Purpose: The incidence of malformations among infants of mothers with epilepsy treated with antiepileptic drugs (AEDs) during pregnancy is higher than that found in the general population. The aim of ...this study was to contribute to providing a definition of the rate of congenital anomalies in the offspring of mothers with epilepsy and to detect possible risk factors.
Methods: Since 1977, 517 pregnancies were followed up at the San Paolo Hospital in Milan by a team of epileptologists and obstetricians. The patients received monthly obstetric and neurologic examinations, and the blood levels of AEDs were tested monthly. During pregnancy the patients underwent ultrasound investigations to evaluate fetal morphology and development. At the time of delivery, the infants were submitted to a standardized examination by a pediatrician, and a more detailed clinical examination was performed on day 5. Malformations were classified as (a) genetic and chromosomic, (b) severe and mild malformations, and (c) deformities.
Results: The overall rate of malformations was 9.7%: of these, 5.3% were structurally severe, 2.2% were mild, 0.4% were chromosomic‐genetic, and 1.8% were deformities. No malformation was detected in the 25 untreated patients.
Conclusions: The risks of teratogenicity have been regarded as multifactorial, involving such factors as genetic predisposition, although most prospective studies show that AED‐related factors are the primary risk factors for an increased incidence of congenital malformations.
The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs ...(AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2–8.0) or Canadian children (RR 2.6; 95% CI: 1.1–6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2–6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4–9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5–13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6–10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.
To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting.
Retrospective, case-matched ...pharmacokinetic evaluation.
Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication.
Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed.
In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis.
Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.
Purpose: To assess the influence of aging on the steady‐state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting.
...Methods: The database of a large TDM service was used to identify retrospectively steady‐state serum CBZ concentrations in 157 elderly patients with epilepsy (65 years and older) treated with CBZ alone or in combination with phenobarbital (PB). CBZ apparent oral clearance (CL/F) values were calculated and compared with those determined in an equal number of controls aged 20 to 50 years, and matched for gender, body weight, and comedication.
Results: Compared with corresponding controls, mean CBZ CL/F values were 23% and 24% lower, respectively, in the groups of elderly patients receiving monotherapy (57.1 ± 20.6 vs. 74.6 ± 28.3 ml/h/kg; p < 0.0001) and PB comedication (74.7 ± 25.5 vs. 98.7 ± 34.9 ml/h/kg; p < 0.01). Within each age group, patients comedicated with PB showed significantly higher CBZ CL/F values than those on monotherapy. A negative correlation between CL/F and age was found both within the monotherapy and the PB comedicated groups. In addition, CL/F values showed a positive relation with the administered daily dosage, which persisted within subgroups homogeneous for age and comedication. The independent influence of age, CBZ dosage, and comedication on CBZ CL/F was confirmed by multiple regression analysis.
Conclusions: CBZ CL/F is decreased in an age‐dependent manner in elderly patients compared with younger subjects, presumably because a reduction in the rate of CYP3A4‐mediated drug metabolism. Elderly patients retain their sensitivity to dose‐dependent autoinduction and to heteroinduction by enzyme‐inducing AEDs, but their metabolic rates remain considerably below those observed in matched controls. As a result of this, patients in old age will require lower CBZ dosages to achieve serum concentrations comparable with those found in nonelderly adults.
Anti-Purkinje cell antibodies (APCA), believed to be markers of paraneoplastic cerebellar degeneration in females, have been identified in the serum of 3 men with subacute sensory neuronopathies and ...no evidence of tumors 5 years after the onset of the neurological signs. By indirect immunohistochemistry on sections of rat cerebellum and dorsal root ganglia, the patients' IgG bound to the cytoplasms of both Purkinje cells and dorsal root ganglia neurons. By western blot analysis on whole human cerebellum and whole human dorsal root ganglia homogenates, the IgG from 2 patients bound to a 62-kd protein in both homogenates and the IgG from 1 patient bound to a 110-kd protein in the cerebellum homogenate only. Yo autoantibody test was negative in all patients. Our study provides evidence that non-anti-Yo APCA may be associated with subacute sensory neuronopathies and are not necessarily markers of an underlying tumor. The previously described anti-Yo APCA has only occurred in females with cancer.
Purpose: To assess the influence of aging on the pharmacokinetics of phenobarbital (PB) at steady state in patients receiving long‐term therapy.
Methods: Serum PB concentrations from the database of ...the therapeutic drug monitoring service of a large neurological hospital were used to calculate apparent clearance values (CL/F) in 224 patients aged 65 years and older (mean, 73 ± 6.1 years). CL/F values in these patients were compared with those determined in an equal number of controls aged 20 to 50 years (mean, 35.7 ± 7.9 years) and matched for gender, body weight, and type of anticonvulsant comedication. Correlations of CL/F with age, body weight, gender, and comedication also were explored within each age group.
Results: PB CL/F values were significantly lower in elderly patients than in controls (3.2 ± 0.8 vs. 4.1 ± 1.2 ml/h/kg; p < 0.0001). Age was identified as a statistically significant predictor of CL/F at multiple regression analysis, but it accounted for only a modest component of the interindividual pharmacokinetic variation. Comedication with carbamazepine (CBZ) and phenytoin (PHT) was associated with a moderate decrease in PB CL/F, which reached statistical significance in the elderly group (p < 0.01 for CBZ comedication; p < 0.001 for PHT comedication).
Conclusions: Aging is associated with a significant decrease in PB clearance, which might be related to a reduction in glomerular filtration rate or diminished drug‐metabolizing capacity in the liver or both. Because of this, older patients will require lower dosages to achieve serum PB concentrations comparable with those found in nonelderly adults.
The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/
F) in 75 patients aged 65–90 years (mean, ...71.7 ± 5.3 years) receiving phenytoin alone (
n = 58) or in combination with phenobarbital (
n = 17) and in an equal number of control patients aged 20–50 years (mean, 36.7 ± 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/
F values compared with controls (14.6 ± 4.7
ml
h
−1
kg
−1 versus 13.1 ± 4.2
ml
h
−1
kg
−1,
P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 ± 1.1
mg
kg
−1
day
−1 versus 5.3 ± 1.1
mg
kg
−1
day
−1,
P < 0.001) and had lower serum phenytoin concentrations (14.1 ± 5.7
μg
ml
−1 versus 18.6 ± 6.8
μg
ml
−1,
P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/
F. By contrast, in the elderly group, CL/
F values were negatively correlated with age. On average, CL/
F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/
F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug.
Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.
To evaluate the influence of pediatric age and antiepileptic comedication on the single-dose pharmacokinetics of lamotrigine, 19 patients with epilepsy (10 comedicated with enzyme inducers and 9 ...comedicated with valproic acid) aged 8 months to 30 years received a single oral dose of lamotrigine (0.6 to 2.2 mg/kg) after an overnight fast. Blood samples were collected for at least 36 hours and plasma lamotrigine concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were calculated by noncompartmental analysis. Lamotrigine half-life (T1/2) and oral clearance (Cl/F) values were significantly lower and significantly higher, respectively, in patients comedicated with enzyme inducers than in those receiving valproic acid (T1/2 = 8.1 vs. 41.7 hours respectively, P < 0.001; Cl/F = 0.11 vs. 0.04 L/h per kg respectively, P < 0.005, geometric means), whereas Cmax and Tmax values were comparable in the two groups. The differences in pharmacokinetic parameters persisted when comparisons were made within subgroups stratified according to age. Within groups of patients homogeneous for type of comedication, Cmax and AUC values tended to be lower in children aged less than 12 years than in older patients. There was no significant relationship between half-life values and age. The authors conclude that both age and type of comedication influence lamotrigine pharmacokinetics. The reduction in lamotrigine concentrations caused by enzyme inducers and the elevation caused by valproic acid can be explained by stimulation and inhibition, respectively, of lamotrigine glucuronidation. On the other hand, the lower plasma lamotrigine levels in children than in adolescents and older patients may not be explainable solely by differences in metabolic rate.
The interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. ...Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy.
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