Perceived heart rhythm in relation to ECG findings after direct current cardioversion of atrial fibrillation.

OBJECTIVE: To investigate the agreement between perceived heart rhythm and the ECG-registered heart rhythm, as well as between symptoms and the ECG after direct current (DC) cardioversion of atrial fibrillation (AF). METHODS: Consecutive patients with symptomatic AF subjected to DC cardioversion were interviewed about perceived heart rhythm and symptoms one week after restoration of sinus rhythm (SR). An ECG was obtained after the interview. A chance-corrected measure of agreement was calculated by using Cohen's kappa test. RESULTS: 356 patients were enrolled. One week after successful cardioversion 160 patients considered their rhythm to be regular and 222 ECGs showed SR. 130 patients considered their heart rhythm to be regular in agreement with ECG in SR (kappa = 0.34, 95% confidence interval (CI) 0.24 to 0.44), indicating a fair agreement. At the same time 59 patients perceived AF and 134 ECGs showed AF. Thirty eight patients perceived AF, in agreement with AF found on their ECG (kappa = 0.13, 95% CI 0.02 to 0.25), a poor agreement. 141 of 356 patients reported improvement of symptoms in agreement with SR on their ECG (kappa = 0.26, 95% CI 0.15 to 0.36), indicating fair agreement. Perceived SR and improvement of symptoms were strongly associated (n = 129; p < 0.001). CONCLUSION: Agreement between perceived heart rhythm and ECG, as well as between improvement of symptoms and SR recorded on the ECG, is no more than poor to fair after successful cardioversion of patients with persistent AF. The association between perceived SR and improvement of symptoms is strong. These findings support the need for objective criteria to select patients who would benefit most from rhythm control. They also support the need for further studies on quality of life of patients with AF, with due attention paid to patients' perception of their cardiac rhythm.

The effect of lamotrigine on epileptiform discharges in young patients with drug-resistant epilepsy.

PURPOSE: In a double-blind crossover study with lamotrigine (LTG), we investigated a possible relationship between the clinical responses and changes of the amount of epileptiform activity in EEG. METHODS: Twelve patients, aged 4-21 years, with generalized drug-resistant epilepsy who had responded to LTG, completed the study. Twenty-four-hour video-EEGs were taken during control, placebo, and drug phases. The amounts of epileptiform discharges were estimated and compared with the clinical effects. RESULTS: The duration of periods of repeated epileptiform discharges was significantly reduced during the LTG phase compared with the placebo phase (n = 12, p = 0.04). Ten patients showed a reduction of the amount of epileptiform discharges in the LTG phase by a mean of 81% (range, 17-100%). Periods of repeated epileptiform discharges with duration longer than 30 s were significantly reduced in length (p = 0.03) and number (p = 0.04) during the LTG phase compared with the placebo phase. Shorter periods of epileptiform discharges and the numbers of single epileptiform discharges were not affected. In five patients there was a seizure reduction (>/=50%) concomitant with the reduction of epileptiform discharges in the EEG. The behavior improved during LTG treatment in all patients. The patients became more alert, and their concentration and performance improved, according to their parents and the medical personnel. CONCLUSIONS: LTG in dosages of 1-8 mg/kg body weight was found to depress relatively long episodes of interictal, repetitive, epileptiform activity in young patients with drug-resistant epilepsy, whereas short episodes were not affected. It depressed seizures in about half of the patients studied but gave improvements of behavior in all patients.

Reduction of epileptiform activity in response to low-dose clonazepam in children with epilepsy: a randomized double-blind study.

PURPOSE: To evaluate the effect of low-dose clonazepam (CZP) on the amount of epileptiform activity in children with focal and generalized epilepsy. METHODS: In a single-blind pilot study, followed by a double-blind, placebo-controlled, randomized, crossover study, 15 children with epilepsy were evaluated by using 24-h long-term EEG recordings during baseline days and days after injections of placebo and CZP. The drug was given as a single i.m. injection of 0.02 mg/kg BW. Blood samples were obtained regularly for analysis of plasma concentrations of CZP. The number of epileptiform discharges was determined during corresponding periods with the individual child in the same state of alertness, the same real time of day, and with concomitant antiepileptic drugs (AEDs) unchanged. RESULTS: In the double-blind study, low-dose CZP produced a highly significant (p = 0.0015) decrease in the amount of epileptiform activity (mean, -69% vs. placebo, -2%) obtained during periods when median plasma concentrations ranged from 18 to <14 nM. The maximal plasma level (median, 24 nM) was reached before the start of the analysis periods. The pilot study showed reductions of epileptiform discharges within the same range as the double-blind study. In the children with daily seizures, a parallel decrease in seizures and the number of epileptiform discharges was seen after the administration of CZP. CONCLUSIONS: Our data demonstrate a significant reduction of epileptiform discharges on long-term EEGs after a single low dose of CZP with concomitant low plasma levels, which were considerably lower than the doses and plasma levels usually recommended. A concomitant reduction of seizures also was seen.

Variability of epileptiform activity in long-term EEGs with short and long intervals in children with epilepsy.

OBJECTIVE: To evaluate the impact of the time factor on the amount of epileptiform activity in long-term EEG recordings in children with epilepsy. METHODS: Ten children with epilepsy of different types underwent three 24 h EEG examinations during two consecutive days and with a month's interval. The number of epileptiform discharges during selected corresponding periods of time was counted. RESULTS: The number of epileptiform discharges on three repeated examination days showed no significant difference (ANOVA P = 0.88) as intraindividual increases and decreases on different days counterbalanced each other within the group. However the standard deviations of the relative changes were larger between recordings with a month's interval compared to those for consecutive days (86% and 33%). The mean magnitude of change was 55% between days separated by a month compared to 24% on consecutive days. The difference was non-significant but showed a trend towards larger changes with a longer interval (P = 0.07). CONCLUSIONS: The variability of epileptiform activity was larger when the interval between recordings was 1 month compared to consecutive days. The magnitude of the relative changes between intervals of 1 and 30 days showed a trend towards a difference although not statistically significant. When evaluating repeated long-term EEGs in relation to therapy in children, these variations should be considered.

The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study.

PURPOSE: We report a double-blind, placebo-controlled crossover study of lamotrigine (LTG) as add-on treatment in therapy-resistant, generalized epilepsy in children and adolescents (n = 30). METHODS: Twenty patients had Lennox-Gastaut syndrome. Each patient acted as his or her own control. LTG and placebo were randomly added to existing antiepileptic medication (AEDs). The LTG dosage was individualized in an open phase preceding the placebo/treatment phase. Patients who responded to LTG in the open phase went on to the double-blind phase. "Responders " were defined as patients with a >50% seizure reduction or less severe seizures or both, or improved behavior or improved motor skills or both. "Nonresponders" were defined as children who showed no positive effects of LTG with plasma levels of < or = 10 microg/ml or children who had adverse events during the open phase. RESULTS: There was a clear statistically significant reduction of seizure frequency in LTG compared with placebo treatment. None of the children studied showed abnormal biochemical or hematologic findings, or changes in plasma levels of concomitantly administered AEDs. CONCLUSIONS: LTG is a well-tolerated and effective treatment in children with intractable generalized epilepsies, including those with Lennox-Gastaut syndrome. The study design allowed a double-blind placebo-controlled assessment of LTG although the participating children used 19 different AED combinations at entry.

Pharmacokinetic interactions between lamotrigine and other antiepileptic drugs in children with intractable epilepsy.

PURPOSE: We wished to determine the oral pharmacokinetics of lamotrigine LTG and to assess possible interactions with other AEDs in an unselected population of children. Concentration data in plasma and in CSF for lamotrigine as well as for the other AEDs are presented. METHODS: Thirty-one children, children and young adults aged > 2 years with intractable generalized epilepsy despite adequate duration and dose of at least three conventional AEDs were studied. RESULTS: There was a linear relation between the dose administered and the maximal plasma concentration, indicating that saturation of absorption or elimination mechanisms did not occur in the dose range studied. The median elimination half-life (t1/2) in patients receiving concomitant valproate (VPA) was 43.3 h; in patients receiving carbamazepine (CBZ) and/or phenobarbital (PB), it was 14.1 h; and in patients receiving both VPA and CBZ/ PB or other antiepileptic drugs (AEDs), it was 28.9 h. No clinically important changes in the plasma levels of CBZ, VPA, valproate, ethosuximide, or PB were observed in the follow-up period (2-12 months). No dose adjustments of concomitant AEDs were necessary. The plasma concentration of clonazepam (CZP) was reduced when LTG was introduced. CONCLUSIONS: The complex interaction between LTG and other AEDs in children with intractable epilepsy makes therapeutic drug monitoring (TDM) desirable.

Flunarizine of limited value in children with intractable epilepsy.

Fourteen ambulatory children and adolescents with intractable epilepsy were studied in an open phase II study to investigate the pharmacokinetics and pharmacodynamics of flunarizine as an add-on treatment. Flunarizine was given in increasing doses starting with 0.1-0.3 mg/kg/day until effect was observed or a steady-state plasma concentration of 50-60 ng/ml was reached. Treatment was continued for 3 months at steady state. Pharmacokinetics were determined during the immediate posttreatment period. Positive antiepileptic effect (> or = 50% reduction in seizure frequency) was observed in 4 of 14 patients (29%; 95% CI: 52-5). Independently of antiepileptic effect, 10 of 14 parents (71.4%; 95% CI: 95-48) observed positive cognitive effects. In all patients treatment was withdrawn due to either lack of effect or weight gain. Flunarizine was rapidly absorbed; mean time of peak concentration (Tmax) was 2.7 hours (range: 1-8). The mean terminal half-life was 23.2 days (range: 7-48), the total plasma clearance of flunarizine per fraction of the dose absorbed (CLp/F) was 0.28 ml/min/kg (range: 0.07-042), and the volume of distribution of flunarizine per fraction of the dose absorbed (Vd/F) was 187 L/kg (range: 99-348). We conclude that flunarizine (0.1-0.3 mg/kg/day) seems to be of limited antiepileptic value in children with intractable epilepsy. The pharmacokinetic profile of flunarizine complicates its clinical use.

Treatment of spasticity in children with low dose benzodiazepine.

In an attempt to investigate whether benzodiazepines at low dosage have a significant effect in reducing spasticity among children with cerebral palsy, we carried out a double-blind, placebo-controlled, cross-over study. Twelve children with either spastic diplegia or hemiplegia participated in this study. The mean age was 14 years. The restraint of passive knee movements was determined with a dynamic dynamometer and spastic stretch reflexes were measured as EMG activity in muscles stretched. Clonazepam was given at low dosage (0.02 mg/kg body weight). In each child measurements of passive restraint were made on 2 different days immediately before and 3 h after an i.m. injection of either clonazepam or placebo in randomized order. Clonazepam significantly reduced spastic restraint (P < 0.001) compared to non-significant reduction with placebo. The mean plasma concentration of clonazepam at time of spasticity evaluation was 21 mmol/l which is in the low dose range, far below conventional doses. The study thus shows a positive effect of low dose clonazepam in reducing spasticity in children when given as a single dose.

Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases.

The progressive myoclonus epilepsies (PME) are a heterogeneous group of rare genetic disorders. Unverricht-Lundborg disease and Lafora's disease are two major classic forms of PME. We recently assigned the gene for Unverricht-Lundborg disease (EPM1) to human chromosome 21 band q22.3. We have now refined the localization of EPM1 by linkage analysis between the disease phenotype and nine DNA markers in 13 Finnish families. Loci MX1 and CD18 flank the EPM1 interval, which spans a distance of about 3.5 megabases. In this 20-centimorgan interval, no recombinations were detected between EPM1 and marker loci BCEI, D21S19, D21S42, D21S113, D21S154, and PFKL. Within this interval a maximum multipoint lod score of 11.04 was reached at loci D21S154-PFKL. In two Swedish families with Unverricht-Lundborg disease no recombinations were detected. In three Italian families with Lafora's disease the linkage results suggested that EPM1 is not the locus for Lafora's disease.

Receptor function studies in specimens from the proximal human urethra obtained by transurethral resection.

During transurethral resection (TUR) for prostatic hyperplasia, specimens were taken from the proximal urethra. Muscle strips thus obtained were mounted in an organ bath and muscle contraction was induced by adding increasing concentrations of noradrenaline (NA), methoxamine (alpha 1-agonist) and clonidine (alpha 2-agonist). NA and methoxamine induced a dose-dependent muscle contraction, but clonidine had no effect. The influence of prazosin (alpha 1-antagonist) and yohimbine (alpha 2-antagonist) on the NA-induced muscle contraction was also evaluated. Both antagonists had an inhibitory effect, which was much more potent with prazosin. The specimens taken during TUR were found to be suitable for in vitro receptor function studies. The alpha-adrenergic receptor function in the proximal human urethra was found to be mainly of the alpha-type.

Pharmacokinetics of total and free valproic acid during monotherapy in infants.

The pharmacokinetics of free and total valproic acid (VPA) in plasma and whole blood after oral administration during steady state was investigated in seven infants (mean age 10.7 months) receiving monotherapy. The VPA concentrations in whole blood closely followed those in plasma but at a reduced level. A positive correlation was found between dose and mean plasma concentration (r = 0.71). Mean terminal half-lives were similar in plasma and whole blood (12.5 and 15.5 h, respectively), but were considerably longer than for free VPA (6.4 and 6.5 h, respectively; P less than 0.01). There was a significant decrease in half-lives with increasing age (P less than 0.05). Plasma and whole blood clearance for total VPA was higher than reported in older infants and adults (17.8 and 28.9 ml/kg per hour) and was considerably higher for free VPA (127.6 and 188.8 ml/kg per hour, respectively). The increase in clearance compared with that in older subjects is well in concordance with a lower protein binding of VPA (mean 85.3%). Of special importance is that the percentage of unbound VPA increased with increasing concentrations of total VPA. The fraction of unbound VPA in plasma increased even more in subjects with low albumin concentrations (P less than 0.01).

Influence of adrenergic agonists and antagonists on urethral pressure, bladder pressure and detrusor hyperactivity in children with myelodysplasia.

In children with myelodysplasia and a low lumbar or sacral level of spinal cord lesions detrusor hyperactivity with pressure fluctuations is an almost constant phenomenon contributing to incontinence. In thirteen children with this type of dysfunction the effect of adrenergic agonists and antagonists on bladder and urethral pressures were studied by means of intravesical and urethral pressure recordings during the normal bladder-filling phase. Intravenous infusion of noradrenaline during the bladder-filling phase slightly reduced detrusor hyperactivity and the urethral pressure was increased. Following i.m. injection of the alpha-adrenergic antagonist phentolamine both the intravesical and proximal urethral pressures were reduced to about the same extent and the detrusor hyperactivity decreased. It is concluded that noradrenaline mainly changed urethral pressure while alpha-adrenergic blockade caused decreased tone in both the detrusor and the urethra as well as decreased detrusor hyperactivity.

Monitoring of phenytoin in epileptic children: value of the single morning sample.

The intra-individual variation in plasma concentration of phenytoin was studied in ten clinically well controlled children on monotherapy. The drug concentration was determined in routine pre-dose samples taken on three to five different mornings. On two of these occasions, plasma phenytoin was also determined at 0.5, 1, 2, 3, 5 and 7 h after the dose. The difference between the highest and lowest morning concentrations in a patient varied between 7.5 and 40 mumol/l (mean 20.1 mumol/l). Half of all morning concentration values were lower than 40 mumol/l. This often-recommended lower limit for good seizure control should therefore be reconsidered. The two concentration versus time curves in each patient during 7 h after administration differed considerably in shape, and the first curve could not be used for prediction of the second curve. The ratio between unbound and total drug was very stable and amounted to 9.4, SD 0.94% (n = 168). It is concluded that the conventional single morning sample is satisfactory for routine monitoring in well-controlled children on monotherapy with phenytoin. In problem patients, and during combination therapy, however, more extensive investigation will be necessary, including repeated morning samples as well as determination of dose-interval curves and protein binding.

Lidocaine treatment of neonatal convulsions, a therapeutic dilemma.

Three infants with neonatal convulsions were given lidocaine infusions for three days, three weeks and three months, respectively, and the plasma concentrations of lidocaine and its metabolites were analyzed by HPLC. After a prolonged infusion there was considerable accumulation of the metabolites. This may account for the difficulty of stopping the infusion without relapse of the seizures.

Pharmacokinetics of free and total sodium valproate in adolescents and young adults during maintenance therapy.

The pharmacokinetics of total and free valproic acid (VPA) in plasma and whole blood was investigated in seven adolescents and young adults (mean age 17.3 years) during a dosage interval at steady state. The concentration curves of VPA in whole blood after an oral morning dose (mean 8.2 mg/kg body wt.) closely followed those in plasma but at a reduced level. The apparent volume of distribution (Vd) of total VPA was 0.150-0.197 l/kg body wt. and of free VPA 0.911-1.58 l/kg body wt., which indicates considerable distribution of unbound VPA as well as drug binding to extravascular proteins. The terminal half-life of free VPA (6.4-6.7 h) was significantly shorter (P less than 0.05) than the half-life of total VPA (10.4-11.9 h). The binding of VPA in plasma was concentration dependent and fluctuated considerably within the individual dosage intervals. Concentrations of unbound VPA in plasma water of whole blood varied to a corresponding degree, since distribution to blood cells was low (mean 2.2%). It is concluded that there are substantial differences in the pharmacokinetics of free and total VPA. This may contribute to the well-known poor correlation between dose, plasma concentrations and effect of VPA.

Changes in cholinergic innervation and neuropharmacologic properties in idiopathic hypotonic urinary bladders.

Tissue specimens from hypotonic and normotonic human urinary bladders were investigated histochemically, chemically and neuropharmacologically. In hypotonic bladders the density of acetylcholinesterase (AChE)-positive nerves was markedly reduced and the nerve AChE staining intensity was weak. The concentration of acetylcholine was significantly lower than in specimens from normotonic bladders. At field stimulation the contractions were weak. The observations indicated that sparse cholinergic innervation and reduced acetylcholine synthesis are important for the impaired contractility in idiopathic dystonic bladder.

Influence of valproic acid on the gonadotropin-releasing hormone test in puberty.

Twelve epileptic adolescents on valproate (VPA) treatment were studied by means of clinical observation and gonadotropin-releasing hormone stimulation (GnRH) tests. Five patients were investigated before and during VPA treatment. Before treatment the basal and peak levels of gonadotropins were appropriate for age; during treatment both levels were depressed and the areas under the curves were significantly decreased. The long-term effect of VPA was studied in an additional seven patients. The basal levels of gonadotropins were as low and their response to GnRH as poor as in the second test of the first five patients--i.e., during VPA treatment. No recovery was noted in two patients after dose reduction or in a further two patients 10 months after the discontinuation of VPA treatment. In all the patients, however, the usual clinical signs of pubertal development and maturity were unaffected by VPA treatment. The significance of the results for sexual development and fertility is therefore uncertain.

The effect of noradrenaline on the contractile response of the urinary bladder. An in vitro study in man and cat.

In this study, bladder muscle strips from the detrusor of man and cat were used to evaluate the modulating effects of adrenergic agonist and antagonists on the field stimulation induced contractile response. Noradrenaline (NA) inhibited and phentolamine enhanced the contraction in a dose-dependent manner. Propranolol did not influence the field stimulation response. When a study of the combined effect of adrenergic drug influence was performed, the NA-induced inhibition was partly reversed by propranolol but a further increase of the contractile response compared to the control was seen, when phentolamine was added. No species differences were found. The conclusion drawn from these results is, that the inhibiting effect of NA on the contractile response is mediated via alpha- and beta-adrenergic receptors. The former could be located on the short parasympathetic intramural neurons while the latter probably are located on muscle cells.