Malformations in offspring of 305 epileptic women: a prospective study

This paper deals with malformations detected in 26 of 315 newborns of 305 epileptic mothers followed prospectively. In 3 more cases, malformations were detected in utero and therapeutic abortion was performed. Two hundred and seven women were on monotherapy, 102 on polytherapy and 9 were not treated. In total, malformations overall incidence was 9.1%. Minor anomalies were detected in 42 newborns (13.3%). A higher rate of malformations and minor anomalies was found among offspring of mothers treated with valproic acid (VPA). In the VPA group, mothers of malformed babies had higher plasma levels in the first trimester than mothers of babies without malformations. The need for accurate prenatal diagnostic studies in pregnant women with epilepsy is stressed.     

The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients

Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with mono- or poly-therapy of carbamazepine, valproic acid, or phenytoin. The treated epileptic patients were divided into 2 main groups according to the seizure frequency: controlled seizure patients GII (n = 30) and uncontrolled seizure patients GIII (n = 30). GII included the GIIA subgroup (n = 15) which had been seizure free for more than 12 months and the GIIB subgroup (n = 15) which had been seizure free for a period from 6 to12 months. GIII included GIIIA (n = 15) and GIIIB (n = 15) for patients which had a seizure frequency of less than and more than four times/month, respectively. In comparison to the control group (GI), the levels of nitric oxide (NO) and malondialdehyde/creatinine ratio were significantly increased in GIIB, GIIIA, and GIIIB, while vitamins A and E levels were significantly decreased in GIIIB. Serum NO levels had significant negative correlations with serum vitamin E in the GIIA and GIIB groups, and with vitamin A in the GIIIA and GIIIB groups. However, serum NO had positive correlation with urinary MDA/Cr ratio. The imbalance between free radical generation and antioxidant system in epileptic patients may be a factor in seizure frequency.     

Efficacy and tolerability of zonisamide as add‐on in brain tumor‐related epilepsy: preliminary report

Background –  Zonisamide (ZNS) is an antiepileptic drug (AED) with broad spectrum action that demonstrated a good efficacy in controlling seizures as add‐on in adult and pediatric epilepsy. To date there have been no studies on ZNS in patients with brain tumor‐related epilepsy (BTRE). Aim of the study –  To evaluate efficacy and tolerability of ZNS as add‐on in BTRE. Methods– We followed six patients suffering from BTRE who had already been treated with other AEDs and who had had not experienced adequate seizure control. Three patients underwent chemotherapy while being treated with ZNS. Mean duration of follow‐up was 8 months. Results –  Mean seizure number in the last month prior to the introduction of ZNS had been 27.7/month. ZNS mean dosage was of 283.3 mg/day. At last follow‐up, the mean seizure number was reduced to 8.8/month. Responder rate was 83.3%.Two patients discontinued the drug because of side effects. There were no other reported side effects. Conclusions –  Preliminary data on the use of ZNS in add‐on in patients with BTRE indicate that this drug may represent a valid alternative as add‐on in this particular patient population. However, larger samples are necessary to draw definitive conclusions.     

Intrauterine growth in the offspring of epileptic mothers

The present paper concerns the fetal growth of 315 newborns of epileptic mothers prospectively followed from the beginning of pregnancy. In comparison with Italian standards, neonatal weight, length and head circumference at birth were below the 10th percentile in respectively 15.7%, 1.1% and 19.2% of the newborns. Weight at birth was above the 90th percentile in 8 cases. Observed frequencies were significantly higher than expected frequencies for both weight and head circumference. The percentage of newborns with a small head circumference increased significantly according to the number of drugs taken by the mother during the first three months of pregnancy: 7.1% with no drug, 16.8% with one drug, 23.6% with two drugs and 50% with three drugs. A statistically significant correlation was found between gestational age-adjusted head circumference and drug-level scores during the first trimester. Head circumferences below the 10th percentile were fewer among newborns treated with CBZ than among newborns treated with either PB or VPA.     

Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy

Background   Antiepileptic drugs (AEDs) like phenytoin (PHE), carbamazepine (CBZ), barbiturates and valproic acid (VPA) interfere with folic acid absorption and metabolism, which in turn can be the cause of adverse pregnancy outcome. Objective   To study the prophylactic effect of folic acid supplementation with regard to spontaneous abortion and preterm delivery (fetal demise after week 20 of gestational age) in pregnant women receiving AED therapy, as well as benefits of most common dosage and preconceptional commencement. Methods   Prospective examination of 104 patients, registered in EURAP from 1999–2004 at a single center and a retrospective analysis of data from our epilepsy databank completed with medical records and patients interviews of the Department of Neurology of Innsbruck University Hospital from 1971 to 1999. Results   388 pregnancies in 244 patients were analyzed. Pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. With regard to monotherapies, in the group of women taking VPA, supplementation of folic acid had significant benefit. Other examined monotherapies (CBZ, PHE, and PB) known to interfere with folic acid showed no significant results. Conclusions   This study confirms the prophylactic effect of folic acid supplementation on spontaneous abortion. For AED therapy, folic acid supplementation should be part of the therapy of every pregnant epileptic woman, especially for those treated with VPA.     

Lowering the extracellular potassium concentration elicits epileptic activity in neocortical tissue of epileptic patients

The increase in the extracellular potassium concentration ([K(+)](o)) is a well-established model of epilepsy (the so-called high potassium model). Therefore, it is generally accepted that for the prevention of abnormal excitability and seizure generation, increases of [K(+)](o) must be avoided. In this paper, however, we show that on the contrary, a reduction of [K(+)](o) also elicits epileptic activity in brain slices of man.     

The ideal characteristics of antiepileptic therapy: an overview of old and new AEDs

New and improved anti-epileptic drugs (AEDs) have made the concept of choice, according to the individual prognosis and probable response to specific regimens, increasingly feasible. Inter-individual variability in syndrome severity and complexity make individualization necessary. We propose three categories of disorder control according to the individual objectives of the patient: (1) seizure control, (2) epilepsy control and ultimately, (3) "epilepsy cure"; the latter remaining a largely idealistic target today. An AED is likely to be successful if it exhibits "optimal" characteristics, such as drug efficacy, tolerability, pharmacokinetics, interactions and cost-effectiveness. This review discusses the "optimal" characteristics of add-on AEDs, which, in addition to seizure control, will contribute to the achievement of epilepsy control and therefore address the currently unmet clinical needs of epilepsy treatment.     

Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience

PURPOSE: We reviewed the impact of planned discontinuation of antiepileptic drugs (AEDs) in seizure-free patients on seizure recurrence and the seizure outcome of reinstituted treatment. METHODS: A literature review was performed yielding 14 clinical observations of seizure recurrence after discontinuation and its treatment outcome. RESULTS: Seizure recurrence rate after AED discontinuation ranged between 12 and 66% (mean 34%, 95%CI: 27-43) in the 13 reviewed studies (no data in one study). Reinstitution of AEDs after recurrence was efficacious between 64-91% (mean of 14 studies, 80%, 95%CI: 75-85%) at follow-up. Mean follow-up ranged from 1-9 years. Seizure outcome of resumed treatment was not different for series in children and adolescents (84%, mean of 4 studies, 95%CI: 75-93) or in adults only (80%, mean of 9 studies, 95%CI: 74-86). Although seizure control was regained within approximately one year in half of the cases becoming seizure free, it took some patients as many as 5-12 years. In addition, in 19% (mean of 14 studies, 95%CI: 15-24%), resuming medication did not control the epilepsy as before, and chronic drug-resistant epilepsy with many seizures over as many as five years was seen in up to 23% of patients with a recurrence. Factors associated with poor treatment outcome of treating recurrences were symptomatic etiology, partial epilepsy and cognitive deficits. CONCLUSIONS: These serious and substantial risks weigh against discontinuation of AEDs in seizure-free patients, except perhaps for selected patients with idiopathic epilepsy syndromes of childhood or patients with rare seizures.     

Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy

The risks associated with use of antiepileptic drugs during pregnancy are a major concern for all women with epilepsy with childbearing potential. These risks have to be balanced against foetal and maternal risks associated with uncontrolled seizures. This report from the International League Against Epilepsy Task Force on Women and Pregnancy aims to provide a summary of relevant data on these risks as a basis for expert opinion recommendations for the management of epilepsy in pregnancy. The report reviews data on maternal and foetal risks associated with seizures as well as teratogenic risks associated with antiepileptic drug exposure, including effects on intrauterine growth, major congenital malformations, and developmental and behavioural outcomes. The impact of pregnancy on seizure control and on the pharmacokinetics of antiepileptic drugs are also discussed. This information is used to discuss how treatment may be optimized before conception and further managed during pregnancy.     

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.     

Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit

Stephen LJ, Parker P, Kelly K, Wilson EA, Leach V, Brodie MJ. Adjunctive pregabalin for uncontrolled partial‐onset seizures: findings from a prospective audit.
Acta Neurol Scand: 2011: 124: 142–145.
© 2011 John Wiley & Sons A/S. Aims – Pregabalin (PGB) was licensed in Europe as an add‐on antiepileptic drug (AED) for the treatment of partial‐onset seizures in 2004. This audit assessed the response to adjunctive PGB in patients with uncontrolled seizures. Methods – PGB was titrated in 135 patients [73 men; 62 women, aged 18–76 (median 44 years) until one of the following occurred: ≥6 months’ seizure freedom, ≥50% or <50% seizure reduction over 6 months; PGB withdrawal because of adverse effects, lack of efficacy or both. Results – Of the 135 patients, 14 (10.4%) became seizure‐free for ≥6 months (median PGB dose 300 mg/day; range 75–600 mg). A ≥ 50% seizure reduction occurred in 33 (24.4%) patients; 20 (14.8%) had <50% reduction. PGB was withdrawn in 68 (50.4%) (40 adverse effects, seven lack of efficacy and 21 both). Commonest problems resulting in withdrawal were sedation (n = 18), weight gain (n = 14) and ataxia (n = 9). There was a positive correlation between increasing dose and weight gain (r = 0.42, P = 0.045). Conclusions – Add‐on PGB benefited 50% of patients, but only 10% achieved 6 months’ seizure freedom. Adverse effects, most commonly sedation, dose‐related weight gain and ataxia, led to drug discontinuation by 45%. Prospective audits of novel AEDs are a useful adjunct to randomized, controlled trials in managing epilepsy.     

Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight‐adjusted dose ratio (C/D; [μg/mL]/mg kg^?1 d^?1) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12‐66 years), 114 plasma samples were collected. Twenty‐eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (?56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.     

Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

OBJECTIVE: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). METHODS: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. RESULTS: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). CONCLUSIONS: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.     

Antiepileptic drugs and mechanisms of epileptogenesis. A review

This paper analyzes the effect of conventional (phenobarbital, phenytoin, carbamazepine, ethosuximide, valproate) and some novel (vigabatrin, lamotrigine, felbamate) AEDs on some basic mechanisms involved in focal and/or generalized epileptogenesis (Na⁺ voltage-dependent channels and sustained repetitive firing, L-, N-, and T-type Ca²⁺ currents, GABA-mediated inhibition, Glu/Asp-mediated excitation, after-hyperpolarization). According to this analysis, AEDs can be divided into two main categories, those with only one specific action and those with multiple actions. A speculative correlation is proposed between AED effects on the mechanism of epileptogenesis and their known clinical effect on seizures.

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Sommario Vengono analizzate le azioni dei farmaci antiepilettici convenzionali (fenobarbital, fenitoina, carbamazepina, etosuccimide, valproato) e di quelli appartenenti alla nuova generazione (vigabatrin, lamotrigina, felbamato) sui meccanismi di base implicati nella genesi dell' epilessia focale e/o generalizzata. I meccanismi considerati sono: (1) canali Na⁺ voltaggio-dipendenti e scarica ripetitiva prolungata; (2) correnti Ca²⁺ dipendenti di tipo L, N e T; (3) inibizione GABA-mediata; (4) eccitazione Glu/Asp-mediata; (5) iperpolarizzazione postuma. Sulla base di queste variabili, i farmaci antiepilettici possono essere divisi in due principali categorie, quelli che presentano una sola azione specifica e quelli che agirebbero in più modi. Inoltre, si è cercato di correlare gli effetti che i farmaci antiepilettici hanno sui meccanismi di base dell' epilettogenesi con la loro azione clinica sulle crisi.

     

Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital

Serum lipids, lipoproteins and apolipoproteins A and B were measured in 101 epileptic patients receiving chronic treatment with valproic acid, carbamazepine or phenobarbital and in 75 age- and sex-matched control subjects. In relation to controls, subjects treated with valproic acid showed significantly lower values of total and LDL-cholesterol levels; subjects treated with carbamazepine showed significantly higher values of HDL-cholesterol and apolipoprotein A concentrations and subjects treated with phenobarbital showed significantly higher values of total cholesterol, HDL-cholesterol, apolipoprotein A and apolipoprotein B levels. The total cholesterol/HDL-cholesterol ratio was significantly lower in patients receiving valproic acid or carbamazepine but not in the phenobarbital-treated group. Changes in serum lipids profile did not correlate with drug plasma concentrations nor the duration of the treatment.