Biomedical subjects

Theodor W May

Publications and source records attributed to Theodor W May.

10 recordsLinked to original sources

PubMed2006

Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy.

PURPOSE: The mechanisms of drug resistance in epilepsy are only incompletely understood. According to a current concept, overexpression of drug efflux transporters at the blood-brain barrier may reduce levels of antiepileptic drugs (AEDs) in epileptogenic brain tissue. Increased expression of drug efflux transporters such as P-glycoprotein has been found in brain tissue surgically resected from patients with medically intractable epilepsy, but it is not known whether this leads to decreased extracellular (interstitial) AED concentrations in affected brain regions. This prompted us to measure concentrations of AEDs in the extracellular space of human neocortical tissue by using intraoperative microdialysis (IOMD) in those parts of the brain that had to be removed for therapeutic reasons. For comparison, AED levels were determined in brain tissue, subarachnoid CSF, and serum. METHODS: Concentrations of carbamazepine (CBZ), 10-hydroxy-carbazepine (10-OH-CZ, metabolite of oxcarbazepine), lamotrigine (LTG), levetiracetam (LEV), topiramate, or phenytoin were determined by using one to four catheters during IOMD in the medial temporal gyrus. Furthermore, to calculate the individual recovery of every catheter, an in vitro microdialysis was performed with ultrafiltrate of serum concurrently obtained from the respective patient. In addition, AED levels were determined in the resected brain tissue, CSF, and serum of the same patients. Altogether 22 pharmacoresistant epilepsy patients (nine male, 13 female patients; age 15-54 years) with complex partial seizures or secondarily generalized seizures were involved. In a first series, IOMD samples 40 min after beginning of the microdialysis (flow rate, 1 microl/min), and in a second series, continuous measurements 25, 30, 35, and 40 min from the beginning were evaluated (flow rate, 2 microl/min). With in vitro recovery data of the individual catheters, the concentration in the extracellular space (ECS) was estimated. RESULTS: AED concentrations in the ECS of the cortex measured by catheters located at a distance of 0.6 cm differed markedly in some patients, whereas concentrations in the ultrafiltrate of the serum of the respective patients measured with the same catheters varied only slightly. Furthermore, ECS concentrations related to the ultrafiltrate of serum showed considerable interindividual variations. The high intra- and interindividual variation of ECS concentrations is demonstrated by the low correlation between concentrations in ECS and the ultrafiltrate of serum (CBZ, r= 0.41; 10-OH-CZ, r= 0.42; LTG, r= 0.27) in contrast to the high correlation between brain tissue concentration and the ultrafiltrate of serum (CBZ, r= 0.97; 10-OH-CZ, r= 0.88; LTG, r= 0.98) in the same group of patients. When comparing AED concentrations in the ECS with those in the CSF, ECS concentrations were significantly lower for CBZ, 10-OH-CZ, LTG, and LEV. CONCLUSIONS: The data demonstrate that AED concentrations show a considerable intraindividual and interindividual variation in the ECS of cortical regions. Furthermore, the ECS concentration of several AEDs is significantly lower than their CSF concentration in patients with intractable epilepsy. However, in the absence of data from nonepileptic tissues, it is not possible to judge whether the present findings relate to overexpression of multidrug transporters in the brain. Instead, the present study illustrates the methodologic difficulties involved in performing IOMD studies in patients and may thus be helpful for future approaches aimed at elucidating the role of multidrug transporters in epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Perioral reflex myoclonias: a controlled study in patients with JME and focal epilepsies.

PURPOSE: Perioral reflex myoclonias (PORM) are obvious, frequent, but often unobserved focal seizures in different epileptic syndromes and the leading seizure type in reading epilepsy. PORMs remain often undiagnosed because the patients are not aware that these are epileptic seizures and fail to report them. Their semiology is not fundamentally different in various epileptic syndromes. METHODS: We studied the frequency of PORM in patients with juvenile myoclonic epilepsy (JME) compared with patients with focal epilepsies. Twenty-five patients with JME were investigated with a standardized neuropsychological test program and compared with 25 matched patients with focal epilepsies. Statistical significance was calculated by using Fisher's exact test. RESULTS: We found significant differences between the groups regarding both frequency of PORM and activation of epileptic discharges. These observations seem to indicate that PORM, like praxis-induced seizures, are typical traits in JME. CONCLUSIONS: PORM are more frequent in JME compared with focal epilepsies. The distinction between focal and generalized epileptic ictogenesis may be less clear than is traditionally believed.

Adolescent↗

PubMed2005

Topiramate: a prospective study on the relationship between concentration, dosage and adverse events in epileptic patients on combination therapy.

RATIONALE: The relationship between topiramate (TPM) concentration, dosage and adverse events in patients with epilepsy is still controversial. We therefore performed a prospective study in patients with poorly controlled epilepsy treated with TPM, predominantly in combination with other antiepileptic drugs. The goal of the study was to investigate the relationship between the occurrence of adverse events due to TPM and its serum concentration or dosage, respectively. METHODS: The relationship between the occurrence of adverse events and TPM serum concentration or dosage, respectively, was examined in a group of 42 young adult and adult patients with poorly controlled epilepsy. Within 22 months, all patients treated with TPM had been included in the study. The 8 adverse events occurring most frequently (difference > or = 10%) in TPM-treated patients in 5, double-blind, placebo-controlled, parallel group studies, were checked regularly. This side effect profile has been presented by Reife et al. (1995a). Other possible or probable adverse events were also documented. RESULTS: The difference in TPM serum concentrations and TPM dosages (mg/kg) for patients without an adverse event, and patients with a given adverse event was statistically significant for "abnormal thinking, impaired concentration, weight loss, dizziness, speech problems, somnolence, ataxia, increased seizure frequency and paresthesia". To avoid adverse events, we recommend an initial "maintenance serum concentration" of below 4 microg/mL. As regards the TPM dosage, our results suggest initial maintenance dosages of 100 TPM or lower, 1.5 mg/kg or lower, respectively. These conclusions are limited by the relatively small number of patients.

Adolescent↗

PubMed2003

Are geomagnetic disturbances a risk factor for the sudden unexplained death of epileptic children?

The relationship between geomagnetic disturbances (with amplitudes above 50 nT) and the sudden unexplained death (SUD) of epileptic adults has been controversial up to now. In an autopsy-based cohort study (from 1964 to 1992) 15 epileptic children with SUD aged 1-14 years were compared to 63 epileptic children whose cause of death was known (KCD). The time of death as well as two international geomagnetic indices were assessed: Bartels' planetary 3-h signs (Kp) for the time of death and 2 h before, and the mean planetary daily amplitudes (Ap) on the day of death and on the 4 critical days before (and on the 4 post-mortem days as a control). Among the 15 SUD patients 9 died between 6 a.m. and 9 a.m. (universal time) whereas the KCD group showed an approximately uniform distribution of the time of death ( P = 0.026, Kolmogorov-Smirnov test). The Kp signs at death and 2 h before as well as the Ap indices at death and for the 4 pre-mortem days or after were not different in comparisons between the SUD and the KCD group ( P > 0.2, Mann-Whitney test). Furthermore the frequency of sudden storm commencement at death and for the 4 days before revealed no deviation of the SUD (26.7%) from the KCD group (23.8%) ( P > 0.2, Fisher test). The results do not support the hypothesis that geomagnetic disturbances are a risk factor for the sudden unexplained death of epileptic children.

Autopsy↗

PubMed2003

Serum concentrations of Levetiracetam in epileptic patients: the influence of dose and co-medication.

Levetiracetam (LEV) is a new antiepileptic drug approved as add-on therapy. Previous studies indicated that LEV has no relevant interactions with other antiepileptic drugs. The aim of this study was to investigate the influence of LEV dose, age, and co-medication on the serum concentration of LEV. In total, 363 samples of 297 inpatients who fulfilled the inclusion criteria (e.g., trough concentration, body weight available) were investigated. A patient was considered twice only if his co-medication had been changed. The LEV serum concentration in relation to LEV dose/body weight [level-to-dose ratio, LDR, (microgram/mL)/(mg/kg)] was calculated and compared for the most frequent drug combinations. Analysis of covariance (using age as covariate) carried out on the log-transformed data showed that co-medication had a highly significant (P < 0.001) effect on LEV serum concentrations. The median LDR of LEV was 0.32 for LEV + phenytoin, 0.32 for LEV + carbamazepine, 0.34 LEV + oxcarbazepine, 0.45 for LEV + lamotrigine, 0.46 for LEV + phenobarital, 0.52 for LEV monotherapy, 0.53 for LEV + valproic acid, and 0.54 LEV + valproic acid + lamotrigine. In co-medication with phenytoin (P < 0.001), carbamazepine (P < 0.001), and oxcarbazepine (P < 0.004), the LDR of LEV was significantly lower than it was with LEV monotherapy, whereas the LDR of LEV of patients on co-medication with valproic acid or lamotrigine did not differ significantly from the LDR of LEV of patients on LEV monotherapy (P > 0.05). Regression analysis including all 363 samples confirmed that other drugs (e.g., phenytoin, carbamazepine) lower LEV concentrations. In addition to co-medication, age had a significant effect on clearance of LEV. Children had lower LEV concentrations than adults on the same LEV dose per body weight. In contrast to other studies, our data point out that other enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine) can moderately decrease LEV serum concentrations (by 20-30%). However, our observations should be confirmed by prospective pharmacokinetic studies.

Adolescent↗

PubMed2003

Clinical pharmacokinetics of oxcarbazepine.

Oxcarbazepine is an antiepileptic drug with a chemical structure similar to carbamazepine, but with different metabolism. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of oxcarbazepine. MHD has (S)-(+)- and the (R)-(-)-enantiomer, but the pharmacokinetics of the racemate are usually reported. The bioavailability of the oral formulation of oxcarbazepine is high (>95%). It is rapidly absorbed after oral administration, reaching peak concentrations within about 1-3 hours after a single dose, whereas the peak of MHD occurs within 4-12 hours. At steady state, the peak of MHD occurs about 2-4 hours after drug intake. The plasma protein binding of MHD is about 40%. Cerebrospinal fluid concentrations of MHD are in the same range as unbound plasma concentrations of MHD. Oxcarbazepine can be transferred significantly through the placenta in humans. Oxcarbazepine and MHD exhibit linear pharmaco-kinetics and no autoinduction occurs. Elimination half-lives in healthy volunteers are 1-5 hours for oxcarbazepine and 7-20 hours for MHD. Longer and shorter elimination half-lives have been reported in elderly volunteers and children, respectively. Mild to moderate hepatic impairment does not appear to affect MHD pharmacokinetics. Renal impairment affects the pharmacokinetics of oxcarbazepine and MHD. The interaction potential of oxcarbazepine is relatively low. However, enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital or carbamazepine can reduce slightly the concentrations of MHD. Verapamil may moderately decrease MHD concentrations, but this effect is probably without clinical relevance. The influence of oxcarbazepine on other antiepileptic drugs is not clinically relevant in most cases. However, oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate. Oxcarbazepine lowers concentrations of ethinylestra-diol and levonorgestrel, and women treated with oxcarbazepine should consider additional contraceptive measures. Due to the absent or lower enzyme-inducing effect of oxcarbazepine, switching from carbamazepine to oxcarbazepine can result in increased serum concentrations of comedication, sometimes associated with adverse effects. The effect of oxcarbazepine appears to be related to dose and to serum concentrations of MHD. In general, daily fluctuations of MHD concentration are relatively slight, smaller than would be expected from the elimination half-life of MHD. However, relatively high fluctuations can be observed in individual patients. Therapeutic monitoring may help to decide whether adverse effects are dependent on MHD concentrations. A mean therapeutic range of 15-35 mg/L for MHD seems to be appropriate. However, more systematic studies exploring the concentration-effect relationship are required.

Anticonvulsants↗

PubMed2002

Is sudden unexplained death in adult epileptic patients associated with geomagnetic disturbances at the day of death or the 4 days before?

Geomagnetic disturbances are controversially discussed as risk factor for sudden unexplained death in epilepsy (SUDEP). An autopsy-based cohort of 39 adult patients with definite SUDEP were compared to 102 epileptic patients with known cause of death (KCD), who died between 1981 and 1992. Most of them had suffered from therapy-resistant epilepsies, predominantly characterized by generalized tonic-clonic seizures (about 70%). We analyzed an international geomagnetic index, the mean planetary daily amplitude (Ap), and the appearance of storm sudden commencement (SSC) at the individual day of decease and the 4 days before (and after). The SUDEP and KCD patients did not substantially differ with respect to the Ap values (Mann-Whitney test; P>0.2) and frequency of SSC (Fisher test; P>0.2) at death or the 4 premortem days. In addition, Ap values above 50 nanoTesla, postulated as critical threshold by other authors, showed no significant difference between SUDEP and KCD group for the day of death (5.1 versus 3.9%) or the 4 days before (5.1 versus 11.8%) (Fisher test; P>0.2). Consequently, the current data did not support the hypothesis that geomagnetic activities may act as a relevant risk factor for SUDEP.

Adult↗

PubMed2002

The efficacy of an educational treatment program for patients with epilepsy (MOSES): results of a controlled, randomized study. Modular Service Package Epilepsy.

PURPOSE: To evaluate the efficacy of the educational program MOSES (Modular Service Package Epilepsy). It was developed to improve patients' knowledge and understanding about their epilepsy, its treatment, and psychosocial consequences. The program intends to improve patients' coping with the disease, to strengthen self-esteem, and to support patients to become experts in managing their epilepsy. METHODS: A controlled, randomized study design was used to examine the efficacy of MOSES. Patients from 22 epilepsy centers in Germany, Austria, and Switzerland were randomly allocated to either MOSES group (treatment group) or waiting-list group (control group). The 242 patients were aged from 16 to 80 years. The MOSES group (n = 113) completed the questionnaires immediately before the educational course (T1) and 6 months later (T2), and the control group (n = 129), 6 months before (T1) and immediately before (T2) the course. The questionnaires included generic instruments (SF-36, Rosenberg self-esteem Scale, von Zerssen Depression Scale), and epilepsy-specific scales (Restrictions in Daily Life, Epilepsy-Related Fears, Coping with Epilepsy and Adaptation). Depression was used as a moderator variable. Seizure frequency and satisfaction with therapy also were assessed. Multivariate analysis of variance (MANOVA) with repeated measurements and univariate analyses of variance were performed. RESULTS: The MANOVA showed that participants of the educational program improved significantly. Univariate analyses revealed improvements in knowledge (p < 0.001) and coping with epilepsy (p = 0.004), whereas important effects of MOSES on other epilepsy-specific measures and on generic questionnaires (SF-36, self-esteem) were not found. Participants of the MOSES program also improved in seizure outcome (p = 0.041) and became more satisfied with the therapy [better tolerability of antiepileptic drug (AED) therapy, fewer side effects; p = 0.014]. In addition, participants expressed being highly satisfied with the program. CONCLUSIONS: The study clearly indicates the need for patient education. Even patients with a long history of epilepsy and with additional handicaps or diseases benefitted from the MOSES program.

Adaptation, Psychological↗

PubMed2002

Serum concentrations of topiramate in patients with epilepsy: influence of dose, age, and comedication.

Topiramate is a new antiepileptic drug (AED) approved as add-on therapy. Previous studies have shown that topiramate has only a limited effect on other AEDs, but its own metabolism can be induced by enzyme-inducing drugs. The aim of this study was to investigate the influence of topiramate dose, age, and comedication, especially of carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, and valproic acid (VPA) on topiramate serum concentrations in patients with epilepsy. In total, 480 samples of 344 inpatients who fulfilled the inclusion criteria (e.g., trough concentration, body weight available) were investigated. The topiramate serum concentration in relation to topiramate dose per body weight (level-to-dose ratio) was calculated and compared for patients receiving topiramate monotherapy and for patients receiving topiramate plus one other AED. Analysis of covariance (using age as covariate) showed that comedication had a highly significant influence on the topiramate serum concentrations. Regression analysis including all 480 samples confirmed that in combinations with phenytoin, carbamazepine, phenobarbital, and oxcarbazepine, the topiramate concentrations were significantly lower compared with topiramate monotherapy, whereas VPA and lamotrigine had no significant influence. Moreover, regression analysis indicated that primidone and methsuximide lowered topiramate concentrations, whereas gabapentin, bromide, and sulthiame did not. In addition to comedication, the patient's age was significantly correlated with topiramate clearance. In accordance with the results of previous studies, these results indicated that infants and children had lower topiramate concentrations than adults receiving the same topiramate dose per body weight. Comedication and age should be considered in adjusting topiramate dosage. Determination of topiramate serum concentrations may be useful, especially when enzyme-inducing drugs are withdrawn or added.

Adolescent↗

PubMed2002

Does lamotrigine influence valproate concentrations?

The aim of this study is to investigate the effect of lamotrigine (LTG) on valproate (VPA) concentrations dependent on LTG dose, LTG concentration, and additional enzyme-inducing antiepileptic drugs (AED) as well. For this purpose the following patient groups were compared: VPA monotherapy, VPA + one enzyme-inducing AED, VPA + LTG, and VPA + LTG + one enzyme-inducing AED. A total of 400 serum concentrations from 372 patients were evaluated. Two or more serum samples from the same patient were considered only if the comedication had been changed. For statistical evaluation, regression analytical methods and an analysis of variance were performed. For the analysis of variance, the VPA serum concentration in relation to VPA dose:body weight (level:dose ratio, LDR) was calculated and compared for different drug combinations. The analysis of variance revealed a significant effect of enzyme-inducing comedication (as expected) and age on the VPA LDR. Patients on LTG had a slightly lower VPA LDR, but this effect was not statistically significant. In addition, nonlinear regression analysis confirmed that patients on enzyme-inducing AED (carbamazepine, phenytoin, phenobarbital, methsuximide) had significantly lower VPA concentrations. Patients on ethosuximide had slightly but not significantly lower VPA concentrations. Patients on LTG also had significantly lower VPA levels, but this effect was only minor (-7%) and most probably not of any clinical relevance. Furthermore, the regression analysis showed that the relationship between the VPA dose per body weight and the serum concentration deviates significantly from linearity. Children less than 6 years old had lower VPA levels than older children and adults on a comparable VPA dose per body weight. Gender had no significant influence on VPA serum concentration. In addition, a subgroup of 40 patients was analyzed to see whether changing the LTG dose influences VPA serum concentrations. It did not. Thus, the authors conclude that the effect of LTG on VPA concentrations is not of clinical relevance.

Adolescent↗