Anders Sundqvist

Epilepsy and Pregnancy: A Prospective Study of Seizure Control in Relation to Free and Total Plasma Concentrations of Carbamazepine and Phenytoin

Summary: Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population‐based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy‐seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or im proved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of base‐line during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear‐cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention

The present review aims at highlighting selective aspects of the medical risks in epilepsy and their prevention. Emphasis is put on accidents and physical injuries, including risk factors and effectiveness of prevention; mortality, its causes, risk factors and prevention of seizure-related deaths, as well as traffic accidents, their risk factors and the effectiveness of prevention. Accidents and injuries are slightly more frequent among people with epilepsy than in the general population. This increased risk is probably most prevalent in patients with symptomatic epilepsy and frequent seizures, most often in combination with associated handicaps. The majority of accidents are trivial and occur at home. The most frequent injuries among patients with epilepsy are contusions, wounds, fractures, abrasions and brain concussions. The standardised mortality ratio (SMR; the ratio of observed number of deaths in a population with epilepsy to that expected, based on age and sex-specific mortality rates in a reference population) in population-based studies of epilepsy is 2-3 compared to the general population. This increased mortality is largely related to the etiology of the epilepsy and is probably not influenced by the treatment of the epilepsy. On the other hand, most fatalities in patients with chronic, therapy resistant epilepsy seem to be seizure-related and often sudden unexpected deaths (SUDEP). The frequency of such seizure-related deaths is most likely to be reduced by intensified treatment aiming at early seizure control, although appropriate studies for definitive evidence are still lacking. Apparently, there is an increased rate of traffic accidents in drivers with epilepsy, even if population-based prospective data are lacking. Many of these accidents are seizure-related. Probably, the extent to which physicians report their patients with uncontrolled epilepsy to the authorities is too low, but this has not yet been explored. Moreover, the preventive measures in legislation may be ignored by many people with epilepsy.

Disposition of carbamazepine and phenytoin in pregnancy

Summary: Free and total plasma concentrations of phenytoin (PHT) and carbamazepine (CBZ) and its active metabolite carbamazepine‐10,11‐epoxide (CBZ‐E) were determined in a prospective study of 86 pregnant epileptic women. The pharmacokinetics of PHT and CBZ during the three trimesters were compared with kinetics at least 10 weeks postpartum. Plasma clearance and unbound CBZ clearance were slightly decreased during the last trimester. Total and free plasma CBZ‐E concentrations did not change significantly during pregnancy. Plasma PHT clearance, on the other hand, increased from the first trimester. A less pronounced increase was observed for clearance of unbound PHT; the increase was statistically significant only during the third trimester.

Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14

A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.

Valproate as monotherapy for juvenile myoclonic epilepsy : Dose-effect study

Sodium valproate enteric-coated tablets were used in this double-blind, randomized, cross-over study of 16 patients with juvenile myoclonic epilepsy comparing 1000 mg and 2000 mg VPA daily in b.i.d. administration with 6 months of observation on each dose. Myoclonic, absence, and generalized tonic-clonic seizures were registered separately. Subjective side-effects were monitored, and a computerized neuropsychologic test battery was performed on each dose. There was no significant difference in seizure frequency between the two doses. Only 25% of the patients were seizure free throughout the study despite concentrations well within the normally proposed therapeutic range for VPA. During the higher dose, 37.5% of the patients had an improved seizure control, but 25% of the patients had an increase in seizure frequency compared to the lower dose. However, there was no correlation between VPA concentrations and subjective side-effects or neuropsychologic test results. Our observations point out the possibility that the common strategy of increasing plasma levels in difficult-to-treat patients until side effects occur should perhaps be reconsidered, but this suggestion needs further confirmation.

Pharmacokinetics of valproic acid in patients with juvenile myoclonic epilepsy on monotherapy.

Two different doses of sodium valproate (VPA), 500 mg b.i.d. and 1,000 mg b.i.d. as enteric-coated tablets, were used in this randomized, double-blind, cross-over monotherapy study of 16 patients with juvenile myoclonic epilepsy. Observation time was 6 months on each dose and included admittance for a 12-h serum concentration-time curve. There was a nonlinear relation between dose and concentration, with a negative deviation from the linear relation for total concentration and a positive deviation for the unbound fraction. Clearance for total concentration increased during high-dose treatment, but intrinsic clearance did not differ between doses. We measured the variation of repeated total and unbound VPA concentrations in up to 6 monthly samples on each dose. The coefficient of variation was 20.7% for total and 29.9% for unbound concentration on the lower dose, and 16.5% for total and 28.5% for unbound concentration on the higher dose. This difference between doses is not statistically significant. There was good correlation between the concentration taken before morning dose and AUC for one dose interval, especially during high dose, but the morning concentration was not the trough level. We conclude that the pharmacokinetic requirements for therapeutic drug monitoring of VPA are established.

Valproate monotherapy in juvenile myoclonic epilepsy: dose-related effects on electroencephalographic and other neurophysiologic tests.

A neurophysiologic test battery (consisting of a 24-hour, seven-channel electroencephalogram [EEG], EEG spectral analysis, multiple sleep latency test, visual evoked potentials, critical flicker fusion, and visual contrast sensitivity) was administered twice to 16 patients with juvenile myoclonic epilepsy (JME) in a double-blind, randomized, crossover study comparing two daily doses of sodium valproate (VPA), 1000 mg and 2000 mg. Clinical observation time was 6 months for each dose. Mean total VPA concentration during low-dose treatment was 470.4 mmol/L and during high-dose treatment was 700.0 mmol/L. Ten patients had seizures during low-dose treatment, but only three of these showed spike-wave activity on EEGs. During high-dose treatment, nine patients had seizures; five of these had spike-wave activity. EEG power spectrum did not change between doses. The other tests also showed no change between doses. Our results suggested that EEG and our selection of other neurophysiologic tests were of limited value for monitoring seizure frequency and clinical effects of VPA.

Juvenile myoclonic epilepsy: Events before diagnosis

Abstract Seventy-four outpatients aged 13.8–69.0 years with juvenile myoclonic epilepsy were studied. The female-to-male ratio was 2.2:1. Epilepsy in relatives was found in 28.4%. Median age at epilepsy onset was 15.0 years (range, 8.1–27.9). Median age at correct diagnosis was 26.1 years. Generalized tonic-clonic (GTC) seizures were present in 94.6%, and absence seizures were seen in 25.6%. Seizure type at epilepsy onset was absence in 4%, GTC in 14.9%, and myoclonic in 81.1%. A distinction is made between the order of onset of seizures and the set of seizure types presented at the time of correct diagnosis. Accordingly, prior to the occurrence of myoclonic jerks, the correct diagnosis could be reconstructed to juvenile absence epilepsy or grand mal on awakening syndrome in 18.9% of the patients. The instability of the juvenile epilepsies prompts iterated evaluation of the medical history.

Red cell folate levels in pregnant epileptic women.

Red cell folate concentrations were determined in 74 epileptic women in early pregnancy in a prospective study. All patients were treated continuously with antiepileptic drugs since before conception. The most frequently used drugs were carbamazepine (n−39) and phenytoin (n−26). Sixty-four patients (86%) were on monotherapy. Blood samples for red cell folate and antiepileptic drug concentrations were drawn before folate supplementation. Red cell folate levels in patients, 468 nmol·l−1, did not differ from those in non-epileptic, drug-free, pregnant women, 416 nmol·l−1 or from those in non-pregnant age-matched healthy controls, 412 nmol·l−1. No correlation was found between red cell folate concentrations and doses or plasma levels of phenytoin or carbamazepine.

Vertebral arch nonfusion and juvenile myoclonic epilepsy

Summary: Neural tube defects (NTD) are known to occur at a higher rate in pregnancies of women with epilepsy. Antiepileptic drugs (AEDs), notably valproate (VPA) and carbamazepine (CBZ), have been identified as risk factors, but a familial aggregation of this condition also occurs in the absence of pharmacologic teratogens. Spina bifida occulta, defined as a nonsymptoinatic non‐fusion of vertebral arches, has been suggested to be genetically determined, with an increased prevalence in patients with primary generalized epilepsy, and that the presence of this trait in fetal development can be enhanced pharmacologically to produce NTD such as meningomyelocele. In this study, plain abdominal radiographs were obtained from 56 patients with juvenile myoclonic epilepsy (JME) and 56 ageand sex‐matched controls. The radiographs were presented in a random order to an unbiased radiologist. No difference in prevalence of vertebral arch nonfusion (VAN) was noted between the two groups. Even if it has no increased frequency in patients with epilepsy, however, VAN is a common radiologic finding, and its relation to symptomatic neural tube defects should be clarified in future studies.