Cerebrospinal fluid HIV viral load in different phases of HIV-associated brain disease.

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.

Long-term safety and efficacy of NNRTI within the central nervous system.

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.

Central and peripheral nervous system functions are independently disturbed in HIV-1 infected patients.

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.

HIV Dementia Scale and psychomotor slowing--the best methods in screening for neuro-AIDS.

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.

Chronic inflammatory demyelinating polyneuropathy--update on pathogenesis, diagnostic criteria and therapy.

PURPOSE OF REVIEW: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable but possibly underdiagnosed disorder of the peripheral nerve. This review covers the growing literature of the past years that deals with the pathogenesis, diagnostic criteria and treatment of CIDP. RECENT FINDINGS: The recent development of a biphasic animal model of experimental autoimmune neuritis may provide further insights into the pathogenesis of inflammatory demyelination of the peripheral nerve, such as in CIDP, and may allow the development of further innovative therapeutic strategies. In patients, the contribution of immune processes to the dysfunction in hereditary polyneuropathies and the association of hereditary neuropathy and CIDP has been described. Commonly used therapies remain corticosteroids, intravenous immunoglobulin and plasmapheresis; however, newer immunosuppressant approaches using mycophenolate mofetil or cyclosporin A, or immunomodulating therapies using monoclonal antibodies or interferons are presently under investigation. SUMMARY: The growing body of knowledge on the pathogenesis of CIDP and further diagnostic differentiation of subforms may help to develop more-effective therapies for CIDP in the next few years.

Disturbance of cultured rat neuronal network activity depends on concentration and ratio of leucine and alpha-ketoisocaproate: implication for acute encephalopathy of maple syrup urine disease.

Increased concentrations of leucine and its respective ketoacid alpha-ketoisocaproate (KIC) in plasma and cerebrospinal fluid are related to acute and reversible encephalopathy in patients with maple syrup urine disease. We studied electrophysiological properties of primary dissociated rat neurons at increased extracellular concentrations of leucine and KIC (1-10 mM). Spontaneous neuronal network activity was reversibly reduced or blocked by leucine as well as by KIC in a dose-dependent manner. Simultaneous incubation with both substances led to a minor inhibition compared to the effect of each substance alone. Neuronal resting potential, voltage dependent Na(+) (I(Na)) and K(+) (I(K)) currents, the GABA- and glycine-elicited membrane currents, and glutamate-induced intracellular Ca(2+) increase of single neurons, however, were unaffected by both substances. We conclude that acute neuronal network dysfunction in maple syrup urine disease is mainly based on an imbalance of the presynaptic glutamatergic/GABAergic neurotransmitter concentrations or their release.

Cyclic AMP and tumor necrosis factor-alpha regulate CXCR4 gene expression in Schwann cells.

Rat peripheral nerve Schwann cells have been shown to express the alpha-chemokine receptor CXCR4 as well as the corresponding ligand stromal cell-derived factor-1 (SDF-1). We have investigated gene regulatory mechanisms acting on the expression of CXCR4 in cultured rat Schwann cells and found that receptor expression at transcript- and protein levels is directly dependent on intracellular cyclic AMP. Such increased levels of CXCR4 expression were found to be efficiently reversed by the action of tumor necrosis factor-alpha (TNFalpha). We also provide evidence that the POU box transcription factor Oct-6/SCIP is involved in the control of CXCR4 transcription. Finally, we could demonstrate that CXCR4 activation by SDF-1alpha increases the number of dying Schwann cells, indicating that this receptor/ligand interaction is modulating cell survival. Our data, therefore, suggest that in the Schwann cell lineage signal transduction cascades controlled by the activation of TNF- and CXCR4 receptors are functionally coupled.

Serum and cerebrospinal fluid levels of interleukin-18 in human immunodeficiency virus type 1-associated central nervous system disease.

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.

Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HIV-1-infected patients.

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.

Functional CXCR4 receptor development parallels sensitivity to HIV-1 gp120 in cultured rat astroglial cells but not in cultured rat cortical neurons.

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.

Psychomotor slowing in hepatitis C and HIV infection.

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.