R. Canger

Congenital malformations due to antiepileptic drugs

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Malformations in Offspring of Women with Epilepsy: A Prospective Study

Summary: 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.

Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy

OBJECTIVE This was the first proof of principle clinical trial assessing the efficacy and safety of rufinamide as adjunctive therapy in epileptic patients. The pharmacokinetic (PK) profile of rufinamide was also determined. METHODS Fifty patients with diagnoses of partial or primary generalized tonic-clonic seizures were enrolled in this 28-day double-blind, placebo-controlled, weekly rising dose (400-1600 mg/day) trial. PK profiles were obtained after administration of single-dose rufinamide prior to and after the Double-blind phase. RESULTS In the evaluable patient population, seizure frequency decreased by 41% in the rufinamide group and increased by 52% in the placebo group (P=0.040). Thirty-nine percent (39%) of rufinamide-treated and 16% of placebo-treated patients experienced reduction in seizure frequency of at least 50% relative to baseline (P=0.096). SAFETY Treatment-emergent adverse events (AEs) consisted mainly of neurologic signs and symptoms commonly associated with antiepileptic drugs (AEDs). PHARMACOKINETICS At steady state, rufinamide reached a peak plasma concentration with a mean time (Tmax) of 3.4 h and a mean half-life (t1/2) of 7.3 h. No autoinduction of rufinamide metabolism occurred. Rufinamide did not influence the plasma concentration of carbamazepine, phenytoin or valproate when added to these single AED regimens. CONCLUSION Rufinamide has been shown, in this proof of principle trial, to be safe and effective in reducing seizure frequency in epileptic patients with no relevant influence on the metabolism of other AEDs.

Depression and Anxiety in Patients with Epilepsy

The aim of this investigation was to study the interaction between depression/anxiety and epilepsy. One hundred fifty individuals with partial epilepsy, 70 with idiopathic generalized epilepsy, and 100 controls were administered two self-rating mood questionnaires (Zung and Stai) for the evaluation of depression and anxiety, respectively. The group with epilepsy was much more severely impaired than the controls according to both mood questionnaires; the patients with partial epilepsy, especially those with temporal lobe epilepsy (TLE), were more depressed and anxious than the patients with generalized epilepsy. The group with left TLE appeared to have the highest levels of depression and anxiety. The final results of our study confirmed that some mood disorders are common throughout the epilepsy population, especially in patients with left TLE. No correlation was noted between the frequency of seizures and onset of epilepsy and the results of the mood questionnaires. Moreover, no differences were found in depression and anxiety between males and females among both left focus and right focus epilepsy patients.

Frontal cognitive dysfunction in juvenile myoclonic epilepsy

Purpose: The aim of the present study was to investigate the possible frontal cognitive dysfunction in patients with juvenile myoclonic epilepsy (JME) and to compare the results with those of patients with frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE), as well as with controls.

The perception of memory failures in patients with epilepsy

The aim of the study is to evaluate the correlation between subjective memory complaints and neuropsychological tests in the epilepsy population.

Chromosome 20 Ring : A Chromosomal Disorder Associated with a Particular Electroclinical Pattern

Summary: Purpose: The chromosome 20 ring [r(20)] is a rare chromosomal disorder without clear phenotypical markers. We describe the electroclinical pattern in a group of patients with r(20).

4p(-) syndrome: a chromosomal disorder associated with a particular EEG pattern.

Summary: We report an electroclinical and cytogeneticstudy of 4 patients with Wolf‐Hirschhorn syndrome (WHS). In all cases, we observed a stereotyped EEG and clinical picture characterized by generalized or unilateral myoclonic seizures followed later by brief atypical absences. Electrographically, these were accompanied by a sequence of centroparietal or parietotemporal sharp waves; high‐voltage wave with a superimposed spike becoming unusual spike‐wave complexes, often elicited byeye closure; bursts of diffuse spikes and waves; and frequent jerks. This electroclinical pattern is very similar to the one described in Angelman syndrome (AS) in which a defect in GABAA receptor function has been suggested. Moreover, the genes encoding the GABAA receptor subunit have been mapped to the p12–pl3 bands of chromosome 4. Even though the deletion in these cases does not encompass the 4p12–p13 region, we suggest that the electroclinical picture common to WHS and AS might represent a characteristic type of epilepsy linked to a common genetic abnormality.

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

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.

Levetiracetam: an improvement of attention and of oral fluency in patients with partial epilepsy.

PURPOSE The aim of the present study is to verify whether patients with partial epilepsy receiving levetiracetam (LEV) as an add-on treatment show an improvement in cognitive function. METHODS A neuropsychological battery of tests was administered to 35 patients with partial epilepsy before the assumption of LEV and after the achievement of the therapeutical dose of this drug, 7 weeks later. A control group of 35 patients with partial epilepsy was administered the same battery of tests twice, at the same time interval as the LEV group. The controls were administered the same pharmacological treatment, which did not include LEV in either of the two sessions. RESULTS We found a statistically significant improvement in cognitive functioning, i.e. in attention and oral fluency, in patients receiving LEV compared to the controls. The responders to LEV were 28.6%. CONCLUSIONS LEV as an add-on therapy improved attention level and verbal fluency in our sample of patients with partial epilepsy. It is reasonable to assume that LEV may influence the metabolism of attention and of language area, as already suggested for piracetam (PIR) from which LEV derives. Further studies are needed to confirm these findings.