Walter Royal

Variable progression of HIV‐associated dementia

A consecutive series of 71 patients diagnosed with HIV-associated dementia (HAD) (1984–1994) were studied to characterize the clinical course of HAD, and to identify predictive markers of rapid neurologic progression. Neurologic progression rate was determined from the change in the Memorial Sloan Kettering (MSK) dementia severity score from diagnosis to death. Those with the most rapid progression in neurologic disability were compared with those with slow or no progression. Autopsy material was immunostained for macrophage activation markers and gp41 in 30 individuals. Median survival was 3.3 months and 6.1 months for rapid-progression and no-progression patients, respectively. Rapid progression was associated with injection drug use but not with race, gender, or age. CD4+ cell counts were lower at diagnosis among rapid-progression than no-progression patients but no differences in AIDS-defining illnesses or patterns of antiretroviral therapy were found. At presentation, rapid-progression patients had more prominent symptoms of mental slowing than those with no progression; however, no other clinical features, CSF, or imaging features distinguished the groups. Less abundant macrophage activation in both basal ganglia and midfrontal gyrus regions, as judged by HAM56 immunostaining, was noted in 9 no-progression patients, compared with 12 rapid-progression patients. Neurologic progression and survival with HAD is highly variable. A significant proportion of individuals with dementia have prolonged survival of more than 12 months and remain cognitively stable. A history of injection drug use and presentation with prominent psychomotor slowing is associated with more rapid neurologic progression, and these patients tend to show more abundant macrophage activation within the CNS.

The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS

To explore the respective roles of highly active antiretroviral therapy (HAART) and alpha-interferon in improving survival of patients with AIDS-related PML, we retrospectively analyzed all patients with AIDS and PML who were referred to Johns Hopkins University HIV Neurology Program from 1985 to 2000. For 97 evaluable patients, we compared survival of those who were on HAART (three or more antiretroviral drugs) to those who were not on HAART. The effect of alpha-interferon was also studied. Multivariate analysis showed no difference in survival among patients on none, one, or two forms of antiretrovirals; however, survival was significantly greater for those on HAART. Whereas alpha-interferon use was shown to be associated with longer survival (P < 0.057), this effect was not independent of the effects of HAART. HAART significantly increases survival for patients with PML and AIDS; however, alpha-interferon does not appear to provide additional benefit.

HIV Infection and Cognition in Intravenous Drug Users Long-term Follow-up

A cohort of 185 HIV-infected injection drug users (IDUs) and seronegative controls was followed with semiannual neuropsychological assessments for up to 4.5 years. Changes in cognitive performance over time were evaluated, and results of seronegative controls were used to adjust for level of education and practice effects. The effects of duration of follow-up, decline in CD4+ count, development of clinical symptoms, antiretroviral use, and diagnosis of AIDS on changes in neuropsychological performance over time were assessed with regression models using the generalized estimating equation approach. Improvement in performance over time, consistent with practice effects, was observed for all measures. The only subtest for which the magnitude of the practice effects was mildly attenuated relative to the seronegative controls was Grooved Pegboard, dominant hand. After adjusting for disease progression and antiretroviral therapy use, none of the time trends for the neuropsychological test scores were significant, suggesting no decline in performance of the seropositive patients relative to the seronegative controls. With development of clinical symptoms, there was a trend in the direction of declining performance. For subjects reporting two or more symptoms but not using antiretroviral therapy, the trend was not significant, whereas having two or more symptoms and using antiretroviral therapy was associated with significantly worse performance on tests of psychomotor speed and memory. With development of AIDS, a significant decline in performance was observed on measures of motor and psychomotor speed as well as memory. There is thus no evidence to suggest that HIV infection in the context of chronic drug and alcohol use significantly alters the frequency or rate of progression of cognitive symptoms. These findings suggest that the natural history of cognitive changes secondary to HIV infection is similar among HIV-infected IDUs and other risk groups such as homosexual/bisexual men. NEUROLOGY 1997;48: 223-230

HIV-1 infection and intravenous drug use: longitudinal neuropsychological evaluation of asymptomatic subjects.

A previous baseline cross-sectional comparison of cognitive performance of a group of AIDS-free, HIV-seropositive intravenous drug users with seronegative control intravenous drug users revealed no significant differences attributable to HIV. We now present longitudinal follow-up results from the same cohort of 160 intravenous drug users. There were no differences in performance by serostatus group at either 6- or 12-month follow-up visits, although differences by age and education were observed. Improvement in performance secondary to practice effects was comparable in both serostatus groups. These findings confirm that chronic intravenous drug use may be associated with a wide range of neuropsychological deficits, but there is no evidence that such preexisting deficits interact with HIV infection to produce additional cognitive impairment in otherwise asymptomatic intravenous drug users. Together with results from other high-risk groups such as homosexual/bisexual men and hemophiliacs, these results confirm that neurocognitive abnormalities during the presymptomatic stages of HIV infection are rare, regardless of the route of acquisition of the virus.

HIV‐1 infection and nervous system abnormalities among a cohort of intravenous drug users

A group of 109 HIV seropositive and 51 seronegative intravenous drug users was evaluated for the presence of HIV-1-related neurologic disease using clinical, neurologic, neuropsychological, and electrophysiologic evaluations. About 80% of HIV seropositive subjects had less than two constitutional symptoms. CD4 cell counts were less than 500/mm3 among 56% of seropositive participants; three individuals were receiving zidovudine. Neurologic abnormalities were found frequently among the cohort, independently of HIV-1 serostatus; electrophysiologic abnormalities were uncommon. Participants from both serologic groups scored significantly lower on neuropsychological tests as compared with norms established for a cohort of homosexual men, and there was no clear association between HIV-1 serostatus and performance on these tests. This study suggests that HIV infection was not the dominant cause of neurologic abnormalities among the study cohort.

Normative Data for a Brief Neuropsychologic Test Battery in a Cohort of Injecting Drug Users

Recent epidemiologic studies of the cognitive performance of injecting drug users have demonstrated the need to establish appropriate test norms for this population. This report provides normative data from a group of 150 injecting drug users on a battery of standardized tests of cognitive performance stratified by age group (range 20 to 49 years) and educational level (mean 11.6, standard deviation 2.0). The analysis also includes estimation of partial correlations between neuropsychologic test scores and age and education. The analysis demonstrates that age and education are important determinants of performance for several of these tests, and provides norms that may be of use as a reference for clinical evaluation and research in drug user populations.

Comparison of Neuropsychological Performance between AIDS-Free Injecting Drug Users and Homosexual Men

We performed a cross-sectional comparison of the baseline neuropsychologic performance of 107 injecting drug users and 230 homosexual men participating in two longitudinal studies. Cognitive tests measured attention, memory and psychomotor speed. Using multiple regression modelling, the analysis adjusted for age, IQ score, race, six-month history of alcohol, cocaine, opiates and marijuana use, HIV serostatus and CD4+ lymphocyte count. Injecting drug users showed significantly poorer scores in all neuropsychologic tests in the univariate analysis. However, once adjusted for age, IQ score and race, only Rey Complex Figure tests were significantly worse among injecting drug users. These data indicate that age and IQ score rather than risk group account primarily for the differences in the cognitive performance, regardless of serostatus and CD4+ count.

Vitamin A deficiency and T-cell subpopulations in HIV-infected adults

Although vitamin A deficiency has been linked with higher mortality and increased mother-to-child transmission of HIV, specific immune abnormalities in HIV-infected adults with vitamin A deficiency are unknown. We measured plasma vitamin A levels and selected T-cell subpopulations in 104 adults with HIV infection. 15.4% had plasma vitamin A levels consistent with vitamin A deficiency (<1.05 μmol/L). Mean CD4 T-cell counts were 127±37 cells/μL in vitamin A-deficient adults compared with 237±26 cells/μL in adults with normal vitamin A levels (p<.04). Vitamin A deficiency was associated with lower CD3 T-cells bearing CD28 surface antigen (p<.05) and L-selectin (p<.01). There were no significant differences in the mean number of CD8, CD3CD45RO, or in the LFA high/low ratio of CD3 T-cells between HIV-infected adults with normal and deficient vitamin A levels. Vitamin A deficiency is associated with T-cell subpopulation abnormalities during HIV infection.

High-Risk Sarcoidosis. Current Concepts and Research Imperatives

Sarcoidosis is a disease with heterogeneous manifestations and outcomes, varying in part on the basis of organ involvement. Specifically, patients with sarcoidosis at risk for poor outcomes include individuals with treatment-resistant pulmonary sarcoidosis, including fibrotic pulmonary disease and pulmonary hypertension, as well as those with cardiac, neurologic, and multiorgan disease. The limited but available data relating to these patients with high-risk sarcoidosis, defined as those patients with presentations requiring medical intervention to avoid progressive disability or premature death, was evaluated as part of the National Heart, Lung, and Blood Institutes workshop to improve understanding of these disease manifestations. In particular, knowledge gaps that preclude a greater understanding of the pathogenesis and management of these severe sarcoidosis clinical phenotypes were identified in the workshop. Research strategies are proposed to address critical knowledge gaps that would further our understanding of these disease manifestations and enhance the care of these patients.