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HIV-infected patients are at increased risk of neurological disease. The most common symptom is an altered mental status, depicted by the progressive chronic stages of AIDS Dementia Complex. The ability to recognize this syndrome so as to be able to refer for evaluation is a key factor in the optometrist's role as primary care provider.
Using infrared oculography, we recorded the eye movements in a group of patients with acquired immunodeficiency syndrome (AIDS), with or without the AIDS dementia complex (ADC). Our aim was to determine whether the severity of dementia could be correlated with abnormalities of eye movement and whether eye movement abnormalities could be detected prior to the onset of clinical dementia. Abnormalities of eye movement were present in seven of seven patients with mild, moderate, or severe ADC and in six of seven AIDS or asymptomatic human immunodeficiency virus-seropositive patients without clinical dementia, but at risk for ADC. The eye movement abnormalities detected included disturbances of both saccadic and smooth-pursuit function, and their severity correlated strongly with the severity of dementia. The abnormalities were qualitatively similar to those that occur in Alzheimer's disease but quantitatively less severe. Recording of eye movements may be a valuable, noninvasive technique for the early detection of neurologic dysfunction in asymptomatic patients who are seropositive for human immunodeficiency virus or in patients with AIDS, even prior to other clinical evidence of ADC. In particular, it may be of use in selecting high-risk patients requiring antiviral therapy and in monitoring the neurologic response to such treatment.
The authors review the cases of 40 patients with AIDS who died in 1989, in order to establish the relationships between clinical picture, neuroradiological features and neuropathological findings. Neurological involvement was present in over 75% of the patients, with HIV-related encephalopathy and toxoplasmosis as the most frequent diseases (52.5% and 20.0%). With regard to the cases of AIDS dementia complex (ADC) the authors observed a good correlation between the severity of the clinical manifestations, central nervous system atrophy as observed on computed tomography scan and pathological findings. The survival of AIDS patients with ADC was higher when compared to patients without ADC, suggesting the time-relationship of ADC. AS in the case of toxoplasma encephalitis, a strong relationship between radiological and pathological findings was observed. The presence of toxoplasma encephalitis in patients with radiologic features of healed lesions confirms the need for life-long prophylaxis.
Human immunodeficiency virus type I (HIV), the etiology of AIDS is also the cause of a primary infection of the central nervous system. The AIDS Dementia Complex is a common and important cause of morbidity in patients in advanced stages of infection. Subacute encephalitis demonstrating, the neuropathogenicity of HIV 1 constitute an human model for slow virus encephalitis.
To examine the neuropsychiatric effects of infection with HIV, 220 drug users (27 HIV negative, 193 HIV positive) completed tests evaluating premorbid intelligence, memory, non-verbal performance, information processing speed, and mood. When these measures were compared cross-sectionally by the severity of HIV illness, symptomatic patients (in CDC stage IV) were impaired on Trails B, two-choice decision time, delayed recall of the Wechsler Logical Memory Test and most components of the Auditory Verbal Learning Test. These findings imply reduced capacity for concentration, speed of thought and memory. When 101 patients were retested a mean of 16 months after their initial assessment, performance on Trails A and B, Block Design and delayed recall of the Wechsler Logical Memory Test deteriorated more for patients at, or progressing within, CDC stage IV, than performance of patients at stage III. The results broadly correspond to the cross-sectional findings. However, there was a decline in all tests of memory function for the sample independent of clinical staging. This may be evidence of brain involvement before the appearance of other symptoms. Self-rated measures of mood did not change cross-sectionally, progressively, or interactively with time and stage of HIV illness, and cannot account for the changes in cognitive function observed. Change in drug use, similarly, does not account for the cognitive findings. Four (5%) of the retested subjects developed AIDS dementia complex, but most of the performance and memory impairments seen were subclinical despite the destructive neuropathology presumed to underlie intellectual decline in patients with HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3-hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease, raising the possibility that interference with their actions or synthesis could lead to new forms of pharmacotherapy for these conditions.
OBJECTIVE: To determine whether or not soluble factors produced by peripheral blood mononuclear cells (PBMC) can predict AIDS dementia. DESIGN AND METHODS: PBMC were isolated from individuals with and without AIDS dementia complex (ADC) to determine if the levels of cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL)-6, or the production of a neurotoxic substance, were significantly different. PBMC were studied after determining that the numbers of monocyte-derived macrophages isolated by adherence were highly variable from patients with ADC compared with individuals without ADC. We prospectively studied 16 AIDS dementia patients, 13 healthy HIV-seropositive individuals, and eight sero-negative controls. Supernatants from PBMC were assayed for TNF-alpha, IL-6 and alone for neurotoxicity on human neural cells in vitro. RESULTS: We observed a trend towards worse cognitive and motor performance in patients suffering from ADC but who had no opportunistic infections ('pure dementia'; n = 8). Levels of PBMC IL-6 were significantly higher in 'pure dementia' patients. There was a trend towards lower levels of PBMC TNF-alpha in the group of patients who had both dementia and opportunistic infections compared with "pure dementia' patients. Supernatant from PBMC of ADC patients was significantly more neurotoxic than that from healthy HIV-seropositive individuals. CONCLUSIONS: Macrophage isolation from PBMC of patients with ADC was altered. Soluble factors produced from PBMC were significantly more neurotoxic than soluble factors from PBMC of healthy HIV-seropositive individuals. PBMC production of TNF-alpha and IL-6 was not a significant predictor of ADC.
The neurologic disease most frequently seen during acquired immunodeficiency syndrome (AIDS) is AIDS dementia complex (ADC) or HIV encephalopathy, which is a direct consequence of HIV-1 infection of the central nervous system (CNS). A limited expression of HIV-1 in CNS and peripheral nervous system (PNS) tissue of AIDS patients in contrast to widespread functional and pathologic abnormalities suggests indirect or immunopathogenetic mechanisms of ADC and HIV-1-associated predominantly sensory neuropathy. Proposed mechanisms include injury of oligodendrocytes by tumor necrosis factor-alpha (TNF-alpha) released from macrophages, calcium dependent excitoneurotoxicity induced by gp120 HIV-1 envelope protein, N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity by quinolinic acid, cell injury by HIV-1-specific cytotoxic T cells, and apoptosis of oligodendrocytes or neurons. The amplification of cellular activation by cytokine network and cell-to-cell contact between activated macrophages and neural cells by upregulation of adhesion molecules dramatically enhance toxic effect of macrophage products.
The early manifestation of HIV infection of the brain, HIV encephalitis, is due to the invasion of HIV infected mono- and multinuclear macrophages into the brain tissue and cerebrospinal fluid. These cells are intensely PAS reactive, auto-fluorescent and express the macrophage antigen CD68. They clearly prefer the white matter of cerebral hemispheres, corpus callosum and internal capsule. Lymphocytic infiltrates and microglial nodules are additional, unspecific changes. HIV encephalopathy following HIV encephalitis is patho-anatomically characterized by brain tissue damage. Its clinical correlate is so-called AIDS dementia complex. It presumably is caused by neurocytotoxic and myelinotoxic factors released by activated macrophages and/or by shedding HIV retrovirus proteins. HIV encephalopathy includes leukoencephalopathy, diffuse poliodystrophy, disseminated basal ganglia damage and brain atrophy. In some cases, granulomatous angiitis may occur.
We report five cases of psychosis in patients with antibody to human immunodeficiency virus. All patients was man and intravenous drug abuser. The age range was 22 from 31 years with a mean of 25 years. In all cases acute schizophrenia was the first clinical picture of the HIV. Four patients had opportunistic infections and AIDS-Dementia Complex months later. If there is a genuine biological association between HIV carriage and schizophrenia illness, then HIV infection should be considered in the differential diagnosis of such an illness.
A majority of human immunodeficiency virus type I (HIV-1)-infected-individuals manifest a plethora of central nervous system (CNS) diseases unrelated to opportunistic infections, including acquired immune deficiency syndrome (AIDS)-dementia complex (ADC), encephalitis, and various other disorders of the CNS. A series of devastating clinical conditions in the CNS of certain HIV-1-infected-individuals may be caused by infection of cells in the brain parenchyma. ADC is characterized by cognitive dysfunction, motor difficulties, coordination abnormalities and other neurological signs and symptoms, which develop in many HIV-1-infected-individuals. The precise molecular mechanisms leading to AIDS dementia remain incompletely explained. Various mechanisms including cytokine dysregulation, toxic effects of viral proteins and release of certain toxic substances from macrophages, especially nitric oxide, have been implicated as pathogenic mediators in the development of ADC. We have examined post mortem CNS tissues collected from 22 patients, previously diagnosed with AIDS, to explore if nitric oxide is responsible for the observed pathology in ADC. As controls, we utilized tissues collected from the brains of patients who expired without AIDS or other CNS pathologies. In addition, we also utilized post-mortem brain tissues from eight patients who were diagnosed with multiple sclerosis (MS) and were found to express inducible nitric oxide synthase (iNOS) in our previous studies, as positive controls. Highly sensitive in situ reverse transcriptase-initiated polymerase chain reaction (RT-IS-PCR) studies demonstrated that iNOS mRNA was present in the CNS tissues from all the positive MS controls, but were absent in all 22 specimens from AIDS patients, as well as in the brain tissues from normal controls. We have also analyzed the tissues for the presence of the NO reaction product, nitrotyrosine, to evaluate the presence of a protein nitrosalation adduct. Nitrotyrosine was not demonstrable in any of the AIDS brains. These findings indicate that iNOS may not play a significant role in the neuropathogenesis of most cases of ADC.
The aim of this study is to evaluate the usefulness of different markers to diagnose neurologic and psychiatric diseases due to HIV-1 infection Increased concentration of quinolenic acid has been implicated in the neurologic deficits and brain atrophy that may accompany infection with the HIV-1 virus. CFS concentrations of quinolenic acid have been implicated in the pathogenesis of the AIDS dementia complex. Cytokines liberation are very altered and this factor may be correlated with direct toxicity about central nervous system cells. Also are increased the values of neopterin. In the different stages of AIDS, the highest values are obtained in dementia complex. Neopterin, tryptofan and kinorenina, in blood and CFS are directly correlated with neurologic and psychiatry sintomatology. The highest values of soluble intercellular adhesion molecule 1 are found in HIV encephalopathy As well as are important the values, in CSF and blood of beta-2-M, Ag HIV, Ac41, tumor necrosis factor-alpha in the neurologic disease in HIV-1 infection
UNLABELLED: Measurements of cerebrospinal fluid (CSF) concentrations of gangliosides can be used as markers of central nervous system (CNS) neuronal involvement. We have analysed the CSF concentrations of the four major brain gangliosides GM1, GD1a, GD1b, and GT1b at different stages of HIV-1 infection. CSF samples were collected from 44 HIV-1-infected patients and from 24 HIV-negative, healthy controls. A significantly higher mean CSF concentration of the ganglioside GM1 was found in HIV-1-infected patients than in HIV-negative controls (27 and 19 nmol/l, respectively, P<0.01). The HIV-infected patients also had a higher mean GM1 proportion of the total ganglioside concentration (11% compared with 8.5%, P < 0.01). Nine out of 27 patients with asymptomatic HIV-1 infection, three of ten with AIDS without neurological complications, and three of seven with AIDS dementia complex had CSF GM1 concentrations above the mean+2SD in the HIV-negative control group. CONCLUSION: Biochemical signs of ongoing neuronal involvement could be found in about one third of HIV-1-infected patients. The same frequency was found regardless of stage, although the highest levels of CSF gangliosides were found in patients with AIDS.
A clinical evaluation of visual and central oculomotor defects are presented in a series of 56 patients who were HIV carriers, of whom 47 fulfilled criteria for AIDS. Changes were detected in 22% of the asymptomatic patients (2/9), in 36% of the AIDS patients with no neurological complications and in 93% (15/16) of the AIDS patients with neurological involvement. Some changes were seen in 55% of the patients with AIDS. The commonest defects were alterations of saccadic movements and visual pursuit (35% respectively) and of opticokinetic nystagmus (28%). Only one homonymous visual defect was found. No brain stem syndromes were seen, except for one case of bilateral internuclear ophthalmoplegia. The commonest neurological complications were toxoplasmosis, the AIDS dementia complex (ADC) and multifocal leukoencephalopathy (MLP). Neuro-ophthalmological changes are described, in the literature, in 2-12%. Central oculomotor disorders, including supranuclear, nuclear and internuclear ophthalmoplegias are frequent and probably underestimated. Nystagmus is a common sign and there are isolated descriptions of flutter, opsoclonus and ocular dipping. The causes of visual and oculomotor changes reflect the incidence of parenchymatous neurological complications of AIDS. MLP is the commonest cause of change in the retrogeniculate optic pathways. Oculographic studies show changes in saccadic movements and ocular pursuit and signs of unstable visual fixation. These changes are seen in all ADC patients, in a large proportion of those without dementia and also in asymptomatic carriers, suggesting that oculography may be useful for prognosis.
The neuronal loss often described at post-mortem in the brain neocortex of patients suffering from AIDS has been proposed to be responsible for the development of the AIDS dementia complex. Neuroinvasive strains of the HIV virus infect macrophages, microglial cells, and multinucleated giant cells, but not neurones. Processing of the virus by cells of the myelomonocytic lineage yields viral products known to initiate a complex network of events that may lead to the death of neurones and to the development of AIDS-associated neurological syndrome. The HIV-1 coat protein gp120, in particular, has been proposed as a likely etiologic agent of the described neuronal loss because it causes the death of neurones in culture. More recently, it has been shown that brain cortical cell death caused in rats by intracerebroventricular injection of gp120 occurs via apoptosis. This observation broadens our knowledge of the pathophysiology of the reported neuronal cell loss and opens a new avenue of experimental research for the development of novel therapeutic strategies for the treatment of patients suffering from AIDS-associated neurological syndrome.
(1) We evaluated efficacy of several treatments for HTLV-I-associated myelopathy (HAM) on the basis of our study on 254 HAM patients and of literature review. Improvement of motor disability more than fair response was obtained as follows: 82% in prednisolone, 69% in interferon-alpha, 92% in fosfomycin, 82% in high-dose vitamin C, 72% in blood purification therapy, 70% in heparin, 59% in salazosulfapyridine, 56% in thyrotropin-releasing hormone, 55% in erythromycin, 50% in mizoribine. (2) In the absence of clear guideline, the efficacy of zidovudine in the AIDS dementia complex has been demonstrated. There are also efficacy of amytriptylinein controlling HIV headache, corticosteroid in mononeuritis multiple and inflammatory myositis, hydrocortisone in autonomic neuropathy and plasmapheresis in distal sensory neuropathy respectively. Otherwise, it is emphasized that ddI, ddC and d4T have peripheral neuropathy as major, dose related side effect.
Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) causes AIDS dementia complex (ADC) in certain infected individuals. Recent studies have suggested that patients with ADC have an increased incidence of neuronal apoptosis leading to neuronal dropout. Of note, a higher level of the HIV-1 accessory protein Vpr has been detected in the cerebrospinal fluid of AIDS patients with neurological disorders. Moreover, extracellular Vpr has been shown to form ion channels, leading to cell death of cultured rat hippocampal neurons. Based on these previous findings, we first investigated the apoptotic effects of the HIV-1 Vpr protein on the human neuronal precursor NT2 cell line at a range of concentrations. These studies demonstrated that apoptosis induced by both Vpr and the envelope glycoprotein, gp120, occurred in a dose-dependent manner compared to protein treatment with HIV-1 integrase, maltose binding protein (MBP), and MBP-Vpr in the undifferentiated NT2 cells. For mature, differentiated neurons, apoptosis was also induced in a dose-dependent manner by both Vpr and gp120 at concentrations ranging from 1 to 100 ng/ml, as demonstrated by both the terminal deoxynucleotidyltransferase (Tdt)-mediated dUTP-biotin nick end labeling and Annexin V assays for apoptotic cell death. In order to clarify the intracellular pathways and molecular mechanisms involved in Vpr- and gp120-induced apoptosis in the NT2 cell line and differentiated mature human neurons, we then examined the cellular lysates for caspase-8 activity in these studies. Vpr and gp120 treatments exhibited a potent increase in activation of caspase-8 in both mature neurons and undifferentiated NT2 cells. This suggests that Vpr may be exerting selective cytotoxicity in a neuronal precursor cell line and in mature human neurons through the activation of caspase-8. These data represent a characterization of Vpr-induced apoptosis in human neuronal cells, and suggest that extracellular Vpr, along with other lentiviral proteins, may increase neuronal apoptosis in the CNS. Also, identification of the intracellular activation of caspase-8 in Vpr-induced apoptosis of human neuronal cells may lead to therapeutic approaches which can be used to combat HIV-1-induced neuronal apoptosis in AIDS patients with ADC.
To evaluate the potential role of the uPAR/uPA/PAI-1 system in HIV-induced blood-brain-barrier (BBB) disruption, CSF uPA-dependent plasminogen activation (PdPA) was analyzed by casein zymography, and CSF protein levels of all three molecules were measured by ELISA. CSF uPAR, but not uPA, PAI-1, or PdPA levels was significantly increased in neurologically compromised HIV+ patients. Only individual patients with severe AIDS dementia complex had increased levels of uPA (but not PAI-1) which fell upon initiation of antiretroviral therapy. The levels of all three molecules did not correlate with the CSF to serum albumin ratio suggesting not an important role in HIV-induced BBB disruption.