Long-term cognitive sequelae of acyclovir-treated herpes simplex encephalitis.

Survival from untreated herpes simplex type 1 encephalitis is well known to be accompanied by severe cognitive impairments. Recently, acyclovir has been proven to be the most effective available treatment for this disease, with the expectation that it would appreciably reduce morbidity. We performed detailed assessments of four consecutive patients who received acyclovir in the early stages of biopsy-proven herpes encephalitis and who now have been followed up for 1.5 to 4 years. All four patients showed definite residual on either clinical or formal neuropsychological testing, most commonly dysnomia and impaired new learning for both verbal and visual material, even though three had normal performance on a standard clinical mental status test. All four patients were unable to function at their prior level of achievement. Therefore, despite early administration of acyclovir in herpes encephalitis, long-lasting neuropsychological residua are likely. Furthermore, cognitive deficits of prognostic importance may not be detected by clinical screening.

Factors associated with incident human immunodeficiency virus-dementia.

BACKGROUND: Antecedents to human immunodeficiency virus-dementia (HIV-D) are poorly understood. OBJECTIVE: To identify risk factors for HIV-D. METHODS: Subjects who are positive for HIV who have CD4+ counts either below 200/microL or below 300/microL with evidence of cognitive impairment were enrolled in this study. Neurologic, cognitive, functional, and laboratory assessments were done semiannually for up to 30 months. Human immunodeficiency virus-dementia was diagnosed using American Academy of Neurology criteria for probable HIV-1-associated dementia complex. RESULTS: One hundred forty-six nondemented patients were enrolled, 45 of whom subsequently met criteria for incident HIV-D. In univariate analyses using the Cox proportional hazards regression model, the following variables were significantly associated with time to develop dementia: cognitive: abnormal scores on Timed Gait, Verbal Fluency, Grooved Pegboard, and Digit Symbol tests; attention-memory, psychomotor, and executive function domain scores; and the diagnosis of minor cognitive/motor disorder; neurologic and medical: increased abnormalities on the neurologic examination, extrapyramidal signs, history of HIV-related medical symptoms; functional: higher reported role or physical function difficulties. Depression was also a strong risk factor, along with sex, hematocrit, hemoglobin, and beta2-microglobulin levels. In a multivariate model that used cognitive domain scores, covariates with significant hazard ratios included depression, executive dysfunction, and the presence of minor cognitive/motor disorder. CONCLUSION: Cognitive deficits, minor cognitive/motor disorder, and depression may be early manifestations of HIV-D.

Cognitive changes 5 years after coronary artery bypass grafting: is there evidence of late decline?

OBJECTIVE: To determine the long-term (preoperative to 5 years postoperative) and late (1-5 years postoperative) changes in cognitive test performance in patients after coronary artery bypass grafting. SETTING: The departments of surgery and neurology at The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS: A group of 102 patients who completed preoperative and follow-up cognitive testing up to 5 years after coronary artery bypass grafting. MAIN OUTCOME MEASURES: A battery of neuropsychological tests, assessing 8 cognitive domains (attention, language, verbal and visual memory, visuoconstruction, executive function, and psychomotor and motor speed), was administered preoperatively and at 1 month, 1 year, and 5 years postoperatively. RESULTS: Significant changes in neuropsychological test scores from baseline to 5 years were observed in only 3 of the 8 domains: there were declines in visuoconstruction and psychomotor speed and an improvement in executive function. When the period from baseline to 5 years was divided into 2 intervals, we found that cognitive test scores generally improved from baseline to 1 year. By contrast, between 1 and 5 years, there was significant decline in all cognitive domains except for attention and executive function. Some potential explanatory covariates (demographic, medical history, and surgery variables) were associated with changes from baseline to 5 years in some cognitive domains, but few covariates were statistically significant in more than 1 cognitive domain. CONCLUSIONS: The change in cognitive test performance between baseline and 5 years is likely related to several factors, including low baseline performance and practice effects. The significant decline in performance between 1 and 5 years, however, raises the possibility that a late cognitive decline may be occurring in this population. Additional studies, with the use of a nonsurgical control group, are needed to determine if the observed cognitive decline is related to bypass surgery itself, normal aging in a population with cardiovascular risk factors, or some combination of these and other factors.

Incidental white matter hyperintensities on magnetic resonance imaging in HIV-1 infection. Multicenter AIDS Cohort Study.

Magnetic resonance (MR) scans were performed as part of a prospective neuropsychological study within the Multicenter AIDS Cohort Study. Fifty HIV-1-seronegative men, 85 HIV-1-seropositive men without constitutional symptoms, and 14 with symptomatic HIV disease underwent MR imaging using a uniform protocol. Scans were rated by neuroradiologists blinded to all clinical details except age. The majority of MR scans were normal in all of the clinical groups and no covert mass lesions or diffuse white matter abnormalities were identified. Focal hyperintensities in the white matter were observed in 24% of the HIV-1 seronegatives, 26% of HIV-1 asymptomatic seropositives (CDC II/III), and 17% of those with ARC/AIDS. No significant associations were noted between the white matter hyperintensities and HIV-1 serostatus, neurological abnormalities, CD4 count, alcohol or drug use, hypertension, or smoking. In one individual classified with early HIV-1 dementia, MR demonstrated several hyperintensities in the deep parietal white matter, but at autopsy no microscopic abnormalities corresponding to the MR findings were identified. Our studies imply that focal white matter hyperintensities identified on MR are not specific for HIV-1 infection and are probably incidental and of no clinical significance.

Low education as a possible risk factor for cognitive abnormalities in HIV-1: findings from the multicenter AIDS Cohort Study (MACS).

The present study reports new and unexpected results of cognitive abnormalities among human immunodeficiency virus type 1 (HIV-1) asymptomatic subjects in the Multicenter AIDS Cohort Study. The major purpose of our analyses is to estimate the separate and combined effects of serostatus and education level on the prevalence of cognitive abnormality. Cognitive "abnormality" was defined as performance that deviated > or = 2 SDs below the mean of the total seronegative group on at least one of the five neuropsychological screening tests (Grooved Pegboard, Verbal Fluency, Digit Span, Symbol Digit Modalities, Rey Auditory Verbal Learning). The predicted prevalence of cognitive abnormality was 38% in seropositive individuals with no more than 12 years of education, compared with < 17% in the other education-serostatus groups. This interaction between education level and serostatus remained after controlling for the possible confounding effects of age, ethnicity, CD4 level, depression, prior drug history, and learning disability using logistic regression. To account for these findings, we suggest that low education might reflect an indirect index of lower reserve capacity (i.e., a risk factor) that lowers the threshold for neuropsychological abnormalities in cases of early HIV-1 infection.

Language dysfunction in early- and late-onset possible Alzheimer's disease.

Disproportionate involvement of language has been claimed to be a distinguishing feature of Alzheimer's disease (AD) with onset before age 65. We tested this hypothesis in a group of 133 patients with possible AD by NINCDS criteria. Sixty-one had onset of symptoms prior to age 65; the remaining 72, at 65 or later. The two groups were well matched on overall dementia severity as measured by the Mini-Mental State Exam. Using standardized tests, we did not find any significant differences in the severity of language dysfunction between the two groups, particularly after controlling for greater attention/concentration deficits in the early-onset group. Previous reports of differences in language dysfunction between early- and late-onset AD may have been due to small sample sizes and nonstandardized testing.

Recovery of naming in aphasia: relationship to fluency, comprehension and CT findings.

We assessed oral naming skill after left hemisphere ischemic stroke in 54 right-handed aphasics. Initially, almost all had moderate to severe disability in oral naming. After 6 months, normal scores were achieved by one-third of the patients, all with lesions less than 60 cm3 in volume. Only 2 of 18 patients who were nonfluent at 6 months had normal naming then. Among patients with lesions less than 60 cm3 and persistently poor naming, there were two discrete lesion sites: posterior superior temporal-inferior parietal (semantic paraphasic errors) and insula-putamen (phonologic paraphasic errors). Individual variability was notable, with several patients regaining normal naming ability despite posterior temporal or insula-putamen lesions.

Clinical-neuropathologic correlation in HIV-associated dementia.

The structural abnormalities that correlate with the clinical manifestations of HIV-associated dementia (HIVD) are unclear. In a prospectively categorized group of patients with and without HIVD who were followed to autopsy, we correlated HIV-related neuropathologic changes with the presence and severity of HIVD. We also assessed the effect of antiretroviral therapy on the neuropathologic changes. Finally, using reverse transcriptase-polymerase chain reaction on homogenized brain tissue, we correlated the relative expression of mRNA for tumor necrosis factor-alpha (TNF-alpha) with cognitive impairment and with the patterns of neuropathologic changes. The presence of multinucleated giant cells and diffuse myelin pallor were specific for HIVD, but these pathologic changes occurred in only 50% of patients with dementia. Patients treated with antiretroviral agents for > 12 months were less likely to show multinucleated giant cells or diffuse myelin pallor. Levels of mRNA for TNF-alpha from frontal subcortical white matter were significantly greater in patients with HIVD than in AIDS patients without dementia or in seronegative controls. We conclude that routine histopathologic examination of the brain fails to detect multinucleated giant cells and diffuse myelin pallor in 50% of patients dying with HIVD. This suggests that more subtle neuropathologic correlates for the clinical manifestations of HIVD exist. Our observations of elevated levels of TNF-alpha mRNA in HIVD indicate that indirect mechanisms of brain dysfunction, such as abnormal cytokine expression, may contribute to the pathogenesis of HIVD.

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.

A longitudinal study of speech fluency in aphasia: CT correlates of recovery and persistent nonfluency.

The anatomic correlates of speech fluency were studied in 54 right-handed patients with aphasia due to stroke. Speech fluency was assessed at 1 month postonset and then monthly for 5 months. CTs obtained at 5 months postonset were used for lesion localization and volume determination. Persistent nonfluency was associated with lesions in the rolandic cortical region and underlying white matter. Recovery from nonfluency occurred in 6 of 27 patients. Lesions in these six patients were less extensive than lesions in patients with persistent nonfluency. Patients who were fluent by 1 month lacked extensive rolandic lesions.

HIV-1 infection: no evidence of cognitive decline during the asymptomatic stages. The Multicenter AIDS Cohort Study.

Cross-sectional studies have not adequately resolved the question of whether subjects infected with HIV-1 may suffer cognitive decline during the early, asymptomatic stages of the infection. We studied longitudinally 238 asymptomatic healthy HIV-1-infected homosexual/bisexual men (CDC groups 2 and 3) and 170 uninfected controls in the Multicenter AIDS Cohort Study with neuropsychological testing at semiannual intervals. A comparison of change in scores between visits 1 and 4 as well as a multivariate autoregressive analysis revealed no evidence of decline in test performance over time in the HIV-1-infected group compared with the seronegative controls. These findings suggest that a gradual cognitive decline does not occur during the early, asymptomatic stages of HIV infection.

Temporal trends in the incidence of HIV-1-related neurologic diseases: Multicenter AIDS Cohort Study, 1985-1992.

OBJECTIVE: To describe temporal trends in the incidence of human immunodeficiency virus (HIV)-related neurologic diseases in the Multicenter AIDS Cohort Study from 1985 to 1992. METHODS: The incidence rates of six neurologic disorders were examined: toxoplasmosis, cryptococcal meningitis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, HIV dementia, and sensory neuropathy. Poisson modeling was used to test linear trends over time and the effects of progressive immunosuppression, antimicrobial prophylaxis, and antiretroviral drug therapy. RESULTS: There was an upward temporal trend in all incidence rates, except for HIV dementia. Progressive immunosuppression in the cohort explained all calendar trends except for sensory neuropathy, where an increasing temporal trend remained even after adjusting for CD4+ cell count, and for HIV dementia where a slight decline was noted, although the effects were not statistically significant. We noted a protective trend of antimicrobial prophylaxis on toxoplasmosis and cryptococcal meningitis, but, in contrast, use of antiretroviral agents was not protective against HIV dementia. Men receiving didanosine, zalcitabine, or stavudine were more likely to develop sensory neuropathy. CONCLUSION: Despite the earlier and more widespread use of antimicrobial and antiretroviral agents, neurologic conditions still occurred frequently in this cohort, with annual rates above 1.5 per 100 person-years for HIV dementia and sensory neuropathy. Sensory neuropathy seems to be increasing in incidence and HIV dementia declining slightly in this cohort. As the epidemic matures and more people with profound immunosuppression live longer, the overall incidence of HIV-related neurologic diseases can be expected to rise.

Patterns of cerebral atrophy in HIV-1-infected individuals: results of a quantitative MRI analysis.

Cerebral atrophy is a common radiologic manifestation of HIV dementia. To evaluate the relationship between cognitive impairment and cerebral atrophy, adjusting for age and immune status, we used standardized planimetry to measure the ventricle-brain ratio (VBR) and the bifrontal (BFR) and bicaudate (BCR) ratios, three measures of cerebral atrophy. We analyzed cranial MRIs of 23 HIV-1-seronegative controls (SN) and 116 HIV-1-infected individuals. Of the HIV-1-seropositive individuals, 37 had HIV dementia (DM group), 40 had neurologic or neuropsychological abnormalities insufficient for HIV dementia (NP+ group), and 39 were neurologically normal (NML group). We performed comparisons using analysis of covariance with correction for multiple comparisons. Both the VBR, a general measure of overall cerebral atrophy, and the BCR, a measure of atrophy in the region of the caudate nucleus, are significantly associated with dementia. The association is stronger for BCR enlargement than for VBR enlargement, suggesting that selective caudate region atrophy is associated with HIV dementia. These results indicate that overall cerebral atrophy and prominent caudate region atrophy are important radiographic features of HIV dementia.

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-associated neurologic disease incidence changes:: Multicenter AIDS Cohort Study, 1990-1998.

This study examined the temporal trends in the incidence rates of HIV dementia, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma from January 1990 to December 1998 in the Multicenter AIDS Cohort Study. The incidence rates for HIV dementia, cryptococcal meningitis, and lymphoma decreased following the introduction of highly active antiretroviral therapy (HAART). The proportion of new cases of HIV dementia with a CD4 count in a higher range (i.e., 201 to 350) since 1996 may be increasing.

CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing.

The authors evaluated whether highly active antiretroviral therapy (HAART) with multiple CSF-penetrating drugs results in greater improvement in HIV-associated psychomotor slowing than HAART with a single CSF-penetrating drug. Both groups had improvement in CD4 count, plasma viral load, as well as two tests of psychomotor speed. Comparing the two groups, there were no differences in the mean change for CD4 count, viral load, or any of the neuropsychological tests. Multiple and single CSF-penetrating HAART may be equivalent for treating HIV-associated psychomotor slowing.

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.

Cognitive performance after progression to AIDS: a longitudinal study from the Multicenter AIDS Cohort Study.

OBJECTIVE: To describe changes in cognitive functioning before and after development of an acquired immune deficiency syndrome (AIDS)-defining illness or CD4+ lymphocyte count < 200/mm3 in participants in the Multicenter AIDS Cohort Study. METHODS: The study population included participants who either were diagnosed with an AIDS-defining illness (n = 52) or had at least one measurement of CD4+ count < 200/mm3 (n = 57) and who had at least four neuropsychological (NP) evaluations, two or more before and two or more after the AIDS diagnosis. A group of subjects with clinical diagnosis of dementia (n = 29) was also included for comparison. The NP test battery included measures of attention, memory, constructional abilities, and psychomotor speed. Longitudinal data analysis, using the generalized estimating equation, was performed separately for each NP measure. Time was measured in months from the date of clinical AIDS or CD4+ < 200/mm3. RESULTS: Before AIDS< the dementia group showed significant decline (slope different from zero) only on measures of psychomotor speed. For all other measures, there was no evidence of decline in performance before AIDS for the other groups. After development of AIDS, the group with clinical AIDS showed significant decline on psychomotor speed but none on the other cognitive measures. The group with CD4+ < 200/mm3 did not show significant decline on any of the cognitive measures after AIDS. As expected, the dementia group showed significant decline on all measures. Sensory neuropathy was associated with a significant decline in performance on measures of psychomotor speed after AIDS. Antiretroviral therapy was not associated with any measurable changes in NP performance. CONCLUSION: These results are consistent with previous findings showing no significant decline in cognitive functions before AIDS, unless overt dementia is present, and no decline in immunosuppressed subjects who have had no AIDS-defining illness. By contrast, in subjects who have developed clinical AIDS, there is mild decline in fine motor skills but no significant change in other cognitive domains.

Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy.

OBJECTIVE: To determine the predictive value of plasma HIV RNA and CD4 lymphocytes for HIV-associated dementia and sensory neuropathy. METHODS: A total of 1,604 AIDS-free HIV seropositive men from the Multicenter AIDS Cohort Study were followed over a 10-year period (1985 to 1995). HIV-associated dementia and sensory neuropathy were diagnosed according to standard definitions. Baseline samples were used to measure plasma HIV RNA levels with a branched DNA assay and levels of beta2-microglobulin, CD4 lymphocyte counts, and hemoglobin levels. RESULTS: Seventy-seven patients with HIV-associated dementia and 213 patients with sensory neuropathy were identified. Baseline HIV RNA levels above 3,000 copies/mL and CD4 counts below 500 cells/mm3 were predictive of both neurologic outcomes, but neither hemoglobin, body mass index, nor beta2-microglobulin were independently predictive. After adjusting for age and level of education, individuals with baseline plasma HIV RNA >30,000 copies/mL had a relative hazard for dementia 8.5 times (p < 0.001) that of those with <3,000 copies/mL, and those with CD4 counts <200 cells/mm3 had a 3.5-fold (p = 0.003) greater hazard relative to those with CD4 counts >500 cells/mm3. Individuals with HIV RNA >10,000 copies/mL had a 2.3-fold (p = 0.008) greater hazard of sensory neuropathy than those with <500 copies/mL, and men with <750 CD4 cells/mm3 had a 1.4-fold (p = 0.03) greater hazard than those with >750 CD4 cells/mm3. CONCLUSIONS: High levels of systemic HIV replication may "drive" the initiation of neurologic disease; effective suppression of HIV may reduce the incidence of dementia and neuropathy. Levels of plasma HIV RNA and CD4 counts, determined before the initiation of antiretroviral therapy, were predictive of HIV-associated dementia and sensory neuropathy.

Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study.

We determined incidence and future projections of dementia after AIDS onset in 492 homosexual men with AIDS in the Baltimore/Los Angeles sites of the Multicenter AIDS Cohort Study, 64 of whom developed dementia. We studied various risk factors for dementia, including demographic and clinical features, medical history, markers of immune status before AIDS, and zidovudine use. During the first 2 years after AIDS, HIV dementia developed at an annual rate of 7%. Overall, 15% of the cohort followed through death developed dementia. The median survival after dementia was 6.0 months. Using a proportional hazards model, risk factors for more rapid development of dementia were lower hemoglobin (relative hazard, 0.59 per additional 2 g/dl; p = 0.0005) and body mass index (relative hazard, 0.64 per additional 5 kg/m2; p = 0.05) 1 to 6 months before AIDS, more constitutional symptoms 7 to 12 months before AIDS (relative hazard, 1.68 per additional symptom, p = 0.005), and older age at AIDS onset (relative hazard, 1.60 per decade older; p = 0.009). In a multivariate model, pre-AIDS hemoglobin remained the most significant predictor of dementia. There were no significant risks defined from demographic characteristics, specific AIDS-defining illnesses, zidovudine use before AIDS, or CD4+ lymphocyte count before AIDS. We project that 12 months after the first AIDS diagnosis, 7.1% of survivors will have dementia. The observed association between anemia, low weight, constitutional symptoms, and dementia suggests a role for cytokines inducing both systemic and neurologic disease.