antiepileptic drug monotherapy for more than 1 month.Methods A total of 913 urinary samples from antiepileptic drug-treated patients were compared with 780 age-matched control samples, and with 112 samples from epilepsy patients who had not been treated with antiepileptic drugs. The antiepileptic drugs administered were carbamazepine, valproate, phenobarbital, zonisamide, sulthiame, and phenytoin.Conclusions The proportion of the acid urine in the valproate-treated patients was lower than that in controls. The proportion of the alkaline urine in the valproate-treated patients was higher than that in controls. This effect was independent of age, sex, and the serum valproate concentration. There was no significant difference in urinary pH among the epilepsy patients treated with other antiepileptic drugs, the epilepsy patients who had not been treated with antiepileptic drugs, and the controls.     

A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy

Antiepileptic drugs (AEDs) can affect bone metabolism, but the exact mechanisms or differences in individual drugs are still unknown. The purpose of this study was to prospectively investigate the alterations in bone mineral density (BMD) and markers of bone metabolism induced by different AEDs in Koreans with epilepsy. Subjects included 33 drug-naïve, newly diagnosed patients with epilepsy aged between 18 and 50. BMD at right calcaneus and various markers for bone metabolism were measured before and after 6 months of AED monotherapy including carbamazepine, valproic acid, and lamotrigine. Carbamazepine caused a significant decrease in BMD, which was accompanied by a decrease in the level of vitamin D (25-OHD₃). BMD and vitamin D were not affected by 6 months of valproic acid or lamotrigine therapy. Interestingly, valproic acid and lamotrigine, but not carbamazepine, significantly increased osteocalcin, a marker of bone formation. All AEDs almost doubled the parathyroid hormone level, whereas urinary Pyrilinks, a marker of bone resorption, was not affected by those AEDs. These findings suggest that carbamazepine, a hepatic enzyme-inducing drug, decreases BMD.     

Cortical excitability during prolonged antiepileptic drug treatment and drug withdrawal.

OBJECTIVE: Previous reports characterized the effects of administration of single oral doses of antiepileptic drugs (AED) on cortical excitability. However, AED effects on cortical excitability, and their relationship to plasma blood levels, during chronic drug administration at therapeutic doses are not known. The objective of the study was to determine whether plasma blood levels during chronic administration at therapeutic doses would accurately predict changes in corticomotor excitability. METHODS: We used transcranial magnetic stimulation (TMS) to measure cortical excitability during 5 weeks administration of carbamazepine (CBZ) and lamotrigine (LTG), and subsequent AED withdrawal in 20 healthy volunteers. Data were analyzed using ANOVA(RM) and regression analysis. RESULTS: Resting motor thresholds (r-MT) increased with increasing total and free CBZ and LTG levels during drug administration, but not drug withdrawal. After acute AED withdrawal, r-MT elevation persisted in most individuals with CBZ despite undetectable plasma levels, compared to a rapid normalization with LTG. In contrast, acute drug withdrawal resulted in a transient decrease in r-MT in 3/10 individuals with CBZ and 2/10 with LTG. CONCLUSIONS: Plasma levels provide information on motor cortical function during active treatment phases but not during AED withdrawal. SIGNIFICANCE: The transient decrease in r-MT associated with acute AED withdrawal could represent a physiological substrate contributing to AED withdrawal seizures.     

Capillary microscopy and hemorheology in children during antiepileptic monotherapy with carbamazepine and valproate

The interactions of epilepsy and antiepileptic therapy an one hand and cardiovascular system on the other hand are multiple and complex. Antiepileptic drugs (AEDs) cause alterations of serum lipids and of the fatty acid composition of the membranes. Homocystein, known to induce vascular endothelial damage was found to be elevated in patients on valproate (VPA) and carbamazepine (CBZ) therapy. Marked coronary artherosclerosis and myocardial infarction may already occur in children treated with CBZ. Community based studies corroborated a higher incidence of myocardial infarction, peripheral vascular diseases hypercholesterinemia, left ventricle hypertrophy and stroke in patients with epilepsy. In this context, we wanted to elevate changes of microcirculation related to AEDs commonly prescribed such as VPA and CBZ. Capillary microscopy is a non-invasive technique for measuring the velocity of red blood cells and for determining nutritional blood flow in the capillaries of the skin. It can easily be performed in children. The aim of this study was to look for possible effects an antiepileptic monotherapy with carbamazepine or valproate has on the peripheral microcirculation in epileptic children. We were able to examine 14 children with CBZ and 24 children with VPA, recruited in our neuropediatric Unit. The results were compared to normative values, determined in former analyses of 207 healthy children. We found significant differences in capillary density, tortuous index of the capillaries, capillary diameter and flow rate of erythrocytes for both antiepileptic drugs. Additionally, there were changes in plasma viscosity and the aggregation of erythrocytes. These microcapillary effects could be of special interest in the relationship of a long-term antiepileptic therapy and the development of vascular diseases. We suggest that the influence of AEDs on microcirculation should also be considered in further studies on cardiovascular changes in patients with antiepileptic long-term medication.     

New antiepileptic drug therapies

The introduction of these new antiepileptic drugs, from felbamate to levetiracetam, raised hope of control of epilepsy with fewer adverse effects and improved quality of life. Unfortunately, many patients continue to experience refractory epilepsy despite the use of these new agents, and dose-related adverse effects and idiosyncratic reactions continue to be problematic. A recent report describes six new compounds in preclinical development, and five in clinical trials [131]. As the number of available, effective, but imperfect antiepileptic drugs increases, many challenges remain. These include: choosing the drug appropriate for the epileptic syndrome, assessing accurately the range of a drug's adverse effects in an individual patient, and considering carefully the drug's interactions in combination drug therapy. In considering drug combinations, differing mechanisms of drug action and favorable pharmacodynamic interactions (an area requiring additional studies) are of importance. Clinicians caring for children who have epilepsy anticipate further advances in the pharmacogenetics and molecular pathophysiology of epilepsy, leading to individually tailored, effective, and safe therapy.     

Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy

We hypothesized that elevated plasma homocysteine concentrations (hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and a long-term administration of AED may result in an increased risk of occlusive vascular disease in these patients. A total of 62 patients who received AED monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in this study. Blood concentrations of homocysteine, folate, vitamin B-12 and pyridoxal-5'-phosphate (PLP, a coenzyme form of vitamin B-6) were measured, and thermolabile genotypes of 5, 10-methylenetetrahydrofolate reductase (MTHFR) were also determined. Of 62 patients, only seven (11.4%) had hyperhomocysteinemia. Of 20 patients who received phenytoin, three (15.0%) had hyperhomocysteinemia, whereas 85% of these had plasma folate concentrations below the normal range. However, erythrocyte folate concentrations were abnormally low in only 25% of the patients who received phenytoin. Valproate administration increased serum vitamin B-12 concentrations. Over 55% of the entire patients had PLP concentrations below the normal range, although the reason is unknown. Only three patients had the homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical analysis was not possible in this study. However, one patient with homozygous genotype who received phenytoin therapy had hyperhomocysteinemia with poor folate nutritional status, and the other two had normal homocysteine concentrations with normal folate status. Our data suggest that hyperhomocysteinemia is not a serious clinical concern in epileptic patients when folate nutriture is adequate.     

Self-reported symptoms in patients on antiepileptic drugs in monotherapy

Wieshmann UC, Tan GM, Baker G. Self‐reported symptoms in patients on antiepileptic drugs in monotherapy.
Acta Neurol Scand: 2011: 124: 355–358.
© 2011 John Wiley & Sons A/S. Objective – To ascertain the frequency of self‐reported symptoms in patients taking antiepileptic drugs (AED). Methods – We included patients on carbamazepine (CBZ) n = 36, valproate (VPA) n = 21, levetiracetam (LEV) n = 12, phenytoin (PHT) n = 11, lamotrigine (LTG) n = 20, patients not taking anticonvulsive drugs n = 19, and healthy control subjects (CTRL) n = 41 to complete the Liverpool Adverse Event Profile (LAEP). Results – The mean LAEP scores were CBZ/PHT/LEV/VPA/LTG/noAED/CTRL = 44.97/42.00/41.00/40.33/32.42/42.00/30.80. LEV scored overall in the same range as the older AED but had a different adverse effect profile with self‐reported anger (33%) and shaky hands (42%) particularly frequent. Patients with depression or uncontrolled epilepsy had significantly higher LAEP scores than patients without depression or uncontrolled epilepsy. Conclusion – Our unblinded observational study of self‐reported symptoms suggested LTG was overall the drug with the least self‐reported symptoms. Larger studies are needed to determine whether this was a truly significant difference. LEV had a different side effect profile to older AED. Confounding factors were depression and uncontrolled epilepsy. This observation should be further tested with randomized studies.     

Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long‐term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent‐to‐treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940–2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta‐analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered.     

Slight improvement in mood and irritability after antiepileptic drug withdrawal: a controlled study in patients on monotherapy

OBJECTIVE: Most antiepileptic drugs (AEDs) are considered to have effects on mood and to be effective in a number of affective disorders. There are, however, conflicting reports in the literature with respect to the psychotropic properties of AEDs. Many of the studies have a number of methodological problems, and much uncertainty still exists regarding the behavioral and mood effects of AEDs. The aim of this study was to assess, in a randomized, double-blind, placebo-controlled study of seizure-free patients with epilepsy, the effect of withdrawal of AEDs in patients on monotherapy on measures of mood and behavior. METHODS: One hundred fifteen subjects who had been seizure-free >2 years on drug monotherapy went through a randomized, double-blind, placebo-controlled study. Each patient was included for 12 months or until seizure relapse. Behavioral function was assessed with the Minnesota Multiphasic Personality Inventory 2 (MMPI-2) at baseline and 7 months after withdrawal. RESULTS: Discontinuation of AEDs resulted, to a greater extent than continued treatment, in a slight improvement in symptoms of depression and irritability. Comparable results were achieved in the subgroup taking carbamazepine. For patients with a high degree of depressive and somatic symptoms at baseline, no significant differences in symptoms emerged in the withdrawal group compared with the non-withdrawal group. CONCLUSION: The results suggest that seizure-free patients with epilepsy on monotherapy can obtain a slight improvement in symptoms characteristic of depression and irritability if they discontinue treatment with AEDs. The described changes are limited, and the functional impact is of uncertain significance.