[Cerebral metabolic changes and chronic back pain: Study taking into consideration clinical and psychological parameters]. / Hirnmetabolische Veränderungen bei chronischem Rückenschmerz : Studie unter Berücksichtigung von klinischen und psychischen Parametern.

BACKGROUND: The manifestation of chronic pain and psychological impairments are related to alterations of neurotransmitter metabolism in cerebral pain processing regions, e.g., anterior cingular cortex (ACC), insula. Magnetic resonance spectroscopy ((1)H-MRS) enables in vivo quantification of neurotransmitters in the brain and was applied in this study to examine the hypothesized chronic pain-related imbalance between excitatory (glutamatergic) and inhibitory (GABA-ergic) neurotransmitter turnovers in the brain of patients with nonspecific chronic pain. MATERIALS AND METHODS: A total of 19 patients with nonspecific chronic (> 3 months) back pain and 19 age- and gender-matched healthy subjects participated in this study. Glutamate and GABA as well as glutamate/GABA ratios were determined in the ACC and insula using (1)H-MRS. Sociodemographic, psychological, and pain-related features were measured with standardized questionnaires. RESULTS: There was a strong variance of glutamate/GABA ratios for both patients and healthy subjects with no significant difference between the two groups. Regression analysis revealed certain significant predictors, such as anxiety as causal variable for reduced glutamate and depression and age as predictors for reduced GABA in ACC. In the patient group, intensity of pain was a significant predictor for glutamate and GABA levels in the insula. CONCLUSIONS: Despite the uniform diagnosis of nonspecific chronic back pain, we observed a strong variance of neurotransmitters in cerebral pain processing regions. It is necessary to include psychological as well as clinical parameters (e.g., intensity of pain or depression) for a proper interpretation of neurotransmitter turnovers.

Prevention of episodic migraine with topiramate: a prospective 24-week, open-label, flexible-dose clinical trial with optional 24 weeks follow-up in a community setting.

OBJECTIVE: To explore efficacy and safety outcomes of topiramate for episodic migraine prevention in community practice. RESEARCH DESIGN AND METHODS: Open-label, multicenter, flexible-dose clinical trial consisting of a 4-week baseline phase, 24-week core phase and an optional 24-week follow-up phase in patients (18-80 years) with episodic migraine treated in community practices outside tertiary care centers. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change in the number of migraine days/28 days (baseline vs. the last 4 weeks of core treatment) Secondary efficacy parameters included aspects of quality of life (QoL) and subjective patient ratings. RESULTS: A total of 360 patients entered the core phase (ITT population); 37.6% (97 patients) discontinued prematurely, mainly due to adverse events (AEs; 23.6%). Mean topiramate dosage was 90 mg/day. Migraine days decreased from 8.30/28 days to 5.65/28 days and QoL (HIT-6 and MIDAS) was improved. Efficacy, tolerability and satisfaction were rated as 'good' or better by 56, 61 and 63% of patients, respectively. A total of 321 of 364 patients (88.2%) reported at least one treatment emergent AE, and the most common during the core phase were paraesthesia (46.4% of 364 patients), fatigue (17.0%), nausea (15.4%), dizziness (12.9%), viral infection (12.9%), weight decrease (12.6%) and impaired concentration (10.2%). Of 227 patients completing the core phase, 199 (88%) participated in the follow-up phase. A total of 187 patients received topiramate and 38 (20.3%) of these stopped treatment prematurely due to insufficient efficacy (6.4%), AEs (4.8%) or other reasons (10.2%). Reduction in migraine days and improvements in QoL (HIT-6) were maintained or improved (MIDAS) during follow-up, and 84% rated their satisfaction with topiramate therapy as 'good to very good'. CONCLUSIONS: This community practice study showed that long-term treatment with topiramate in the prevention of episodic migraine was effective and well-tolerated, and it was associated with clinically relevant improvements in several aspects of QoL.

A functional-structural model to understand cardiac autonomic nervous system (ANS) dysregulation in affective illness and to elucidate the ANS effects of antidepressive treatment.

Numerous studies provide evidence that major depression (MD) is associated with certain disorders of cardiac autonomic nervous system (ANS) function, in particular, with an autonomic neurocardiac imbalance characterized by a low cardiovagal modulation, a raised sympathetic nerve activity and a high resting heart rate. We assume that such MD-associated cardiac ANS disorders are mainly caused by functional-structural abnormalities within the central autonomic network (CAN), in particular, by well-defined abnormalities of hypothalamic structures in MD. In view of the well-known association between an autonomic neurocardiac imbalance and the risk for cardiac arrhythmias, we assume that MD-associated cardiac ANS disorders are at least partly responsible for the high cardiovascular mortality risk in MD. It is, however, still unclear whether antidepressive treatment will lower the risk for cardiovascular complications in MD. There is convincing evidence that a successful antidepressive treatment with electroconvulsive therapy, cognitive behavioral therapy, or pharmacotherapy with primarily non-antimuscarinergic antidepressants can improve an initially disturbed cardiac ANS function in MD. These studies correspond well to our findings that treatment with both, nefazodone or reboxetine, can induce a reduction of central sympathetic nerve activity and an increase of the initially lowered cardiovagal modulation depending on the improvement of depressive symptoms after treatment. Since both effects occured obviously independent from the primarily serotonergic or noradrenergic action of the antidepressants, our findings suggest the existence of a generally supraordinate and uniform mechanism underlying the ANS effects of antidepressive treatment with drugs inhibiting serotonin- or noradrenaline reuptake.

Standardized tests of heart rate variability: normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate.

The authors undertook this study to determine the effects of age, gender, and heart rate (HR) on the results of cardiac autonomic function tests for measuring heart rate variability (HRV) in a large sample of healthy subjects (n = 309). Conventional tests (deep breathing, maximum/minimum 30:15 ratio), and a standardized 5-minute resting study, including spectral analysis of HR, were used. The main findings included (1) the indices of all tests, except for the ratio of the low- (LF) to high-frequency (HF) spectral power (LF/HF ratio) and HR itself, are inversely related to age in both sexes; (2) the 5-minute spectral bands (except for the LF/HF ratio), the variation coefficient, expiratory-inspiratory ratio during deep breathing, and the maximum/minimum 30:15 ratio are independent of HR; (3) women up to the age of 55 years have a higher resting HR compared with men; (4) young and middle-aged women show a significantly lower LF power and LF/HF ratio compared with age-matched men, whereas no significant gender differences are observed in the absolute HF power. The authors computed age- and gender-dependent normal values for each of the HRV indices studied here and discuss the clinical consequences arising from gender differences in HRV.

The Goltz-Ferrier debates and the triumph of cerebral localizationalist theory.

OBJECTIVE: To analyze the significance of the Goltz-Ferrier debates held at the International Medical Congress of 1881 for the development of ideas on cerebral localization. BACKGROUND: Cerebral localization was the subject of vigorous debate throughout the 19th century. At the Congress of 1881, David Ferrier, a leading proponent of cerebral localization, and Friedrich Leopold Goltz, an equally prominent anti-localizationist, had the opportunity to present their experimental research before 3,000 of the world's leading medical figures. METHODS: The authors reviewed and translated the presentations by Goltz and Ferrier at the Congress and supporting publications in contemporary medical journals. RESULTS: In his presentation to the Physiology Section, Goltz criticized localizationists for their widely divergent conclusions about the exact anatomic sites of cortical centers and for their failure to adequately explain functional restitution after cortical ablations. He noted that localizationist theories could, like an apple, "look very tempting and still have a worm inside." He described his own studies on massive decerebrations in dogs and noted that despite complete destruction of the cortices of both hemispheres these animals failed to exhibit motor weakness or deficits in primary sensation. Ferrier noted that Goltz's results were irreconcilable with his own experiments in monkeys, in which circumscribed lesions produced clear and reproducible functional deficits. Both investigators exhibited animals with cortical ablations. Ferrier's presentation of a hemiplegic monkey prompted Charcot's famous utterance, "C'est un malade!" ["It's a patient!"]. A distinguished committee examined the brains of the animals, and confirmed that Ferrier had indeed succeeded in producing a circumscribed lesion in the frontoparietal cortex, whereas the cortical ablations in Goltz's dogs were much less widespread than anticipated. CONCLUSIONS: Ferrier's dramatic demonstration of the effects produced by localized lesions in macaques triumphed over Goltz's unitary view of brain function, providing a major impetus for the subsequent successful development of neurologic surgery.

Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy.

OBJECTIVE: To evaluate the efficacy and safety of alpha-lipoic acid given intravenously, followed by oral treatment in type 2 diabetic patients with symptomatic polyneuropathy. RESEARCH DESIGN AND METHODS: In a multicenter randomized double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN] III Study), 509 outpatients were randomly assigned to sequential treatment with 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by 600 mg alpha-lipoic acid three times a day orally for 6 months (A-A; n = 167); 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (A-P; n = 174); and placebo once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (P-P; n = 168). Outcome measures included the Total Symptom Score (TSS) for neuropathic symptoms (pain, burning, paresthesias, and numbness) in the feet, and the Neuropathy Impairment Score (NIS). Data analysis was based on the intention to treat. RESULTS: No significant differences between the groups were noted for the demographic variables and the nerve function parameters at baseline. The TSS in the feet decreased from baseline to day 19 (median [range]) by -3.7 (-12.6 to 5.0) points in the group given alpha-lipoic acid intravenously and by -3.0 (-12.3 to 8.0) points in the placebo group (P = 0.447), but the area under curve on a daily basis was significantly smaller in the active as compared with the placebo group (85.6 [0-219] vs. 95.9 [5.5-220]); P = 0.033). After 7 months, the changes in the TSS from baseline were not significantly different between the three groups studied, which could be due to increasing intercenter variability in the TSS during the trial. The NIS decreased after 19 days by -4.34+/-0.35 points (mean +/- SEM) in A-A and A-P and -3.49+/-0.58 points in P-P (P = 0.02 for alpha-lipoic acid versus placebo) and after 7 months by -5.82+/-0.73 points in A-A, -5.76+/-0.69 points in A-P, and -4.37+/-0.83 points in P-P (P = 0.09 for A-A vs. P-P). The rates of adverse events were not different between the groups throughout the study. CONCLUSIONS: These findings indicate that a 3-week intravenous treatment with alpha-lipoic acid, followed by a 6-month oral treatment, had no effect on neuropathic symptoms distinguishable from placebo to a clinically meaningful degree, possibly due to increasing intercenter variability in symptom scoring during the study. However, this treatment was associated with a favorable effect on neuropathic deficits without causing significant adverse reactions. Long-term trials that focus on neuropathic deficits rather than symptoms as the primary criterion of efficacy are needed to see whether oral treatment with alpha-lipoic acid over several years may slow or reverse the progression of diabetic neuropathy.

Differences between the pressure- and temperature-induced denaturation and aggregation of beta-lactoglobulin A, B, and AB monitored by FT-IR spectroscopy and small-angle X-ray scattering.

We examined the temperature- and pressure-induced unfolding and aggregation of beta-lactoglobulin (beta-Lg) and its genetic variants A and B up to temperatures of 90 degrees C in the pressure range from 1 bar to 10 kbar. To achieve information simultaneously on the secondary, tertiary, and quaternary structures, we have applied Synchrotron small-angle X-ray diffraction and Fourier transform infrared spectroscopy. Upon heating a beta-Lg solution at pH 7.0, the radius of gyration Rg first decreases, indicating a partial dissociation of the dimer into the monomers, the secondary structures remaining essentially unchanged. Above 50 degrees C, the infrared spectroscopy data reveal a decrease in intramolecular beta-sheet and alpha-helical structures, whereas the contribution of disordered structures increases. Within the temperature range from 50 to 60 degrees C, the appearance of the pair distance distribution function is not altered significantly, whereas the amount of defined secondary structures declines approximately by 10%. Above 60 degrees C the aggregation process of 1% beta-Lg solutions is clearly detectable by the increase in Rg and intermolecular beta-sheet content. The irreversible aggregation is due to intermolecular S-H/S-S interchange reactions and hydrophobic interactions. Upon pressurization at room temperature, the equilibrium between monomers and dimers is also shifted and dissociation of dimers is induced. At pressures of approximately 1300 bar, the amount of beta-sheet and alpha-helical structures decreases and the content of disordered structures increases, indicating the beginning unfolding of the protein which enables aggregation. Contrary to the thermal denaturation process, intermolecular beta-sheet formation is of less importance in pressure-induced protein aggregation and gelation. The spatial extent of the resulting protein clusters is time- and concentration-dependent. The aggregation of a 1% (w/w) solution of A, B, and the mixture AB results in the formation of at least octameric units as can be deduced from the radius of gyration of about 36 A. No differences in the pressure stability of the different genetic variants of beta-Lg are detectable in our FT-IR and SAXS experiments. Even application of higher pressures (up to 10 kbar) does not result in complete unfolding of all beta-Lg variants.

Exploring the temperature-pressure phase diagram of staphylococcal nuclease.

The temperature dependence of the pressure-induced equilibrium unfolding of staphylococcal nuclease (Snase) was determined by fluorescence of the single tryptophan residue, FTIR absorption for the amide I' and tyrosine O-H bands, and small-angle X-ray scattering (SAXS). The results from these three techniques were similar, although the stability as measured by fluorescence was slightly lower than that measured by FTIR and SAXS. The resulting phase diagram exhibits the well-known curvature for heat and cold denaturation of proteins, due to the large decrease in heat capacity upon folding. The volume change for unfolding became less negative with increasing temperatures, consistent with a larger thermal expansivity for the unfolded state than for the folded state. Fluorescence-detected pressure-jump kinetics measurements revealed that the curvature in the phase diagram is due primarily to the rate constant for folding, indicating a loss in heat capacity for the transition state relative to the unfolded state. The similar temperature dependence of the equilibrium and activation volume changes for folding indicates that the thermal expansivities of the folded and transition states are similar. This, along with the fact that the activation volume for folding is positive over the temperature range examined, the nonlinear dependence of the folding rate constant upon temperature implicates significant dehydration in the rate-limiting step for folding of Snase.

Cardiovascular autonomic reactivity in schizophrenics under neuroleptic treatment: A potential predictor of short-term outcome?

In schizophrenics cardiovascular autonomic reactivity (CAR) can be used as an indicator of autonomic arousal. Using a standardized autonomic test battery (modified according to Ewing and Clarke) we prospectively compared the CAR between 46 actually ill schizophrenics (diagnosis according to DSM-III-R) treated with either haloperidol (n = 26) or clozapine (n = 20) and 30 well-matched healthy volunteers. Multivariate analysis demonstrated a significant effect of neuroleptic medication (haloperidol vs. clozapine) on heart rate and diastolic blood pressure under resting conditions as well as on the heart rate variance (30:15 ratio, deep-breathing, Valsalva) and blood pressure tests (sustained handgrip, Schellong). In addition a positive treatment response (using predefined outcome criteria of the Brief Psychiatric Rating Scale) was independently associated with lower resting heart rates and less impaired 30:15 ratios under neuroleptic medication. Our data indicate that clozapine treatment was associated with a substantial impairment of CAR, which can be explained by the drug's anticholinergic properties in combination with an increase in norepinephrine outflow. The greater heart rate variability in responders might be due to an early neuroleptic-induced decrease of sympathetic activity in the autonomic nervous system, which may precede clinical improvement. Our findings are discussed in relation to neuroleptic-induced changes in plasma catecholamine levels suggested to be useful biological markers in predicting treatment outcome.

Sensitivity of carbohydrate-deficient transferrin (CDT) in relation to age and duration of abstinence.

Carbohydrate-deficient transferrin (CDT) serum concentrations were prospectively determined in 162 subjects (alcoholics n=62, controls n=100) using three different methods of detection (IEF, CDTect, Axis%CDT). Repeated testing in alcoholics after 3 and 5 days of abstinence demonstrated a significantly higher sensitivity of CDT in patients above 40 years of age compared to younger patients.

[Benefits and risks of electroconvulsive therapy (ECG) in elderly patients with cardiovascular risk factors]. / Nutzen und Risiken der Elektrokrampfbehandlung (EKT) bei älteren Patienten mit kardiovaskulären Risikofaktoren.

Between January 1995 and June 1996, 24 inpatients at our hospital (mean age 55.6 years) were treated with electroconvulsive therapy (ECT). Clinical improvement was observed in 80% of the patients, including those without risk factors (NRG, n = 16), as well as those with concomitant cardiovascular diseases (RG, n = 8). During a mean period of observation of 224 days after the end of ECT 7 patients (35%) relapsed. The rate of relapse was higher in RG than in NRG patients (57.1 vs 23.1%). In all cases ECT was well tolerated; 285 applications of ECT did not result in mortality or persistent morbidity. However, RG patients may be at increased risk for the development of minor cardiovascular complications, which were noted in three RG patients (37.5%), but only in one patient (6.2%) in the NRG (Fisher's test, P = 0.09). Taken together, our results demonstrate that ECT is a safe treatment regimen for depression even in medically ill patients of old age.

Structural characterization of the pressure-denatured state and unfolding/refolding kinetics of staphylococcal nuclease by synchrotron small-angle X-ray scattering and Fourier-transform infrared spectroscopy.

The pressure-induced unfolding of wild-type staphylococcal nuclease (Snase WT) was studied using synchrotron X-ray small-angle scattering (SAXS) and Fourier-transform infrared (FT-IR) spectroscopy, which monitor changes in the tertiary and secondary structural properties of the protein upon pressurization. The experimental results reveal that application of high-pressure up to 3 kbar leads to an approximate twofold increase of the radius of gyration Rg of the native protein (Rg approximately 17 A) and a large broadening of the pair-distance-distribution function, indicating a transition from a globular to an ellipsoidal or extended chain structure. Analysis of the FT-IR amide I' spectral components reveals that the pressure-induced denaturation process sets in at 1.5 kbar at 25 degrees C and is accompanied by an increase in disordered and turn structures while the content of beta-sheets and alpha-helices drastically decreases. The pressure-induced denatured state above 3 kbar retains nonetheless some degree of beta-like secondary structure and the molecule cannot be described as a fully extended random coil. Temperature-induced denaturation involves a further unfolding of the protein molecule which is indicated by a larger Rg value and significantly lower fractional intensities of IR-bands associated with secondary-structure elements. In addition, we have carried out pressure-jump kinetics studies of the secondary-structural evolution and the degree of compactness in the folding/unfolding reactions of Snase. The effect of pressure on the kinetics arises from a larger positive activation volume for folding than for unfolding, and leads to a significant slowing down of the folding rate with increasing pressure. Moreover, the system becomes two-state under pressure. These properties make it ideal for probing multiple order parameters in order to compare the kinetics of changes in secondary structure by pressure-jump FT-IR and chain collapse by pressure-jump SAXS. After a pressure jump from 1 bar to 2.4 kbar at 20 degrees C, the radius of gyration increases in a first-order manner from 17 A to 22.4 A over a timescale of approximately 30 minutes. The increase in Rg value is caused by the formation of an extended (ellipsoidal) structure as indicated by the corresponding pair-distance-distribution function. Pressure-jump FT-IR studies reveal that the reversible first order changes in beta-sheet, alpha-helical and random structure occur on the same slow timescale as that observed for the scattering curves and for fluorescence. These studies indicate that the changes in secondary structure and chain compactness in the folding/unfolding reactions of Snase are probably dependent upon the same rate-limiting step as changes in tertiary structure.

Improved autonomic neurocardial balance in short-term abstinent alcoholics treated with acamprosate.

Standardized investigations on resting heart rate variability (HRV) should provide more information on acamprosate's human pharmacodynamic properties because acamprosate interacts with several neurotransmitter systems which are also involved in maintaining autonomic neurocardiac balance. We performed HRV measurements prospectively in 69 healthy controls and 19 chronic alcoholics to prove the hypotheses that: (1) compared to healthy controls, chronic alcoholics show disturbances in neurocardiac vagal function; and (2) in alcoholics, acamprosate treatment (6-8 days) should further decrease parasympathetic activity if acamprosate interacts with central gamma-aminobutyric acidA receptors in vivo. Cardiovagal dysfunction was initially present in 21% of the alcoholics. After treatment. however, their neurocardiac sympathetic-parasympathetic balance improved significantly.

Alcoholism, peripheral neuropathy (PNP) and cardiovascular autonomic neuropathy (CAN).

In contrast to diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN) in long-term alcoholics has been studied rarely. Using both standardized bedside tests and computer-assisted analysis of heart rate variability (HRV), we prospectively compared autonomic neurocardial function between 35 strictly selected, detoxified alcoholics (DSM-III-R), and 80 well matched healthy controls. Evidence for a potential CAN was found in 25.7% of all the alcoholics studied and in 41% of those with clinically manifest PNP (n=22). Overall, our results demonstrated a significant association between the presence of a CAN and peripheral neuropathy (PNP) amongst chronic alcoholics (chi-square test P<0.05); there was no evidence of a CAN in any of the alcoholics without a clinically manifest PNP. The CAN was characterized by a dissociated appearance of parasympathetic and sympathetic disorders. Our findings provide reason to suspect that the total lifetime dose of alcohol and the duration of alcohol dependence are the most important factors contributing to the pathogenesis of both PNP and sympathetic dysfunction. As is the case with diabetics, computer-assisted measurements of HRV including spectral analysis appear to be far superior to conventional bedside tests for detecting evidence of cardiovagal dysfunction in long-term alcoholics.

Disseminated cerebral hemorrhages as unusual manifestation of toxoplasmic encephalitis in AIDS.

Hemorrhagic lesions are uncommon in central nervous system (CNS) toxoplasmosis. We report here the case of a patient with multiple cerebral hemorrhages as the initial manifestation of HIV infection due to CNS toxoplasmosis.

Increased neuropeptide Y-like immunoreactivity in cerebrospinal fluid and plasma of human immunodeficiency virus-infected patients: relationship to HIV encephalopathy.

Neuropeptide Y (NPY) is one of the most abundant and phylogenetically best conserved peptides in the mammalian central and peripheral nervous system where it plays an important role in the regulation of cardiovascular, metabolic, endocrine, immunological and cognitive functions. In a prospective study we determined neuropeptide Y-like immunoreactivity (NPY-LI) in cerebrospinal fluid (CSF) and plasma of 95 HIV-seropositive (n = 49) or seronegative (n = 46) patients who underwent diagnostic CSF examination. CSF and plasma NPY-LI but not noradrenaline concentrations were higher in seropositive than in seronegative patients indicating that raised levels of NPY-LI did not result from a non-specific activation of the sympathetic nervous system. Increased CSF NPY-LI was positively correlated with the degree of HIV encephalopathy (P < 0.01, Kruskal-Wallis test). Inflammatory disorders of the central nervous system and dementia due to other causes in HIV-seronegative patients were not associated with increased CSF NPY-LI. Our data suggest that increased CSF NPY-LI is a relatively specific phenomenon of HIV encephalopathy and may be involved in the pathogenesis of HIV-related neurological dysfunction. The links between retroviral infection and increased expression of neuropeptide Y and their pathophysiological implications remain to be determined.

Oligosymptomatic neurosyphilis with false negative CSF-VDRL in HIV-infected individuals?

The true prevalence of neurosyphilis in HIV-infection is unknown, since a sufficiently sensitive and specific test is lacking. In a prospective study we found reactive serum TPHA and FTA-ABS IgG tests in 95 (31%) of 307 HIV-infected patients. Three of 11 patients with latent syphilis revealed reactive CSF-VDRL tests, six others only demonstrated CSF abnormalities. Resolution of CSF abnormalities during a six month follow up after high dose antibiotic therapy led to the diagnosis of oligosymptomatic or asymptomatic neurosyphilis in all nine patients. Thus, the specificity of the CSF-VDRL was 100%, but the sensitivity was only 33%. The overall prevalence of neurosyphilis was 2.9%, increasing to 9.5% in patients with a reactive serum TPHA. Our study emphasizes the importance of antibiotic therapy for presumptive neurosyphilis in HIV-infected patients with latent syphilis and CSF abnormalities but nonreactive CSF-VDRL tests, even if they are neurologically asymptomatic or present with complaints inconclusive of neurosyphilis.