[Which factors have an impact on levetiracetam serum concentrations? An analysis in 163 patients with epilepsy]. / Welche Faktoren beeinflussen die Serumkonzentration von Levetiracetam? Eine Analyse bei 163 Patienten mit Epilepsie.

We evaluated factors possibly influencing serum concentrations of levetiracetam (LEV-SC). The study included 163 patients with epilepsy (91 men, 72 women; mean age 39.6 years). The duration of treatment on first analysis was 226 days; the mean daily dose amounted to 2,434 mg. In each patient between one and seven measurements were carried out (mean 2.2). LEV-SC significantly depended on daily dosage and the interval between the time the medication was taken and the time of blood extraction. A marked drop in LEV-SC was observed 4-5 h following ingestion. Carbamazepine, oxcarbazepine and clobazam reduced LEV-SC, whereas valproate elevated LEV-SC significantly. When assessing evaluation of compliance these factors have to be taken into consideration when comparing intraindividual LEV-SC.

Right ventricular dysfunction and the incidence of implantable cardioverter-defibrillator therapies.

INTRODUCTION: Implantable cardioverter-defibrillator (ICD) therapy is well established in preventing sudden cardiac death in patients with left ventricular dysfunction. The influence of right ventricular (RV) function on ICD therapy for sudden cardiac death (SCD) is not known. METHODS: We retrospectively studied 222 patients receiving an ICD for primary prevention of SCD. Baseline clinical and echocardiographic data were gathered. RV systolic function was qualitatively assessed as normal or abnormal (described as mildly, moderately, or severely reduced). Primary endpoint was combined ICD therapy or death and secondary endpoint was ICD therapy alone. RESULTS: The mean follow-up was 940 +/- 522 days. The mean left ventricular ejection fraction was 0.23 +/- 0.07. By Kaplan-Meier analysis, RV dysfunction was predictive of combined ICD therapy or death when comparing between normal and abnormal RV function (P = 0.008) and among qualitative ranges of RV function (P = 0.012). RV dysfunction was not predictive of ICD therapy alone with either type of classification. After adjusting for clinical covariates, severe RV dysfunction was predictive of the combined endpoint of ICD therapy or death (HR 2.02, 95% CI 1.04-3.92, P = 0.037). CONCLUSION: Severe RV dysfunction appears to be an independent predictor of the combined endpoint of ICD therapy or death. RV dysfunction does not reliably predict the incidence of ICD therapy alone.

Which patients become seizure free with antiepileptic drugs? An observational study in 821 patients with epilepsy.

OBJECTIVES: Analysis of factors influencing seizure outcome in antiepileptic drug treatment of epilepsy. PATIENTS AND METHODS: Retrospective analysis of 500 patients with complete seizure control and 321 patients with refractory epilepsy (mean ages 33.3 and 32.1 years respectively). RESULTS: The seizure-free group consisted of 377 patients with symptomatic/cryptogenic epilepsy (SCE; mean seizure control 45 months) and 123 patients with idiopathic generalized epilepsy (IGE; mean seizure control 61 months) (P = 0.02). Of the patients with SCE, 35.7% had achieved seizure control with monotherapy (MT), 29.6% with >or=2 AEDs. No single AED was superior in MT. Of the patients with IGE, 35.9% had become seizure free with MT, 15.6% on combination therapy (CT). Valproate MT was more commonly associated with seizure freedom than lamotrigine (P < 0.05). CONCLUSIONS: The results indicate that, in SCE, seizures can be controlled with carefully selected CT more commonly than suggested by previous studies. The seizure prognosis of patients with IGE presenting to a specialist in epilepsy may be worse than previously thought.

Elevated plasma adrenocorticotropin (ACTH) with adrenal hyperplasia: a new factor in ACTH regulation?

We report a patient with Cushing's syndrome in whom the etiology of the hypercortisolemia could not be definitely established despite extensive biochemical investigations. Results included raised basal serum cortisol, plasma ACTH, and urinary free cortisol; failure to suppress even a paradoxical rise in serum cortisol after dexamethasone (1 mg overnight, 2, 8, and 16 mg/day); and a definite but not exaggerated rise in 11-deoxycortisol after metyrapone. After iv CRF, plasma ACTH rose from 22 to 30 pmol/L. Abdominal computed tomographic scanning showed adrenal hyperplasia; the presence of an adrenal adenoma, although suspected, was not established. An unusual finding was the presence in the urine of large amounts of 21-deoxycortisol metabolites, including 3 alpha,11 beta,17 alpha-trihydroxy-5 beta-pregnan-20-one and 5 beta-pregnane 3 alpha,11 beta,17 alpha,20 alpha-tetrol. On the basis of preoperative biochemical/radiological findings, a provisional diagnosis of ACTH-dependent Cushing's syndrome associated with autonomous bilateral adrenal hyperplasia was made. Incomplete bilateral adrenalectomy was performed; adrenal hyperplasia was histologically confirmed, but no tumor was found. However, ACTH was measured 1) just before operation when the patient was receiving treatment with metyrapone, and 2) postoperatively when the patient was receiving steroid replacement only, and on these occasions ACTH levels were lower than during the initial investigations. Pituitary scans before and after adrenalectomy were similar, offering no evidence of pituitary infarction. We propose that abnormal production of 21-deoxycortisol contributed to the aberrant regulation of ACTH and cortisol in this case, providing an example of a previously unreported cause of hypercortisolemia.

Subdural electrodes.

Physical aspects favour subdural registrations: as the solid angle under which a source is seen from a nearby electrode, the potential is large; there is no distortion by high impedence between source and electrode, nor by perpendicular short circuits; the frequency response is quasi-linear. Technical aspects and implantation strategy are outlined. Interictal and ictal ECoG patterns of diagnostical relevance and activation procedures are discussed. Advantages of subdural electrodes are: They provide detailed information on the epileptogenic zone, data on prognosis, are free of artefacts, allow electrical stimulation to determine eloquent cortex areas; by mathematical analysis methods the localizing power is increased. Disadvantages are: closed fields can be missed (recordable only by depth electrodes), in comparison to EEG, costs are considerably higher. Risks are practically absent with strip electrodes. In about half of the investigated patients, subdural electrodes were necessary to minimize the area of resection on a rational basis.

Nightmares and trauma: a comparison of nightmares after combat with lifelong nightmares in veterans.

In this study the chronic traumatic nightmares of men who had been in combat were found to differ from the lifelong nightmares of veterans with no combat experience in that they tended to occur earlier in the sleep cycle, were more likely to be replicas of actual events, and were more commonly accompanied by gross body movements. Traumatic nightmares may arise out of varying stages of sleep and are not confined to REM sleep alone. The group with lifelong nightmares showed evidence of thought disorder on the Rorschach. The men with posttraumatic stress disorder had failed to psychologically integrate their traumatic experiences and used dissociation as a way of dealing with strong affects.

Effects of surgical stress and corticotrophin on the peripheral metabolism of thyroid hormones in rabbits.

The effect of surgical stress and ACTH injection on the peripheral monodeiodination of thyroxine (T4) was studied in the rabbit. These stimuli resulted in a switch from the peripheral formation of tri-iodothyronine (T3) to reverse T3 in normal rabbits and in rabbits whose thyroidal secretion was suppressed by administration of T4. This is analogous to the situation in man. These changes were not due to alterations in the serum binding capacity for thyroid hormones.

Functional and morphological abnormalities in temporal lobe epilepsy: a comparison of interictal and ictal EEG, CT, MRI, SPECT and PET.

Ten patients suffering from drug-resistant complex partial seizures, with EEG abnormalities in the temporal region, were studied by means of non-invasive electrophysiological techniques (video-monitored, 16-channel, prolonged surface and sphenoidal EEG) as well as by imaging techniques (CT, MRI, SPECT and PET). Analysis of interictal and ictal EEG indicated the localization of epileptic activity in one side in eight cases. CT demonstrated focal abnormalities in three, SPECT in five unequivocally (in another four questionably, with the same lateralization as indicated by PET), MRI in eight, and PET in all cases. While only EEG provided specific diagnostic information, the focus definition was consistently good on PET images, poor on CT scans, and generally good but less consistent on MRI.

Seizure occurrence during ovulatory and anovulatory cycles in patients with temporal lobe epilepsy: a prospective study.

We investigated the influence of ovulatory and anovulatory menstrual cycles on seizure occurrence in female patients with complex partial seizures. We prospectively documented seizures in relation to menstrual cycles (defined by measurement of basal body temperature and progesterone serum concentrations) in 39 female patients. One hundred and thirty-two cycles of 35 patients entered final analysis. Only eight patients had anovulatory cycles, in 18 patients all cycles were ovulatory. In the remaining nine patients anovulatory as well as ovulatory cycles were documented. In ovulatory cycles the mean frequency of seizures during the days of menstruation was significantly higher as compared to the periovulatory or the luteal phase of the cycles. During anovulatory cycles seizure frequency was significantly lower during menstruation than in the remaining days of the cycles. Since progesterone is known to exhibit anticonvulsant effects, seizure occurrence during menstruation seems to be related to ovulatory cycles, possibly due to the premenstrual decrease of progesterone. Therapeutic recommendations for the treatment of seizures related to the menstrual cycle (catamenial seizures) include the administration of hormones, as progesterone (recommended especially for women with catamenial epilepsy who have a documented inadequate luteal phase) or the suppression of the menstrual hormonal cycle by synthetic gonadotropin releasing hormone analogs.

Progabide for previously untreated absence epilepsy.

Ten patients suffering from absence epilepsy and showing generalized spike-wave paroxysms in the EEG were treated by progabide monotherapy. Findings concerning clinical data and serial 24 h long-term EEG recordings were compared for the pre-treatment and treatment period. The average total spike-wave duration in 24 h decreased slightly from 810 sec to 699 sec; at follow-up, in 4 cases this trend was found to have reversed. Concerning seizure frequency, a marked anticonvulsant effect could not be confirmed; an initial slight anti-absence activity in some cases seemed to be subjected to the development of tolerance. Side effects were rarely observed and if so were not severe.

Double-blind placebo-controlled trial with flunarizine in therapy-resistant epileptic patients.

The anticonvulsant efficacy and side-effect liability of flunarizine (15 mg/day) was investigated in a randomized, double-blind, placebo-controlled, crossover design in 30 outpatients with drug-resistant complex partial seizures. Flunarizine or placebo was added to the preexisting medication and each patient was followed up for 10 months. At the end of the study data from 22 patients were available for evaluation. In patients taking first flunarizine and then placebo, plasma levels of flunarizine were still detectable at the end of the 4 months' placebo phase. In the group of 13 patients starting therapy with placebo, a significant seizure frequency reduction was observed during the flunarizine period in 11 patients, whereas one patient showed no change and seizure frequency increased in another patient. Two patients had a 50% reduction in seizure frequency. Flunarizine was well tolerated and few side effects were noted.

Free level monitoring of carbamazepine and valproic acid: clinical significance.

The recently available ultrafiltration technique facilitates determination of the free drug serum concentration of several antiepileptic drugs. For this reason a reappraisal of the clinical significance of free level monitoring was thought necessary. In this study on 203 patients receiving carbamazepine monotherapy and 101 patients receiving valproic acid monotherapy, the total and free drug levels were correlated with therapeutic outcome and side effects. Our investigations indicated no closer correlation between free concentration and seizure reduction or side effects than between total concentration and effectiveness or side effects. However, we found a close correlation between total and free concentrations.

A reassessment of 8-anilino-1-naphthalene sulphonic acid as a thyroxine binding inhibitor in the radioimmunoassay of thyroxine.

The effectiveness of 8-anilino-1-naphthalene sulphonic acid (ANS) in the radioimmunoassay (RIA) of thyroxine (T4) as an inhibitor of the binding of T4 to serum T4-binding proteins is assessed. The optimum ANS concentration is dependent upon the antiserum and the method used for separating free and bound T4. If T4 binding to serum proteins is not completely inhibited, resin separation methods may yield low values, while polyethylene glycol and double-antibody methods may produce high values for T4 concentration. Even with optimum ANS concentration gross errors in measurement of T4 may occur in patients with high thyroxine-binding globulin (TBG) concentrations.

Course of chronic focal epilepsy resistant to anticonvulsant treatment.

Sixty-three patients (32 women, 31 men), chronically treated with carbamazepine, phenytoin, valproate and/or phenobarbital, were investigated. Mean age at manifestation of epilepsy was 16.4 years; mean age at onset of documentation of seizure frequency was 33.7 years; mean duration of follow-up was 104.8 months; mean number of documented seizures per patient was 313.2. A statistical analysis of seizure diaries was performed. For each day the entries were the number of seizures per day. Linear trends, the amount of variance of the seizure frequency compared to randomly distributed events, were computed with the resulting coefficients fitting a general linear regression model. Non-random aggregations (clusters) were searched for as well as gaps of seizure manifestation. A similar number of patients exhibited a decrease (30%) or increase (29%) of seizure frequency during the course of epilepsy. The variance of the daily seizure frequency was in most patients (78%) significantly higher or lower (5%) than corresponding random distributions. The coupling coefficient to the day before was significantly larger than zero (indicating seizure clustering) in 57% of patients. Significant rhythmic components in seizure profiles (quasi-weekly or quasi-monthly) were found in 31 patients (both male and female). Periods of increased seizure frequency (clusters) manifested in 62% of patients; seizure gaps of at least 1 year occurred in 29 patients followed by seizure relapses in 20 patients. In conclusion, there is no evidence for a unique type of course in chronic focal epilepsy in patients on antiepileptic drugs.

Report on the Development of the Advanced Encryption Standard (AES).

In 1997, the National Institute of Standards and Technology (NIST) initiated a process to select a symmetric-key encryption algorithm to be used to protect sensitive (unclassified) Federal information in furtherance of NIST's statutory responsibilities. In 1998, NIST announced the acceptance of 15 candidate algorithms and requested the assistance of the cryptographic research community in analyzing the candidates. This analysis included an initial examination of the security and efficiency characteristics for each algorithm. NIST reviewed the results of this preliminary research and selected MARS, RC™, Rijndael, Serpent and Twofish as finalists. Having reviewed further public analysis of the finalists, NIST has decided to propose Rijndael as the Advanced Encryption Standard (AES). The research results and rationale for this selection are documented in this report.

Current status of biological indicators to detect and quantify previous exposures to radiation. Biological Indicators Working Group.

Hematologic changes following whole-body exposure to gamma or x-ray radiation have been used to estimate dose. The usefulness of this biological indicator is limited because of the recovery of these cells with time, thus making it unsuitable for estimation of dose years after exposure. The same is true for spermatogenic indicators; recovery and restoration of sperm numbers and fertility makes this biological indicator impractical for assessing radiation dose decades after radiation exposure. As noted in the text of the report, immunological concepts are in a state of rapid development, and it is possible that improved methods for applying immunologic procedures as biological indicators of radiation may be developed in the future. However, at the time, immunological indicators are not useful, even in an early time period, for quantitating radiation dose after total-body irradiation. A semiquantitative effect is observable in the early phase after total-body irradiation over a period of days to weeks, but there is little data available to indicate whether any of the immunological parameters can be indicative of a dose when the test is applied several years after radiation exposure. More detailed information regarding immunological indicators for estimating irradiation dose has been summarized elsewhere (Wasserman 1986). There is good agreement that ionizing radiation causes biochemical changes in the body; however, attempts to apply these changes to provide a reliable biological dosimetry system have not been particularly successful. The status of this research has been summarized by Gerber (1986). One of the difficulties has been the problem of establishing clear dose-effect relationships in humans. The lack of specificity in the response for radiation is another problem. Additional problems are due to the strict time dependency of biochemical changes and the limited duration of the changes during the postexposure period. Information on biochemical indicators is based on animal experiments; human experience is limited to a relatively few accidental human exposures and investigations involving patients undergoing radiation therapy. It appears that none of the biochemical indicators studied are currently useful for radiation dosimetry. Even if further developed, it is questionable whether or not biochemical indicators could be of use in estimating radiation dose received years and decades prior to the assay.

Current status of whole-body counting as a means to detect and quantify previous exposures to radioactive materials. Whole-body Counting Working Group.

This report discusses the principles, techniques, and application of whole-body counting with respect to previous radiation exposure. Whole-body counting facilities are located nationwide and have a wide range of capabilities. A listing of these facilities is provided in Appendix A. However, only a few facilities are truly state-of-the-art and have the sophisticated capabilities required to attempt detection of low-level activity in vivo. Measurements made many years after exposure can be extremely difficult to interpret. The precision and accuracy of resulting dose estimates are functions of such factors as the assumptions made concerning intake, time since intake, radionuclide metabolism, and level of intake. The indiscriminate application of metabolic models to current body contents or minimum detectable amounts of radionuclides with relatively short effective half-lives (such as 137Cs) can lead to absurd results when used as a basis for calculating intakes 25 and 40 y ago. Skull counting for 90Sr-90Y and 239,240Pu can set upper limits on possible uptakes and radiation doses, but in the case of 239,240Pu, the limits are rather high. In both cases, the accuracy of the limits depends on the metabolic models used in the calculations. These models (ICRP 1979) were developed to set safety standards for the intakes of radionuclides by workers and are not intended to be used to back-calculate uptakes and radiation doses from measurements made long after the uptake. There are, therefore, large uncertainties in any conclusions derived from these calculations. The experience gained over the years with whole- and partial-body counting has consistently shown that they are of little use in determining body contents of radionuclides resulting from exposure to weapons debris decades earlier. The development of new detectors such as an array of lithium-drifted silicon devices offers some hope of lowering the minimum detectable amount (MDA) for Pu and Am, but such detectors are still several years from routine application and do not represent current state-of-the-art. Furthermore, it is doubtful that such improvements will be sufficient to meet the need of assessing radiation exposures that occurred decades earlier.

Current status of bioassay procedures to detect and quantify previous exposures to radioactive materials. Bioassay Procedures Working Group.

This report was prepared by a working group established by the Oak Ridge Associated Universities (ORAU) for the purpose of assessing the current capabilities of bioassay methods that can be used to determine the occurrence and magnitude of a previous internal deposition of one or more radionuclides. The first five sections discuss general features of the use of in-vitro bioassay samples to achieve this purpose. The remainder of the report is focused on the possible use of urine bioassay procedures to detect and quantify internal depositions of radionuclides that may have occurred in United States occupation troops in Hiroshima or Nagasaki, Japan, prior to 1 July 1946, or to personnel who participated in atmospheric nuclear weapons tests conducted between 1945 and 1962. Theoretical calculations were made to estimate the quantities of various radionuclides produced in a 20-kiloton (kt) nuclear detonation that might still be present in measurable quantities in people today if they were exposed 25 to 40 y ago. Two radionuclides that emerged as good choices for this type of bioassay analysis were 90Sr, which emits beta particles, and 239,240Pu, which emits alpha particles. The current status and future prospects of chemical procedures for analyzing in-vitro urine bioassay samples for these two radionuclides were examined to determine the minimum amounts that could be detected with current methods and how much one might expect the sensitivity of detection to improve in the near future. Most routine 239,240Pu bioassay analyses involve detection by alpha spectrometry. The current minimum detectable amount (MDA) is about 0.74 mBq L-1 (20 fCi L-1), but this could be lowered to 74 muBq L-1 (2 fCi L-1). An MDA of 0.74 mBq L-1 (20 fCi L-1) is adequate for routine bioassay analyses but is too high to detect most uptakes of 239,240Pu that may have occurred 25 to 40 y ago. Methods under development that are or can be much more sensitive and have lower MDAs than alpha spectrometry for 239Pu are fission track analysis and mass spectrometry. Currently, the fission track analysis method has an MDA of about 19 muBq L-1), and this may eventually be lowered to 1.9 muBq L-1 (0.005 fCi L-1). The current MDA for 239Pu by mass spectrometry is about 7.4 mBq L-1 (200 fCi L-1), but the potential exists that it could be lowered to a value of about 0.37 muBq L-1 (0.01 fCi L-1).(ABSTRACT TRUNCATED AT 400 WORDS)

[A brief psychotherapeutic synergistic approach in child and adolescent psychiatry]. / Ein kurztherapeutisch synergetischer Ansatz in der Kinder- und Jugendpsychiatrie.

The controversy between the concepts of family therapy and systemic therapy is one issue to design a synergetic concept of brief therapy in the psychiatric treatment of children and adolescents. Some principles of the radical-constructivism, systemic theory an the psychology of narratives will be discussed and related to concepts of solution-oriented brief therapy. A case example demonstrates the perspectives of this approach in the ambulant psychiatric treatment.