Biomedical subjects
H Meinardi
Publications and source records attributed to H Meinardi.
General description of projects supported by EPICADEC.
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Generalized convulsive status epilepticus: pathophysiology and treatment.
The treatment of generalized convulsive status epilepticus according to a protocol, including a time schedule, prevents unnecessary delay and improves outcome. Based on a literature study and our own clinical experiences a treatment protocol is discussed with special emphasis on medical complications, choice of antiepileptic drugs, route of administration and a proper time schedule.
Epilepsy treatment in The Netherlands. Comparison of two medical centres.
In order to test if it is feasible to compare epilepsy treatment policies, a secondary (University Hospital) and a tertiary referral care centre (i.e. an Epilepsy Centre) were compared with respect to their characteristics, the treatment approaches, and the outcome of treatment using clinimetric indexes. At the Epilepsy Centre a greater variety of seizure types was seen than at the University Hospital. At the University Hospital more patients were treated with monotherapy (62.5%) than at the Epilepsy Centre (28.0%). The Composite Index of Impairments (CII), which reflects all treatment related impairments i.e. seizures and adverse events, was significantly higher at the Epilepsy Centre than at the University Hospital. No difference was seen in the groups of patients with a high score of the CII (> 100). Further analysis is needed to obtain an answer as to why differences between the two groups exist.
Fetal motility and chronic exposure to antiepileptic drugs.
The potential influence of antiepileptic drugs (AEDs) on fetal CNS function was studied with respect to motility patterns. Quantitative and qualitative aspects of spontaneous fetal activity were investigated for chronic AED-exposed fetuses and controls at three intervals during pregnancy: i.e. 20, 32 and 38 weeks. Movements were observed applying real-time ultrasound. Third trimester rest-activity cycles were determined according to the fetal behavioural state concept. Quantitative analysis revealed no marked differences in gross fetal motility between AED-exposed fetuses and controls. Both groups demonstrated the same developmental trend from midterm towards the third trimester. The number of trunk movements decreased, while their median duration increased. The incidence of fetal eye movements during C2F was lower for AED-exposed fetuses than for controls (significant for 38 weeks). In qualitative analysis, general movements of AED-exposed fetuses were more often labeled as suspect or abnormal than those of control fetuses (respectively, 8 out of 31 and 1 out of 20; P = 0.06). Future studies concerning chronic fetal AED-exposure and fetal CNS function should focus on qualitative rather than quantitative aspects of motility.
Mental deterioration at epilepsy onset: a hypothesis.
In this study, we hypothesized a type of mental deterioration in epilepsy, characterized as a discontinued, cascading process, i.e. a sudden mental decline in a limited time interval, immediately after the onset of the seizures. The posttraumatic epilepsy model (PTE) may appear to be exceptionally useful in avoiding one of the major methodological obstacles for testing this hypothesis, i.e. the unavailability of test results obtained with the same battery of tests prior to and directly after the onset of the seizures. We propose a multicentre study in which a large group of patients are assessed, after recovering from the direct aftermath of head injury, but before the onset of PTE. This baseline provides an opportunity for longitudinal follow-up. Full recovery from head injury before the onset of PTE is to be expected in the mild and moderate groups of closed head injury patients. In this category, approximately 2000 head injured patients have to be assessed to obtain a reasonable group of approximately 100-200 PTE patients. This group will be followed during the critical period of 2-3 years after the onset of epilepsy.
Aspects of pharmacotherapy in epilepsy.
Notwithstanding important advances in the treatment of epilepsy basic knowledge about the epilepsies and about the mechanism of action of antiepileptic drugs is still fragmentary. This statement is illustrated with examples from the laboratory and clinical practice. In particular it is emphasized that not only is little known about the mechanism of side-effects but also little work appears to be in progress to change that situation.
Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations.
We analyzed the influence of changes in the prescribing of antiepileptic drugs to pregnant women on frequency and pattern of malformations in their offspring by comparing two consecutive cohorts (1972 to 1979, cohort A; 1980 to 1985, cohort B). In cohort A, 15 (10%) of 151 exposed, live-born infants had one or more congenital anomalies, which consisted primarily of congenital heart defects, facial clefts, and syndromes of dysmorphia with developmental retardation, in association with polytherapy (carbamazepine plus phenobarbitone plus valproate, with or without phenytoin, or phenobarbitone plus phenytoin plus primidone). In cohort B, the prescribing of phenobarbitone, phenytoin, or primidone had dropped markedly, whereas monotherapy with valproate and carbamazepine had increased. Thirteen (7.6%) of 172 exposed, live-born infants had congenital anomalies. The most frequent anomalies were spinal defects (four) and glandular hypospadias (three), all in association with maternal therapy with valproate, carbamazepine, or both. The results underline the need for continuation of prospective studies to monitor the effect of change in prescribing policies and to evaluate the role of metabolic interactions between drugs prescribed in combination.
Reversible motor disturbances induced by vigabatrin.
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Clinimetrics and epilepsy care.
In order to study the practicability of rating scales in the regular care of people with epilepsy, indices have been developed and tested on their validity. These indices consist of the Index of Seizures, representing seizure activity, and the Composite Index of Impairment concerning the severity of impairment caused by the seizure type and frequency and the side-effects of anti-epileptic drug treatment. The indices have been applied in a retrospective quantitative evaluation of anti-epileptic drug therapy. The medical records of 250 randomly selected patients registered at an adult out-patient clinic have been reviewed. Their seizures have been classified as generalized tonic-clonic, simple partial and/or complex partial. The distribution of this population according to these indices has been studied, which leads us to the following conclusions: the global indices are valid for clinical application; in 18.6% of the patients studied there was severe impairment and unacceptable seizure control; combined types of seizure are difficult to control; no significant difference is demonstrated between monotherapy and polytherapy regarding the amount of neurotoxicity. The indices can be determined rapidly and therefore may become valuable aids for the physician in an out-patient clinic to support a decision whether or not to revise current anti-epileptic drug therapy.
Flumazenil as an anti-epileptic agent.
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The effect of intravenous flumazenil on interictal electroencephalographic epileptic activity: results of a placebo-controlled study.
The effect on interictal electroencephalographic epileptic activity of intravenous flumazenil (Ro 15-1788), a benzodiazepine antagonist and potential antiepileptic drug, was studied in 10 patients. Comparison was made with intravenous diazepam (10 mg) and placebo using a single-blind, single-dose, cross-over design. A dose of 3 mg flumazenil was well tolerated and produced a significantly greater reduction in the number of epileptic transients during the first 40 minutes after injection than did placebo (p less than 0.05). This effect was similar to that of diazepam in magnitude and duration. When flumazenil (3 mg) was administered immediately after intravenous diazepam (10 mg), the reduction in interictal epileptic activity was not significantly different from that produced by diazepam alone. The results suggest that either flumazenil has intrinsic antiepileptic activity and in this respect acts as a partial agonist at the benzodiazepine receptor, or that it is antagonising an endogenous proconvulsant ligand in these patients.
Mental deterioration in a population with intractable epilepsy.
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Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.
1. The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. 2. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of clearance and volume of distribution were 28 +/- 2 ml min-1 kg-1 and 2.6 +/- 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. 3. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 +/- 27 microA and 0.11 +/- 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. 5. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 +/- 18%. The value of the minimal effective concentration was in each animal and on each occasion close to zero within the relatively narrow range of 0.01-0.30mgI. 6. The results of this study showed that it is possible to determine in vivo concentration-anticonvulsant effect relationships of oxazepam under non-steady-state conditions in individual rats. The anti-convulsant effect of oxazepam appeared to be a rapidly reversible direct effect and acute tolerance did not develop within the time frame of the experiments.
Epilepsy and sports.
Millions of healthy people participate in sport on a regular basis. Moreover, in the last decade patients with chronic disorders have been encouraged to take part in sporting activities as a part of their rehabilitation. Can epileptic patients freely participate in sport or whether they are restricted to a certain extent by their disorder? An important factor is freedom from seizures. If seizures have been controlled for over 2 years the risk of relapse is the same as the risk of a first seizure. The risk of patients drowning or falling, or their epilepsy worsening because they are engaged in sport is thought to be low. Clinical data suggest that the incidence of seizures during sports and exercise is reduced. In the cooling down period, however, seizures tend to occur more frequently. Physicians should encourage epileptic patients to participate in sporting activities to enhance their physical fitness, self-esteem, and social integration. Before giving advice about the most suitable type of sport, the physician should known the patient's medical history, have a good insight into the different types of sport and be able to judge the role and function of sport to the particular patient. With certain precautions virtually all sports are suitable for most epileptic patients and should therefore be encouraged. However, a small minority of hospitalised patients with severe epilepsy need the supervision of qualified trainers, coaches and volunteers.
Problems of drug therapy of epilepsy in developing countries.
Unavailability of drug therapy to patients with epilepsy in developing countries is probably the most important obstacle to effective primary care of epilepsy in these countries. At the recent international Merritt-Putnam Symposium in New Delhi, poor availability of drug supply and poor access to drug therapy were identified as major constraints to availability of drug therapy. The extent and magnitude of the problems are examined in this communication and methods of improving drug therapy of epilepsy in developing countries are suggested.
Serum protein binding of antiepileptic drugs in Sri Lankans.
The percentage protein binding of antiepileptic drugs was investigated in epileptic patients (n = 90) undergoing treatment with phenobarbitone, phenytoin and carbamazepine either as a single drug therapy or in different combinations. When administered individually, the percentage (mean +/- SEM) protein binding of phenobarbitone, phenytoin and carbamazepine were 50.84 +/- 7.03, 87.23 +/- 2.98 and 76.80 +/- 6.30 respectively. Combination of phenobarbitone and phenytoin resulted in percentage (mean +/- SEM) protein binding of 51.94 +/- 6.09 for phenobarbitone and 83.54 +/- 7.01 for phenytoin, while the combination of phenobarbitone and carbamazepine resulted in percentage (mean +/- SEM) protein binding of 49.60 +/- 2.59 for phenobarbitone and 79.10 +/- 3.31 for carbamazepine. When phenytoin was given with carbamazepine percentage (mean +/- SEM) protein binding was 87.22 +/- 4.48 for phenytoin and 72.50 +/- 5.92 for carbamazepine.