Plasma concentrations of carbamazepine and carbamazepine 10,11-epoxide during pregnancy and after delivery.

Plasma concentrations of carbamazepine were monitored in 9 pregnant epileptic patients treated with the drug alone at constant doses during pregnancy and for at least 3 months after delivery. In addition, plasma concentrations of the metabolite, carbamazepine 10,11-epoxide were measured in 6 of the 9 patients. Plasma carbamazepine concentrations were fairly stable during pregnancy, and carbamazepine relative plasma clearances were significantly higher in weeks 4 to 24 than in weeks 25 to 32. After the end of the second trimester, there were no variations in plasma carbamazepine 10,11-epoxide concentrations and carbamazepine 10,11-epoxide:carbamazepine ratios. Both parameters were significantly higher in weeks 4 to 24 than in weeks 25 to 32 of pregnancy.

Twin vessels in familial retinal cavernous hemangioma.

We investigated the presence of twin vessels in two patients and in four of their relatives at risk from one family with autosomal-dominant hereditary cavernous hemangioma of the retina associated with central nervous system involvement. Twin vessels were detected in four of the six patients examined. The proband had bilateral retinal vascular hamartomas with central nervous system involvement but no twin vessels. The proband's mother had vascular hamartomas of the retina and brain with twin vessels. In the other three family members, twin vessels were associated either with retinal cavernous hemangiomas (one patient) or with normal fundi (two patients). Because twin vessels may be an ocular manifestation of von Hippel-Lindau disease, their presence in one of our two patients and in the otherwise healthy three family members suggests that twin vessels may be associated with different retinal vascular hamartomas, including capillary and cavernous hemangiomas.

Worsening in seizure frequency and severity in relation to folic acid administration.

We report a case of increase in seizure frequency and severity in a 26-year-old woman receiving folic acid at a dosage of 0.8 mg/day. She had symptomatic partial epilepsy with simple and complex seizures treated with carbamazepine. She was planning pregnancy and we prescribed folic acid for prevention of neural-tube defects. In the next few days she had a generalized tonic-clonic seizure for the first time and a significant increase in seizure frequency. Because of the temporal relation between the seizure worsening and the administration of folic acid, we hypothesize a role of folic acid in provoking seizures, as has been reported in the literature.Copyright Lippincott-Raven Publishers

Felbamate in refractory partial epilepsy.

This open-label study was performed to evaluate efficacy and safety of Felbamate (FBM) add-on therapy in drug-refractory partial epilepsy. We evaluated 36 patients (12 males) aged 11-68 years (mean 29.8) in which FBM was titrated gradually from 300 mg/day to a mean total maintenance daily dose of 1936 mg. Patients were monitored according to clinical practice and performed regularly laboratory tests. Mean follow-up of FBM therapy was 10 months (range 2-27). In this study, 5% of patients resulted to be seizure-free, 11% showed a seizure reduction more than 75%, 23% decreased their seizure frequency between 50% and 75% (P = 0.0001). The adverse events which were reported more frequently were: nausea, vomiting, anorexia and weight loss. Even if the patients sample is small FBM proves its efficacy in partial epilepsy, showing a relatively well tolerated profile.

Felbamate in therapy-resistant epilepsy: an Italian experience. Felbamate Italian Study Group.

We evaluated the use of felbamate in 379 adults and children with refractory epilepsies in an open-label, compassionate clinical use setting. Prior to the termination of the program, because of reports of aplastic anemia, 351 patients had completed 2 months of treatment with felbamate at a dose of 2400-3600 mg/day for adults or 30-45 mg/kg/day for children. Of the 246 patients who had a diagnosis of therapy-refractory localization-related epilepsy with or without secondary generalization, 52% (126/246) achieved a seizure reduction of 50% or more, including 10% (25/246) who became seizure free. There was no difference in response rate between adults and children. Of the 80 patients who had a diagnosis of Lennox-Gastaut syndrome (LGS), 60% (48/80) achieved a seizure reduction of 50% or more, including 6% (5/80) who became seizure free. Of the 25 patients with a diagnosis of generalized epilepsy (other than LGS) or undetermined epilepsy whether focal or generalized, 60% (15/25) achieved a seizure reduction of 50% or more, including 12% (3/24) who became seizure free. The results of this uncontrolled study suggest that felbamate could be useful in patients with epilepsies which are refractory to other antiepileptic drugs after careful risk-benefit assessment and consideration of all circumstances involved.

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.

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.

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.

Juvenile myoclonic epilepsy of Janz: clinical observations in 60 patients.

We studied 60 patients with juvenile myoclonic epilepsy (JME). There was a high positive family history for epilepsy (33.3%). Age at onset of epilepsy ranged from 4 to 18 years with an average of 13.9 years. 88.3% of patients were seizure-free. The most effective drug was valproate. In eight patients drug withdrawal was attempted but all patients relapsed during a follow-up period of 1 year. Video-EEG studies were performed in eight newly diagnosed patients; myoclonic jerks were recorded in five patients.

Symptomatic epilepsy with facial myoclonus triggered by language.

We report on a patient with a left frontal lesion who, many years after an injury, developed non-fluent aphasia and facial myoclonic jerks triggered by speaking and listening to spoken language. At age 57, the patient first noted that he would begin to stutter when delivering lectures at conferences. The stuttering would worsen if he continued talking. The video-polygraphic EEG recording shows brief paroxysms of spikes and polyspikes, followed by a slow wave, more evident in the left fronto-temporal region. The myoclonic jerks originating from the submental area correlate with EEG abnormalities. Clinically, these jerks determined a form of stuttering. The triggering factors were reading, speaking and listening to spoken language. This case had several characteristic features: facial myoclonus was the only seizure type experienced by the patient; the seizures and language impairment had a very late onset--about 50 years after the traumatic event that produced a dramatic lesion in the left fronto-polar region. (Published with videosequences.)

PB:PRM ratio in patients with epilepsy treated with primidone.

Phenobarbitone (PB) and primidone (PRM) plasma concentrations were measured in 88 patients of both sexes with different types of epilepsy and treated with PRM, alone or in association with carbamazepine (CBZ), phenytoin (PHT), ethosuximide (ESM) or valproic acid (VPA). A correlation was observed between the dose and the levels of both PRM and PB. Plasma PB:PRM ratio was high variable, especially interindividually. These changes seemed to be linked to age and particularly to pharmacological associations. In fact, PB:PRM ratio was increased with CBZ, ESM, VPA and PHT respectively. Moreover, a correlation was observed between the PB:PRM ratio and PHT plasma levels. The possibility of monitoring PB and PRM plasma levels during long-term treatment with PRM is discussed.

Therapeutic plasma levels of some anticonvulsants in focal epilepsy in relation to computerized axial tomography.

The authors investigated 37 patients with established focal epilepsy in terms of the antiepileptic drug (AED) blood levels needed to achieve control or significant abatement of seizures; then they examined the patients by computerized axial tomography (CAT) and grouped them according as they did or did not show evidence of an organic food lesion of the brain. Statistical elaboration of the data revealed that CAT-positive patients required significantly higher mean AED blood levels for clinical effectiveness than did CAT-negative patients; also, single drugs failed to produce control at any plasma level, necessitating recourse to multidrug regimes, significantly more often in the CAT-positive than in the CAT-negative patient group. In the discussion the authors examine the possible reasons for the observed difference of therapeutic responses.

The role of formative courses in the professional integration of patients with epilepsy. An Italian experience.

The aim of the present paper was to describe some formative projects on work integration of patients with epilepsy and mild cognitive deficits, so that similar initiatives may be promoted. The different phases of the formative projects were described: the inclusion criteria, the selection of participants, the assessment instruments, the courses themselves and the final results in terms of working experience. Thirteen participants were selected for each course. Patients were treated in different Lombardy Epilepsy departments, which addressed them to the Epilepsy Center, S. Paolo Hospital, Milan, where the selection took place. Seventy percent of the participants in the formative courses found a job in 1 year, even though most of the positions were temporary. The work integration seemed to be mainly related to the level of intelligence and to verbal memory. We stress the importance of organising similar courses in the future, in the context of wider networks. This will help more patients in acquiring both economic and psychological autonomy from their families.

Italian neuropsychological instruments to assess memory, attention and frontal functions for developmental age.

In this study, a series of tests exploring long-term verbal memory (the Short Story Test), attention (a modified version of Attentional Matrices and the Trail Making Test) and frontal functions (a modified version of the Frontal Assessment Battery) have been standardised on an Italian population of 283 children aged 5-14. Raw scores for each test have been adjusted for a series of variables (child's age, years of parents' education, handedness, gender) and transformed in equivalent scores enabling direct comparison across measures. This study was promoted by LICE (the Italian League Against Epilepsy) in order to provide Italian instruments standardised on the developmental age population and to study some of the most frequently impaired cognitive functions in epilepsy.

Public attitudes toward epilepsy in Italy: results of a survey and comparison with U.S.A. and West German data.

In May 1983, the Italian Institute of Public Opinion DOXA ran, for the Italian League Against Epilepsy, a survey to evaluate public attitudes toward epilepsy in Italy. Eight questions were addressed to a sample of 1,043 adults. Twenty-seven percent did not know what epilepsy was. The least knowledge was observed among elderly people, in the southern regions and the islands, in villages more than in cities, and, in particular, among the poorest social classes. Sixty-one percent had known someone who had epilepsy, and 52% had seen someone having a seizure. When those familiar with epilepsy were asked if they would object to having their children in school or at play associate with persons with seizures, only 11% replied they would object. Seventy percent thought that persons with epilepsy should be employed in jobs like other people, and only 8% thought epilepsy to be a form of insanity. When those familiar with epilepsy were asked if epilepsy is a curable illness, one-third answered negatively, one-third answered affirmatively, and one-third had no personal opinion. The Italian data seem to fall within the standard of the American (1979) and West German (1978) surveys.