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。     

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 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.     

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)     

Predicting antiepileptic drug response in children with epilepsy

In clinical practice, after diagnosis and when treatment has begun, it is important to predict as soon as possible which children will become seizure-free and which are likely to develop medically intractable seizures. This article summarizes factors predicting seizure remission in childhood-onset epilepsy treated with antiepileptic drugs (AEDs). Sustained seizure remission can be expected in over 90% of idiopathic epilepsies of childhood and in neurologically normal children with epilepsy having infrequent seizures showing early remission after starting treatment with AEDs. Even in the presence of symptomatic etiology of epilepsy--focal seizures and syndromes; high seizure frequency prior to or during treatment; seizure clustering; and poor or delayed response to first adequate drug therapy--up to 60% of children with treated epilepsy are able to enter long-term remission. However, remission can be expected in only 30% or less of those with catastrophic epilepsies of childhood.     

Outpatient sleep recording during antiepileptic drug monotherapy

The effects of sleep and sleep deprivation on epilepsy are well known, but the effects of seizures and antiepileptic drugs (AEDs) on sleep have been less well studied. We recorded nocturnal sleep in 17 patients receiving antiepileptic monotherapy with ambulatory cassette EEG devices. Twelve patients had complex partial seizures and five had tonic-clonic convulsions. Two patients' seizures were largely nocturnal, and no seizures occurred during sleep recording. Five patients each were taking phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), and two were taking clonazepam (CZP), all with therapeutic serum levels and no toxic symptoms. Total sleep time was reduced, wakefulness increased, and sleep latency prolonged in partial seizures as compared with generalized epilepsy. REM sleep was reduced and its latency decreased in partial seizure patients. Both groups had decreased slow wave sleep; that of partial seizure patients was decreased more markedly. PHT increased sleep latency and decreased sleep time, and CBZ increased awakening and diminished slow wave and REM sleep. Patients taking VPA had slight reduction in slow wave sleep; those taking CPZ had decreased sleep and REM latencies. Epilepsy may affect nocturnal sleep, and the effects of partial and generalized seizure disorders may be different. AEDs may also have differential effects on nighttime sleep. These may prove important in the long-term management of epileptic patients.     

Bone consequences of epilepsy and antiepileptic medications

Childhood and adolescence are critical periods of skeletal mineralization. Peak bone mineral density achieved by the end of adolescence determines the risk for later pathological fractures and osteoporosis. Chronic disease and medication often adversely affect bone health. Epilepsy is one of the most common neurological conditions occurring in persons under the age of 21. Epilepsy may affect bone in a number of ways. Restrictions of physical activity imposed by seizures, cerebral palsy or other coexisting comorbidities adversely affect bone health. It has been observed that treatment with phenytoin and phenobarbital can be associated with rickets. More recently, established agents such as carbamazepine and valproate have been shown to be associated with decreased bone mineral density. The literature related to bone health in pediatric epilepsy is reviewed.     

Bone mineral density with lamotrigine monotherapy for epilepsy

Bone mass, largely accumulated during childhood and adolescence, may be reduced in patients with epilepsy as a result of epilepsy or of antiepileptic medications. Enzyme-inducing medications increase bone-turnover markers, although the effects of newer medications on bone accrual are not well-defined. Total z-score bone mineral density was measured in 13 children, treated with lamotrigine monotherapy, who had never been exposed to other medications, and compared with 36 control subjects and 40 patients exposed to polytherapy. All patients were normally ambulatory and had similar physical activity and calcium intake. The z-scores of bone mineral density for lamotrigine and control subjects were similar (0.52 +/- 0.76 versus 0.49 +/- 0.7) and higher than those receiving polytherapy for 1-5 years (0.14 +/- 0.8, P = 0.12) and >or=6 years (-0.27 +/- 01.15, P < 0.003). Increasing duration of epilepsy was associated with lower bone density for 1-5 years of polytherapy (Spearman's correlation coefficient r = +0.006, P = 0.74) and >or=6 years of polytherapy (Spearman's correlation coefficient r = +0.12, P = 0.13), but not for lamotrigine. These data suggest that lamotrigine may not interfere with bone accrual.     

新型和传统抗癫痫药治疗新诊断癫痫患者的评价

目的评价新型和传统抗癫痫药(AEDs)单药治疗新诊断癫痫患者的疗效及安全性。方法前瞻性收集143例新诊断癫痫患者,分为卡马西平(CBZ)、丙戊酸钠(VPA)、托吡酯(TPM)和拉莫三嗪(LTG)治疗组,其中CBZ用于癫痫部分性发作,VPA用于癫痫全面性发作,而TPM和LTG用于各种类型癫痫发作,至少观察1年。采用生存分析Kaplan-Meier法比较治疗后癫痫初次发作时间、治疗失败时间,同时比较各组患者达"6月、1年无发作"比例和药物不良反应。结果 4组AEDs单药治疗后至癫痫初次发作时间、治疗失败时间的差异均无统计学意义(P0.05);CBZ、VPA、TPM和LTG组"6月无发作"率分别为80%、78%、87.9%、63.3%(均P0.05);"1年无发作"率分别为70%、66%、66.7%、50%(均P0.05)。TPM组不良反应率为63.3%,高于CBZ组(20%)、VPA组(24%)(均P0.01),而LTG组不良反应率为16.7%,与CBZ、VPA组相当(均P0.05)。结论从疗效和安全性综合考虑,新型AEDs治疗癫痫并不优于传统AEDs,其中TPM轻、中度不良反应还明显高于传统AEDs。     

Seizure frequency and sex steroids in women with partial epilepsy on antiepileptic therapy

Purpose:   Neuroactive sex steroids influence neuron excitability, which is enhanced by estradiol (E2) and decreased by progesterone (Pg). In epilepsy, the production, metabolism, biologic availability, and activity of sex hormones may be affected by seizures themselves or by antiepileptic drugs (AEDs). This cross-sectional observational study was aimed at evaluating the relationships between sex steroids, seizure frequency, and other clinical parameters in women with partial epilepsy (PE) on AED treatments.
Methods:   Serum E2, Pg, sex hormone binding globulin (SHBG) levels, free E2 (fE2), and E2/Pg ratios were determined during the follicular and luteal phases in 72 adult women with PE, and in 30 healthy controls. Hormonal data were correlated with seizure frequency, age, body weight, body mass index (BMI), disease onset and duration, and AED therapies.
Results:   In patients, E2, fE2, and Pg levels were lower in both ovarian phases, whereas those of SHBG were higher than in controls. No significant changes in hormone levels and in prevalence of anovulatory cycles were observed between patients grouped according to their seizure frequency. However, when compared with those in healthy controls, luteal fE2 and Pg levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures.
Conclusions:   The actual changes in sex steroid levels and E2/Pg ratios did not explain an increased seizure frequency in adult women with AED-treated PE, but patients with more severe disease showed more relevant changes in their sex hormone profile and impaired Pg levels during the luteal phase.     

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.     

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.     

Principles of antiepileptic drug treatment of epilepsy

For the successful treatment of epilepsy, accurate diagnosis of epilepsy and epileptic seizures, and proper selection of antiepileptic drugs (AED) according to the classification of epileptic syndromes are fundamentally important. Efficacy of AED treatment, however, depends not only on its pharmacological action but also on its efficient use, namely a rationally thinking tailor-made treatment considering the characteristics of each patients, i.e. individual differences in pharmacokinetics, factors influencing AED concentrations, AED interactions, and comprehensively their life style and psychosocial factors.     

Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy

BACKGROUND: In the face of availability of newer antiepileptic drugs (AEDs) such as lamotrigine and topiramate, there is need to reassess the role of older AEDs in the treatment of juvenile myoclonic epilepsy (JME). OBJECTIVES: To explore whether lamotrigine and topiramate monotherapy or polytherapy can be effective options in the treatment of JME, and to determine whether older AEDs, such as phenytoin and carbamazepine, have a role in the treatment of JME. DESIGN: A retrospective cohort study. SETTING: A large academic teaching hospital. PATIENTS: Seventy-two consecutive JME patients treated with valproic acid, lamotrigine, topiramate, phenytoin, or carbamazepine between April 1, 1991, and March 31, 2001. METHODS: We compared the efficacy of valproic acid, lamotrigine, and topiramate monotherapy or polytherapy in the control of different seizure types of JME, and compared their efficacy and tolerability with the efficacy and tolerability of phenytoin and carbamazepine. RESULTS: Seizure outcome did not differ when patients receiving valproic acid monotherapy (n = 36) were compared with those receiving lamotrigine monotherapy (n = 14), and when patients receiving valproic acid polytherapy (n = 22) were compared with those receiving lamotrigine polytherapy (n = 21) or topiramate polytherapy (n = 15) (P>.05 for all). The combined data of myoclonic seizure control by all 3 AEDs were poorer when compared with the combined data of generalized tonic-clonic seizure control by all 3 AEDs (P =.03), but not when compared with the combined data of absence seizure control by all 3 AEDs (P =.43). Valproic acid, lamotrigine, and topiramate, when compared with phenytoin or carbamazepine, demonstrated significantly better control of myoclonic seizures (P<.01 for all), but not of generalized tonic-clonic seizures (P>.11 for all). CONCLUSIONS: Lamotrigine and topiramate are effective alternative options to valproic acid in the treatment of JME. Lamotrigine is an effective option as monotherapy and polytherapy. Topiramate is an effective option as polytherapy, but more data are needed to determine if it is an effective option as monotherapy. More effective therapy is needed to improve myoclonic seizure control. Older AEDs, such as phenytoin and carbamazepine, may not be indicated in JME patients.     

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.