[Sleep apnea syndrome. Differential diagnostic reflections from the point of view of sleep medicine].
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Cognition Disorders↗
Biomedical subjects
W M Herrmann
Publications and source records attributed to W M Herrmann.
A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease.
Two doses of idebenone were studied in a prospective, randomized, double-blind, placebo-controlled multicentre study in patients suffering from dementia of the Alzheimer type (DAT) of mild to moderate degree. Diagnosis was based on DSM-III-R (primary degenerative dementia) and NINCDS-ADRDA criteria (probable Alzheimer's disease). A total of 300 patients were randomized to either placebo, idebenone 30 mg t.i.d. or 90 mg t.i.d. (n = 100, each) and treated for 6 months. The primary outcome measure was the total score of the Alzheimer's Disease Assessment Scale (ADAS-Total) at month 6. Secondary outcome measures were the ADAS cognitive (ADAS-Cog) and noncognitive scores (ADAS-Noncog), the clinical global response (CGI-Improvement), the MMSE, the Digit Symbol Substitution test (DSS) and several scales for the assessment of daily activities (the self- and observer-rating scales NAA and NAB of the Nuremberg Age Inventory NAI and Greene's Assessment). Safety parameters were adverse events, vital signs, ECG and clinical laboratory parameters. Clinical and psychometric evaluations were performed at baseline, and after 1, 3 and 6 months of treatment. After month 6 idebenone 90 mg t.i.d. showed statistically significant improvement in the primary efficacy variable ADAS-Total and in ADAS-Cog. An analysis of therapy responders performed for 3 outcome measures (CGI-global improvement, ADAS-Cog, ADAS-Noncog), selected to represent different domains of assessment, revealed significant superiority of idebenone 90 mg t.i.d. with respect to placebo in each of the 3 variables and in the concordance of responses across the 3 measures. Exploratory results for a subgroup of patients (ADAS-Total > or = 20) showed dose-related superiority of idebenone additionally on ADAS-Noncog and the CGI-Improvement scale. Safety results were inconspicuous for all assessments. The study results demonstrate the efficacy and safety of idebenone in the treatment of DAT patients.
Aged↗
The AMDP modules I-IV: recommendations for a standardized acquisition of EEG data in psychiatry. Association for Methodology and Documentation in Psychiatry.
During the last few years, the working group 'Psychophysiology' of the Association for Methodology and Documentation in Psychiatry (AMDP) discussed the possibility of the establishment of defined EEG modules in psychiatry. It was the aim to create a common data pool in order to be able to have access to larger data sets. The installation of such a common data pool was regarded as an important prerequisite for a future diagnostic application of EEG and EP data in clinical practice. The most relevant arguments are: From a statistical point of view, multivariate investigations can be improved when relatively large data sets are available. Subgrouping of patients is facilitated. Different centers have access to different populations of patients. Furthermore, compliance with the recommendations contributes to a reduction in misunderstanding and false interpretation of other investigators' results. The working group 'Psychophysiology' of the AMDP now recommends EEG modules to be registered in psychiatry. The recommendations are based on investigations using these modules in clinical research and practice as well as several years of discussion within the working group. Four AMDP modules (I-IV) are presented: MI: resting EEG (closed eyes), MII: resting EEG (eyes open), MIII: EEG during videotracking, and MIV: EEG during choice reaction time. Recommendations for additional modules are planned in the near future: MV: EEG during geometry test, MVI: EEG during labyrinth test, and MVII: amplitude stimulus intensity function. MIII-MVI is paralleled by an EEG recording so that psychomotor performance can be measured and EEG data under different activation conditions are available. Compliance with the recommendations guarantees the possibility of access to the common data pool. Computer software is available in Berlin.
Electroencephalography↗
On the use of neural network techniques to analyse sleep EEG data. First communication: application of evolutionary and genetic algorithms to reduce the feature space and to develop classification rules.
To automate sleep stage scoring, the system sleep analysis system to challenge innovative artificial networks (SASCIA) has been developed and implemented. The aims of our investigation were twofold: In addition to automatic sleep stage scoring the hypothesis was tested that the information of only 1 EEG channel (C4-A2) should be sufficient to automatically generate sleep profiles which are comparable with profiles made by sleep experts on the basis of at least 3-channel EEG (C4-A2), EOG and EMG, as EOG and EMG are seen as epiphenomena during sleep and the full information about the sleep stage should--according to our hypothesis--be available in the EEG. The main components of the SASCIA sleep analysis system are designed to meet the requirements of flexible adaptation to the interindividual differences of the sleep EEG. The core of the SASCIA sleep analysis system consists of neural networks. Supervised learning was implemented and the experts' scorings were included into the learning set and test set. The feature selections out of a large number (118) are performed by genetic algorithms and the topologies of the networks are optimized by evolutionary algorithms. Different mathematical procedures were used to evaluate and optimize the efficiency of the system. The profiles generated by SASCIA are in reasonable agreement with the sleep stages scored by experts according to RKR. The development of the system is communicated in three parts: the first communication deals with the application of the neural network techniques using evolutionary and genetic algorithms and with the selection of feature space. The second communication shows the training of these evolutionary optimized network techniques with multiple subjects and the application of context rules, while the third communication shows an improvement in the robustness by the simultaneous application of 9 different networks obtained from 9 subject types which were used in combination with context rules.
Algorithms↗
Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia.
The efficacy of the ginkgo biloba special extract EGb 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multi-center study. After a 4-week run-in period, 216 patients were included in the randomized 24-week treatment period. These received either a daily oral dose of 240 mg EGb 761 or placebo. In accordance with the recommended multi-dimensional evaluation approach, three primary variables were chosen: the Clinical Global Impressions (CGI Item 2) for psychopathological assessment, the Syndrom-Kurztest (SKT) for the assessment of the patient's attention and memory, and the Nürnberger Alters-Beobachtungsskala (NAB) for behavioral assessment of activities of daily life. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761, with p < 0.005 in Fisher's Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type and multi-infarct dementia was confirmed. The investigational drug was found to be well tolerated.
Aged↗
Effect and efficacy--on the function of models in controlled phase III trials and the need for prospective pharmacoepidemiological studies.
While the "effect" of a drug can be observed or deduced from observational data, the concept of "therapeutic efficacy" represents mainly a theoretical construction of a high degree of abstraction which is inconceivable without reciprocal combination with other theoretical constructs. The "therapeutic efficacy" of drugs can be investigated only via clinical-pharmacological or clinical "models". Several examples are given and discussed against the background of the actual considerations for shortening phase III studies and extending pharmacoepidemiological phase IV studies for scientific, practical and economic reasons. Of special relevance is the question whether study data of phase III allow an extrapolation to the wider patient population which it is intended to treat. Thus, it is well known that the criteria for representativeness in the investigated population are rarely achieved in phase III studies. Furthermore, observations have shown that various intervening moderator variables, such as the investigated subgroup or the trial setting (e.g. Inpatient or respectively out-patient treatment), might influence therapeutic efficacy and the possibility of generalizing the results. This again raises the crucial question of clinical relevance of significant effects. Possible ways of overcoming this unsatisfactory situation are suggested.
Clinical Trials, Phase III as Topic↗
The future of computer-assisted investigation of the polysomnogram: sleep microstructure.
Previous attempts at automated analysis of sleep were mainly directed towards imitating the Rechtschaffen and Kales rules (RKR) in order to save scoring time and further objectify the procedure. RKR, however, do not take into consideration the sleep microstructure of REM, stage 2, and SWS. While the microstructure of stage 2 has been analyzed in the past decade, the microstructure of REM and SWS are virtually unknown. In stage 2 the amount and distribution of spindles, K complexes, and arousal reactions have been studied. At least two types of spindles (12/s and 14/s) with different dynamics and locations have been identified. Two different shapes for K complexes have been described: one related to external sensory stimuli with similarities to evoked potentials and another one more related to sinusoidal slow wave activity seen in SWS. These two different K complex shapes have different distributions and, obviously, different functions. The authors also suggest that one should differentiate between arousal reactions and true arousals. Recent investigations suggest two types of delta waves in SWS. The more sinusoidal 1-3/s delta waves with a frontal maximum are already seen with lower amplitude in late stage 2 and increase their amplitude and incidence towards stage 3 and Stage 4. The other delta-wave type is slower (< 1/s), polymorphic, and has varying amounts of theta and higher frequency waves superimposed. During REM sleep it seems to be important to separate phases with rapid eye movements from those with none (REM sine REM), and count the amount and distribution of sawtooth activity. Background activity during REM and REM sine REM, as well as intra- and interhemispheric coherence should be analyzed separately. Only if the microstructure of the sleep EEG can be analyzed automatically using newer techniques such as transformation into wavelets and pattern classification with neuronal networks, and only if we learn more about the importance of microstructure elements, can automated sleep analysis go beyond the limited information obtained from scoring according to RKR.
Arousal↗
The use of diurnal vigilance changes in the EEG to verify vigilance-enhancing effects of memantine in a clinical pharmacological study.
In elderly subjects there is a vigilance decrease from morning to noon which was used in a clinical pharmacological model as a state condition to verify vigilance-enhancing effects of an antidementia drug. In this model the effects of Memantine (20 mg, single-dose application) on the quantified EEG were investigated in 16 elderly (mean age: 65 +/- 5 years), healthy subjects (10 females, 6 males) in a randomised, twofold cross-over design vs. placebo under double-blind conditions. EEG was recorded before medication, and 2 and 4 h after medication under reaction time (RT) and resting (RS) conditions. EEG data were subjected to spectral analysis and the topographic distribution of the amplitude values was mapped. The results show that a time-dependent decrease (from morning to noon) in vigilance (indicated by an increase in average EEG amplitudes caused by increased synchronisation in the alpha and beta range and an increase in delta) occurred under placebo which was counteracted by Memantine. The diurnal variations of the EEG and their compensation by a pharmacological agent represent an effective model for investigating the vigilance-enhancing effects of antidementia drugs.
Aged↗
Different modes of data processing and statistical testing applied to the same set of pharmaco-EEG recordings: effects on the evaluation of a selective and reversible MAO A inhibitor (brofaromine).
The comparison of two different modes of data processing and two different approaches to statistical testing both applied to the same set of EEG recordings was the main objective of this pharmacological study. Brofaromine (CGP 11,305 A), a new selective and reversible monoamine oxidase type A inhibitor was used as an example for investigating a potentially antidepressant drug in clinical development. The two modes of pharmaco-EEG (PEEG) data processing differed mainly in the sampling frequency and definition of spectral parameters. Patterns of significant changes were noted in terms of descriptive data analysis using either a nonparametric Wilcoxon signed-rank test or an ANOVA of transformed data, as suggested by Conover and Iman. These data clearly demonstrate that slight discrepancies in the results may simply arise from differences in data processing and statistical approach applied. In spite of these discrepancies, the pattern of brofaromine-induced PEEG changes was very similar regardless of the mode of data handling used.
Adult↗
Therapeutic efficacy of vincamine in dementia.
This trial was performed to investigate the therapeutic efficacy of vincamine in the treatment of primary degenerative and vascular dementia. 152 male and female patients aged between 50 and 85 years from two psychogeriatric centers and two nursing homes were initially included in the trial and screened for eligibility. 142 patients completed the trial. Clinical diagnosis was established according to DSM-III-R criteria. Allocation of the patients to the primary degenerative dementia of the Alzheimer type (DAT) group or the multi-infarct dementia (MID) group was based on computed tomography scans, electroencephalographic findings and the Hachinski Ischemic Score. In a 12-week double-blind treatment either 30 mg vincamine or placebo was given twice daily. Confirmatory statistics included item 2 of the Clinical Global Impression (CGI), the total score of the Sandoz Clinical Assessment Geriatric (SCAG) scale, the subscale 'need for help' of the nurse's rating of geriatric patients (Beurteilungsskala für geriatrische Patienten; BGP) and the total score of the Short Cognitive Performance Test (Syndrom-Kurztest; SKT). In addition, data on tolerance and on therapy response were evaluated based on descriptive statistics. The therapeutic efficacy of vincamine was clearly demonstrated by confirmatory analysis as the drug was statistically significantly superior to placebo in all four target variables. The clinical relevance of the outcome was further underlined by the results of the responder analysis of the variables SCAG, BGP and SKT. Based on the results of this trial, it can be accepted that the therapeutic effect of vincamine is superior to placebo in patients with mild to moderate dementia of degenerative and vascular etiologies.
Aged↗
[Electroencephalography in psychiatry--current status and outlook].
The "Psychophysiology Working Group" of AMDP (Arbeitskreis für Methodik und Dokumentation in der Psychiatrie) intends to establish a broad database of EEG data in psychiatry. The purpose is to determine whether the EEG can contribute to the diagnostic classification of psychiatric disorders, the description of the course of the illness and prediction of the therapeutic outcome. Since several studies have shown promising results in recent years, members of the working group have investigated literature and written reviews that are summarized in this contribution. This includes a critical evaluation of the studies cited. We restrict ourselves to schizophrenia, affective disorder and anxiety disorder. Out of more than 3000 available contributions in the world literature, 500 have been evaluated by the group, and around 90 are taken for this summary. The critical review is the basis for future research of the working group and gives the following working hypothese. Under resting EEG conditions anxiety does not show typical deviations from normality. However, EEG recordings under experimentally induced anxiety do show typical changes: in normal persons there is usually an increase in desynchronous fast beta activity (hyperarousal accompanied by cognitive coping), whereas patients with anxiety disorder show hypersynchronized alpha activity, as is usually found in deep relaxation. Thus, hypersynchronized alpha activity might be an expression of a compensatory effort of the system to relax. Anxiolytics induce synchronous 14-18 Hz beta or sub-alpha activity, which may force the system into more rigid patterns (relaxation) and thus could counteract anxiety in normal persons if hyperarousal together with desynchronization is not sufficient. Furthermore, benzodiazepines also show an increase in desynchronous fast beta activity, preferably in the frontocentral areas, which could be useful in chronic anxiety in order to support cognitive efforts. While depressive disorders cause a variety of changes in the awake EEG that can only partly be linked with the clinical picture (neurotic versus endogenous), the sleep EEG shows a decrease in REM latency, and increase in REM density and a decrease in sleep efficiency in patients with depressive symptoms. However, nosological specify is not yet established. Successful antidepressive therapy counteracts these changes. The common feature in the awake EEG is the interaction with vigilance-dependent variables in both directions: stimulation and sedation. Schizophrenia shows different patterns for acute and chronic states. In acute schizophrenia there is a dysrhythmic activity with an increase in beta activity. This is counteracted by neuroleptics, inducing a slowing of frequency and an increase of synchronization. In chronic schizophrenics, there is increased synchronization with low variability of amplitude. In contrast to the treatment in acute schizophrenics, in chronic schizophrenia the therapy response under neuroleptics is indicated by an increase in beta activity and a decrease in synchronization.
Anxiety Disorders↗
Standard operating procedure (SOP) for the registration and computer-supported evaluation of pharmaco-EEG data. Working Team "EEG in Phase I" of CIPS.
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Drug Evaluation↗
Do the B-vitamins exhibit antinociceptive efficacy in men? Results of a placebo-controlled repeated-measures double-blind study.
Additive analgesic effects of long-term application of a combination of the vitamins B1, B6, B12 (thiamine diphosphate 100 mg, pyridoxsine-HCl 200 mg, cyanocobalamin 20 micrograms, p.o.) on a single dose of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac (diclofenac-Na, 50 mg, p.o.) were investigated with a noninflammatory experimental pain model in 38 healthy volunteers. B-vitamins were given with 3 dosages/day for 1 week. Then experimental sessions of 3 h followed to test the analgesic efficacy of the NSAID. In these sessions, phasic pain was induced by intracutaneously applied brief electrical pulses (20 ms). Measured were the pain ratings, the cerebral potentials and the EEG delta power in responses to the stimuli as target variables for the analgesic test. Unspecific effects upon the vigilance system were evaluated by spontaneous EEG, auditory-evoked potentials and reaction times. The investigation was performed as a placebo-controlled, double-blind cross-over study. Blood samples were taken to monitor the plasma concentrations of the active agents. Whereas in the first block of stimuli (40-60 min after diclofenac medication) no analgesic effects of diclofenac could be observed, either given alone or after pretreatment with the B-vitamins, in the second stimulus block (100-120 min after medication) significant effects appeared in all target variables describing analgesia. Pain ratings were decreased by about 5%, late cerebral potentials by about 9% and stimulus-induced delta power of the EEG by about 14%. These effects were significant (p < 0.05, p < 0.01) against those under placebo, but came out to be independent of the B-vitamin pretreatment. No B-vitamin effects of the B-vitamins could be detected, either additive analgesic effects on diclofenac analgesia or on the concomitant variables describing unspecific sedative effects. Clearly the B-vitamin pretreatment for 1 week enlarged the plasma levels for vitamin B6 by 700%, for vitamin B1 by 70% and for vitamin B12 by 50%. All B-vitamin concentrations were independent of each other.
Adult↗
On the dimensionality of sleep-EEG data. Using chaos mathematics and a systematic variation of the parameters of the Corex program to determine the correlation exponents of sleep EEG segments.
Sleep-EEG data of 16 healthy subjects, classified according to the Rechtschaffen and Kales criteria, were taken to determine the correlation exponent (CE) or dimensionality (D2) of the data using the Corex program. We tested the applicability of this program to the analysis of sleep-EEG data changing systematically the embedding dimension (ED), the time lag (tau), the number of involved pairs of vectors and the EEG segment by split half. We could confirm the results of other authors according to which the complexity of the EEG signal decreases from stage 'awake, eyes closed' to sleep stages 1, 2, 3 and 4. The differences between the various sleep stages were significant. Stage REM could be differentiated from every stage but stage 1. The most important finding of our study was that the absolute value of the dimensionality depends on almost all the parameters tested: with increasing tau up to tau = 200 the CE increases, which means a 1.56-second shift. A higher number of pairs is needed when the signal is more complex. The ED is selected well between 6 and 11, that means reasonably higher or close to the dimensionalities for that purpose as presented in the literature. Different segments of one sleep stage in 1 subject led to different CE values, thus demonstrating that the EEG signal is not stationary over a segment of 2 min time. Although using chaos mathematics seems to be a useful tool in analyzing EEG data to explore their complexity, we could demonstrate the urgent need of calibrations and conventions to be able to interpret the absolute values.
Adult↗
Bivariate global frequency analysis versus chaos theory. A comparison for sleep EEG data.
Various quantitative descriptors for EEG data will be compared taking sleep as an example. In this contribution, Hjorth's mobility and complexity measures will be used to classify sleep stages. The results will be compared with those of a dimensionality analysis. Several authors have shown that the correlation exponent can describe the complexity of sleep EEG data and is able--with the exception of REM sleep--to distinguish significantly between sleep stages. The discriminative power of a bivariate global frequency analysis appears to be superior to that of the correlation exponent. Furthermore a very high statistical correlation between the estimator of fractal dimension and Hjorth's mobility was obtained.
Adult↗
Standard operating procedure for the registration and computer-supported evaluation of pharmaco-EEG data. 'EEG in Phase I' of the Collegium Internationale Psychiatriae Scalarum (CIPS).
The working team 'EEG in Phase I' of the Collegium Internationale Psychiatriae Scalarum presents a standard operating procedure (SOP) for the registration and computer-supported evaluation of pharmaco-EEG data, which is based on published guidelines. The minimum standard for recording, amplifying and filtering, validation of hardware and software, artifact treatment and fast Fourier analysis is described in a tabulated from and further explained as accompanying comments. The available SOP can be the basis for the working out of laboratory-specific SOPs. Compliance with the SOP guarantees the possibility of citation by the International Pharmaco-EEG Group (IPEG), Association for Methodology and Documentation in Psychiatry (AMDP), and Collegium Internationale Psychiatriae Scalarum (CIPS). Furthermore, an optimal standard is recommended where appropriate, which functions as a guideline.
Electroencephalography↗
BMS-181168 for protection of the human brain against hypoxia: double-blind, placebo-controlled EEG mapping studies.
In a double-blind, placebo-controlled, cross-over trial, the antihypoxidotic properties of BMS-181168 (previously BMY 21502)--a 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone alleviating impairment of learning and memory in the animal--were studied utilizing EEG mapping under an experimental hypoxic hypoxidosis. The latter was induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found at 6000 m altitude), which was inhaled for 23 minutes under normobaric conditions by 16 healthy male volunteers (aged 23-35 years, mean 27.2 years). After an adaptation session, they received in randomized order at weekly intervals oral single doses of placebo, or of 100 mg, 200 mg, and 400 mg BMS-181168. Evaluation of blood gases (PO2, PCO2, SO2), adverse events, and EEG mapping was carried out prior to drug administration and 2, 4, 6 and 8 hours post-drug, on each occasion under normoxic and transient hypoxic conditions. Hypoxemia was controlled by drawing arterialized capillary blood samples from the earlobes after hyperemization of the latter (after 0, 14, and 23 minutes of hypoxic gas inhalation) and by oximetry. After 23 minutes of inhalation, analysis showed a drop in PO2 from 98 to 48 mm Hg, in PCO2 from 41 to 31 mm Hg, and in SO2 from 97 to 80%. Descriptive statistical analyses of EEG mapping data demonstrated under hypoxia/placebo conditions an increase in delta/theta activity and a decrease in alpha activity as well as a slowing of the delta/theta centroid and an increase in the alpha and beta centroid, which suggests a marked deterioration in physiological vigilance.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Long-term tolerance of flupirtine. Open multicenter study over one year].
METHOD: To answer the question as to whether the analgesic flupirtine is suitable for long-term treatment of chronic pain, its side effects and efficacy were investigated over a 12-month treatment period. A total of 191 patients with chronic pain of degenerative and/or inflammatory musculoskeletal diseases were admitted to the open, uncontrolled multicenter study. This was followed by a single-blind placebo follow-up period of two weeks aimed at detecting withdrawal phenomena as a sign of a possible addictive potential of flupirtine. RESULTS: On the basis of patient and investigator documentation, laboratory studies and clinical examinations, flupirtine was found to be both well tolerated and effective. No signs of tolerance, addiction or relevant interactions were observed. The side effect profile differed from that of the opioids or prostaglandin synthesis inhibitors (NSAIDs).
Adult↗