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Several studies carried out in Western countries have demonstrated that a number of virological and immunological markers such as viral loads, cytokines, beta(2)-microglobulin, neopterin, etc., are elevated in the serum and cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-infected individuals with neurological disease. The neurological manifestations of HIV infection noted in Indian patients is different from those reported in Western countries. Moreover, few studies have investigated the role of virological and immunological parameters with respect to the progression of HIV-1 clade C infection in India. In this study, we measured virological (HIV-1 RNA levels) and immunological parameters (CD4 cell count and inflammatory markers) in the plasma and CSF of HIV-1-infected neurologically asymptomatic and symptomatic (with opportunistic infections and/or dementia) subjects. By using clade-specific polymerase chain reaction (PCR), we ascertained that all samples used for the study were infected with HIV-1 clade C. Among the various laboratory parameters evaluated, high viral loads in the CSF, low CD4 counts, and higher levels of interleukin (IL)-1alpha, IL-6, tumor necrosis factor alpha (TNFalpha), beta(2)-microglobulin, and neopterin were noted in HIV-infected subjects with neurological disease as compared to asymptomatic subjects. These data suggest that the markers evaluated in plasma and CSF samples correlated with occurrence of neurological disease in symptomatic individuals as compared to asymptomatic HIV infected subjects.

Objective: To assess whether nonelevated cerebrospinal fluid (CSF) markers could delineate inactive AIDS dementia complex (ADC) in patients receiving highly active antiretroviral therapy (HAART), using neuropsychologic performance change as an indicator of ADC stability., Methods: We used data from the abacavir (ABC) ADC trial (n = 78) and examined the patients' neuropsychologic performance change with the Reliable Change Index according to 3 cutoff groups: (1) CSF viral load (VL) <100 copies/mL, (2) CSF beta-2 microglobulin (beta2m) <2.2 mg/L, and (3) CSF VL and CSF beta2m below cutoffs., Results: CSF marker cutoff groups did not define neuropsychologic change. Linear regression showed that only CSF VL was a weak predictor of neuropsychologic performance change., Conclusion: HAART-treated ADC patients with baseline CSF markers of viral and immunologic inactivity did not necessarily have inactive ADC when followed over 12 weeks. More sensitive CSF markers to judge the activity of ADC are urgently needed, whereas the interpretation of these markers should be considered with caution in HAART-treated ADC patients.

Objectives: To determine the efficacy of the non-nucleoside reverse transcriptase inhibitor atevirdine in the treatment of AIDS dementia complex (ADC)., Design: Open label pilot study., Methods: Ten patients with ADC (stage 1 or 2) who were intolerant to zidovudine or dideoxyinosine, or in whom the antiretrovirals had failed to prevent further decline in CD4 cell levels, were entered into the study. Atevirdine, 1800 mg daily in three divided doses, was given over a 12-week period. Patients were assessed neurologically and neuropsychologically every 4 weeks. Cerebrospinal fluid analysis was performed at entry and at weeks 4 and 12. Technetium-99 exametazine single photon emission computed tomographic cerebral perfusion scans and magnetic resonance imaging brain scans were performed at weeks 0 and 12., Results: Five patients completed the 12 week protocol. Four of these five responded to atevirdine, as judged by quantified neurological and neuropsychological assessments. Atevirdine was well tolerated apart from the development of rash, anxiety, intermittent diarrhoea and fatigue., Conclusions: These preliminary results suggest that atevirdine is efficacious in the treatment of ADC. Larger blinded studies of this class of drug in the treatment of ADC are required.

A predictive marker for AIDS dementia complex (ADC) in a cohort of neurologically asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected patients with < 200 CD4 cells/microL was sought. Patients were assessed neurologically and neuropsychologically at entry. Blood and cerebrospinal fluid (CSF) were taken for assay of beta 2-microglobulin (beta 2M), and neopterin and T cell subsets were assessed from blood. Patients were evaluated every 4 months. Of 37 patients recruited, 35 had sufficient follow-up data. Seventeen patients progressed to ADC stage > or = 1. In univariate analyses, concentrations of CSF beta 2M and neopterin and CD4 cell count were each significantly associated with ADC development. In a multivariate analysis, concentrations of CSF beta 2M remained significant, with levels > 5 mg/L carrying approximately 17 times the risk of ADC. CSF beta 2M and neopterin levels and CD4 cell count are useful in identifying patients at risk of ADC and as such can be used to target high-risk patients so therapy can be optimized.

beta 2-Microglobulin and lysozyme were determined in paired serum and cerebrospinal fluid samples from 137 patients, using immunofluorometry and ELISA, respectively. Of these patients, 54 were infected by human immunodeficiency virus type 1 (HIV1) (including 20 AIDS dementia patients), 73 were HIV1-seronegative with neurological diseases (meningitis (n = 10), multiple sclerosis (n = 29), other neurological diseases (n = 34)) and 10 were controls. Intrathecal synthesis of beta 2-microglobulin occurred in each group. Conversely, lysozyme intrathecal synthesis was found only in meningitis (10/10) and in HIV1-infection (24/54). A pathological increase in beta 2-microglobulin intrathecal synthesis (> or = 2 mg/l) was observed in 45 patients (34 HIV1-infected patients and 11 HIV1-seronegative patients with neurological diseases). Serum concentration and intrathecal synthesis of beta 2-microglobulin were correlated only in the 20 AIDS dementia patients. The cerebrospinal fluid beta 2-microglobulin and lysozyme concentrations were correlated in the 54 HIV1-infected patients only. Blood CD4 + T-cell count was correlated negatively with beta 2-microglobulin intrathecal synthesis but not with lysozyme intrathecal synthesis. These data suggest that in the absence of any central nervous system opportunistic process the increase of beta 2-microglobulin intrathecal synthesis (> or = 2 mg/l) may be a reliable marker of central nervous system involvement in HIV1-infected patients. Intrathecal synthesis of lysozyme was related principally to HIV1-encephalitis and central nervous system opportunistic processes.

Ninety-nine sequential cerebrospinal fluid (CSF) samples from 28 human immunodeficiency virus-1 (HIV-1)-infected patients were analyzed during the follow-up of 9 months to 4 years. Intrathecal synthesis of HIV-antibodies and IgG (p < 0.01), and the levels of beta-2-microglobulin (beta 2m) in the CSF (p < 0.05) and serum (p < 0.01) increased with duration of HIV-1 infection. No effect of duration of HIV-1 infection was observed on the individual CSF white cell counts and the levels of blood-brain-barrier (BBB) permeability. In 13 patients with HIV-1-associated central nervous system (CNS) disease, the effect of duration was seen as an increase of the individual beta 2m levels in serum (p < 0.01). Moreover, 7 of 9 patients who developed neurological disease or showed its progression during the study increased the level of beta 2m in the CSF. All of them increased the level of beta 2m in serum. In 15 neurologically healthy subjects, the effect of duration was expressed as an increase of the level of individual beta 2m in CSF (p < 0.05) and intrathecal IgG synthesis (p < 0.01). In the AIDS group, the level of beta 2m in the CSF increased, but in less severe stages the dependency of the individual CSF parameters on disease duration was not found. Our results indicate that elevated levels of beta 2m in CSF and serum appear to predict progression of neurological and systemic diseases, respectively. Elevated beta 2m in the CSF of clinically intact individuals may indicate subclinical neurological disease caused by HIV-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives and Design: Because macrophages are the predominant immune cell and the predominant infected cell in the brains of patients with HIV encephalitis, we studied macrophage and immune activation-associated factors in the cerebrospinal fluid (CSF) from 39 autopsied AIDS cases for whom complete neuropathologic evaluation of the brain was available., Results: CSF HIV p24 antigen was present in less than one-third of cases (11 out of 39). Less than half of the autopsies with moderate to severe parenchymal infection by HIV had high levels of CSF p24, although all autopsies with elevated levels of HIV p24 had moderate to severe HIV encephalitis. Elevated levels of cytokines, beta 2-microglobulin, neopterin, and quinolinic acid were observed., Conclusions: Although many of the CSF findings showed a strong correlation with each other, none showed a strong correlation with the severity of HIV infection of the brain itself. The absence of a close association between CSF abnormalities and HIV encephalitis could reflect the abundance of complicating opportunistic infections in these terminally ill patients or the inadequacy of CSF as a marker of basal ganglia involvement in HIV encephalitis. These findings complicate interpretation of clinical studies of CSF in patients with AIDS where neuropathologic evaluation is unavailable.

We measured serum and CSF beta 2-microglobulin (beta 2M) levels in HIV-1 seropositive individuals with and without dementia to determine the frequency and diagnostic utility of elevation of CSF beta 2M. We compared 34 samples from 27 patients with HIV-1 dementia with 110 samples from 54 HIV-1 seropositive participants in the Multicenter AIDS Cohort Study, none of whom had progressive dementia. Neurosyphilis and CNS opportunistic processes were excluded in all subjects. We stratified the nondemented subjects by duration of HIV seropositivity and peripheral blood CD4 count. Compared with the nondemented group, demented subjects had significantly higher CSF total protein, IgG%, and CSF albumin/serum albumin ratios. A highly significant association was found between elevated CSF beta 2M and reduced CD4 count (p less than 0.0001). No significant differences were noted between the demented and nondemented groups in CSF WBC count or in the frequency of CSF HIV-1 isolation. The mean CSF beta 2M was 1.9 mg/l in the nondemented subjects compared with 4.2 mg/l in those with dementia (p less than 0.0001). We derived a cutoff of 3.8 mg/l from the distribution of CSF beta 2M in the nondemented group. The determination of CSF beta 2M had a sensitivity of 44%, specificity of 90%, and a positive predictive value of 88% for diagnosis of HIV dementia when compared with nondemented subjects with CD4 counts less than 200. In those without dementia, there was a strong correlation between serum and CSF beta 2M (r = 0.50, p less than 0.0001), but in demented subjects CSF beta 2M was elevated independently of serum levels, suggesting that CSF beta 2M is produced within the brain in HIV dementia. In the absence of CNS opportunistic processes, elevated CSF beta 2M greater than 3.8 mg/l is a clinically useful marker for HIV dementia.

Cerebrospinal fluid (CSF) and serum concentrations of beta-2-microglobulin (beta-2-m) were evaluated in 19 patients with clinically definite multiple sclerosis (MS), in 21 with AIDS dementia complex (ADC), and in 20 subjects with other neurological diseases (OND). CSF beta-2-m and CSF/serum beta-2-m ratio were significantly higher in the patients with ADC than in the MS and OND patients. The CSF and serum levels of beta-2-m in MS patients were not significantly different from those of OND patients. These findings indicate that CSF beta-2-m and CSF/serum ratio may be a useful marker in the diagnosis of ADC. In MS patients the beta-2-m CSF determinations are of no value.

Objective: To determine the relationship between cerebrospinal fluid (CSF) beta 2-microglobulin (beta 2M) and severity of AIDS dementia complex (ADC), and between CSF beta 2M and response of ADC to zidovudine., Design: A prospective study., Setting: Tertiary referral hospital., Patients, Participants: Seventy-eight patients with varying stages of ADC were selected from a subgroup of a cohort of HIV-seropositive patients who are being studied prospectively for the neurological complications of HIV-1 infection. To enter our study, patients had to have an ADC stage of at least 0.5 (equivocal symptoms or abnormal neurological signs in the absence of functional impairment). A control group of 11 HIV-1-seropositive, neurologically normal patients was chosen randomly from the patients followed in the Multicenter AIDS Cohort Study., Interventions: Patients were assessed neurologically and neuropsychologically and computed tomography of the brain and CSF studies were performed., Main Outcome Measures: Patients were staged according to severity of ADC on clinical criteria. Neuropsychological test scores were converted to an impairment score. CSF beta 2M was quantified in both serum and CSF of all patients and in 10 patients with pre- and post-zidovudine assessments., Results: There was a high correlation between CSF beta 2M concentration and severity of ADC (P less than 0.0001); treatment with zidovudine significantly reduced these concentrations (P = 0.013). CSF beta 2M concentration was independent of CSF white-cell count and blood-brain barrier impairment. Other CSF changes in the same patients (including blood-brain barrier permeability to albumin, intrathecal synthesis of immunoglobulin G and HIV-1-p24-antigen levels) were less useful as objective correlates of ADC severity and response to zidovudine therapy., Conclusions: CSF beta 2M may be a valuable marker of ADC severity and response to antiviral therapy.

We measured cerebrospinal fluid (CSF) and serum beta 2-microglobulin (beta 2-M) in Acquired Immunodeficiency Syndrome (AIDS) patients with or without clinical evidence of central nervous system (CNS) involvement. The CSF beta 2-M level was significantly higher than the serum level in AIDS patients with neurological symptoms, but not in AIDS without neurological symptoms, suggesting an increased shedding of this protein in CSF, as a result of rapid cellular turnover within CNS. CSF beta 2-M level increases both in Human Immunodeficiency Virus type 1 (HIV-1) related and in opportunistic CNS syndromes, confirming that beta 2-M is a non specific marker of CNS involvement in AIDS. Nevertheless, the highest CSF beta 2-M values were observed in patients with severe dementia and autoptic diagnosis of multifocal giant cells encephalitis (MGCE) without other opportunistic diseases. This observation could have important implications for monitoring AIDS dementia complex in AIDS patients. Finally, 5 out of 7 (71%) AIDS patients with cryptococcal meningitis showed a decline in CSF beta 2-M level well related to the decrease of cryptococcal antigen (Crypto-Ag) titres and the clinical remission. This data suggests that CSF beta 2-M determination could be used as a useful test in monitoring efficacy of therapy of CNS pathologies in AIDS patients.

Two cases of HIV infection associated with neurological complications are described. The patients had been followed with repeated cerebrospinal fluid (CSF) analyses 1-3 years before the neurological disease and 5 months after zidovudine treatment. CSF mononuclear cell count and the AIDS predictors beta 2-microglobulin and neopterin decreased in CSF after treatment and were lower or at the level seen 1-3 years before treatment. The results suggest that zidovudine has a suppressive effect on the HIV infection in CNS at least for 5 months, even when low zidovudine doses (500 mg daily) were used.