Comparison of Antiepileptic Drugs on Cognitive Function in Newly Diagnosed Epileptic Children: A Psychometric and Neurophysiological Study

Summary: Using a randomized parallel group study design, we compared the cognitive effects of carbamazepine (CBZ), phenobarbital (PB), and valproate (VPA) in children with epilepsy. Seventy-three children with newly diagnosed epilepsy were tested with the Wechsler Intelligence Scale for Children-Revised (WISC-R), Bender-Gestalt test, and auditory event-related potentials (P₃₀₀) before and 6 and 12 months after antiepileptic drug (AED) treatment. There were no significant differences in WISC-R IQs and Bender-Gestalt scores for children in any group at any of the three sessions. P₃₀₀ latencies were increased in the children receiving PB but not in children receiving CBZ and VPA. P₃₀₀ amplitudes were significantly reduced in treated children in all three groups, but amplitudes were not significantly different among the three groups. These findings suggest that PB may affect cognitive function of epileptic children and that the P₃₀₀ may be a sensitive additional procedure that can be used to assess the cognitive effect of AEDs.     

Effects of antiepileptic drugs on delivery and early childhood--comparison among mono-therapies of valproic acid, phenytoin, carbamazepine and phenobarbital

The effects of antiepileptic drugs (AED) on infants during pregnancy and delivery were studied in a total of 82 epileptic mothers on various monotherapies; 29 cases receiving valproic acid (VPA), 20 receiving phenytoin (PHT), 18 on carbamazepine (CBZ) and 15 on phenobarbital (PB). While AED serum concentrations were low in most cases of VPA, PHT and PB except for one case of VPA which exceeded therapeutic limits, concentrations were within therapeutic levels in many cases of CBZ. Conclusion: When compared with normal controls, abnormal deliveries such as caesarian section were seen more frequently in epileptic mothers under AED treatment. In addition, infants in PB cases were shown to have significantly lower mean birth length, weight and head circumference, suggesting that PB may retard fetal growth. The incidence of malformation in cases of VPA, PHT, CBZ and PB, was 10.3%, 5.0%, 0% and 6.7%, respectively. There were five types of malformation: in VPA cases, spina bifida, Siamese twins and ventricular septal defect tended to be severe, while in PHT and PB cases, cor biloculare and hypospadias respectively were observed. In cases of VPA, serum levels in the umbilical cord were found to be 150% higher than those in the mother.     

The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy

The aim of the present study was to assess the effect of long-term carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB) treatment on serum lipids and apolipoproteins in epileptic children. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TGs) were measured and the LDL-C/HDL-C and TC/HDL-C ratios were calculated in 320 children and adolescents (129 receiving CBZ, 127 receiving VPA and 64 receiving PB) suffering from various types of epilepsy. Additionally, in a subgroup of 181 children (68 CBZ; 78 VPA; 35 PB) apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), HDL2-C and HDL3-C were measured and apoA-I/apoB and HDL2-C/HDL3-C ratios were calculated. Results of the measurements were compared with those of 169 age-and sex-matched healthy controls. None of the variables considered was significantly correlated with time elapsed since start of treatment or with drug concentration in serum. TC and LDL-C serum levels were high in children receiving CBZ or PB and low in those treated with VPA. Serum LDL-C level exceeded 130 mg/dl in 27.9% of CBZ-group, 31.8% of the subjects receiving PB, but only in 7% of those receiving VPA and in 11.8% of control group subjects. CBZ-treated children also showed high HDL-C and HDL3-C values. In the group receiving VPA, HDL2-C, HDL2-C/HDL3-C ratio and apo B were significantly lower than in the control group. Mean apoA-I levels were low in all treated groups: by contrast, in neither group did TGs, VLDL-C levels and TC/HDL-C or LDL-C/HDL-C ratios differ significantly from the corresponding control group. Our results suggest that the effects of long-term AED therapy on lipid profile and, particularly, on apolipoprotein serum levels increase risk of atherosclerosis-related disease. Moreover, these results confirm our previously reported increased risk in CBZ and PB-treated patients.     

Reduction in Internal Carotid Arterial Blood Flow Velocity in Children During Antiepileptic Drug Therapy with Clinical Dosages

Summary: We studied the effect of antiepileptic drugs (AEDs) on internal carotid artery (ICA) blood flow velocity, as an index of total cerebral blood flow (CBF). The subjects were 45 newly diagnosed children with febrile convulsion or epilepsy who were seizure-free for a period long enough not to affect the results. They had no neurologic deficit, received fixed monotherapy, and were examined by a noninvasive Doppler ultrasound method, in comparisonwith 13 age-matched normal volunteers with no AED. In 30 patients, the measurements were performed before and after AED administration [10 with phenobarbital (PB), 10 with carbamazepine (CBZ), and 10 with valproate (VPA)], and performed before and after AED discontinuation in the remaining 15 patients (all with PB). Normal volunteers underwent the two consecutive examinations with a mean interval equal to that of the entire patient group, and there was no difference in velocity values between the measurements. In patients receiving CBZ or VPA, a significant reduction was noted in blood flow velocity after drug administration. Although velocity values in the patients receiving PB did not change after drug administration, they were significantly increased after complete discontinuation. In the present study, a slight but significant reduction in CBF caused by AED administration at therapeutic doses in children was suggested.     

Renal tubular function in patients receiving anticonvulsant therapy: a long-term study

PURPOSE: The goal of the study was to evaluate the tubular renal function in children and adolescents who are undergoing monotherapy with sodium valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB). METHODS: The urinary excretion of N-acetyl-beta-glucosaminidase (NAG), beta-galactosidase (beta-Gal), alanine-amino-peptidase (AAP), and alpha1-microglobulin (alpha1M) was measured in 58 epileptic patients (29 girls and 29 boys), aged 12.6 +/- 3.9 years, who were subdivided into three groups according to their therapy. Fifty healthy sex-and age-matched children served as controls. The measurements were taken before the beginning of therapy and after 6 months, 1 year, and 2 years of therapy. RESULTS: Before the beginning of therapy, there were no significant differences in NAG, beta-Gal, AAP, and alpha1M values between the control group and the three groups of epileptic children. After 6 months of therapy, patients treated with VPA and CBZ showed a significant increase in the urinary excretion of NAG and beta-Gal compared with baseline data and control values. After 1 and 2 years, these patients showed a persistence of the changes found after 6 months of therapy. In patients treated with PB, we did not find any significant variation in NAG, beta-Gal, AAP, and alpha1M urinary excretion. CONCLUSIONS: Our study demonstrates that in patients treated with VPA and CBZ, an impairment of tubular function can be present, whereas PB does not cause any significant change.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients.

Twenty-four epileptic patients (16 females, 8 males; aged 13-62 years) were studied before and after the addition of sodium valproate (VPA) 500 mg twice daily for 5 days. All had been established previously on carbamazepine (CBZ) as monotherapy (300-1600 mg daily in divided doses). Sixteen of these patients undertook a battery of cognitive function tests before and after VPA introduction. VPA had no effect on total or free CBZ concentrations. However, median concentrations of the active metabolite, CBZ 10,11 epoxide (CBZ-E), were significantly increased (CBZ-E before VPA 1.3 mg/l, after VPA 2.1 mg/l, P less than 0.01). The median rise was 25%, although the extent of the interaction ranged from a 25% decrease to an increase of 123% in CBZ-E concentrations. This was related to the marked inter-individual variation in circulating VPA (mean 25-69 mg/l), as CBZ-E concentrations correlated significantly with total (r = 0.5, P less than 0.05, 95% CI 0 to +0.08) and free (r = 0.7, P less than 0.001, 95% CI +0.09 to +0.25) VPA levels in individual patients. Although uncontrolled, no deterioration in performance of any of the cognitive function tests was observed following the addition of VPA. This study does not support immediate clinical relevance for this drug interaction between VPA and CBZ.     

Computerized analysis of EEG background activity in mono-therapeutic patients with epilepsy--relationships between antiepileptic drugs and types of seizures

EEG background activity influenced by antiepileptic drugs (AED) was studied in 109 monotherapy and drug-free epileptic patients using t-Statistical Significance Probability Mappings (t-SPMs). Patients taking phenobarbital (PB) had an increase in alpha 1 and a decrease in alpha 2 activity in comparison with drug-free epileptics. Patients taking PB for generalized seizures with tonic-clonic convulsion only (GTC) also had a significant increase in alpha 1 and a decrease in alpha 2, whereas those with partial seizures (PS) had an increase in theta and beta 1 and a decrease in alpha 2 activity. Patients taking valproic acid (VPA) had a decrease in only beta 1 activity. Patients taking VPA for GTC showed an increase in delta activity, but those with PS did not show any changes. Patients taking carbamazepine (CBZ) for PS exhibited marked slowing with an increase in theta and alpha 1 and a decrease in alpha 2 activity. These results mean that changes in EEG due to AEDs differ depending on the type of seizures. More interestingly, discrepancy between EEG background activity and effects of AEDs was found: In PS type of seizures, the most effective CBZ exhibited striking slowing, PB was next, and VPA was last. In GTC, VPA resulted in greater slowing than PB.     

Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism

PURPOSE: The aim of the study was to evaluate serum thyroid hormone balance in children receiving long-term therapy with carbamazepine (CBZ), valproate (VPA), and phenobarbital (PB). METHODS: We determined serum levels of triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), thyroxine-binding globulin (TBG), and thyroid-stimulating hormone (TSH) in 148 healthy children and 141 children with epilepsy who had been receiving CBZ (61 patients), VPA (51 patients), or PB (29 patients) for 12-161 months. In view of TSH values, three categories of subclinical hypothyroidism were considered: I, TSH greater than the control-group mean + 2 SD (4.37 mIU/L in our study) and <6 mIU/L; II, TSH between 6 and 12 mIU/L; and III, TSH >12 mIU/L. RESULTS: In all treated groups, mean T4 and FT4 levels were lower than in the control group, whereas the CBZ- and VPA-treated children additionally showed reduced mean T3 and TBG levels and increased mean TSH levels. In the group receiving CBZ, 8.2% had TSH values higher than the normal-range maximum, by comparison with only 3.6% of healthy children. The increase in TSH levels was particularly marked in VPA-treated children, accounting for 26% of patients with subclinical hypothyroidism. CONCLUSIONS: Our results, in contrast to previous reports, suggest that CBZ and particularly VPA may induce subclinical hypothyroidism. This suggests a need for careful monitoring of TSH levels in children receiving CBZ or VPA.     

Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.     

Computerized Analysis of EEG Background Activity in Epileptic Patients

Background activity was studied in 128 idiopathic epilepsy patients and 30 normal controls using EEG topography and t-statistic significance probability mapping (t-SPM). In epileptic patients, EEG background activity showed a marked increase in delta, theta, alpha 1, and beta 1, and a decrease in alpha 2 activity as compared with controls. Untreated epileptic patients had a significant increase in delta, theta, and alpha 1 as compared with controls. For epileptic patients treated with antiepileptic drugs (AEDs), the most marked slowing was observed in the polytherapy group, followed by the monotherapy group and then the untreated group. Among seizure types, patients with partial seizures (PS) tended to exhibit more slowing than patients with only generalized tonic-clonic seizures (GTC). Moreover, PS had a right-left asymmetry in alpha 2 and beta 1 activities. In a comparison of AEDs, patients receiving carbamazepine (CBZ) and phenobarbital (PB) showed no significant difference as compared with the untreated group. In contrast, patients receiving valproate (VPA) showed a decrease in slow and fast activities. EEG changes associated with each AED were different in GTC and PS. Patients receiving VPA for GTC showed a decrease in theta and beta 1 activities, but those with PS showed a decrease only in delta activity.     

抗癫痫药体外诱导鼠星形胶质细胞多药耐受基因P-糖蛋白的表达

目的：了解常用抗癫痫药（AED）对大鼠大脑上 星形胶质细胞多药耐受基因（MDR1）的诱导作用,探讨难治性癫痫的耐药机制。方法：给予不同浓度的苯巴比妥钠（PB）、苯妥英钠（PHT）、卡马西平（CBZ）和丙戊酸钠（VPA）持续作用于培养的新生鼠大脑皮质星形胶质细胞,分别在给药后10、20和30d,用免疫细胞化学法检测MDR1的标志物P－糖蛋白（Pgp)的表达率。结果,无药物作用的正常星形胶质细胞Pgp的表达率在各时点均小于5％,低浓度组各药在各时点Pgp的表达率与对照组比较差异无显著意义,有效血药浓度组仅PB20mg/L,PB40mg/L和PHT20mg/L在30d时Pgp表达增强;给药后10d,高浓度组各药Pgp表达率无明显增高;20d时PB、PHT和VPA组Pgp表达增强;30d时4种AED均有Pgp表达增强。结论AED可以诱导MDR1表达增强,且与剂量和时间相关。AED诱导的MDR1表达增强可能参与了难治性癫痫的形成。     

UrinaryN-acetyl-β-glucosaminidase and guanidinoacetic acid levels in epileptic patients treated with anti-epileptic drugs

We investigated potential renal functional impairment induced by chronic use of anti-epileptic drugs (AEDs) in 79 epileptic children. They were divided into five groups: valproic acid (VPA) monotherapy where the serum concentration (SC) of VPA was no less than 60 μg/ml (VPA [SC≥ 60]) (15 cases), VPA monotherapy where the SC VPA was less than 60 μg/ml (VPA [SC< 60]) (29 cases), phenobarbital monotherapy (PB) (7 cases), carbamazepine monotherapy (CBZ) (16 cases), and polytherapy containing VPA (12 cases). Urinalysis (proteinuria and hematuria) and serum creatinine were normal except for two cases of proteinuria and two cases of hematuria. The level of urinary excretion of N-acetyl-β-glucosaminidase (u-NAG) was high in 29% of all patients, and 47% of VPA (SC≥ 60), 38% of CBZ, 25% of polytherapy, and 24% of VPA (SC< 60) groups. There was a significant positive correlation between serum concentration of VPA and u-NAG/urinary creatinine (u-Cr). The level of guanidinoacetic acid (u-GAA) excreted in the urine was normal except in one patient. U-NAG/u-Cr may be a more sensitive marker than u-GAA/u-Cr for renal functional impairment in AED therapy.     

Profile of Antiepileptic Pharmacotherapy in a Tertiary Referral Center in South India: A Pharmacoepidemiologic and Pharmacoeconomic Study

Summary: Purpose: To study the current pharmacotherapy practices of epilepsy and its economics in a developing country by correlating the epidemiology and economics of antiepileptic drug (AED) treatment in general epilepsy care and comprehensive epilepsy care.
Methods: We compared the AED-use profiles, efficacy, and tolerability at entry and at last follow-up for 972 patients seen at a comprehensive epilepsy care program in South India from 1993 to 1995. The relative cost was expressed as the average percentage of the per capita gross national product (GNP/capita) each individual spent for AED treatment.
Results: At entry, 562 (57.8%) subjects were receiving poly-therapy; at last follow-up, 743 (76.4%) patients were receiving monotherapy, an increase of 34.3% in the use of monotherapy. One or more adverse drug reactions were reported by 28.6% of patients at entry and by 19.8% at last follow-up. The proportion of patients who were seizure free increased from 29.0 to 44.8%. Carbamazepine (CBZ) was the most frequently used AED, followed by diphenylhydantoin (DPH), valproate (VPA), and phenobarbitone (PB). The relative cost (% GNP/capita) for standard AEDs were as follows: PB, 4.4%; DPH, 7.1%; CBZ, 16.8%; and VPA, 29.5%. The average annual cost of AED treatment per patient in U.S. dollars was $64.32 at entry and $47.73 at last follow-up. Reduction in polytherapy resulted in the net annual saving of $16,128 ($16.59 per patient, or 5.4% GNP/capita).
Conclusions: The more frequent use of relatively expensive drugs like CBZ and VPA and the use of polytherapy—still quite prevalent in developing countries—has escalated the cost of AED therapy. Although in recent years AEDs have become more available in developing regions, primary and secondary care physicians have not been adequately educated about the current trends in the pharmacotherapy of epilepsy.     

The effect of antiepileptic drug therapy on antioxidant enzyme activity and serum lipid peroxidation in young patients with epilepsy

Changes in antioxidant defense mechanisms and the resulting increased lipid peroxidation are involved in the pathogenesis of epilepsy. Research findings concerning the effect of antiepileptic therapies on these processes are discordant. The aim of our study was to estimate, firstly, the activity of the following antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-R), and secondly, malondialdehyde (MDA) serum concentration in children and adolescents newly diagnosed with epilepsy and receiving either carbamazepine (CBZ) or valproate (VPA) monotherapy, or polytherapy. The study group included 90 young patients with epilepsy, aged 6 months to 20 years. In 22 patients epilepsy was newly diagnosed; CBZ monotherapy was administered to 16 patients, VPA monotherapy--to 25, and polytherapy--in 27 cases. The control group consisted of 61 non-epileptic patients aged 4-17 years. SOD, GSH-Px and GSSG-R activities and MDA concentration were measured using spectrophotometry. SOD activity was decreased in newly diagnosed epileptic children receiving VPA or CBZ monotherapy (p < 0.05), or polytherapy (p < 0.01) in comparison to relevant levels in non-epileptic patients. GSH-Px activity was increased in all the patients, but significantly in those receiving polytherapy (p < 0.05). While in patients newly diagnosed with epilepsy no change in GSSG-R activity was found, its level was slightly lower both in those receiving VPA monotherapy and polytherapy, but increased in those with CBZ monotherapy. MDA concentration was elevated in all the epileptic patients, significantly (p < 0.05) both in VPA monotherapy and in polytherapy, while insignificantly--in newly diagnosed epilepsy and in CBZ monotherapy. Our results indicate that in the serum of children and adolescents with epilepsy the oxidants-antioxidants balance is modified by antiepileptic therapy.     

Efficacy and tolerability of antiepileptic drugs in an Omani epileptic population

OBJECTIVE: The aim of this hospital-based study is to get an insight into the efficacy and tolerability of antiepileptic drugs (AED) in Omani epileptic patients. PATIENTS AND METHODS: All Omani patients (aged 14 years and above) suffering from epileptic seizures for at least 2 years and followed-up by board-certified neurologists in Sultan Qaboos University Hospital (SQUH) were evaluated. The treatment retention rate since first visit at SQUH and over the last 2 years was used as primary efficacy measure of AED therapy. Change in seizure-frequency and side effect profiles were also assessed. RESULTS: In this population of 203 confirmed epileptic patients, generalized tonic-clonic (40%) and partial seizures (39%) were most commonly observed, idiopathic/cryptogenic origin (81%) being the most frequent encountered origin. Sixty one percent of the patients were controlled with an AED in monotherapy and overall 34% of patients could be successfully maintained on monotherapy during the whole follow-up period at SQUH (median 6 years). The treatment retention rates for carbamazepine (CBZ) at a daily dose of 400-600 mg, sodium valproate (VPA) at a daily dose of 500-1000 mg, and phenytoin (PHT) at a daily dose of 300 mg, in monotherapy over the total follow-up period was 51, 50, and 21%, respectively. In contrast, over the last 2 years these rates were highest for VPA (91%) followed by CBZ (83%) and PHT (73%). Adverse drug reactions were recorded in 67% of patients, and were most commonly encountered with VPA. CONCLUSIONS: Despite a higher adverse effect profile for VPA, long-term treatment with CBZ and VPA appeared to be equally effective in terms of treatment retention rates and seizure control.     

Effects of Discontinuation of Phenytoin, Carbamazepine, and Valproate on Concomitant Antiepileptic Medication

We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.     

Antiepileptic Drugs and Peripheral Nerve Function: A Multicenter Screening Investigation of 141 Patients with Chronic Treatment

Summary: One hundred forty-one adult patients treated for no less than 6 months with standard daily doses of the commonest antiepileptic drugs (AEDs) were recruited in five Italian centers and submitted to intensive clinical and electrophysiologic investigation to assess the effects of AEDs on peripheral nerves. Eighty percent of the patients were receiving monotherapy. Carbamazepine (CBZ) was the most common AED (51 cases), followed by phenytoin (PHT) (46), phenobarbital (PB) (42), and valproate (VPA) (25). Fifty-three percent of the patients had one or more symptoms of polyneuropathy (paresthesias being the most common complaint). The neurologic examination was abnormal in 32%. Electrophysiologic findings in two or more separate nerves were abnormal in 77 patients (54.6%); of these, 27 (19.1%) had abnormal neurologic findings and 21 (14.9%) also had symptoms of polyneuropathy. Sensory functions were most frequently impaired. Sural nerve biopsy was performed in 4 patients receiving monotherapy with CBZ, PHT, PB, and VPA. Except in patients receiving VPA (in whom no morphologic abnormalities were detected), mild predominantly axonal damage with secondary myelin changes was noted. A correlation was noted between polyneuropathy, age of the patient and, to a lesser extent, receipt of two or more AEDs.