Mauricio Concha

Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare

Progressive multifocal leukoencephalopathy, a formerly rare disease that chiefly occurred in persons with underlying lymphoma and chronic lymphocytic leukemia, is now seen with increasing frequency in the era of acquired immunodeficiency syndrome. Progressive multifocal leukoencephalopathy is currently estimated to arise in 5% of all human immunodeficiency virus-infected individuals. The clinical features of the disorder in patients with acquired immunodeficiency syndrome do not appear to be significantly different from progressive multifocal leukoencephalopathy occurring in association with other immunosuppressive disorders. Radiographically, the appearance of HIV dementia on magnetic resonance imaging is sometimes confused with that of progressive multifocal leukoencephalopathy. Among the characteristics that are helpful in distinguishing between the two disorders are the presence of focal findings, the rate of disease progression, the specific magnetic resonance imaging attributes, including the location of the lesions, and certain cerebrospinal fluid parameters, including surrogate markers for human immunodeficiency virus dementia and the presence of myelin basic protein. The remarkable increase in the burden of progressive multifocal leukoencephalopathy has provided a vital impetus for its study, particularly with respect to diagnosis and therapy. Establishing an unequivocal diagnosis of progressive multifocal leukoencephalopathy currently requires brain biopsy. The application of polymerase chain reaction for JC virus amplification to cerebrospinal fluid samples suggests that it may provide an alternative means of diagnosis. Recent in vitro studies of cytosine arabinoside and camptothecin suggest that they, or similar agents, may prove useful in the treatment of this illness and well-designed clinical trials are underway.

Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality

Older individuals (>50 years of age) now comprise over 11% of patients with AIDS in the United States. This percentage is expected to continue to grow, due both to the improved longevity of patients prescribed highly active antiretroviral therapy (HAART) and to new infections among older individuals. This review focuses on the neuropsychiatric and neurological conditions that are most likely to be affected by advancing age-HIV-1-associated cognitive-motor disorder, peripheral neuropathy, progressive multifocal leukoencephalopathy, primary CNS lymphoma, and risk for cerebrovascular accident. Age associations with incidence of these disorders and with treatment foci are specified. Implications for future changes in management are discussed.

Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) affects about 1 in 20 individuals with the acquired immunodeficiency syndrome (AIDS) and has been associated with poor survival. This report describes the results of a phase II clinical trial using the drug topotecan, a semisynthetic analogue of camptothecan, administered to a cohort of subjects with AIDS-related PML. Data were evaluated on 11 of 12 subjects enrolled in the study. Three responded to therapy. Additionally, one patient was treated off-protocol and showed a response to treatment. Progression occurred after the first course; however, a partial response was noted after five courses. One study patient died from accidental overdose of topotecan. Overall, responders had higher pretreatment Karnofsky and lower Kurtzke expanded disability status scale scores than non-responders. The most frequent toxicities were hematologic (anemia, neutropenia, and thrombocytopenia). Five patients had dose delays; all delays were due to hematologic adverse events. This study demonstrates that topotecan treatment may be associated with decreased lesion size and prolonged survival from the infection. Because of the small number of subjects in the study, further studies are required to evaluate the efficacy of topotecan in treating this disease.

Detection of microemboli by transcranial Doppler ultrasonography in aneurysmal subarachnoid hemorrhage

OBJECTIVE To determine the frequency and characteristics of microembolic signals (MES) in subarachnoid hemorrhage (SAH). METHODS Twenty-three patients with aneurysmal SAH were monitored with transcranial Doppler ultrasonography for the presence of MES and vasospasm. Each middle cerebral artery was monitored for 30 minutes three times each week. Patients were excluded if they had traumatic SAH or cardiac or arterial sources of emboli. Monitoring was initiated 6.3 days (1–16 d) after SAH and lasted 6.6 days (1–13 d). Eleven individuals without SAH or other cerebrovascular diseases who were treated in the same unit served as control subjects. Each patient underwent monitoring of both middle cerebral arteries a mean of three times; therefore, 46 vessels were studied (a total of 138 observations). Control subjects underwent assessment of each middle cerebral artery once, for a total of 22 control vessels. RESULTS MES were detected for 16 of 23 patients (70%) and 44 of 138 patient vessels (32%) monitored, compared with 2 of 11 control subjects (18%) and 2 of 22 control vessels (9%) (P < 0.05). MES were observed for 83% of patients with clinical vasospasm and 54% of those without clinical vasospasm. Ultrasonographic vasospasm was observed for 71 of 138 vessels monitored; MES were observed for 28% of vessels with vasospasm and 36% of those without vasospasm. Aneurysms proximal to the monitored artery were identified in 38 of 138 vessels, of which 34% exhibited MES, which is similar to the frequency for vessels without proximal aneurysms (31%). Coiled, clipped, and unsecured aneurysms exhibited similar frequencies of MES. CONCLUSION MES were common in SAH, occurring in 70% of cases of SAH and one-third of all vessels monitored. Although MES were more frequent among patients with clinical vasospasm, this difference did not reach statistical significance. We were unable to demonstrate a relationship between ultrasonographic vasospasm and MES, and the presence of a proximal secured or unsecured aneurysm did not alter the chance of detection of MES. Further studies are required to determine the origin and clinical relevance of MES in SAH.

HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence for HIV-1-associated dementia

A definitive relation between HIV-1 load and the clinical diagnosis of HIV-1-associated dementia (HAD) has not yet been established. Knowledge of the neuroanatomic distribution of HIV-1 load in the brain of individuals with HAD and HIV-1 encephalitis may facilitate elucidation of this relation. Nine individuals with AIDS were analyzed postmortem by three independent methods with each assessment performed blinded to the others: 1) a neuropsychiatric review of clinical records for evidence of possible HAD, 2) HIV-1 DNA load determination by quantitative polymerase chain reaction (PCR) across several neuroanatomic regions, and 3) a pathologic examination for diagnosis of HIV-1 encephalitis by immunohistochemical techniques. Of eight AIDS cases with clinical records sufficient for neuropsychiatric review, seven were shown to have evidence for HAD. HIV-1 DNA was detected and quantified in specimens from all of the medial temporal lobe regions analyzed but was not detectable in the frontal lobe at the same level of sensitivity in two of these cases (<1 per 1000 cellular genomes). HIV-1 DNA load in the medial temporal lobe region was significantly larger than that in the frontal lobe. Only four of seven cases with evidence for HAD were also diagnosed with HIV-1 encephalitis.

Older age and plasma viral load in HIV-1 infection.

Background: The purpose of the study was to examine the relationship between age and plasma viral load in HIV-1-infected individuals. Design: The experimental method was to recruit older (> 50 years of age) and younger (18–39 years of age) HIV-1-infected individuals. The plasma viral load was measured using the Roche Molecular Systems UltraSensitive Roche HIV-1 Monitor test reflexively with the standard Amplicor HIV Monitor test to quantify viral load in the range of 50–750 000 copies of HIV-1 RNA/ml plasma. Subjects: A total of 135 HIV-1-seropositive individuals (at Centers for Disease Control and Prevention early symptomatic stage B or late symptomatic stage/AIDS C) were enrolled as part of a larger cohort also consisting of HIV-1-seronegative individuals. Results: A generalized linear models statistical analysis was conducted in order to evaluate age category as a predictor of plasma viral load. The result was a significant effect of age category, with older age associated with a lower plasma viral load. The association held controlling for antiretroviral therapy usage, disease stage, antiretroviral medication adherence, HIV-1 serostatus duration, alcohol and substance use, recent sexually transmitted disease, and sociodemographics (except income). Conclusion: Older age was associated with lower levels of HIV-1 replication in this sample, independent of antiretroviral therapy usage, regimen adherence, and disease stage. It is suggested that the effect may be caused by changes in viral evolution or immunological monitoring specific to older individuals with HIV-1 infection.

Cognitive functioning in younger and older HIV-1-infected adults.

Summary: In young adults, a major neurologic complication of HIV‐1 infection is cognitive motor impairment. Epidemiologic findings suggest that increasing age is a significant risk factor for HIV‐1‐associated dementia as the AIDS‐defining illness. Findings from the few studies that have directly measured cognition in younger and older HIV‐1‐infected adults, however, have been mixed, in part, because of small sample sizes and other methodologic differences between studies. The authors present preliminary findings on cognitive functioning in symptomatic HIV‐1‐infected younger (aged 20‐39 years) and older (aged 50 years or older) adults. Independent of age, HIV‐1 infection was accompanied by learning and memory retrieval deficits, which were significantly associated with high plasma viral loads in the young adults. Relative to the younger and older HIV‐1‐negative (HIV‐1‐) groups, only the younger HIV‐1positive (HIV‐1+)group had significantly longer reaction times (RTs). Within the older HIV‐1+ group, however, longer simple and choice RTs were significantly correlated with higher viral loads and lower CD4 cell counts. Although HIV‐1 infection affects cognition independent of age, longitudinal studies involving large numbers of older individuals are needed to determine whether there are age differences in the prevalence, nature, and severity of HIV‐1‐associated cognitive dysfunction.

Angular gyrus syndrome revisited: Acalculia, finger agnosia, right-left disorientation and semantic aphasia

Angular gyrus (Gerstmann) syndrome is classically described as finger agnosia, right-left disorientation, agraphia and acalculia in association to lesions in the left angular gyrus. Aphasia is not typically described as part of this syndrome. Here we report a 58 year old right-handed male, with an ischemic lesion to the left angular gyrus, who developed sudden loss of speech expression and comprehension, and slowly recovered over the following few weeks. After several months he showed significant improvement on his language skills with understanding logic-grammatical relationships, comparison adverbs (e.g. bigger-smaller, younger-older etc., place adverbs (e.g. over-below, on-beneath etc. and time adverbs (e.g. before-after). These language deficits are compatible with a semantic aphasia. Writing difficulties are minimal. In addition, he has important impairments in finger agnosia, right-left discrimination, and in understanding numbers, using numerical concepts, and performing arithmetical operations. We propose that left angular gyrus syndrome should be restated to include acalculia, finger agnosia, right left disorientation and semantic aphasia. A single underlying deficit can account for the simultaneous presentation of these four clinical signs. only mild word-finding difficulties, but with substantial difficulties in

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.