Neurologic Manifestations of HIV Infection

In the early 1980s, as the systemic manifestations of the acquired immunodeficiency syndrome (AIDS) were first described, investigators realized that human immunodeficiency virus (HIV) type 1 infection could affect the nervous system at every level [1-3]. Neurologic disorders associated with HIV infection include central nervous system infections, neoplasms, vascular complications, peripheral neuropathies, and myopathies (Table 1). In the past decade, basic and clinical research advances produced much new information. We review the clinical features, pathogenetic mechanisms, and treatment of neurologic disorders associated with HIV infection. Table 1. Major Neurologic Manifestations of HIV Infection HIV Dementia Clinical Features One of the most frequent and enigmatic neurologic complications of HIV infection is HIV dementia (also called AIDS dementia complex, subacute encephalitis, HIV encephalopathy, and HIV-1-associated cognitive/motor complex). The symptoms of HIV dementia can be subdivided into three main categories: cognitive, motor, and behavioral [4]. The primary cognitive symptom is forgetfulness associated with slowed mental and motor abilities. Loss of balance and leg weakness are early motor signs. The most commonly observed behavioral symptoms are apathy and social withdrawal, which are often mistakenly diagnosed as depression. Sometimes organic psychosis, such as acute mania, may be a primary manifestation of HIV dementia [5]. Early in the course of HIV dementia, symptoms and signs may be too subtle to establish a definitive clinical diagnosis. Neuropsychological tests are useful to show early cognitive dysfunction and to provide quantitative markers of disease progression [6-8]. As dementia advances, cognitive impairment becomes more obvious, with psychomotor retardation and marked behavioral abnormalities. By this time, objective neurologic signs such as paraparesis, incontinence, tremor, and seizures are more common. Sidtis and Price [9] developed a staging system for AIDS dementia complex that classifies patients from normal (grade 0) to end-stage vegetative state (grade 4). Grade 0.5 (subclinical dementia) comprises patients whose disease may be difficult to diagnose. These persons often have equivocal cognitive complaints, accompanied by relatively normal results of neurologic examinations. Because it is not clear if dementia will develop in patients at this early stage, clinical research trials generally have required that patients have objective neurologic impairment (that is, stage 1) for entry into studies of HIV dementia treatment [10]. In 1992, 7.3% of patients with AIDS in the Centers for Disease Control and Prevention (CDC) database were reported to have HIV dementia [11]. However, this Figure is probably an underestimate because CDC figures generally reflect the incidence of a disorder as the initial manifestation of AIDS, whereas dementia often occurs late in the course of HIV disease, following other AIDS-defining events [11]. The Multicenter AIDS Cohort Study found a prevalence of HIV dementia of 0.4% during the asymptomatic phase [12], whereas retrospective studies found HIV dementia during the late stages of HIV disease in 7.5% to 27% of patients [3, 13, 14]. McArthur and colleagues [15] reported a 7% annual incidence of HIV dementia during the first 2 years after AIDS diagnosis. The onset and progression of HIV dementia varies. Most commonly, dementia occurs late in HIV disease, when CD4 lymphocyte counts are less than 200 cells/mm3. Neurologic deficits usually progress insidiously, although rapid progression may occur. Some controversy exists about how early in HIV infection neuropsychological impairment occurs. Grant and colleagues [16] reported substantial neuropsychological impairment in a few otherwise asymptomatic persons with HIV infection. However, these results were not confirmed by the Multicenter AIDS Cohort Study [12], which found HIV dementia in fewer than 1% of asymptomatic persons with positive HIV serum test results and no significant difference in results of neurologic examinations and neuropsychological tests and brain-imaging abnormalities among persons who were seropositive early in the course of HIV disease and a seronegative matched control group. Although a comprehensive review of this complex subject is beyond the scope of this article, most investigators believe that severe neuropsychological impairment is rare in early HIV infection if other potential confounding factors (substance abuse, age, and education, for example) are excluded [17, 18]. Diagnostic Studies No laboratory or neuroimaging study results are specific for HIV dementia, which is a diagnosis of exclusion. Blood and cerebrospinal fluid studies are helpful to screen for systemic infections (that is, VDRL, cryptococcal antigen). Other cerebrospinal fluid abnormalities are frequently present and include elevated total protein, mild pleocytosis, increased total immunoglobulin fraction, intrathecal synthesis of anti-HIV IgG, and oligoclonal bands. However, similar cerebrospinal fluid abnormalities are also common in patients with HIV infection and no neurologic symptoms [19]. Once other potential causes of dementia are excluded, cerebrospinal fluid markers of immune activation, such as 2-microglobulin, neopterin, and quinolinate may be useful in diagnosing HIV dementia [20-23]. Radiologic studies are important to exclude other infectious or neoplastic processes, and they provide information supporting the diagnosis of HIV dementia. Neuroimaging studies generally show various amounts of cerebral atrophy, ventricular enlargement, and diffuse or multifocal white matter abnormalities Figure 1 [4, 24, 25]. Although these findings are nonspecific, several studies have shown a close correlation between the amount of cerebral atrophy on brain magnetic resonance imaging (MRI) scans and the severity of HIV dementia [26, 27]. However, other studies have not confirmed this association [14]. The clinical features of HIV dementia suggest predominantly subcortical disease [28], which is supported by neuroimaging [27] and morphometric [29] studies. Although multiple causes of cerebral atrophy are possible, Gelman [30] showed that an increased number of microglial cells in the cerebral cortex partially accounts for the ventricular expansion shown by computed tomographic scans. Figure 1. Left. Right. Neuropathologic Findings A spectrum of neuropathologic abnormalities has been described in persons with HIV dementia [31], including multinucleate giant cell and other inflammatory cell infiltration (HIV encephalitis), reactive gliosis, and diffuse white matter pallor (HIV leukoencephalopathy). A consensus conference determined that key components of the pathologic diagnosis of HIV encephalitis are multiple foci of microglia, macrophages, and multinucleate giant cells Figure 2 or the presence of HIV-infected cells in the central nervous system [32]. However, the pathologic changes in the brains of persons with HIV dementia are often less prominent than their clinical symptoms would predict. Even in patients with severe dementia, microglial nodules and nonspecific white matter pallor often are the only pathologic findings in the brain, without substantial multinucleate giant cell infiltration [31, 33]. Figure 2. HIV encephalitis. arrows Although white matter pallor has often been attributed to demyelination, another explanation is disease resulting from changes in the blood-brain barrier. Petito and Cash [34] described substantial extravasation of serum proteins in the brains of persons with HIV infection, regardless of whether HIV encephalitis was present. They suggested that cytokine-mediated alteration of the blood-brain barrier may contribute to viral entry into the brain, leading to the demyelination and gliosis observed in these patients. Power and associates [35] reported that patients with HIV dementia have considerable accumulation of serum proteins in the subcortical white matter glia and frontal cortical neurons compared with persons with HIV who have no dementia. Because evidence of primary demyelination was not found, the authors concluded that blood-brain barrier changes contribute to development of HIV dementia. Pathogenesis Identification of HIV as the pathogenetic agent in AIDS made this an obvious candidate as the cause of HIV dementia. Shaw and colleagues [36] initially identified human lymphotrophic virus type III (HIV-1) in the brains of persons with HIV dementia using DNA Southern blot and in situ hybridization. Masliah and coworkers [37] reported abundant HIV gp41 antigen with immunohistochemical techniques in autopsy specimens from the brains of two thirds of 107 persons with AIDS. The gp41 immune reactivity correlated with the loss of neocortical dendritic area and synapses. The polymerase chain reaction has been proposed as a powerful technique to identify HIV-1 DNA in the brain [38]. Using the polymerase chain reaction, Boni and associates [39] reported the presence of HIV-1 in the central nervous system of two thirds of 39 patients with AIDS, with a correlation between the viral DNA load and the presence of encephalopathy. The human immunodeficiency virus predominantly infects cells of the lymphoreticular system. Although HIV invasion of the central nervous system may occur soon after primary infection [19, 40], what mediates the passage of the virus into the brain is uncertain. The virus may be carried into the brain by infected peripheral monocytes (the so-called Trojan horse theory [41]) or may be transported by infected T cells through a disrupted blood-brain barrier [42]. Wiley and colleagues [43] showed that HIV-infected cells are predominantly located in the deep white matter and are mostly of the monocyte-macrophage series; sometimes infected endothelial cells were identified. 2-Microglobulin, a low-molecular-weight protein expressed on the surface of nucleated cells (particula