7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests.

BACKGROUND AND PURPOSE: Validated neuroimaging markers of HIV-associated neurocognitive disorder in patients on antiretroviral therapy are urgently needed for clinical trials. The purpose of this study was to explore the relationship between cognitive impairment and brain metabolism in older subjects with HIV infection. It was hypothesized that MR spectroscopy measurements related to neuronal health and function (particularly N-acetylaspartate and glutamate) would be lower in HIV-positive subjects with worse cognitive performance. MATERIALS AND METHODS: Forty-five HIV-positive patients (mean age, 58.9 ± 5.3 years; 33 men) underwent detailed neuropsychological testing and brain MR spectroscopy at 7T. Twenty-four subjects were classified as having asymptomatic cognitive impairment, and 21 were classified as having symptomatic cognitive impairment. Single-voxel proton MR spectra were acquired from 5 brain regions and quantified using LCModel software. Brain metabolites and neuropsychological test results were compared using nonparametric statistics and Pearson correlation coefficients. RESULTS: Differences in brain metabolites were found between symptomatic and asymptomatic subjects, with the main findings being lower measures of N-acetylaspartate in the frontal white matter, posterior cingulate cortex, and precuneus. In the precuneus, glutamate was also lower in the symptomatic group. In the frontal white matter, precuneus, and posterior cingulate cortex, NAA and glutamate measurements showed significant positive correlation with better performance on neuropsychological tests. CONCLUSIONS: Compared with asymptomatic subjects, symptomatic HIV-positive subjects had lower levels of NAA and glutamate, most notably in the frontal white matter, which also correlated with performance on neuropsychological tests. High-field MR spectroscopy offers insight into the pathophysiology associated with cognitive impairment in HIV and may be useful as a quantitative outcome measure in future treatment trials.

Glenoid notch MRI findings do not predict normal variants of the anterior and superior labrum.

AIM: To determine (1) the relationship of a glenoid notch to the presence of a normal labral variant in the anterior-superior glenoid labrum; (2) the inter- and intra-observer reliability of recognising a glenoid notch; and (3) whether magnetic resonance arthrography (MRA) is more reliable than non-contrast magnetic resonance imaging (MRI) in visualising a glenoid notch. MATERIALS AND METHODS: From 1995 through 2010, 104 patients underwent MRI or MRA before diagnostic shoulder arthroscopy by the senior author. Five blinded musculoskeletal radiologists independently read the images twice to evaluate for the presence or absence of a glenoid notch. Fifty-nine (57%) patients had normal anterior-superior labral variants. The authors calculated the relationship of the readings to the arthroscopically determined presence or absence of a normal labral variant and the reading's diagnostic performance and rater reliability. RESULTS: On average, 38% (range 9-65%) of the glenoid scans were read as notched. The sensitivity, specificity, positive predictive value, and negative predictive value of the notch relative to the presence of a normal variant were 43.1%, 71.2%, 70.2%, and 48% versus 44.3%, 77.5%, 79.4%, and 56.1% for MRI and MRA, respectively. The overall average intra-observer κ-values were 0.438 (range 0.203-0.555) and 0.346 (range -0.102 to 0.570) for MRI and MRA, respectively. The average interobserver intra-class correlation coefficient reliability values were 0.730 (range 0.693-0.760) and 0.614 (range 0.566-0.662) for MRI and MRA, respectively. CONCLUSIONS: A notched glenoid on MRI lacks sufficient diagnostic performance and rater reliability for the clinical detection and prediction of normal anterior-superior labral variants.

Open muscle biopsy in suspected myopathy: diagnostic yield and clinical utility.

BACKGROUND: The purpose of the study was to investigate the diagnostic yield and clinical utility of open muscle biopsy and to identify pre-biopsy factors that might predict useful clinical results for suspected myopathy. METHODS: Two-hundred fifty-eight muscle biopsies, performed for investigation of suspected myopathy, were evaluated. RESULTS: A specific clinical diagnosis following muscle biopsy was made in 43% of cases. As a result of the biopsy, clinical diagnosis was changed in 47% and treatment was changed in 33% of cases. Results either led to a specific clinical diagnosis or changed the diagnosis/treatment in 74% of patients. Positive family history of myopathy and findings of myopathic irritability on electromyography had a negative predictive value for diagnosis change. CONCLUSIONS: Open muscle biopsy is useful in myopathy evaluation in the modern genetic era.

Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.

BACKGROUND: The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which include stavudine, are the most common regimens to treat HIV infection in Uganda and many other parts of Africa. OBJECTIVE: To evaluate the benefits and risks of stavudine-based highly active antiretroviral therapy (HAART) for HIV-associated cognitive impairment and distal sensory neuropathy. The study compared neuropsychological performance changes in HIV+ individuals initiating HAART for 6 months and HIV- individuals receiving no treatment for 6 months. The risk of antiretroviral toxic neuropathy as a result of the initiation of stavudine-based HAART was also examined. METHODS: At baseline, 102 HIV+ individuals in Uganda received neurologic, neuropsychological, and functional assessments; began HAART; and were followed up for 6 months. Twenty-five HIV- individuals received identical clinical assessments and were followed up for 6 months. RESULTS: In HIV+ individuals, there was improvement in verbal memory, motor and psychomotor speed, executive thinking, and verbal fluency. After adjusting for differences in sex, HIV+ individuals demonstrated significant improvement in the Color Trails 2 test (p = 0.025) compared with HIV- individuals. Symptoms of neuropathy developed in 38% of previously asymptomatic HIV+ patients after initiation of the stavudine-based HAART. CONCLUSIONS: After the initiation of highly active antiretroviral therapy (HAART) including stavudine, HIV+ individuals with cognitive impairment improve significantly as demonstrated by improved performance on a test of executive function. However, peripheral neurotoxicity occurred in 30 patients, presumably because of stavudine-based HAART, suggesting the need for less toxic therapy.

Spanish validation of the HIV dementia scale in women.

HIV infection is increasing in minority groups, particularly in African American and Hispanic women. Although the incidence of HIV dementia has decreased since the advent of highly active antiretroviral treatment, prevalence of neurocognitive complications has increased as patients are now living longer. This study's purpose was to determine the psychometric properties of the Spanish-language HIV Dementia Scale (HDS) in a group of HIV-infected women. We recruited 96 women: 60 HIV-seropositive and 36 HIV-seronegative. Modification of the HDS into a Spanish-language version consisted of translating the instructions, substituting four words in Spanish (gato, media, azul, piña), increasing 1 second in the psychomotor speed because the Spanish alphabet has more letters than the English alphabet, and not offering clues for memory recall. Cognitive impairment (CI) was defined according to the modified American Academy of Neurology HIV-dementia criteria including an asymptomatic CI group. Statistical analysis consisted of analysis of variance to determine group differences and receiver operator characteristics (ROC) to determine the optimal cutoff point for the screening of CI. HDS-Spanish total score and subscores for psychomotor speed and memory recall showed significant differences between HIV-seronegative and women with HIV-dementia (p < 0.001) and between HIV-seropositive women with normal cognition and those with HIV-dementia (p < 0.001). The optimal cutoff point of 13 or less had performance characteristics of 87% sensitivity and 46% specificity for HIV-associated CI (50.0% positive predictive value, 85.0% negative predictive value). The HDS-Spanish translation offers a useful screening tool with value for the identification of Hispanic women at risk of developing HIV-associated symptomatic neurocognitive disturbances.

Survival probability in ataxia telangiectasia.

Ataxia telangiectasia is a rare, multiorgan neurodegenerative disorder with enhanced vulnerability to cancer and infection. Median survival in two large cohorts of patients with this disease, one prospective and one retrospective, is 25 and 19 years, with a wide range. Life expectancy does not correlate well with severity of neurological impairment.

Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort.

OBJECTIVE: To explore the association between specific nucleoside reverse transcriptase inhibitors and sensory neuropathies (SNs) and define the modifying roles of hepatitis C (HCV), vitamin B12 deficiency, and impaired glucose tolerance. METHODS: The authors conducted a prospective cohort study of 147 HIV-infected adults at two sites chosen to emphasize demographic differences. Standardized assessments included detailed antiretroviral histories, neurologic examinations, skin biopsies for epidermal nerve quantitation, and quantitative sensory testing. RESULTS: There were significant differences between subjects at Johns Hopkins University (JHU) and Monash University (MU) in gender, race, HIV transmission route, and HCV seroprevalence. Symptomatic SN was present in 49% at JHU and 55% at MU (chi2 = 4.02, p = 0.134) and was significantly more common in those at least age 40 than younger patients (odds ratio [OR] = 2.87, 95% CI = 1.27, 6.49). After adjusting for site, age, and CD4 cell count, exposure to didanosine (ddI) or stavudine (d4T) was associated with an significantly increased likelihood of symptomatic SN (ddI: OR = 3.21, 95% CI: 1.56, 6.60; d4T: OR = 7.66, 95% CI: 2.89, 20.33). Plasma HIV RNA, lactate, and HCV were not associated with SN. Quantitative vibratory testing identified neuropathy with a positive predictive value of 76% and epidermal nerve fiber densities 59%. CONCLUSIONS: Exposure to stavudine and didanosine was significantly associated with a heightened risk for symptomatic sensory neuropathy. Reduced vibration thresholds and epidermal nerve fiber densities had the highest diagnostic efficiency of the laboratory indicators of neuropathy examined, but were relatively insensitive in isolation.

CSF soluble Fas correlates with the severity of HIV-associated dementia.

Soluble Fas (sFas) and soluble Fas ligand (sFasL) are associated with cellular dysfunction and death and are elevated in CSF from patients with HIV dementia (HIV-D). The authors investigated whether these markers correlated with dementia severity and course. sFas and sFasL were measured in 15 highly active antiretroviral therapy (HAART)-naïve HIV-D subjects, 30 HAART-naïve HIV+ controls, and 17 HIV-controls. HIV-D subjects had higher CSF sFas levels than controls. Subjects with moderate/severe dementia had higher CSF sFas levels than those with mild dementia. CSF sFas trended lower in those with progressive dementia.

Response to systemic HIV viral load suppression correlates with psychomotor speed performance.

The authors evaluated the association of a virologic response to highly active antiretroviral therapy, or a subsequent rebound, with performance on two measures of psychomotor speed in HIV-positive subjects. Virologic suppression was associated with improved performance on measures of psychomotor speed, and virologic rebound was associated with psychomotor speed performance decline. Changes in plasma HIV viral load in HIV-positive individuals with cognitive slowing correlate with performance on tests of psychomotor speed.

Thrush and fever as markers of immune competence in the era of highly active antiretroviral therapy.

The presence of clinical manifestations of HIV-1 infection is one measure of immune function failure. We examined the occurrence of clinical manifestations of HIV-1 infection, in particular fever and oral thrush, before and after the initiation of highly active antiretroviral therapy (HAART). Using data collected from 645 participants in the Multicenter AIDS Cohort Study (MACS) who used HAART, 7517 person-visits from January 1992 through March 2000 were stratified by time relative to HAART initiation (> or =1 year preinitiation, <1 year preinitiation, >1 year postinitiation, and > or =1 year postinitiation) and CD4+ T cell count (< or =100, 101-200, 201-350, and >350 cells/microl). Multivariate logistic regression was used to assess the relationship between HAART, CD4+ T cell count, and each self-reported symptom (oral hairy leukoplakia, diarrhea, fever, and oral thrush). After initiation of HAART, clinical manifestations of HIV-1 infection continued to occur and, similar to patterns seen before HAART, were more likely at lower CD4+ T cell counts than at higher (p < 0.001). Except for diarrhea, symptoms did not occur more frequently after HAART. Rather, beyond 1 year after initiation of HAART, there was less oral thrush even at the same CD4+ T cell count. These results provide evidence that increases in CD4+ T cell count due to HAART represent a reconstitution of immune function.

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.

Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors.

A study of neuropsychological performance was conducted in 33 HIV+ patients initiating highly active antiretroviral therapy (HAART). Grooved Pegboard (GP) non-dominant hand performance improved in 23/33 (70%) subjects (P=0.002). Among 23 patients with motor slowing (GP non-dominant hand z score < -1.0) at baseline, 18 (78%) improved on the GP non-dominant hand test after initiating HAART (P=0.001). GP non-dominant hand performance improved longitudinally in HIV+ patients initiating HAART, while matched HIV+ controls not on HAART did not change (P=0.045). Significant improvement in motor performance can occur after HAART in HIV+ patients with impairment.

Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS).

BACKGROUND: Combination antiretroviral therapy including protease inhibitors (combo+PI) is effective in suppressing systemic viral load in HIV infection, but its impact on HIV-associated cognitive impairment is unclear. OBJECTIVE: To determine whether psychomotor speed, a sensitive measure of impairment in HIV dementia, improves with combo+PI compared with other antiretroviral treatments. METHODS: A total of 411 HIV-seropositive (HIV+) homosexual men (with longitudinal neuropsychological testing) in the Multicenter AIDS Cohort Study and, in a separate analysis, 282 HIV+ homosexual men with psychomotor slowing at baseline were classified by treatment into four groups: antiretroviral naive (no antiretroviral medication treatment), monotherapy, combination antiretroviral therapy without protease inhibitors (combo-noPI), and combo+PI. We compared longitudinal performance on three tests of psychomotor speed: the Grooved Pegboard (GP) (nondominant and dominant hands), Trail Making Test B, and the Symbol Digit Modalities Test (SDMT). RESULTS: Relative to antiretroviral-naïve and monotherapy participants, on the GP nondominant hand test, combo+PI participants with abnormal baseline neuropsychological testing showed improved performance (difference = +0.63 standard deviation [SD], p = 0.02). For the SDMT, both combo+PI participants (difference = +0.26 SD, p = 0.03) and combo-noPI participants (difference = +0.29 SD, p = 0.01) with abnormal baseline neuropsychological testing improved compared with antiretroviral-naïve and monotherapy groups. CONCLUSION: Combo+PI and combo-noPI are associated with improved psychomotor speed performance in HIV+ homosexual men with abnormal neuropsychological testing.

HIV-associated primary CNS lymorbidity and utility of brain biopsy.

INTRODUCTION: Human immunodeficiency virus (HIV) infection is associated with several central nervous system (CNS) infections and neoplasms. These opportunistic processes generally occur with advanced immunosuppression, but if an accurate diagnosis is made, effective treatment can frequently be initiated. METHODS: In an attempt to assess the safety, diagnostic yield, and utility of stereotactic brain biopsy in the clinical management of suspected HIV-associated primary CNS lymphoma, we retrospectively studied the performance of biopsy in HIV-seropositive patients presenting with focal intracranial lesions. This analysis included 435 patients undergoing brain biopsy, identified through a local case series (n=47) combined with all published cases (n=388). The years of analysis for this study were 1984 and 1997. We also assessed the survival of HIV-associated intracranial mass lesions and of PCNSL patients treated at JHU. RESULTS: Definitive histopathological diagnoses were established in eighty-eight percent of biopsied cases: primary CNS lymphoma (PCNSL) (30%), CNS toxoplasmosis (CNS TOXO) (16%), progressive multifocal leukoencephalopathy (PML) (25%), and other specific diagnoses (17%). Post-biopsy morbidity within thirty days was 8.4% and mortality was 2.9%. PCNSL was the most common diagnosis among cases biopsied after failure of anti-toxoplasmosis therapy, 134/205 (65%). In the local case series, biopsy-related morbidity was associated with poor functional status, decreased platelet count, and number of lesions at presentation. The median survival of irradiated PCNSL cases was 29 days longer than untreated cases (median survival 50 days versus 21 days, respectively, Chi-square=6.73, P<0.01). DISCUSSION: Stereotactic brain biopsy had a high diagnostic yield for HIV-associated focal intracranial lesions, however, the biopsy complication rate in this patient population was relatively high. PCNSL was diagnosed in the majority of patients failing anti-toxoplasmosis therapy. Survival after irradiation for PCNSL remains very poor.

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.

Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study.

UNLABELLED: A retrospective chart review was conducted to determine the effect of alpha-Interferon (alpha-IFN) on disease progression, symptom palliation, and survival in HIV-associated Progressive Multifocal Leukoencephalopathy (PML). METHODS: Subjects were HIV seropositive patients diagnosed with PML at the Johns Hopkins Hospital between 1985 and July of 1986. Diagnostic criteria for PML included both clinical symptomatology and histologic or radiographic confirmation. All patients with concomitant CNS infections were excluded. Patients receiving a minimum treatment of 3 weeks of 3 million units of alpha-IFN daily were compared to untreated historical controls. From 104 PML cases reviewed, 77 met the defined criteria for PML. Twenty-one patients had received open-label alpha-IFN treatment in a non-randomized manner for at least 3 weeks, and 32 met criteria for inclusion in the untreated group as historical controls. Deceased treated patients were comparable to deceased untreated patients with respect to age, gender, race, HIV risk factors, AIDS-defining illnesses, and CD4+ counts. CD4+ counts and use of anti-retroviral medications within 6 months of PML onset were higher among those who were living at the time of the study. RESULTS: Among deceased patients, median survival of treated patients was 127.5 days longer than that of untreated patients (Chi-square=4.21, P=0.04). When living and deceased treated patients were combined, the median survival was 325 days (range 35 - 1634) versus 121 days (range 46 - 176) in untreated patients (Chi-square=13.47, P < 0.001). When survival times in untreated patients were left-censored to account for possible survivorship bias in treated patients, survival in treated patients remained significantly prolonged (325 days versus 175.5 days, Chi-square=4.65, P=0.03). In addition, use of alpha-IFN was associated with a significant delay in the onset of memory loss (Chi-square=8.59, P < 0.01). Seven alpha-IFN treated patients showed sustained remissions of several months to over a year, with documented improvements in mental status, aphasia, dysarthria, dysphagia, paresis, and dyscoordination. Moreover, four IFN-treated patients had evidence of MRI lesion regression, although this was not always correlated with clinical remission. Four of 32 untreated patients also reported transient symptomatic improvements. CONCLUSION: This open-label study suggests that alpha-IFN may delay progression, palliate symptoms, and significantly prolong survival in HIV-associated PML, and we therefore suggest that a controlled clinical trial is warranted.

Sustained cognitive decline in HIV infection: relationship to CD4+ cell count, plasma viremia and p24 antigenemia.

To determine the clinical and virological correlates of neuropsychological test performance decline in HIV infection, we measured viral burden in blood in 272 HIV-seropositive men without dementia in the Baltimore arm of the Multicenter AIDS Cohort Study (MACS). These measures were then related to neuropsychological (NP) decline, defined as a decline relative to prior best performance of 2.0 standard deviations or more on one or more neuropsychological tests. A short battery of NP tests (Mini-Screen Battery) was administered to all 272 men. NP test performance decline was identified in 53/272 (19.5%) of participants on the Mini-Screen Battery. Follow-up NP data were available for 204 participants who had undergone the Mini-Screen. The frequency of sustained NP test performance decline was 7.8% for the Mini-Screen Battery. A lower CD4+ cell count was weakly associated with sustained NP test performance decline. After adjustment for CD4+ cell count, hemoglobin, body mass index, and presence of AIDS, none of the viral burden measures (p24 antigenemia, plasma viremia, quantitative culture) correlated with sustained NP test performance decline. We conclude that these measures of blood HIV viral burden are not markers for NP decline, but that a lower CD4+ cell count is.

The impact of neurologic disease on hospitalizations related to human immunodeficiency virus infection in Maryland, 1991-1992.

OBJECTIVES: To determine the impact of neurologic disease on length of stay and total hospital charges for hospitalizations related to human immunodeficiency virus (HIV) infection. DESIGN: Review of all HIV-related hospitalizations from all acute nonfederal hospitals in Maryland in 1991 and 1992. Neurologic status and HIV disease status were determined by codes from the International Classification of Diseases, Ninth Revision Clinical Modification, in an administrative database. Total hospital charges and length of stay were also included in this database. RESULTS: Of 12 128 HIV-related hospitalizations (6013 patients with the acquired immunodeficiency syndrome [AIDS], 308 HIV-seropositive patients with symptoms without AIDS, and 5807 HIV-seropositive patients without symptoms), neurologic disease occurred in 1013 (8.4%), predominantly in patients with AIDS. In all HIV-seropositive patients, those with primary neurologic disease had a long mean (+/- SD) length of stay (16.4 +/- 16.5 days vs 9.3 +/- 11.3 days; P < .001) and higher mean (+/- SD) total charges ($12,733 +/- $12,009 vs $8069 +/- $11,247; P < .001) than those without neurologic disease. In patients with AIDS, those with primary neurologic disease also had a longer mean (+/- SD) length of stay (17.2 +/- 17.2 days vs 11.7 +/- 12.7 days; P < .001) and higher mean (+/- SD) total charges ($13,430 +/- $12,470 vs $10,794 +/- $13,537; P < .001) than those without neurologic disease. After adjustment for age, sex, race, and stage of HIV infection in all HIV-seropositive patients, our results indicated that neurologic disease increased the length of stay by 3.3 days (95% confidence interval [CI], 2.9-3.8) and total charges by $2552 (95% CI, $2111-$2993). After adjustment for age, sex, and race in discharged patients with AIDS, the results showed that neurologic disease increased length of stay by 2.24 days (95% CI, 0.73-3.77) and total charges by $1512 (95% CI, $40-$2894). CONCLUSION: Neurologic disease increases the length of stay and total hospital charges of HIV-infected patients.