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Aims: Conventional approaches to the management of neuropathic pain (NeP) often yield unsatisfactory results. We aimed to investigate pregabalin, a gamma-aminobutyric acid (GABA)-analogue, in a wide range of pregabalin naive patients with treatment refractory NeP., Methods: Investigator-initiated, 4-week, open, prospective multicentre study in tertiary care. Pregabalin was prescribed at physicians' discretion based on patients' individual responses and tolerability, with or without concomitant analgesics. Consecutive patients were requested to fill in questionnaires at baseline and after 14 and 28 days with numerical pain rating scales (0, none; 10, worst possible), sleep rating scales, parts of the Brief Pain Inventory, Pain Experience Scale, Short Questionnaire on Current Burden and the SF-12 health-related quality of life scale., Results: In 55 patients, the mean pregabalin dose was 142 +/- 26 mg at day 1 and 348 +/- 161 mg at day 28. The mean pain score decreased from 6.5 +/- 1.7 to 5.5 +/- 1.9 at day 14 and to 4.9 +/- 1.8 at day 28 (-24.6%, p < 0.0001). Significant and rapid improvements were noted in the sleep interference score (p < 0.00001), Short Questionnaire on Current Burden (p < 0.01) and SF-12 (somatic score p < 0.001; psychological score p < 0.01). Pregabalin was well tolerated, and only three patients (5%) discontinued treatment prematurely., Conclusions: Our findings suggest that pregabalin is an effective and well-tolerated drug in difficult-to-treat NeP patients under daily clinical practice conditions. A flexible dosing approach appears appropriate to ensure patient compliance and treatment success.

The non-nucleoside analogue inhibitor of the reverse transcriptase, efavirenz (EFV), has become commonly used in highly active antiretroviral combination therapy in the treatment of HIV infection. Although being effective in suppressing plasma viral load, neuropsychiatric side effects have been reported in individuals treated with EFV. There are early complications, such as acute psychosis resembling reactions to LSD intake, as well as nightmares occurring for several days up to 4 weeks after the start of therapy. Although LSD-like psychosis provokes the necessity of therapy discontinuation, the nightmares, as well as irritability and concentration problems in daily life, disappear after several weeks of treatment. Late complications are depressive episodes that must be carefully differentiated from pre-existing psychiatric disease and virus-induced brain damage. This review describes neuropsychiatric symptoms provoked by EFV, differential-diagnostic procedures and treatment options, and provides pro's and con's for EFV use in clinical practice with respect to drug safety.

Objective: Inflammatory cytokines as well as nitric oxide (NO) play a key role in the pathogenesis of persistent and exaggerated pain states. To document this, we investigated whether a range of cytokines and NO were detectable in the plasma of chronic pain patients and whether cytokine and NO levels correlated with pain severity., Methods: Plasma samples of 94 chronic pain patients and 6 healthy volunteers were obtained. Average pain intensity during the last 24 h was assessed on a 11-point numeric rating scale and patients were distributed to three groups: light, moderate and severe pain. The concentrations of TNF-alpha, GM-CSF, interleukin (IL)-1beta, IL-6, IL-8, interferon (IFN)-gamma, IL-2, IL-4, IL-5, IL-10 and nitrate/nitrite were determined., Results: Patients with light pain demonstrated significantly increased levels of IL-6 compared to controls. In the severe pain group IL-6 and nitrate/nitrite were significantly increased. Serum concentrations of IL-1beta, TNF-alpha, IL-2 and IL-4 were increased but as we adjusted the level of significance at p = 0.0045, most cytokine plasma levels failed to reach statistical significance., Conclusions: Pro-inflammatory cytokines (IL-1beta, IL-2, IL-6, IFN-gamma, TNF-alpha) in the plasma correlate with increasing pain intensity. Chronic pain patients show a significant increase in plasma levels of NO in comparison to healthy controls.

Objective: To evaluate the safety, tolerability and efficacy of mirtazapine in patients with the primary diagnosis of chronic pain and concomitant depression in an open post-marketing surveillance study., Research Design and Methods: 594 patients with a primary diagnosis of at least one chronic pain syndrome (minimum duration of 3 months) and the diagnosis of concomitant depression, appropriately made by a neurologist or psychiatrist, were recruited at psychiatric and/or neurological outpatient facilities throughout Germany. The primary efficacy parameter was pain at baseline and endpoint using a patient self-assessment scale. Secondary analyses were performed at baseline, week 1 (day 7 +/- 2), week 4 (day 28 +/- 4) and at endpoint (day 42 +/- 4 or early termination) and included safety and tolerability assessments. Investigators rated the severity of different potential co-morbidities (including depression) with a four-step rating scale (not present, mild, moderate, severe)., Results: 594 patients were enrolled and treated with mirtazapine (mean daily dose of 34.5 +/- 10.4 mg at study endpoint). A statistically significant (p < 0.0001; one sample sign test) reduction of pain from baseline to endpoint was found for the overall population. The percentage of patients free of pain or with only moderate pain increased significantly, irrespective of patients' age or pain syndromes. Furthermore, we found a substantial improvement from baseline to endpoint regarding co-morbidities such as sleep disturbance, irritability and exhaustion. The number of adverse events was low (<7%; n = 37), with fatigue (n = 13) and weight gain (n = 11) occurring most frequently. No previously-unknown side effects occurred. One hundred and six patients (18%) discontinued mirtazapine during the study. The main reason was lack of efficacy (6%, n = 33), which may be a reflection of sub-optimal response to the anti-depressant or analgesic effect of the drug, but no appropriate rating scale was used to clarify this question. Only a small number of patients stopped the drug due to adverse events (3%; n = 15). At study endpoint, the majority of physicians and patients rated the overall efficacy and tolerability of mirtazapine as good or very good. Most patients (80%) continued the therapy after 6 weeks., Conclusions: Despite the limitations of an open observational study, our findings suggest that mirtazapine is a safe and well-tolerated drug for use in daily clinical practice. It still remains unclear whether the reduction of pain, the enhancement of the depressed mood or the combination of both effects led to these results. Nevertheless, our data point to a potential beneficial effect of mirtazapine in the treatment of patients with pain and concomitant depression. However, more systematic research, including placebo-controlled studies, and further empirical testing are necessary.

Matrix systems for transdermal fentanyl will replace the reservoir systems in Europe. In an industry-independent, prospective, multicenter pilot study, 46 outpatients with chronic pain were asked to assess pain intensity, sleep interference, adverse events, and multiple secondary parameters during administration of the last reservoir and the first two matrix patches. There was no difference in pain intensity, sleep interference, and the rate of adverse events between both systems. Self assessment on a 6-step numeric rating scale (1 = very good, 6 = insufficient) comparing the two systems (reservoir vs. matrix) showed that skin compatibility (2.6 vs. 1.5), adhesive properties (3.2 vs. 1.8), wearability/comfort (2.8 vs. 1.5), and general satisfaction (2.5 vs. 1.8) improved significantly with the new matrix technology. At study endpoint, 91% of patients preferred the matrix system for future use. The new fentanyl matrix system is characterized by a high level of general satisfaction, ease of use, patient acceptance, and improved skin compatibility. Reservoir and matrix systems appear to have comparable efficacy and safety so that outpatients can be switched directly from the reservoir to the matrix system without difficulties and new dose titration.

We compared CSF HIV viral load in 33 asymptomatic HIV seropositive patients, 11 patients with incipient minor motor deficits (MMD), 11 patients with sustained MMD, and 16 patients with HIV-associated dementia. Patients with incipient MMD showed significantly higher CSF viral load than asymptomatic patients. Demented patients also had higher CSF viral loads than asymptomatic patients. This phenomenon is independent of antiretroviral therapy. Thus, correlation of viral load with time suggests a multiphasic course of HIV-associated CNS disease.

The authors examined the correlation between Human Immunodeficiency Virus (HIV) Dementia Scale (HDS) and psychomotor tests, evaluating basal ganglia function in 266 HIV-seropositive, Caucasian, homosexual men. Fifty-five HIV-positive, patients with mild dementia (HDS score < or =10) showed significant slowing of most rapid alternating movements (MRAM) and significantly prolonged contraction times compared to 211 HIV-positive nondemented patients (HDS score >10). Motor performance correlated significantly with the time-dependent HDS subscores for psychomotor speed and construction and HDS sum score. In contrast to contraction times and MRAM, HDS scores also showed significant correlations to age, premorbid and actual intelligence, and duration of HIV seropositivity.

Interleukin-18 (IL-18) is a proinflammatory cytokine released by macrophages that strongly stimulates the production of interferon-gamma, thereby linking innate and acquired immunity. Its role in human immunodeficiency virus (HIV) pathogenesis is under debate and little is known about its role in neuro-AIDS (acquired immunodeficiency syndrome). Serum and cerebrospinal fluid (CSF) levels of IL-18 were determined by a commercially available enzyme-linked immunosorbent assay (ELISA) in 22 HIV-seropositive patients without neurological symptoms (HIV+), 21 patients with AIDS dementia complex (ADC), and 31 patients with AIDS-defining opportunistic infections (OIs) of the brain. Thirty-two HIV seronegative patients (HIV-) served as controls. Compared to HIV- controls, serum IL-18 levels were increased in HIV+ and ADC but not in OI patients. In contrast, CSF IL-18 levels were elevated in OI patients whereas HIV+ and ADC patients were not different from HIV- controls. We provide evidence for an significantly increased IL-18 level in the CSF of HIV+ patients with cerebral OIs, suggestive of a role for IL-18 in the intrathecal host response to OIs.

Background: Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally., Design: Multicenter, prospective, randomised, double-blind, placebo-controlled study., Methods: Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or-if not beneficial-titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4(th) treatment week. A secondary efficacy measure was the median sleep score (VAS)., Results: 15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (-44.1 %) as well as of the sleep VAS to 2.3 (-48.9 %). No significant decrease in the pain (median VAS=3.3, -29.8 %) as well as in the sleep score (median VAS=4.95, -11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients., Conclusions: GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.

Background: Both HIV and hepatitis C virus (HCV) may enter the central nervous system and cause cognitive and/or motor dysfunction. There are limited data on cognition and no data on motor performance in HIV/HCV-coinfected patients., Objective: To provide data on cognition and motor performance in HIV/HCV infected patients., Methods: We compared 43 HIV-seropositive but HCV-seronegative patients, 43 HIV/HCV-coinfected patients, and 44 HIV-negative but HCV-positive patients, all of whom went through neuropsychologic testing and electrophysiologic assessment of basal ganglia-mediated motor function., Results: No significant differences could be found among the groups with regard to premorbid verbal and actual nonverbal intelligence, attention, and memory; the HIV dementia scale; and all somatic and most psychiatric complaints. Affective disorders were less frequent in HIV-negative but HCV-positive patients. This group also scored lower for depression. For all 3 groups, significant pathologic slowing of most rapid alternating movements (right hand) compared with those of HIV/HCV-negative controls as well as significantly prolonged contraction times (both hands) could be diagnosed. Simple reaction times were significantly prolonged only in HIV/HCV-coinfected patients., Conclusions: Although clinically asymptomatic, both HIV-positive and HCV-positive patients may show affective disturbances and significant psychomotor slowing. A potential predictive value for the further course of infection, which is well established in HIV-positive patients, remains to be investigated in HCV-positive or HIV/HCV-coinfected patients.

Purpose: To find out about the long-term safety and efficacy of nonnucleoside reverse transcriptase inhibitors (NNRTIs) within the central nervous system (CNS) in the context of reports suggesting a higher incidence of severe neuropsychiatric disorders resulting from HIV treatment with efavirenz (EFV)., Method: Retrospective analysis of a large cohort with regular neuropsychiatric follow-up. We compared 414 patients on EFV and 320 on nevirapine (NVP) with regard to CD4 cell count, HIV plasma viral burden, CNS dysfunction described by psychomotor speed, HIV dementia scale, neuropsychological tests assessing memory and attention, self-reported psychiatric and somatic complaints, depression, and psychosis., Results: No significant differences between both types of NNRTI treatment regimens were found with regard to duration of therapy and reasons for withdrawal: virological failure, neurological failure, and neuropsychiatric side effects including the manifestation of depression, psychosis, insomnia, or other self-reported complaints., Conclusion: The present data do not provide evidence for a higher incidence of light and/or severe neuropsychiatric side effects associated with NNRTI treatment.

Objectives: To find out about potential involvement of the peripheral and autonomic nervous system in Wilson's disease (WD)., Material and Methods: Seventeen patients with laboratory proven WD were examined with quantitative sensory testing (QST) (thermal, pain and vibratory sensation), pupillometric evaluation and electrophysiological testing of basal ganglia motor function [frequency of most rapid alternating movements (MRAM), reaction time (RT), contraction time (CT)]. Results were compared with those obtained in 20 healthy controls., Results: After correction for multiple comparisons, patients with WD showed significantly higher thresholds for warm sensation [sural and peroneal nerve, thermal sensory limen (TSL), unpaired t-test]. Individual results were pathological in eight (peroneal) and nine (sural nerve) patients, respectively. Pupil function was not altered. Patients with WD showed significant slowing of MRAM and prolongation of RT and CT. There was no significant correlation between RT and QST results., Conclusions: These findings are compatible with a potential involvement of unmyelinated warm-specific C fibers in WD, independent from predominant basal ganglia motor dysfunction.

Objective: To find out whether HIV-associated subclinical psychomotor slowing is present in HIV-infected children despite effective highly active antiretroviral therapy (HAART)., Patients and Methods: An electrophysiological motor test battery shown to sensitively describe HIV-associated CNS disease in adults (tremor peak frequency []TPF], most rapid alternating movements [MRAM], reaction time [RT] and contraction time [CT]) was performed in 17 HIV seropositive (+) right-handed children. Results were compared to 16 HIV seronegative (-) children., Results: HIV (-) children showed slower frequencies (TPF, MRAM) and longer RT and CT than (-) adults. They showed a significant correlation (p = 0.0263) between RT (right = dominant hand) and age. HIV (+) children showed significant prolongations of RT (right hand) and CT (both hands) compared to HIV (-) children. RT right hand did not accelerate with age in HIV (+) children. CT were significantly prolonged in 10 children with detectable HIV plasma viral burden and normal in 7 children with no detectable HIV plasma viral load. There was no correlation between CT and CD 4 cell counts., Conclusions: Despite effective HAART, electrophysiological motor testing in HIV (+) children reveals significant subclinical CNS dysfunction, especially in children with insufficient viral load suppression.

Purpose: To investigate whether advanced magnetic resonance (MR) imaging techniques such as diffusion-weighted (DW) and perfusion-weighted (PW) MR imaging and hydrogen 1 (1H) MR spectroscopy can depict functional and pathophysiologic mechanisms in patients who have minor motor deficits (MMDs) associated with human immunodeficiency virus 1 (HIV-1)., Materials and Methods: Thirty-two patients with results seropositive for HIV-1 and different degrees of HIV-1-related MMD underwent conventional brain MR imaging, as well as DW and PW MR imaging and 1H MR spectroscopy of the basal ganglia. PW MR imaging data were computed pixel by pixel for creation of time-to-peak, relative regional cerebral blood volume, and bolus amplitude parameter maps. In addition, quantitative regional cerebral blood flow (rCBF) maps were calculated with respect to the arterial input function by using the singular value decomposition algorithm. For 1H MR spectroscopy, a stimulated echo acquisition mode 20, or STEAM 20, sequence was used. Spectra were fit for determination of the signal intensities of the different metabolites. According to psychomotor testing results, patients were divided into three groups: group 1, 10 patients with normal motor function; group 2, eight patients with psychomotor slowing for the first time; and group 3, 14 patients who had had sustained pathologic psychomotor slowing for at least 6 months before the MR imaging examination., Results: No patients had an abnormality at either conventional or DW MR imaging. PW MR imaging depicted significantly elevated rCBF in group 2 patients (P =.039, analysis of variance [ANOVA]) and significantly elevated myo-inositol-to-creatine ratio levels in group 3 patients (P =.020, ANOVA)., Conclusion: Quantitative PW MR imaging and 1H MR spectroscopy can depict pathologic changes in patients who have HIV-1-related MMD but normal clinical examination and conventional MR imaging findings.

Data of 204 HIV-1-positive female migrants from Sub-Saharan Africa, Asia and European countries other than Germany were analysed and compared to those of 282 German female virus carriers. Because not much is known about this subpopulation, the first step was to get an overview about the existing data and to describe them statistically in order to design prospective studies. A first result was that female migrants generally are tested for HIV-1 at a younger age than the control subjects. Predominant infection mode in the migrant population was heterosexual intercourse, whereas in the controls there were significantly more i.v. drug users. Distribution to the CDC-stages, CD4+-cell count and plasma viral load did not differ in both groups except for a higher percentage of AIDS-defined individuals among the controls. Surprisingly, significantly more migrants were treated with antiretroviral drugs than in the control group. However, both groups showed the same pattern of AIDS-defining diseases, only tuberculosis occurs more often in migrants. The data show that migrants are a vulnerable subpopulation which can be once being integrated in the health system of the host country effectively treated. - Results are discussed with respect to the international literature. The urgent need for adequate preventive strategies is underlined.

HIV-1 associated dementia is the major manifestation of HIV-1 within the central nervous system and a devastating disease which is characterized by cognitive, motor, and emotional deficits. HIV-1 associated minor motor deficits can manifest as psychomotor slowing and predict the later development of HIV-1 associated dementia, AIDS, and death. These minor motor deficits can be described, e.g., by electrophysiological assessment of basal ganglia motor function (frequency of most rapid alternating finger movements, reaction and contraction times of most rapid index finger extensions). Minor motor deficits quantified by contraction times can be subdivided into a more incipient and a more sustained type of deficit. Parallel examination of motor function and positron emission tomography, magnetic resonance spectroscopy of the basal ganglia, or SPECT helps to point to the basal ganglia as a pivotal point of HIV-1 associated CNS pathology.

The manifestation of HIV-1-associated minor motor deficits or HIV-1-associated dementia indicates viral activity within the CNS. Highly active antiretroviral therapy (HAART) has a prophylactic effect, which does not protect all patients, because different pathomechanisms are involved. A CNS-specific therapeutic efficacy can be demonstrated for nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs; NNRTIs). To be effective in the CNS, HAART should contain either zidovudine or stavudine and NNRTI should be added if there is dinical or preclinical evidence of CNS involvement. Protease inhibitors may be sufficient to lower high systemic viral burden and thus protect the CNS from HIV-1 invasion.

The alpha chemokine receptor CXCR4 is used as the major coreceptor for the cell entry of T-cell-tropic human immunodeficiency virus-1 (HIV-1) isolates. Activation of this coreceptor by its natural ligand SDF1alpha is associated with an intracellular Ca(2+) increase. Because the HIV-1 glycoprotein 120 (gp120) is shedded from the surface of HIV-1-infected cells and is regarded as an injurious molecule in the pathogenesis of HIV-1-associated encephalopathy (HIVE), we investigated the effects of gp120 on the intracellular Ca(2+) regulation of astrocytes and neurons. After 5 days in vitro (DIV), SDF1alpha (50 nM) elicited a pertussis toxin-sensitive intracellular Ca(2+) increase due to Ca(2+) release from internal stores that was reduced by a blocking monoclonal antibody against the CXCR4 receptor in astrocytes and neurons. Parallel with the development of the SDF1alpha response, cells became sensitive to direct application of gp120 (1.25 microg/ml), which, similarly to SDF1alpha, elicited a transient intracellular Ca(2+) increase. However, short-term incubation with gp120 for 60 to 120 min induced a reduction of glutamate- or ATP-evoked intracellular Ca(2+) responses only in astrocytes and not in neurons, although functional CXCR4 receptors were expressed in both cell types. Therefore, our data strongly suggest that the CXCR4 receptor-mediated intracellular signaling pathway of gp120 differs in astrocytes and neurons.

In the era of highly active antiretroviral therapy (HAART) the central nervous system (CNS) becomes increasingly important as a sanctuary site for the human immunodeficiency virus (HIV-1). HIV-1-associated brain disease is subdivided into the minor cognitive/motor disorder, the minor cognitive/motor complex and the AIDS dementia complex, all of which are predictive for patients' deaths. CNS effective therapy therefore influences the prognosis of each individual patient. Thus, there is urgent need both for prophylactic and therapeutic strategies preventing or treating HIV-1-associated CNS disease. HAART consisting of two nucleoside analogues (NAs), one or two protease inhibitors (PIs) and/or one non-nucleoside inhibitor of the reverse transcriptase (NNRTI) has a neuroprophylactic value with regard to the manifestation of HIV-I associated CNS disease. With regard to therapeutic effects, the NAs zidovudine and stavudine penetrate into the cerebrospinal fluid and positively influence HIV-1-associated brain disease. Adding a second NA has no additional therapeutic effect. NNRTIs (nevirapine and efavirenz) are also CNS effective. However, there is a subgroup of non-responders, who obviously need other forms of therapeutic interventions. The very few existing studies point out that patients with high plasma viral loads and neurological abnormalities should be treated with a combination of two NAs and one NNRTI. The value of PIs for CNS protection remains to be evaluated.

We examined the peripheral nervous system (PNS) (nerve conduction velocity (NCV)) and the central nervous system (CNS) (basal ganglia-mediated psychomotor speed) in 93 males seropositive for human immunodeficiency virus type 1 (HIV-1) with no prior history of opportunistic brain disease, antiretroviral treatment or intravenous drug use. Patients with different degrees of slowing of peroneal and sural NCV showed no significant differences in psychomotor speed as assessed by tremor peak frequency, most rapid alternating movements, reaction times and contraction times. There was no significant correlation between psychomotor measures and NCV. Psychomotor slowing test findings were independent from peripheral nervous system damage indicating uncorrelated disturbances of CNS and PNS function in HIV-1 infection. Differences in HIV-1 viral quasispecies or host responses may determine the predominance of CNS or PNS injury.

An effective highly active antiretroviral therapy (HAART) can prevent the manifestation of HIV-1-associated encephalopathy. Also, HIV-1-associated minor cognitive/motor deficits--an early form of HIV-1-associated dementia--are improved. Clinically manifest HIV-1-associated encephalopathy is an indication for HAART treatment, irrespective of immune status. To date, minor cognitive and/or motor deficits in the presence of good immune status have not been identified as an indication for HAART treatment. Any CNS-effective treatment should be based on either zidovudine or stavudine, since these substances readily enter the CSF; however, NNRTI can also be applied. Side effects of HAART on the central and peripheral nervous system, as well as interactions with known neurological medicaments must be taken into account.

Psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS, and death independent of immune status. We retrospectively selected all patients who showed pathologic psychomotor slowing as a sign of central nervous system (CNS) dysfunction before the onset of therapy and who were then treated with nonnucleoside reverse-transcriptase inhibitors-either efavirenz (EFV) (n = 65 patients) or nevirapine (NVP) (n = 39 patients), each given in combination with two nucleoside analogues (NAs). Patients who were treated only with two NAs (n = 66) served as controls. Patients were observed for 6 months. Both EFV and NVP combinations improved CNS function as determined by electrophysiologic motor tests. The therapeutic effects of EFV and NVP did not depend on the type of NA added. Although results did not reach significance, NVP combinations were more effective than EFV combinations or therapy regimens with NAs alone in patients who were naïve to all antiretroviral therapy. EFV and NVP combinations were equally effective in patients pretreated with highly active antiretroviral therapy, including protease inhibitors.

The authors examined the effects of depressive mood (Hamilton Rating Scale for Depression [Ham-D]) on basal ganglia-mediated psychomotor speed (motor test battery) in 202 HIV-1 seropositive homosexual males with no prior history of antiretroviral treatment. HIV-1 seropositive patients showed a significant slowing of most rapid alternating movements (MRAM) and significantly prolonged contraction times (CT) compared with 66 HIV-1 seronegative male control subjects. Factor analysis of Ham-D scores isolated a factor containing the items depressed mood, suicide, and psychic and somatic anxiety. This factor did not correlate with MRAM or CT. Depression and psychomotor speed are independent in HIV-1infection.

The trans-activator protein Tat of the human immunodeficiency virus type 1 (HIV-1) is regarded as an injurious molecule in the pathogenesis of HIV-1 associated encephalopathy (HIVE). We investigated the effects of Tat on neuroligand-induced intracellular Ca2+ increase in cultured astroglial cells. Rat cortical astrocytes, human glioblastoma cells and glial restricted precursor cells, from a human embryonic teratocarcinoma cell line, were incubated with recombinant Tat (100 ng/mL for 60 min) which induced a significant reduction of glutamate or ATP-induced intracellular Ca2+ increase ("glutamate response", "ATP response"). The reduction of the glutamate response was also observed following cell incubation with cell extracts of HeLa-T4+ cells transiently transfected with an expression plasmid coding for Tat. However, inactivation of the transcriptional trans-activity of Tat, by using a mutant form of Tat, as well as inhibition of de novo protein synthesis by cycloheximide abolished the effect on the glutamate response. This suggests that Tat acts upon induction of a so far unknown cellular gene whose gene product causes the reduction of glutamate responses. As the effect of Tat resembles the effect of TNFalpha on glutamate responses [Köller et al. (2001) Brain Res., 893, 237-243] which is locally released within the brains of HIVE patients, we also tested for synergistic effects of Tat and TNFalpha on the glutamate response. Low concentrations of Tat in combination with subthreshold concentrations of TNFalpha also elicited a marked reduction of astroglial glutamate responses. Our data suggest that Tat and TNFalpha, both by itself and synergistically, induce astroglial dysfunction.

Objectives: To investigate the effect of cerebrospinal fluid (CSF) of HIV-1-seropositive patients with and without HIV-1-associated dementia complex (HADC) on the intracellular Ca2+ regulation of cultured cortical astrocytes., Design: In a blinded study the effects of CSF samples from HADC patients and from HIV-1-seropositive but not demented patients on intracellular Ca2+ regulation of cultured cortical astrocytes were investigated. Astrocytes were chosen because they contribute to both electrophysiological and immunological processes within the brain., Methods: Astrocytes were incubated in CSF samples for 1 h, loaded with the Ca2+ indicator dye Fura-2 and intracellular Ca2+ responses upon glutamate application were measured., Results: CSF samples from 10 out of 11 HADC patients induced a significant reduction of the intracellular Ca2+ increase upon glutamate application. On the contrary, seven out of 10 CSF samples from HIV-1-seropositive patients without HADC as well as 10 out of 10 CSF samples from HIV-1-seronegative controls did not affect the intracellular Ca2+ response., Conclusions: Our data strongly confirm the hypothesis that CSF samples of HADC patients contain soluble factors which interfere with the function of astrocytes. These factors may include HIV-1 proteins, locally released cytokines or neurotoxins.

Background: Minor motor disorders (MMDs) associated with human immunodeficiency virus type 1 (HIV-1) predict HIV-1 dementia and death. Little is known about the time course and neuropathologic mechanisms of HIV-1 MMDs., Objective: To investigate the relationship between HIV-1 MMDs, as assessed by psychomotor speed, and metabolic alterations in the basal ganglia, as detected by proton magnetic resonance spectroscopy., Patients and Methods: A total of 32 HIV-1-seropositive patients (10 with no MMD, 8 with incipient MMD, and 14 with sustained MMD, assessed through electrophysiologic testing of psychomotor speed including contraction times; 29 treated with highly active antiretroviral therapy) and 14 HIV-1-seronegative control subjects were examined for cerebral metabolite abnormalities in the basal ganglia by means of magnetic resonance spectroscopy., Results: The 3 patient groups showed significantly different ratios of myoinositol/creatine (P =.02) in the basal ganglia. Whereas patients with no MMD or incipient MMD showed normal ratios, patients with sustained MMD showed higher values for myoinositol/creatine as a sign of glial proliferation. No differences in N-acetyl compounds, indicative of neuronal loss, were found., Conclusion: Whereas metabolic alterations in the basal ganglia were not detected in patients with incipient HIV-1 MMD, patients with sustained HIV-1 MMD did have significantly altered metabolic spectra indicative of glial proliferation.

Although pain is a common symptom in HIV-positive and AIDS patients, in particular the chronic variety is frequently not adequately treated in this population. The present review article identifies possible reasons for this situation, summarizes the most common causes of chronic pain, and draws attention to the therapeutic problems specific to these particular groups.

Objective: Since psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS and death independently of the immune status, there is urgent need for a neurological therapeutic rationale., Methods: The therapeutic efficacy of nucleoside analogues with different abilities to penetrate into the cerebrospinal fluid was assessed in 410 HIV-1-seropositive patients using the results of detailed fine motor tests, which detect minor motor deficits. Patients were selected who showed pathological psychomotor slowing as signs of central nervous system (CNS) dysfunction before therapy onset and who were then treated only with nucleoside analogues for at least 6 months., Results: Both zidovudine and didanosine improve CNS function to an equal degree when given as monotherapy. Adding a second nucleoside analogue (didanosine, lamivudine, zalcitabine) to zidovudine does not further improve psychomotor performance. However, adding a second nucleoside after a period of zidovudine monotherapy does result in a second but less remarkable therapeutic effect. Combinations containing stavudine are as effective as those including zidovudine when given as first antiretroviral treatment. Furthermore, stavudine effectively improves motor performance even after pretreatment with zidovudine.

Background: We tested whether metabolic abnormalities in the prefrontal-striatal circuitry as demonstrated by positron emission tomography (PET) were present in patients seropositive for human immunodeficiency virus type 1 (HIV-1) with HIV-1-associated minor motor deficits as demonstrated by quantitative motor testing., Patients: We examined 19 HIV-1-positive patients, covering the range from normal results of quantitative motor testing to clearly pathologic psychomotor slowing indicative of HIV-1-associated minor motor deficits. None fulfilled the clinical criteria for HIV-1-associated dementia. Results were compared with those of 15 healthy volunteers., Methods: All subjects underwent clinical examination, routine magnetic resonance (MR) imaging, and electrophysiologic motor testing at the time of PET., Results: Seven HIV-1-positive patients showed significant hypermetabolism in the basal ganglia. Nine patients showed a significant frontomesial hypometabolism., Conclusions: The data of our cross-sectional study strongly suggest a characteristic time course in the development of HIV-1-associated minor motor deficits. Hypermetabolism in the basal ganglia is associated initially with normal motor performance. Moderate motor slowing appears at a later stage when basal ganglia hypermetabolism drops toward hypometabolism. More severe functional deficits and highly pathologic motor slowing become manifest when hypometabolism is most widespread in the basal ganglia. This stage leads to dementia.

Background: To find out about the prophylactic value of antiretroviral therapy on HIV-1-associated subclinical and clinical psychomotor slowing as one marker of HIV-1-associated CNS disease., Methods: Prospective study with regular clinical and neurophysiologic examination every three months of 1482 consecutive HIV-1-seropositive and AIDS patients seen at our department till June 30, 1999., Results: Antiretroviral therapy has a significant prophylactic value over an individual observation period of ten years with regard to the first, potentially transient manifestation of HIV-1-associated subclinical psychomotor slowing and with regard to the clinical manifestation of motor signs. However, a subgroup of patients is characterized through a second, more sustained manifestation of subclinical psychomotor slowing which cannot be prevented by any type of currently available antiretroviral therapy., Conclusions: These findings suggest the existence of different pathomechanisms underlying HIV-1-associated brain disease which may in part be effectively prevented, but which in part also escape all antiretroviral treatment strategies in use today.

Twenty-four beagle dogs underwent a lower leg lengthening on the right side of 2.5 cm at a distraction rate of 2 times 0.5 mm per day using a circular fixator system. After a latency phase of 5 days and a distraction phase of 25 days, 12 dogs (30-day dogs) underwent electromyography (EMG) of the gastrocnemius muscle on the lengthened and on the control side. The remaining half of the dogs underwent EMG after a consolidation phase of 25 days following the end of distraction (55-day dogs). During every EMG, at least 20 different muscle potentials were analyzed, and the duration, amplitude, and number of phases were determined of each individual potential. The 30-day dogs had significantly longer potential phases on the lengthened side and insignificantly smaller amplitudes compared with the control side. Furthermore, we observed a slightly larger number of polyphasic potentials on the distraction side. In the 55-day dogs, no significant differences were observed in the various parameters between the lengthened and the control side. Comparing 30- and 55-day dogs, the duration of the potentials on the distraction side was not significantly shorter in the 55-day dogs, and the amplitude significantly higher. These findings could indicate combined neurogenous and myopathic alterations of the muscles during the early distraction phase which will be compensated during the later distraction period and the consolidation phase by reparative and reinnervation processes, leaving no lasting functional damage.

Human Immunodeficiency virus can affect the peripheral (PNS) and central nervous system (CNS). In the ART / HAART era especially the CNS is said to be a virus reservoir so that neurologists have to be more and more integrated in therapy planning. Therefore the present paper describes neurological indications for ART, ART side effects involving the PNS and CNS and pharmacological interactions of ART with current neurological drug regimen.

Background: Meningococcal septicemia is still associated with high mortality with most deaths occurring within the first 24 hours., Case Report: We report on 3 patients with severe meningiococcemia. All patients had an aprupt onset of clinical illness with fever and unspecific prodomi like arthralgias, myalgias and abdominal pain. On admission all patients had severe prostration, hypotension and tachycardia. Two patients presented purpuric rash and petechiae, meningitis was found in only 1 patient. Gram-negative diplococci were demonstrated in spinal fluid primarily in 2 patients, in all patients meningococcae could be cultured in serial blood specimens. Because of severe cardiorespiratory distress all patients required mechanical ventilation and catecholamine support within 24 hours of diagnosis. Complications of meningococcemia demonstrated by these patients were coagulopathy, meningitis, myocarditis with alterations of echocardiographic and ECG records and elevations of CK levels and surgical relevant peripheral gangrene. Antibiotic therapy was initiated with penicillin on the day of admission, which resulted in stabilisation and recuperation in all patients., Conclusions: In patients with aprupt onset of acute illness, which include fever and sudden petechial rash, severe meningococcal septicemia has to be taken in consideration without clinical signs of meningitis. The prompt diagnosis, the use of parenteral antiobiotics in suspected meningococcal disease as well as the management of meningococcemia and its complications in intensive care units is crucial for the prognosis of the individual patient.

A disagreement exists as to whether extraintestinal parasympathetic autonomic function is altered in patients with esophageal achalasia. Therefore, we assessed autonomic dysfunction in esophageal achalasia and considered the most relevant parameters of parasympathetic autonomic function in these patients. In a prospective study, heart rate variation and pupillary function were investigated in 15 patients with achalasia of the esophagus and in 15 controls by application of a battery of standardized autonomic function tests. Significant differences between patients and controls were detected for various parameters of heart rate variation and pupillometry. When compared to values obtained from large groups of healthy subjects, none of the controls but 11 patients had at least one abnormal parameter of parasympathetic autonomic function. It is suggested that in esophageal achalasia parasympathetic dysfunction that extends beyond the gastrointestinal tract can be frequently detected. This finding supports the view of a generalized alteration of the autonomic nervous system in achalasia.

Objectives: We compared clinical long-term course and outcome in all AIDS patients admitted to our outpatient department from January, 1989 to June, 1998 with toxoplasma encephalitis (TE) as first AIDS-defining infection (n= 106) and in 106 patients with Pneumocystis carinii pneumonia (PCP) as first AIDS-defining disease., Material and Methods: The 2 groups were matched with respect to age, sex, risk group, degree of immunodeficiency as measured by CD4 cell counts and duration of HIV-1-positivity. TE was diagnosed radiologically and by response to treatment., Results: Forty-three TE patients surviving the first TE symptoms > 14 months developed dementive symptoms, leucoencephalopathy in imaging procedures and died from dementia. In contrast only 5 patients surviving PCP for an equally long period showed dementive symptoms., Conclusion: Cerebral infections like toxoplasma encephalitis (TE) may negatively influence HIV-1-activity so far latent in the brain.

Previous studies on macrophages have shown that Toxoplasma gondii alters the metabolism of arachidonic acid with subsequent inability to generate leukotrienes (LT)s. LTB4 and LTC4 were analyzed in cerebrospinal fluid of 3 groups of human immunodeficiency virus (HIV) type 1-seropositive patients: with toxoplasmic encephalitis (TE) (n=10), with herpes simplex encephalitis (n=5), and without encephalitis (n=10) and in HIV-1-seronegative controls without inflammatory diseases (n=30) by specific immunoassays and gas chromatography-mass spectrometry. In HIV-1-seropositive subjects with TE, LTB4 and LTC4 were below the detection limit (<5.0 pg/mL) and thus significantly decreased (P<.01) compared with HIV-1-seropositive patients with herpes simplex encephalitis (LTB4, 148.5+/-47.6 pg/mL; LTC4, 116.4+/-36.9 pg/mL) and in those without encephalitis (LTB4, 46.1+/-16.8 pg/mL; LTC4, 48.3+/-21.3 pg/mL), and in controls (LTB4, 43.6+/-21.2; LTC4, 45.2+/-18.9 pg/mL). These results point to an essential role of inhibition of 5-lipoxygenase with subsequent failure of LT release as an important mechanism for the survival of T. gondii in vivo.

Stavudine (2',3'-didehydro-3'deoxythymidine) is a pyrimidine analogue that may be of great value in combination antiretroviral therapy (ART) for treating patients infected with human immunodeficiency virus type 1 (HIV-1). We assessed potential neurotoxic side effects by comparing peripheral nerve function in patients receiving ART including stavudine (n = 107) with that of patients receiving ART with zidovudine (n = 103). A cross-sectional analysis of electroneurographic data revealed no significant differences. In a follow-up examination of 31 patients newly started on ART with stavudine we observed no significant effects of the drug on electrophysiological measures. At a daily dose of 1.0 mg/kg the incidence of peripheral nervous system disease in our patients was about 10%. Repeated follow-up analysis of 13 patients on stavudine showed a significant reduction in sural nerve amplitude. Quantitative sensory testing in 13 patients revealed no systematic effect of stavudine on small nerve fibers. Peripheral nerve function in HIV-1 seropositive patients on ART with stavudine did not differ significantly from that in patients on ART with zidovudine. Therefore stavudine at a daily dose of 1.0 mg/kg is an alternative for patients who do not tolerate, or who have become resistant to zidovudine and can be recommended as a first-line drug in combination ART.

The diagnosis of definite progressive multifocal leukoencephalopathy (PML) has been a neuropathological domain. We reviewed all Human Immunodeficiency Virus Type 1 (HIV-1) seropositive patients in our institution between 01.01.1989 and 31.12.1994 and identified 20/823 cases with PML by clinical and imaging criteria. Diagnosis was neuropathologically confirmed in 5 cases. Diagnostic criteria included rapid onset (< 2 weeks) of multifocal neurological signs and symptoms, advanced immunosuppression and asymmetric uni- or multifocal white matter lesions without mass effect, contrast enhancement or cortical atrophy in magnetic resonance imaging (MRI). The overall incidence of PML was stable over the observation period (approximately equal to 2.5%). The mean age at onset (41.7 years) was significantly lower compared to HIV-1 seronegative PML patients (peak in the sixth decade of life), male patients prevailed (100%). Mean survival (3.9 months) was extremely short. Human polyoma virus JC (JCV) polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) demonstrated a considerable rate of possible cerebral co-infection with HIV-1 and JCV as well as subclinical infection with JCV. Therefore demonstration of JCV deoxyribonucleic acid by PCR in the CSF alone is not sufficient for clinical PML diagnosis. We present diagnostic criteria on the basis of epidemiological, neuroradiological and CSF parameters that allow us to make the clinical diagnosis of PML. Although quick and safe, routine stereotactic brain biopsy is not necessary to confirm the diagnosis.

Objective: A comparison of anal sonography with conventional electromyographic mapping in the evaluation of anal sphincter defects was the aim of this study., Methods: In 23 patients with defecatory problems referred for conventional needle electromyography (EMG), anal endosonography, with a 7.5-MHz, 355 degrees scanner, was performed before EMG to determine the structural integrity of the external anal sphincter. If lesions were found, they were described in terms of location and extent. Subsequently, concentric needle EMG of the external sphincter was performed circumferentially to locate muscle parts exhibiting normal and diminished or missing muscle activity. Lesions found by EMG were also described like those found by sonography., Results: Of 23 patients, eight exhibited no abnormalities on EMG, and no muscle defects were identified endosonographically in any of these patients. In the remaining 15 patients, EMG showed either an incomplete pattern of interference or a complete absence of voluntary activity; in all of these patients endosonography also identified structural deficit. In 14 of these 15 patients, abnormalities were found at the same location with both endosonography and EMG. In the remaining patient, the two techniques identified structural and functional abnormalities at different locations., Conclusion: Although EMG is the gold standard for assessment of the functional relevance of muscle defects, anal endosonography yields a sensitivity and specificity of almost 100%.

Patients with the Bing Neel type of Waldenström's macroglobulinemia often present with global neurological symptoms. In this case report, we investigated the effects of cerebrospinal fluid (CSF) of a such a patients (CSF-WM), who presented with seizures and psychomotor slowing, on the electrophysiological properties of cultured rat neurons and astrocytes. Membrane potential and Na+ and K+ currents of neurons were unaffected. Astrocytes, however, were significantly depolarized from -77.6 +/- 8.2 mV to -48.0 +/- 7.6 mV (38%) by CSF-WM. The depolarization was markedly reduced after CSF-WM heat inactivation or after pre-incubation of astrocytes with dexamethasone (1 microM). Astrocytes are electrophysiologically active cells, which control local ionic micro-environment. Therefore, we conclude that global neurological symptoms in the Bing Neel type of Waldenström's macroglobulinemia like generalized seizures can result from an impairment of glial cells electrophysiological functions.

Motor tests comprising the analysis of postural tremor, most rapid voluntary alternating index finger movements (MRAM) and the rise time of most rapid index finger extensions (CT) allow us to quantify HIV-associated minor motor deficits electrophysiologically. The electrophysiological results in 57 HIV-positive individuals who acquired HIV infection by intravenous drug abuse (IVDA) were compared with those of 57 matched HIV-positive homosexuals and 98 HIV-negative controls to evaluate a possible additional influence of IVDA on motor performance. Motor deficits showed no differences between HIV-positive i.v. drug abusers and homosexuals, revealing a highly significant slowing of MRAM and prolongation of CT to an almost identical extent. Thus, in HIV-infected individuals minor motor deficits are characteristic early signs of subclinical central nervous system involvement regardless of the mode of HIV infection.

In 4 male patients (age range 50-73 years) with unilateral motor hemineglect as a sequelae of circumscribed cerebral infarction, depressions of the regional cerebral glucose metabolism (rCMRGlu) were mapped to identify the metabolically affected cerebral structures. Motor neglect was defined according to Castaigne by lack of spontaneous and pain-induced motor activity on one side of the body in the absence of paresis, pyramidal signs, and sensory loss. The depressions of the rCMRGlu as determined by positron emission tomography (PET) were found to exceed the areas of structural damage but to be restricted to the affected cerebral hemisphere. Significant mean rCMRGlu depressions followed a focal pattern involving the premotor, prefrontal, parietal and cingulate cortex, as well as the thalamus. In correspondence to the lack of significant mean rCMRGlu depressions in primary sensorimotor cortex, basal ganglia, and cerebellum the cortico-spinal pathway was spared as indicated by preserved magnetic evoked motor potentials. Our data provide evidence suggesting that motor hemineglect is a disturbance in a cerebral network of higher order cortical areas subserving motor activity in the presence of an intact motor cortical output system.

Magnetic brain stimulation was performed on 24 patients with Wilson's disease (WD). Responses to the right and left first dorsal interosseus muscle (FDI) and to the right and left tibialis anterior muscle (TA) were analysed. In 45% of the patients prolonged central motor conduction times (CCTs) to the FDIs were found, whereas only 12% of the patients presented with prolonged CCTs to the TA muscles. No consistent significant correlations between copper metabolism and pyramidal tract function tested by magnetic brain stimulation were found. An improvement of CCTs and response amplitudes with copper elimination therapy was observed only at early phases of therapy. There was no correlation with duration of therapy or neurological symptoms. Thus magnetic brain stimulation turns out to be sensitive to detect subclinical pyramidal tract impairment in WD but seems to test a too specific aspect of motor impairment in WD to reflect the overall neurological status of the patients. Therefore, it has to be combined with other tests to be used for therapy control.

One hundred HIV-positive individuals without clinically evident central nervous system (CNS) deficits entered this follow-up study and were examined clinically and with a well-defined motor test battery every 3 months over 2 years or until they decreased. They underwent magnetic resonance tomography once a year. None received any form of therapy at onset of the study. Three groups were analyzed: (A) patients without electrophysiologically detectable motor impairment (n = 23), (B) patients with electrophysiologically detectable motor impairment but no virostatic medication (n = 33), and (C) patients with motor deficits undergoing AZT treatment (n = 44) after study onset. Group A patients, although slightly deteriorating over time, had the best clinical and electrophysiological outcome compared to the other groups, whereas group B patients deteriorated markedly in both clinical and electrophysiological tests, even though the majority did not develop cerebral complications during the observation period. Those group C patients belonging to early CDC stages (II and III) improved electrophysiologically under AZT therapy, while 76% of the patients in more advanced stages (CDC IVA-D) died of cerebral AIDS manifestations. Four patients of this group, being alive at the end of the study, were completely demented. It is suggested that early detectable motor impairment predicts future cerebral involvement in AIDS. Late onset of virostatic treatment did not influence the clinical outcome.