Measurement of Human Immunodeficiency Virus p24 Antigen in Human Cerebrospinal Fluid With Digital Enzyme-Linked Immunosorbent Assay and Association With Decreased Neuropsychological Performance.

New tools are needed to understand human immunodeficiency virus central nervous system involvement. Testing 15 cerebrospinal fluid (CSF) samples for p24 antigen, using a high-sensitivity assay, we found a strong correlation trend between CSF p24 concentration and worse neuropsychological performance.

Cerebrospinal fluid p24 antigen levels and intrathecal immunoglobulin G synthesis are associated with cognitive disease severity in HIV-1.

OBJECTIVE: To test the hypothesis that selected cerebrospinal fluid (CSF) markers [intrathecal immunoglobulin G (IgG) synthesis rate, oligoclonal IgG bands, and p24 antigen levels] are associated with the presence and severity of clinical HIV-1 neurologic disease. DESIGN AND METHODS: CSF and blood parameters from 142 HIV-seropositive subjects from the baseline examination of a longitudinal study were measured and analyzed in relationship with clinically derived cognitive impairment groups (none, mild, moderate) and with other neurologic and clinical classification groups. Subjects with opportunistic infections, lymphomas or neurosyphilis were excluded. RESULTS: The mean intrathecal IgG synthesis rate and mean CSF p24 antigen levels both differed significantly among cognitive impairment groups; more impairment was associated with a higher rate or level. Mean CSF p24 antigen levels were significantly higher in HIV-1-seropositive subjects with any HIV-1 neurologic disease than in subjects without neurologic disease. In contrast, there were no significant differences among seropositive groups in any CSF parameter when stratified by systemic disease classification (asymptomatic HIV-seropositives, AIDS-related complex, or AIDS), independent of neurologic status. CONCLUSION: We conclude that there may be a relationship between the severity of HIV cognitive disease and increasing levels of intrathecal IgG synthesis and CSF p24 antigen levels.

Relationship of cerebrospinal fluid immune activation associated factors to HIV encephalitis.

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.

Review of antiretroviral therapy in the prevention of HIV-related AIDS dementia complex (ADC).

Following the introduction of zidovudine, a major decline was noted in the incidence of AIDS dementia complex (ADC). Several factors point to a causal relationship. It is important now to review the evidence derived from clinical, cerebrospinal fluid (CSF) and neuropathological studies to determine whether the protective effect of zidovudine on the brain of patients with HIV infection has implications for clinical practice. It has been demonstrated in clinical studies that patients with ADC may improve with zidovudine treatment and that the development of ADC is rare in patients receiving the nucleoside analogue long term. In support of these clinical findings, CSF studies have revealed that the presence of HIV-1 p24 antigen has diagnostic value in patients with suspected ADC and that p24 antigen levels decline with zidovudine treatment. Supporting evidence has also come from neuropathological studies, which have demonstrated that zidovudine decreases HIV-specific neuropathological abnormalities. Recently, the Multicenter AIDS Cohort Study reported conflicting data which suggested that antiretroviral therapy is not protective against ADC; however, several methodological weaknesses of this study limit the general applicability of the findings and the conclusions. In view of the increasing body of evidence in support of the efficacy of zidovudine in the prevention and management of ADC in patients with HIV-1 infection, it seems reasonable to include this antiretroviral agent in any combination treatment regimen. Many questions remain to be answered, however, before management of such patients is optimised. Meanwhile, in order to increase both insight and evidence, it is imperative that ongoing and future clinical trials with antiretroviral drugs closely monitor all cases of progression to ADC.(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective cerebral MR study of HIV seropositive and seronegative men: correlation of MR findings with neurologic, neuropsychologic, and cerebrospinal fluid analysis.

PURPOSE: As part of a longitudinal study of human immunodeficiency virus type 1 (HIV) infection, we attempted to identify early cerebral MR findings that might correlate to clinical evidence of central nervous system involvement. METHODS: We studied 65 seropositive and 40 seronegative homosexual males using cranial MR, neurologic, immunologic, and neuropsychologic examinations. RESULTS: The incidence of mildly enlarged ventricles, sulci, and punctate areas of abnormal signal in both groups was similar in both groups. Diffuse, poorly defined areas of abnormal white matter signal were difficult to consistently identify in seropositives. Enlarged adenoidal lymphoid tissue was found in 30 (46%) of seropositives and 2 (5%) of seronegatives (P = .0001). The incidence of sinus inflammatory change was similar in the two groups. CONCLUSION: MR of intracranial contents is substantially normal in a non-AIDS HIV(+) population.

Prolactin levels in the cerebrospinal fluid of patients with HIV infection and AIDS.

The objective of this study was to assess the levels of prolactin (PRL) in cerebrospinal fluid (CSF) of HIV-infected patients with regard to nonHIV-infected patients, and to assess the levels of prolactin in the CSF of HIV-infected patients with and without neurological HIV-involvement. Seventeen HIV-infected patients with different degrees of immunological and neurological involvement were studied. A second group of six HIV-seronegative patients with varying clinical conditions requiring lumbar punctures were included as controls. CSF was collected from patients and controls. Patients were studied neurologically and neuropsychologically, and computed tomography of the brain were performed. They were staged according to CDC clinical classification for HIV infection, and on the basis of tomographic findings into one of five stages. An additional classification for neurological involvement in AIDS was used. CD4+ cell counts, CSF studies, serum-prolactin levels and CSF-prolactin levels were performed as principal laboratory tests. CSF PRL concentrations were significantly higher in the HIV-infected group (n = 17) than the nonHIV infected control group (n = 6) (mean +/- s.d.; 5.77 +/- 2.22 vs. 3.53 +/- 0.69 x 10(-6) g l-1, respectively; p = 0.009, Mann-Whitney U-test). Moreover, even CSF-PRL concentration was higher in HIV-infected patients without cognitive impairment (stage 0 of the clinical classification), (n = 12) in comparison with nonHIV infected controls (n = 6) (mean +/- s.d.; 5.51 +/- 2.31 vs. 3.53 +/- 0.69 x 10(-1) g l-1, respectively; p = 0.028, Mann-Whitney U-test). There was a good correlation between serum and CSF-PRL levels in HIV-infected patients when measured by the Spearman Rank Test (rs = 0.773; p = 0.005). PRL raised serum levels were found in 4 out of 13 patients (30.73%). We conclude that higher levels of CSF-PRL are more frequently found in HIV-infected patients in comparison to uninfected controls. High levels of circulating PRL were also found in HIV-infected patients corroborating results from other work. A good correlation coefficient was found between circulating and CSF-PRL levels in HIV-infected patients, suggesting that disruption of the blood-brain barrier might account for a possible pathogenic mechanism.

Cerebrospinal fluid analysis in human immunodeficiency virus infection.

Cerebrospinal fluid (CSF) analytes were evaluated in 59 human immunodeficiency virus (HIV+) individuals to assess neurological involvement. Glucose, total protein, cell counts, p24 antigen, CSF: serum albumin/IgG ratios, and oligoclonal bands were measured. Eighty percent of samples showed abnormalities in one or more analyte. In some patients samples, these abnormalities could mimic those of secondary opportunistic infection when none was present. The presence of oligoclonal banding in CSF (31 percent) and disturbances in CSF: serum albumin/IgG ratio (30 percent) were related to decreases in serum CD4+ lymphocytes. Disturbances in CSF: Serum albumin/IgG ratio were also related to severity of non-neurological HIV disease staging. Cerebrospinal fluid oligoclonal bands were distinct from that found in serum in the same subjects. Since immune complexes between immunoglobulins and enzymes are observed in these same patients, these oligoclonal bands may result in artifactually elevated enzyme results secondary to decreased clearance leading to erroneous clinical decisions. There was no significant relationship between any abnormalities and the presence of neurologic disease as established by a wide variety of other studies. It is important to recognize the limits of CSF interpretation in this patient group.

[Previous dissociative psychiatric disorder and status epilepticus in a case of acute HIV infection]. / Trastorno disociativo psiquiátrico previo y status epiléptico en un caso de infección aguda por VIH.

We described an 18 old homosexual man who after 5 days developed a neurologic picture associated with Human Immunodeficiency Viruses (HIV) seroconversion. The patient had developed a dissociative psychiatric disorder 6 months before, and after resolution of the acute neurologic disease a mild neuro-psychiatric disorder remained. After mononucleosis-like syndrome of three weeks, the patient developed a meningo-encephalitic process 48 h post admission. He evolved with tonic seizures and twilight state and was admitted into Intensive Care Unit because of epileptic status and deep coma. Evolution was favourable after 72 h of treatment with acyclovir and antiepileptic drugs. Laboratory data showed an inverted T4/T8 ratio and seroconversion to HIV-antibodies and p24-antigen both in serum and CSF. These observations confirm the existence of psychiatric as well neurological alterations in acute HIV infection, and also the significance of p24-antigen and Western-Blot in serum and CSF in showing the seroconversion profile.

Cerebrospinal fluid HIV-1 p24 antigen and culture: sensitivity and specificity for AIDS-dementia complex.

We prospectively evaluated 94 patients with AIDS-dementia complex (ADC) and a smaller group of 27 patients with other HIV-1 related neurological conditions to determine the usefulness of cerebrospinal fluid (CSF) p24 antigen and HIV-1 culture in the diagnosis of ADC. The presence of ADC correlated with detectable CSF p24, but not with a positive culture. However, only 54% of the patients with severe or end stage (stages 3 and 4) ADC had detectable CSF p24 and only 25% had a positive culture. Among those with detectable CSF p24, there was no discernible relationship between the severity of ADC and the amount of CSF p24. The diagnostic sensitivity of CSF p24 in ADC was 21% whereas the specificity was 98%. CSF HIV-1 culture had a sensitivity of 30% and a specificity of 80%. To address the possibility of binding of p24 in immune complexes, thereby escaping detection, an acid hydrolysis procedure was performed on the CSF and serum samples. This did not, however, make an appreciable difference in the detection rate of p24. To delineate whether the finding of cell free virus in the CSF was associated with ADC, CSF culture for HIV-1 was performed on both cell depleted and cell associated fractions. It was uncommon for CSF to be culture positive in only the cell free fraction and there was no relationship to the presence or severity of ADC.

Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) p24 antigen levels in HIV-1-related dementia.

Human immunodeficiency virus type 1 (HIV-1) p24 antigen, a putative marker of virus load, was assayed in 79 blood and 83 cerebrospinal fluid (CSF) samples from 90 HIV-1-seropositive individuals with or without dementia. Twenty-eight subjects had no evidence of neuropsychological impairment, 17 had mild impairment without objective evidence of dementia, and 45 were demented. HIV-1 p24 antigen was detected more frequently in CSF samples from demented (19/40) than normal (1/26) or mildly impaired (1/17) subjects and in 67% of individuals with significant dementia (MSK stages 2-4). p24 Antigen was detected less frequently in CSF from demented subjects on antiretroviral drugs than untreated demented individuals. Overall, the sensitivity of the antigen capture assay in CSF among demented individuals was 47.5%; the specificity, 95.0%; positive predictive value, 90.4%; negative predictive value, 66.1%; and the efficiency, 72.2%. A direct relationship was also noted between the degree of cognitive impairment and blood p24 antigen detection frequency and antigen concentration. CD4+ blood lymphocyte counts were lower for demented individuals, and HIV-1 p24 antigen was detected more frequently and p24 antigen concentration was higher in blood and CSF from individuals with low CD4+ blood lymphocyte counts. beta 2-Microglobulin levels were higher in CSF from demented subjects and correlated directly with CSF p24 antigen concentration. However, in contrast to CD4+ blood lymphocyte counts and beta 2-microglobulin levels, only p24 antigen concentration correlated with dementia severity. Therefore, p24 antigen can be a useful marker for dementia related to HIV-1 infection.

Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine.

BACKGROUND: Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people. METHODS: 28 antiretroviral-naive individuals with CD4 cell counts of 200/microL or more and plasma HIV-1-RNA concentrations of 10,000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n = 17) or zidovudine (n = 11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid. FINDINGS: All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4.64 log10 copies/mL and 4.20 log10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r = 0.18, p = 0.35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine. INTERPRETATION: The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

Acute diffuse leukoencephalitis in HIV-1 infection.

The clinical, neuroradiological, and cerebrospinal fluid findings of a case with acute diffuse leukoencephalitis, a demyelinating disease associated with human immunodeficiency virus infection of the brain, is reported. The patient presented with acute tetraparesis as the primary manifestation of a previously symptom free HIV infection. Cerebrospinal fluid analysis showed enhanced inflammatory abnormalities with high concentrations of P24 antigen. MRI showed diffuse white matter hyper-intensities in both hemispheres. In the follow up over 22 months, the neurological deficits disappeared after antiretroviral treatment in good correlation with improvements in MRI as well as in inflammatory cerebrospinal fluid abnormalities.

Neuroophthalmological examination in children with AIDS.

Evaluation of HIV disease status includes physical examination (anthropomorphic measurements, neurological assessment, etc.) and laboratory examination. Consideration should be given to changes from baseline values, age adjusted normal values and the rapidity of changes. Here we compare results of neuroophthalmologic assessment with Western Blo (WB) profiles in cerebrospinal fluids (CSF) of 54 children with AIDS. Children were classified by Denver Developmental Screening Test (DDST) administration in encephalopathy positive (n = 44) and encephalopathy negative (n = 10) groups. Neuroophthalmological examination which included nine items with good test-retest reliability showed that two of them (nystagmus on following and visual memory impairment) appeared early in the encephalopathy free group and correlated with the loss of some gag band in Western Blot (lower gag score). No correlation was however, found with respect to p24 antigen level in cerebrospinal fluid, a marker which reflects CNS viral load.