AIDS dementia

For the geriatrician who commonly evaluates cognitive and psychiatric disorders in the elderly, the neurologic consequences of infection with the human immunodeficiency virus (HIV) are of particular importance. The most frequent neurologic disease is the AIDS dementia complex characterized by cognitive, behavioral, and motor changes, occurring in two-thirds of AIDS patients. The pathophysiology of central nervous system HIV infection has been advanced with important implications for both the diagnosis and the potential treatment of this devastating disease.     

Neurologic disorders associated with AIDS retroviral infection

Neurologic disease occurs frequently in patients infected with the human immunodeficiency virus (HIV), and a large body of literature now exists detailing the various infections, neoplasms, and other conditions that can affect the central nervous system (CNS) or the peripheral nervous system in children and adults with AIDS, persistent generalized lymphadenopathy, or (in some cases) only serologic evidence of retroviral infection. Although certain opportunistic infections (toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and herpesviral infections) and CNS lymphomas often produce CNS disease in patients with AIDS, it is now clear that many cases of neurologic disease are caused by a group of disorders thought to be related to direct CNS infection by the AIDS retrovirus. Disease of the peripheral nervous system is also being increasingly recognized; some cases probably have an autoimmune basis.     

Subclinical central nervous system infection with JC virus in patients with AIDS.

Immunocompromised patients, particularly those with AIDS, develop progressive multifocal leukoencephalopathy (PML) due to central nervous system infection with JC virus (JCV). It is unknown whether JCV infection in the central nervous system can occur in the absence of PML symptoms. To address this question, autopsy specimens from patients with AIDS were examined. The brains of a group of patients without AIDS or central nervous system disease were also examined. JCV DNA was detected by the polymerase chain reaction in brain tissue from 4 (31%) of 13 human immunodeficiency virus (HIV)-positive patients. JCV was also detected in 1 elderly HIV-negative patient but not in the 11 other control brains. JCV was not detected in 22 myocardial specimens obtained at autopsy from HIV-negative patients nor 10 peripheral blood specimens from HIV-positive patients. The presence of JCV in brains of patients without clinically evident PML suggests that JCV may be present in the central nervous system without clinical disease.     

Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients.

Dysfunction of the central nervous system (CNS) is a prominent feature of the acquired immune deficiency syndrome (AIDS). Many of these patients have a subacute encephalitis consistent with a viral infection of the CNS. We studied the brains of 12 AIDS patients using in situ hybridization to identify human immunodeficiency virus [HIV, referred to by others as human T-cell lymphotropic virus type III (HTLV-III), lymphadenopathy-associated virus (LAV), AIDS-associated retrovirus (ARV)] nucleic acid sequences and immunocytochemistry to identify viral and cellular proteins. Nine patients had significant HIV infection in the CNS. In all examined brains, the white matter was more severely involved than the grey matter. In most cases the infection was restricted to capillary endothelial cells, mononuclear inflammatory cells, and giant cells. In a single case with severe CNS involvement, a low-level infection was seen in some astrocytes and neurons. These results suggest that CNS dysfunction is due to indirect effects rather than neuronal or glial infection.     

Central nervous system involvement in HIV infection

Central nervous system (CNS) involvement occurs frequently in patients with the acquired immunodeficiency syndrome (AIDS), but at present only a few reports have addressed the analysis of intrathecal IgG synthesis in human immunodeficiency virus (HIV)-seropositive patients with no signs of HIV-related neurologic syndromes. In this study, intrathecal IgG synthesis was investigated using several techniques in patients with different stages of HIV infection and then correlated with the state of the blood-brain barrier. Almost all patients had specific anti-HIV IgG synthesis within the CNS, suggesting the presence of HIV in the brain. These findings further stress that direct CNS infection occurs early in the course of systemic virus spread.     

Intra-blood-brain barrier synthesis of human immunodeficiency virus antigen and antibody in humans and chimpanzees.

The presence of human immunodeficiency virus (HIV) antigens in cerebrospinal fluid (CSF) was associated with progressive encephalopathy in adult and pediatric patients with acquired immunodeficiency syndrome (AIDS). HIV antigen was detected in CSF from 6 of 7 AIDS patients with progressive encephalopathy. By contrast, HIV antigen, whether free or complexed, was detected in CSF from only 1 of 18 HIV antibody seropositive patients without progressive encephalopathy and from 0 of 8 experimentally infected chimpanzees without clinical signs. Intra-blood-brain barrier synthesis of HIV-specific antibody was demonstrated in the majority of patients with AIDS (9/12) or at risk for AIDS (8/13) as well as in the experimentally infected chimpanzees, indicating HIV-specific B-cell reactivity in the brain without apparent neurological signs. In 6 of 11 patients with HIV infection, antibodies synthesized in the central nervous system were directed against HIV envelope proteins. Active viral expression appears to be necessary for both the immunodeficiency and progressive encephalopathy associated with HIV infection.     

Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid

Infectious human immunodeficiency virus (HIV) was recovered from 30 of 48 cerebrospinal fluid specimens from seropositive persons with and without neurologic symptoms or disease. Of 16 patients with only neurologic problems or other HIV-related conditions, but not the acquired immunodeficiency syndrome (AIDS), 11 had virus recovered; over half of those with AIDS also had virus isolated. Patients with headache or altered mental status had the highest recovery rate of HIV from cerebrospinal fluid. Although virus was primarily found in patients with detectable neurologic disease, it was also isolated from 5 of 8 patients with normal neurologic examinations. Two of these patients had fever alone. The presence of virus in cerebrospinal fluid did not necessarily correlate with isolation of virus from the serum. These findings suggest that HIV may at times replicate preferentially in the brain and that its presence may not immediately cause neurologic signs or symptoms.     

Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism.

Neuropathologic studies of AIDS patients have shown that brain capillary endothelial cells are a cellular target for human immunodeficiency virus (HIV) in vivo. We have established in vitro cultures of primary human brain capillary endothelial (HBCE) cells. Using this model system, we have shown a significant HIV infection of HBCE cells that is productive yet noncytopathic. The infection is mediated by a cellular interaction with gp120 that does not involve CD4 or galactosylceramide. HIV infection of HBCE cells may contribute to AIDS-associated neuropathology by disturbing the physiology of the endothelium and directly or indirectly facilitating dissemination of virus to the central nervous system.     

Intrathecal production of antibodies against Toxoplasma gondii in patients with toxoplasmic encephalitis and the acquired immunodeficiency syndrome (AIDS)

We attempted to determine whether patients with the acquired immunodeficiency syndrome (AIDS) and toxoplasmic encephalitis produce Toxoplasma antibodies in the central nervous system, and whether these antibodies would be useful for diagnosing toxoplasmic encephalitis. Thirty-seven patients with AIDS and toxoplasmic encephalitis and 11 patients with AIDS alone were studied. All patients had serum IgG but not IgM Toxoplasma antibodies. Twenty-three of the patients with AIDS and toxoplasmic encephalitis had Toxoplasma antibody in cerebrospinal fluid compared to none of the patients with AIDS alone. Of the patients with AIDS alone who had serum antibodies to T. gondii, none had Toxoplasma antibodies in cerebrospinal fluid. Production of antibodies in the central nervous system was seen in 11 of 16 patients with AIDS and toxoplasmic encephalitis but not in 4 patients in the control group who only had Toxoplasma antibody in their cerebrospinal fluid. These results suggest that production of T. gondii antibodies in the central nervous system may be diagnostic of toxoplasmic encephalitis.     

Evidence for early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS) and other human immunodeficiency virus (HIV) infections. Studies with neuropsychologic testing and magnetic resonance imaging

Although a high prevalence of central nervous system disease is seen in persons with the acquired immunodeficiency syndrome (AIDS), the natural history of brain involvement with human immunodeficiency virus (HIV) remains poorly understood. Neuropsychologic evaluations of 55 ambulatory homosexual men revealed abnormalities in 13 of 15 with AIDS, 7 of 13 [corrected] with AIDS-related complex, 7 of 16 [corrected] with HIV-seropositivity only, and 1 of 11 with HIV-seronegativity. Common neuropsychologic problems included impaired abstracting ability, learning difficulties, and slowed speed of information processing. Magnetic resonance imaging had abnormal findings in 9 of 13 patients with AIDS and 5 of 10 patients with AIDS-related complex who were available for scans. The commonest abnormalities were sulcal and ventricular enlargement and bilateral patchy areas of high signal intensity in the white matter. We postulate that central nervous system involvement by HIV may begin early in the course of AIDS and cause mild cognitive deficits in otherwise asymptomatic persons.     

Toxoplasmic encephalitis in AIDS.

Involvement of the central nervous system (CNS) is common in patients with advanced disease due to human immunodeficiency virus (HIV). Symptoms range from lethargy and apathy to coma, incoordination and ataxia to hemiparesis, loss of memory to severe dementia, and focal to major motor seizures. Involvement may be closely associated with HIV infection per se, as in the AIDS dementia complex, but is frequently caused by opportunistic pathogens such as Toxoplasma gondii and Cryptococcus neoformans or malignancies such as primary lymphoma of the CNS. The clinical presentations of attendant and direct CNS involvement are remarkably non-specific and overlapping, yet a correct diagnosis is critical to successful intervention. Toxoplasmic encephalitis is one of the most common and most treatable causes of AIDS-associated pathology of the CNS. A great deal has been learned in the last 10 years about its unique presentation in the HIV-infected patient with advanced disease. Drs. Benjamin J. Luft of the State University of New York at Stony Brook and Jack S. Remington of the Stanford University School of Medicine and Palo Alto Medical Foundation's Research Institute have studied T. gondii for many years and are two of the leading experts in the field. This commentary comprises an update of their initial review (J Infect Dis 1988;157:1-6) and a presentation of the current approaches to diagnosing and managing toxoplasmic encephalitis in HIV-infected patients.     

HIV isolation from cerebrospinal fluid in relation to immunological deficiency and neurological symptoms

Human immunodeficiency virus (HIV) could be isolated from the cerebrospinal fluid (CSF) of the majority (62%) of 72 patients in various stages of HIV infection. This high rate of successful virus isolation was achieved only when the time from lumbar puncture to initiation of the cell cultures was short, i.e. not exceeding 5 h. The HIV isolation rates were equally high in patients with persistent generalized lymphadenopathy (PGL), AIDS-related complex (ARC) and AIDS. Although the HIV recovery rate was low in patients with normal immunological parameters it was not correlated with the degree of severity of the immunodeficiency in the other patients. Furthermore, the recovery rates were not significantly correlated to the duration of the infection. HIV was recovered as often from patients with neurological symptoms as from patients without such symptoms. These findings suggest that in the majority of patients there is central nervous system (CNS) involvement early in the course of HIV infection and that HIV replication in the CNS may occur in the absence of a pronounced systemic cellular immunodeficiency and frequently without causing overt neurological symptoms.     

Neurologic manifestations of AIDS

An understanding of the biologic characteristics and cellular tropism of human immunodeficiency virus (HIV) is critical to appreciate the diverse neurologic manifestations of HIV infection in patients with the acquired immunodeficiency syndrome (AIDS). Only carefully designed prospective studies can provide information regarding prevalence, incidence, and natural history of the full spectrum of neurologic complications of HIV infection. A degree of tropism for monocyte/macrophages and possibly for cells within the CNS seems certain. One of the most frequent complications is AIDS-related dementia, which reflects central nervous system invasion by HIV. Despite the evidence linking unchecked viral replication within the brain and progressive dementia, the basic pathogenetic mechanisms remain obscure. Further characterization of the cellular targets of HIV within the brain, and the mechanisms which ultimately lead to the dementia, is critical. The demonstration that HIV enters the central nervous system during the earliest stages of infection has major implications for antiviral agents which must penetrate brain parenchyma to clear the virus effectively. Other neurologic complications occur frequently, including myelopathies, peripheral neuropathies, opportunistic CNS infections, and CNS neoplasms. Many of these disorders are novel and incompletely characterized and their etiology is uncertain. While treatment is available for several of these conditions, it is generally not curative, and is often poorly tolerated because of adverse effects. Research directions will focus on better understanding of pathogenetic mechanisms, on earlier and more precise detection of these diverse conditions, and on improved therapeutic agents. For the future, efforts toward the development of a safe, effective vaccine are of critical importance. There are, however, already up to 2 million individuals in the United States who are already infected with HIV and who are thus at risk for developing 1 or several of these neurologic complications. Vaccination, even if it were available now, is not likely to benefit these individuals. While it is hoped that only a fraction of this infected population will develop neurologic symptoms, the prospects of an epidemic of AIDS-related dementia are ominous, particularly as antiviral therapy alone is unlikely to either eradicate the virus or restore brain function. In Africa and worldwide the numbers at risk for HIV-related diseases are enormous, and the risk factors for transmission of HIV less well defined. There, economic and medical resources are less than adequate to deal with a problem of this magnitude.     

Is age a negative prognostic indicator in HIV infection or AIDS?

To better understand disease progression in older persons with human immunodeficiency virus (HIV infection or acquired immunodeficiency syndrome (AIDS), we studied patients aged 50 years and older hospitalized with a diagnosis of HIV infection or AIDS between January 1985 and October 1995. Data collected included demographics, opportunistic infections, comorbid disease, neurologic dysfunction, and antiretroviral therapy. A total of 86 patients with a mean age of 54.3 years was identified. Pneumocystis carinii pneumonia was the most frequent opportunistic infection (43%). Hypertension was the most common previous medical condition (38%). Other comorbid disease was present in less than 15% of the subjects. Fifty-seven patients (66%) had neurologic impairment, with 30 requiring treatment for delirium. In these 30, 23 (77%) had anemia, infection, or both. The median length of survival following the diagnosis of AIDS was 18.5 months, for HIV it was 48 months. The median survival following the diagnosis of AIDS in patients who received antiretroviral therapy was 22 months compared with 11 months for those who did not receive antiretroviral therapy (p < 0.0004). Multivariable analysis found that antiretroviral therapy was the only independent predictor of survival after the diagnosis of AIDS. In contrast to previous studies, the present findings suggest that older age may not necessarily be associated with more rapid disease progression and reduced survival times in persons with HIV infection or AIDS. In those patients with delirium, many may have readily treatable conditions (anemia and/or infection). The absence of significant comorbid disease and the access to antiretroviral therapy may be in part responsible for the longer survival times obtained in this cohort compared to that reported previously.     

Detection of human immunodeficiency virus type 2 in brain tissue.

Infection due to human immunodeficiency virus (HIV) type 2 is believed to cause a clinical picture similar to that of HIV-1, although extensive data are not available. In 2 patients with West African exposure and neurologic symptoms, HIV-2 was detected in the central nervous system using DNA and RNA polymerase chain reaction, in situ hybridization, and immunohistology. In the first patient, the neurologic disease was most likely due to productive infection with HIV-2. In the second, a combination of neuropathologic abnormalities (including the presence of HIV-2) explained the clinical features. Thus HIV-2, like HIV-1, can be readily detected in brain tissue in patients with neurologic abnormalities, although the exact role of HIV-2 in pathogenesis of AIDS-associated neurologic disease requires further study.     

Leg weakness in a lung transplant patient

Progressive multifocal leukoencephalopathy (PML) is associated with JC polyomavirus (JCV) infection of central nervous system oligodendrocytes resulting in demyelinization and progressive focal neurologic deficits. Reactivation of dormant JCV occurs in the setting of immunosuppression, most commonly in patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) or hematological malignancies. PML has also been reported in solid organ transplant recipients. We report the case of a 61‐year‐old man after bilateral lung transplantation for chronic hypersensitivity pneumonitis who presented with leg weakness, cognitive decline, and expressive aphasia at 5 months post transplantation. Magnetic resonance imaging and brain biopsy were consistent with PML. Treatment attempt with cytarabine was unsuccessful, and immunomodulation resulted in recurrent grade A3 rejection. The difficulty of managing PML in lung transplant patients is highlighted by the lack of directed therapy and risk of graft rejection or failure with attempts at decreasing immunosuppression.     

Human immunodeficiency virus-associated progressive multifocal leukoencephalopathy: apparent response to 3'-azido-3'-deoxythymidine

We present the case of a 26-year-old human immunodeficiency virus-seropositive man who developed progressive multifocal leukoencephalopathy as the initial manifestation of AIDS. He appears to have responded dramatically to therapy with 3'-azido-3'-deoxythymidine (AZT). His neurologic status deteriorated shortly after an AZT dose reduction. He has stabilized since resuming his previous AZT dose. Although it remains unclear whether AZT is useful in the treatment of JC virus infection, we think that all AIDS patients with progressive multifocal leukoencephalopathy should be offered treatment with AZT, especially in light of recent reports describing a possible potentiation of human immunodeficiency virus infection of the central nervous system in this setting.     

Human immunodeficiency virus (HIV) infection in brains with AIDS-related leukoencephalopathy

In addition to central nervous system (CNS) opportunistic infections and neoplasms, patients with acquired immunodeficiency syndrome (AIDS) develop unexplained dementia and encephalopathy and degeneration of the white matter. We studied autopsied brains from 20 adult patients who expired from AIDS to determine the relationship of human immunodeficiency virus (HIV) infection to white matter lesions and to clinical findings. In four patients with dementia/encephalopathy and abnormalities of the white matter, there was evidence of HIV infection as shown by in situ hybridization. In contrast, the remaining 16 patients who had no evidence of white matter degeneration revealed no hybridization to the HIV probe. The cells infected with HIV included endothelial cells, perivascular macrophages/monocytes, and multinucleated giant cells and were found in or adjacent to white matter degeneration. These results demonstrate a correlation between HIV-infected cells and AIDS leukoencephalopathy and provide further evidence for HIV-related dementia/encephalopathy.     

HIV target cells: effect of their infection by HIV on the pathogenesis of AIDS

Pathogenesis of HIV infection and expression of retroviral proteins are gradually being elucidated. Antibody to HIV is a marker of past or present viral infection. The virus can be isolated from cultured lymphocytes of seropositive but not seronegative patients. Sero-epidemiological studies show that the majority of infected patients are asymptomatic carriers without biological sign of immune depression. Some then show immune abnormalities such as a decrease of CD4 cells in the blood; some patients present with lymphadenopathies or signs of AIDS-related complexes. Frank AIDS is a late stage of the disease. Some cofactors increase the immunodeficiency and then accelerate the passage from asymptomatic carrier to persistent generalized lymphadenopathies or AIDS by spreading the virus into target cells, susceptible T4 cells, bone marrow precursors, or brain. These AIDS patients then present with opportunistic infections and/or malignancies like Kaposi's sarcoma, lymphoma, and/or brain diseases (dementia or encephalitis).     

Isolated primary hepatic lymphoma in a patient with acquired immunodeficiency syndrome.

Non-Hodgkin lymphoma (NHL) of the B-cell type is the second most common neoplasm in patients with human immunodeficiency virus (HIV) infection after Kaposi sarcoma (KS). The majority of cases of NHL in patients with acquired immunodeficiency syndrome (AIDS) involve extranodal sites; most frequently the gastrointestinal tract (GIT) and the central nervous system (CNS). Hepatic NHL in patients with AIDS was first described by Reichert et al in 1983 in an autopsy series. It usually presents with multiple large hepatic masses and involvement of other abdominal organs or lymph nodes. The authors present a case of primary hepatic NHL in a patient with AIDS, presenting with innumerable small intrahepatic masses without the involvement of any other organs.