Neurologic Manifestations of HIV Infection

  1. David M. Simpson, MD; and
  2. Michele Tagliati, MD
  1. From The Mount Sinai Medical Center, New York, New York. Requests for Reprints: David Simpson, MD, Department of Neurology, Box 1052, The Mount Sinai Medical Center, One gustave L. Levy Place, New York, NY 10029. Acknowledgments: The authors thank Drs. Susan Morgello and David Wolfe for neuropathologic specimens, Dr. Aryeh Stollman for neuroradiologic studies, Dr. Henry Sacks for reviewing the manuscript, and the staff of the Mount Sinai Neuro AIDS Research Center. Grant Support: In part by grants from the National Institute of Neurological Disorders and Stroke (RO1-NS28630), National Institute of Allergy and Infectious Disease (UO1-A1-27667), and the National Center for Research Resources (5M01 RR00071).
     
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    Abstract

    Purpose: To review the clinical features, pathogenetic mechanisms, and management of neurologic manifestations of human immunodeficiency virus (HIV) infection.

    Data Sources: Studies published from 1983 to 1994 identified by MEDLINE literature search; Centers for Disease Control and Prevention reports; recent communications and abstracts; and authors' published and unpublished data.

    Study Selection: We selected studies that described the clinical characteristics of neurologic disorders in the acquired immunodeficiency syndrome (AIDS), basic science studies addressing the mechanisms of direct or indirect neurologic damage in HIV infection, and clinical trials investigating the effects of therapeutic agents on the neurologic complications of AIDS.

    Data Extraction: We evaluated information and data on epidemiologic characteristics, clinical manifestations, pathogenetic mechanisms, and therapy for neurologic complications of HIV disease and outlined a practical approach to assess and manage these disorders.

    Data Synthesis: In the past decade, basic and clinical studies have provided considerable information about neurologic manifestations of AIDS. Dementia is the most important “primary” neurologic complication of HIV infection. Focal lesions of the central nervous system include cerebral toxoplasmosis, lymphoma, and progressive multifocal leukoencephalopathy. Other opportunistic infections include cytomegalovirus encephalitis, cryptococcal meningitis, and neurosyphilis. Various peripheral neuropathies and myopathies may occur in association with HIV infection or as toxic effects of antiretroviral agents.

    Conclusions: The prevalence of neurologic complications associated with HIV disease will increase as more effective therapies allow persons with AIDS to live longer. Early recognition and treatment of these disorders substantially affect patients' quality of life and survival.

    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.

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    Table 1. Major Neurologic Manifestations of HIV Infection
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    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 β2-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. Normal brain magnetic resonance imaging scan of a 40-year-old woman. A T2-weighted magnetic resonance imaging scan of the brain in a 34-year-old man with HIV dementia showing diffuse enlargement of the lateral ventricles and cerebral sulci and hyperintense signal throughout the periventricular white matter, consistent with leukoencephalopathy.
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      Figure 1. Normal brain magnetic resonance imaging scan of a 40-year-old woman. A T2-weighted magnetic resonance imaging scan of the brain in a 34-year-old man with HIV dementia showing diffuse enlargement of the lateral ventricles and cerebral sulci and hyperintense signal throughout the periventricular white matter, consistent with leukoencephalopathy. 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. Photomicrograph showing a microglial nodule with multinucleated giant cells ( ) within the centrum semiovale. (Hematoxylin and eosin stain; original magnification, × 25.).
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        Figure 2. Photomicrograph showing a microglial nodule with multinucleated giant cells ( ) within the centrum semiovale. (Hematoxylin and eosin stain; original magnification, × 25.). 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. β2-Microglobulin, a low-molecular-weight protein expressed on the surface of nucleated cells (particularly lymphocytes and macrophages), is elevated in the cerebrospinal fluid of patients with HIV dementia, independent of serum level [20]. Brew and coworkers reported that cerebrospinal fluid β2-microglobulin [21] and neopterin [22] levels correlate with the severity of dementia. Neither cerebrospinal fluid pleocytosis nor disruption of the blood-brain barrier could account for their elevation, suggesting that these are more than nonspecific markers of inflammation.

        Whether the presence of HIV-infected cells in the brain is pathogenetically important is unclear. The amount of HIV detected immunohistochemically is not commensurate with the severity of histopathologic features [39]. Although several investigators have reported neuronal loss in patients with HIV encephalopathy [44, 45], no evidence of neuronal HIV infection exists. Infection of glial cells with HIV-1 was recently shown in children with AIDS encephalopathy [46, 47]. The virus seems to express only early regulatory gene products in astrocytes, which suggests the presence of a nonproductive, persistent infection that may constitute a reservoir of latent virus [46, 47].

        Because HIV may not act as the primary pathogenetic agent in HIV dementia, investigators have postulated many indirect mechanisms. Dreyer and colleagues [48] reported that gp120, a surface protein of HIV, can cause neuronal death in an in vitro model. Cellular death was accompanied by calcium channels opening in the neuronal membrane. These investigators showed that the calcium channel blocker nimodipine prevented neuronal death in an HIV-infected cell culture system [48]. Based on this in vitro model, a placebo-controlled clinical trial of nimodipine in HIV dementia was recently completed (AIDS Clinical Trials Group). The results indicated a trend toward neuropsychological improvement in the high-dose nimodipine group, although this did not reach statistical significance because of the limited size of the study (Lipton S. Personal communication). A larger placebo-controlled study of nimodipine and memantine in HIV dementia is under development.

        One hypothesis proposes that cell-to-cell interaction between HIV-1-infected monocytes and astrocytes amplifies the effects of HIV infection, generating neurotoxic factors and glial proliferation [49]. A complex autocrine loop involving the production of cytokines, such as tumor necrosis factor-α and interleukin-6, and metabolites of the arachidonic acid cascade could finally cause neurotoxic damage [49, 50]. Several investigators [51, 52] have proposed that cytokines are cofactors in HIV dementia. Brains of patients with HIV infection and dementia express high levels of tumor necrosis factor-α messenger RNA [53], which correlate with the level of cognitive impairment and neuropathologic alteration [33].

        Some investigators have suggested that the final common pathway of neuronal damage in HIV disease involves activation of the n-methyl-d-aspartate receptors [49, 54], similar to that described in other neurodegenerative disorders [55]. Experiments showing that the neurotoxicity induced by gp120 can be blocked in vitro by n-methyl-d-aspartate antagonists [56] and glutamate depletion [51, 57] support this hypothesis. Furthermore, Heyes and associates [58] found increased levels of the excitotoxin quinolinic acid, an n-methyl-d-aspartate agonist, in the cerebrospinal fluid of macaques infected with simian AIDS retrovirus and in humans with AIDS [23, 59].

        Treatment

        Although the pathogenesis of HIV dementia remains obscure, HIV probably plays an important role, either by direct or indirect mechanisms. Thus, soon after it became available, antiretroviral therapy was begun in patients with HIV dementia. Several studies reported a beneficial effect of zidovudine in adults with HIV dementia [60] and in children with progressive encephalopathy [61]. Some investigators have observed a reduced incidence of HIV dementia and its neuropathologic hallmarks, in parallel with increasing use of zidovudine [62-64]. Whereas several studies found that early treatment with zidovudine may protect patients from the development of cognitive impairment in AIDS [14, 65], results of the Multicenter AIDS Cohort Study do not support those conclusions [15]. Furthermore, no data indicate what dose of zidovudine may be prophylactic in preventing the onset of HIV dementia.

        Several controlled studies have shown that high doses of zidovudine are most effective in treating HIV dementia. Schmitt and coworkers [66] reported that patients with AIDS who received zidovudine at a dose of 1000 mg/d had improved neuropsychological performance compared with patients who received placebo. A double-blind, dose-response study of zidovudine in advanced HIV disease showed a trend toward fewer cases of dementia when higher doses were administered [67]. A randomized, double-blind, placebo-controlled study of zidovudine in HIV dementia found considerable improvement in neuropsychological performance in the zidovudine group, with the most substantial effect in the highest-dose (2000 mg/d) arm [10]. Controlled trials have not yet established the efficacy of lower doses of zidovudine (300 to 600 mg/d), as conventionally used, or of other antiretroviral agents in HIV dementia.

        For current management of HIV dementia in patients who are either zidovudine naive or have been treated with lower doses, we and other investigators recommend zidovudine at doses of at least 1000 mg/d [10, 66]. In persons with progressive HIV dementia despite these high doses of zidovudine or in those who cannot tolerate zidovudine, therapy with an alternative antiretroviral agent (that is, dideoxyinosine, 400 mg/d) may be initiated, although data to indicate the efficacy of this approach are limited [68]. Several experimental agents are being investigated to treat HIV dementia, including nimodipine (calcium channel blocker), pentoxyphylline (tumor necrosis factor antagonist), memantine (n-methyl-d-aspartate antagonist), delavirdine (non-nucleoside reverse transcriptase inhibitor), and peptide T (pentapeptide analog of gp120 [69]).

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        Focal Lesions of the Central Nervous System

        Toxoplasmosis

        Cerebral toxoplasmosis is the most common cerebral mass lesion in patients with AIDS, occurring in 3% to 40% of patients [1, 3, 70-72]. In most cases, toxoplasmosis represents the reactivation of a previously acquired endogenous infection, as shown by the lack of IgM antibodies in most patients [73]. The high frequency of multicentric lesions and evidence of choroid plexus infection with toxoplasmosis suggests hematogenous dissemination of parasites from systemic organs, rather than reactivation of latent organisms within the brain [73, 74]. Central nervous system toxoplasmosis usually occurs in advanced HIV infection, when CD4 counts are less than 200 cells/mm3[72, 75]. Toxoplasmosis is the AIDS index diagnosis in one half of the cases [72].

        Toxoplasma encephalitis can occur with focal or generalized symptoms and signs of central nervous system involvement [71-73]. In one large series [72], the most frequent clinical manifestations of central nervous system toxoplasmosis were headache (55%), confusion (52%), fever (47%), lethargy (43%), and seizures (29%). Focal neurologic signs, present in 69% of patients, included hemiparesis, ataxia, and cranial nerve palsies. Patients with diffuse encephalopathy usually develop focal neurologic signs as the disease progresses, which usually occurs subacutely during a period of weeks or months.

        Computed tomographic scans of the brain show single or multiple contrast-enhancing lesions in more than 90% of patients with toxoplasmosis, with nodular or ring-enhancing structures Figure 3, left). Magnetic resonance imaging studies often show more lesions and, in some cases, show abnormalities undetected by computed tomographic scans [72, 73]. Serum antitoxoplasma antibodies are usually detectable in patients with infection, although a low titer or an absence of antibody does not exclude the diagnosis [72]. Immunofluorescence assay may be less sensitive than enzyme-linked immunosorbent assay in detecting antitoxoplasma IgG [72]. Use of the polymerase chain reaction to detect toxoplasma DNA in the cerebrospinal fluid may be a promising diagnostic tool [76, 77].

        Figure 3. Brain computed tomographic scan in a patient with toxoplasmosis shows a ring-enhancing lesion with surrounding edema in the right basal ganglia that compresses the frontal horn of the lateral ventricle, with midline shift. Brain computed tomographic scan in a patient with a primary central nervous system lymphoma shows a homogeneously contrast-enhancing lesion ( ) with edema adjacent to the frontal horn of the right lateral ventricle.
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          Figure 3. Brain computed tomographic scan in a patient with toxoplasmosis shows a ring-enhancing lesion with surrounding edema in the right basal ganglia that compresses the frontal horn of the lateral ventricle, with midline shift. Brain computed tomographic scan in a patient with a primary central nervous system lymphoma shows a homogeneously contrast-enhancing lesion ( ) with edema adjacent to the frontal horn of the right lateral ventricle. Focal central nervous system lesions in AIDS.Left.Right.arrow

          Figure 4 is an algorithm for managing intracranial lesions in AIDS. In patients with characteristic radiologic findings and detectable antitoxoplasma antibody, one may presume the clinical diagnosis of central nervous system toxoplasmosis and initiate empirical therapy [78]. Most patients with cerebral toxoplasmosis respond favorably to the combination of oral pyrimethamine (loading dose of 50 to 200 mg/d followed by maintenance doses of 25 to 75 mg/d) and sulfadiazine (4 to 8 g/d) 2 to 6 weeks after treatment is started [72, 79]. Both of these drugs cross the blood-brain barrier effectively [80]. However, adverse effects such as rash and nephrotoxicity [81, 82], which are particularly related to sulfadiazine, complicate this regimen in more than 40% of patients. Hematologic toxicity of pyrimethamine can be ameliorated with folinic acid (5 to 10 mg/d) given for 6 weeks [83].

          Figure 4. Headache, mental status alteration, focal neurologic signs. High-dose zidovudine, clinical trial. Antiretroviral, Ara-C (intravenous, intrathecal) clinical trial. Radiation therapy. Pyrimethamine + sulfadizine or pyrimethamine + clindamycin. CNS = central nervous system; Crypto = ; CT = computed tomography; IT = intrathecal; IV = intravenous; LP = lumbar puncture; MRI = magnetic resonance imaging; PML = progressive multifocal leukoencephalopathy; TB = tuberculosis; Toxo = toxoplasmosis.
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            Figure 4. Headache, mental status alteration, focal neurologic signs. High-dose zidovudine, clinical trial. Antiretroviral, Ara-C (intravenous, intrathecal) clinical trial. Radiation therapy. Pyrimethamine + sulfadizine or pyrimethamine + clindamycin. CNS = central nervous system; Crypto = ; CT = computed tomography; IT = intrathecal; IV = intravenous; LP = lumbar puncture; MRI = magnetic resonance imaging; PML = progressive multifocal leukoencephalopathy; TB = tuberculosis; Toxo = toxoplasmosis. Algorithm for the management of brain lesions in patients with HIV infection.12345Cryptococcus neoformans

            Combination therapy with clindamycin and pyrimethamine is an effective alternative treatment for toxoplasma encephalitis [84, 85]. A randomized trial found that the percentage of favorable clinical responses at 3 weeks in patients treated with pyrimethamine and sulfadiazine (79%) was similar to the percentage in those given pyrimethamine and clindamycin (77%) [75]. Luft and associates [85] reported that 71% of patients treated empirically for cerebral toxoplasmosis with pyrimethamine (at 75 mg/d) and clindamycin (at 600 mg/d) responded favorably, with 86% of the responders showing improvement by the seventh day of therapy. Thus, if clinical or radiologic improvement does not occur within 1 to 2 weeks of starting empirical therapy for toxoplasmosis, an alternative diagnosis should be pursued using stereotactic brain biopsy (Figure 4). Patients with HIV infection and central nervous system toxoplasmosis require life-long maintenance therapy to prevent relapses [73]. Use of pyrimethamine alone has been proposed for maintenance therapy in patients who cannot tolerate sulfadiazine [86].

            Primary Central Nervous System Lymphoma

            The incidence of primary central nervous system lymphoma, previously a rare disorder, has increased in parallel with the AIDS epidemic [1, 87, 88]. Lymphoma generally develops late in HIV disease in association with CD4 counts of less than 100 cells/mm3[89, 90]. Many investigators have detected the presence of Epstein-Barr virus in AIDS-related central nervous system lymphoma tissue, with an incidence approaching 100% [91-95]. Cinque and associates [96] reported that Epstein-Barr virus DNA in cerebrospinal fluid detected by polymerase chain reaction has diagnostic value.

            Patients with central nervous system lymphoma generally are confused, are lethargic, and have memory loss, often accompanied by headache and focal neurologic signs [87, 97-99]. Radiologic studies show single or multiple homogeneously contrast-enhancing lesions Figure 3, right). It may be difficult to differentiate between lymphoma and toxoplasmosis on clinical and radiologic grounds [87, 100], although evidence of a single lesion on MRI, particularly in persons with no antitoxoplasma antibodies, favors the diagnosis of lymphoma [101]. Because they can detect metabolic activity of brain lesions, thallium-201 single-proton emission computed tomography [102] and positron emission tomography [103] are reported to be promising tools in the differential diagnosis of intracerebral mass lesions, but they are not generally available to most clinicians. Stereotactic biopsy definitively diagnoses focal brain lesions in patients with AIDS in more than 85% to 90% of cases [104-106].

            Primary central nervous system lymphoma associated with AIDS usually has a poor prognosis, with a median survival time of less than 1 month from diagnosis in untreated cases [97, 98]. Radiation therapy may improve neurologic outcome and quality of life in more than 75% of patients [98, 99, 107] and may prolong survival for a median of 4 to 6 months [88, 97-99, 107]. Although considerable variability exists in current practice, we and other investigators [87, 98-100] favor early biopsy and treatment of brain lesions when clinical, serologic, and radiologic findings favor the diagnosis of central nervous system lymphoma (Figure 4). Radiation therapy combined with chemotherapy to treat AIDS-related primary central nervous system lymphoma is being evaluated in prospective clinical trials.

            Progressive Multifocal Leukoencephalopathy

            Progressive multifocal leukoencephalopathy (PML) results from infection with JC virus, a human papillomavirus [108]. Berger and colleagues [109] reported that PML develops in 4% of patients with AIDS and was the initial manifestation of AIDS in 29% of these cases. The presenting symptoms of PML include altered mental status, speech and visual disturbances, gait difficulty, hemiparesis, and limb incoordination. Computed tomographic scans typically show single or multiple confluent, hypodense, nonenhancing lesions, predominantly located in the parieto-occipital white matter, and without mass effect [110]. Progressive multifocal leukoencephalopathy lesions are visualized more prominently and are often more numerous on T2-weighted spin-echo MRI scans Figure 5, establishing MRI as the preferred radiologic procedure in patients with suspected PML [111-113].

            Figure 5. T2-weighted magnetic resonance imaging scan showing a large confluent area of increased signal ( ) within the white matter of the right cerebral hemisphere. The diagnosis of progressive multifocal leukoencephalopathy was confirmed by brain biopsy.
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              Figure 5. T2-weighted magnetic resonance imaging scan showing a large confluent area of increased signal ( ) within the white matter of the right cerebral hemisphere. The diagnosis of progressive multifocal leukoencephalopathy was confirmed by brain biopsy. Progressive multifocal leukoencephalopathy in AIDS.arrow

              Despite the characteristic radiologic findings, pathologic confirmation is necessary to definitively diagnose PML. Neuropathologic findings are characterized by multiple areas of pronounced white matter demyelination, with frequent involvement of the gray-white matter junction and cortical gray matter in the most severe cases [113]. A higher incidence of large confluent lesions and marked perivascular inflammatory infiltrates have been described in patients with AIDS [113]. The typical histologic features of PML are large “ballooned” oligodendroglial cells, with nuclear inclusions containing many virions [113]. In situ hybridization techniques for JC virus show more infected oligodendrocytes than predicted by light microscopic examination [113, 114]. Whether PML results from reactivation of latent JC virus within the brain or from transport of virus to the central nervous system from other infected organ systems is unclear. Tornatore and coworkers [115] detected JC virus DNA in peripheral blood lymphocytes in 89% of patients with AIDS-associated PML.

              Patients with HIV-associated PML have a median survival time of 2 to 4 months [109, 113, 116]. However, approximately 10% of patients have a more benign course, with remission and prolonged survival, or even spontaneous recovery [117]. Information about the treatment of PML in patients with AIDS is limited, but high-dose antiretroviral therapy may be beneficial in some patients [113, 118-120]. Several case reports and small series have shown encouraging results with intravenous cytarabine (Ara-C) therapy [121, 122]. Britton and colleagues [123] reported a case series with no control arm in which intrathecal cytarabine improved the course of PML in patients with AIDS. A controlled randomized study examining the efficacy of antiretroviral agents and intravenous and intrathecal cytarabine has been initiated by the AIDS Clinical Trials Group.

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              Other Central Nervous System Infections

              Cytomegalovirus

              Cytomegalovirus may cause a spectrum of central and peripheral nervous system abnormalities in AIDS, including necrotizing focal encephalitis, ventriculoencephalitis, vasculitis, and radiculomyelitis [124-126]. Cytomegalovirus encephalitis has been diagnosed at autopsy in 6% to 40% of patients with AIDS and dementia [1, 2, 125]. The most common pathologic abnormality in the brain is a microglial nodule encephalitis, with rare cytomegalovirus inclusions Figure 6 A. The brain stem and spinal cord appear to be common targets of this infection [125, 127, 128]. Cytomegalovirus encephalitis is usually limited to patients with CD4 counts of less than 50 cells/mm3 and is often accompanied by cytomegalovirus infection of other organ systems [125], particularly adrenalitis [129]. Central nervous system infection with toxoplasma, herpesviruses, cryptococcus, or PML may coexist with it [125].

              Figure 6. Cytomegalovirus encephalitis. High-power photomicrograph showing a microglial nodule with associated cytomegalovirus inclusion ( ). (Hematoxylin and eosin stain; original magnification, × 250.) B. Vacuolar myelopathy in AIDS. High-power photomicrograph from the white matter of the spinal cord, showing large vacuoles. Macrophages ( ) are evident within the vacuoles. (Hematoxylin and eosin; original magnification, × 250.) C. Cytomegalovirus neuritis. High-power photomicrograph of axillary nerve from a patient with multifocal demyelinative neuropathy in late HIV disease. Note endoneurial inflammation and cytomegalovirus inclusion ( ). (Toluidene blue; original magnification, × 100.) D. HIV-associated myopathy. Photomicrograph of a quadriceps muscle biopsy specimen shows basophilic, degenerating fibers ( ) without substantial inflammatory infiltrate. (Hematoxylin and eosin; original magnification, × 100.).
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                Figure 6. Cytomegalovirus encephalitis. High-power photomicrograph showing a microglial nodule with associated cytomegalovirus inclusion ( ). (Hematoxylin and eosin stain; original magnification, × 250.) B. Vacuolar myelopathy in AIDS. High-power photomicrograph from the white matter of the spinal cord, showing large vacuoles. Macrophages ( ) are evident within the vacuoles. (Hematoxylin and eosin; original magnification, × 250.) C. Cytomegalovirus neuritis. High-power photomicrograph of axillary nerve from a patient with multifocal demyelinative neuropathy in late HIV disease. Note endoneurial inflammation and cytomegalovirus inclusion ( ). (Toluidene blue; original magnification, × 100.) D. HIV-associated myopathy. Photomicrograph of a quadriceps muscle biopsy specimen shows basophilic, degenerating fibers ( ) without substantial inflammatory infiltrate. (Hematoxylin and eosin; original magnification, × 100.). A.arrowarrowsarrowarrows

                The clinical diagnosis of cytomegalovirus encephalitis is problematic and difficult to differentiate from HIV dementia. A relatively abrupt onset of mental status changes and radiologic findings including hydrocephalus [130] and periventricular or meningeal enhancement favor a diagnosis of cytomegalovirus encephalitis [129]. The retinal fundi should be examined for signs of cytomegalovirus retinitis [129, 131]. Electrolyte abnormalities consistent with adrenal insufficiency are frequently present, but there are no specific serologic or laboratory findings to confirm the diagnosis of cytomegalovirus encephalitis [129]. Recent data indicate that cytomegalovirus DNA can be identified reliably using polymerase chain reaction in the cerebrospinal fluid of neurologically impaired patients with AIDS, and its presence correlates with neuroradiologic and histopathologic evidence of cytomegalovirus disease of the central nervous system [128, 129, 132, 133].

                Managing cytomegalovirus is difficult. The median survival time of patients with this type of encephalitis is only about 5 weeks, and the role of antiviral therapy in changing this rapid course is not yet established [129]. In several cases, patients with cytomegalovirus neurologic involvement responded to ganciclovir or foscarnet treatment, alone or in combination [134-136]. However, there have been no controlled trials of antiviral agents to treat cytomegalovirus disease of the central nervous system. Ganciclovir has limited penetration of the blood-brain barrier (38% of blood levels [137]), providing a rationale for comparative trials with foscarnet and other antiviral agents to treat cytomegalovirus encephalitis [138].

                Cryptococcal Meningitis

                Cryptococcal meningitis is the most common central nervous system fungal infection in patients with HIV in the United States [139]. The etiologic agent, Cryptococcus neoformans, may cause minimal inflammation in persons with AIDS and impaired immune defenses. This may explain why classic symptoms and signs of meningitis, such as neck stiffness and photophobia, are often absent [140, 141]. The presenting clinical features of cryptococcal meningitis are often subtle and nonspecific and include malaise, fever, and nausea and vomiting, accompanied by headache in 75% to 90% of patients [140-143]. Other less frequent findings are cranial nerve palsies, psychiatric abnormalities, speech disturbances, and seizures [140].

                Cryptococcal meningitis can be diagnosed using a positive result of cerebrospinal fluid India ink stain [144, 145], a cerebrospinal fluid cryptococcal antigen titer of more than 1:8 [141, 142], or a positive cerebrospinal fluid culture [144, 145]. Cerebrospinal fluid opening pressure should be measured routinely because elevated intracranial pressure may have important prognostic implications, particularly for visual impairment [146]. Other unfavorable prognostic factors are changed mental status [147], a high cerebrospinal fluid cryptococcal antigen titer, a low cerebrospinal fluid leukocyte count, a positive extrameningeal culture for cryptococcus, and hyponatremia [141, 142, 144, 147, 148].

                Several issues must be considered in treating cryptococcal meningitis in AIDS: management of raised intracranial pressure, treatment of acute infection, and administration of maintenance therapy to prevent relapses [141]. Intracranial hypertension may be controlled with mechanical drainage (that is, repeated lumbar punctures, intraventricular shunt) or with acetazolamide treatment [141]. Corticosteroids to manage elevated intracranial pressure associated with cryptococcal meningitis are being studied by the AIDS Clinical Trials Group in a controlled prospective trial.

                Several clinical studies of acute cryptococcal meningitis support the efficacy of amphotericin B (0.7 mg/kg body weight per day) and flucytosine (100 to 150 mg/kg per day) for 2 to 3 weeks, followed by fluconazole (400 mg/d) for an additional 8 to 10 weeks [141, 147, 149]. Fluconazole used to treat acute cryptococcal meningitis in AIDS has been reported to be as effective as amphotericin B, although fluconazole causes delayed clearance of cryptococcus from the cerebrospinal fluid [147, 148, 150].

                Amphotericin B treatment is limited by frequent side effects such as fever and renal dysfunction [151] and, rarely, leukoencephalopathy [152]. Experience with a liposomal form of amphotericin B has shown promising results without some of the adverse effects [153]. Flucytosine treatment is also limited by toxic effects, including myelosuppression and gastrointestinal toxicity. Triazole antifungal agents (fluconazole and itraconazole) have a more favorable toxicity profile [154, 155] and may be preferable for long-term suppressive treatment necessary to avoid the high incidence of relapse (> 50%) in patients with AIDS [144, 151, 156, 157].

                Syphilis

                Syphilis must be considered in the differential diagnosis of neurologic disease in patients with HIV infection [158]. However, overlap is considerable between the spectrum of neurologic diseases caused by HIV and that resulting from Treponema pallidum: Both may result in acute or chronic meningitis, cranial and peripheral neuropathies, dementia, cerebrovascular disease, and myelopathy [3, 159]. In addition, neurosyphilis and HIV may produce similar cerebrospinal fluid abnormalities, particularly persistent pleocytosis [160]. Although a positive result of a cerebrospinal fluid VDRL test is diagnostic of neurosyphilis, this assay has a sensitivity of only 30% to 70% [159, 161]. In a patient with HIV infection and symptoms consistent with neurosyphilis and a positive serum VDRL test, even in the absence of a positive cerebrospinal fluid VDRL, a reactive cerebrospinal fluid profile may justify treatment with intravenous high-dose penicillin. However, prospective studies are necessary to determine which criteria can predict a favorable therapeutic response.

                Concurrent HIV infection may alter the natural history of syphilis. Johns and associates [160] described four patients who had relapse with neurosyphilis after conventional therapy for primary syphilis. Morgello and Laufer [162] described a patient with HIV infection with “quaternary” neurosyphilis, characterized by a fulminant, necrotizing encephalitis with massive treponemal invasion. Patients with HIV infection may not respond adequately to conventional treatment for syphilis [160, 163-165] and may progress early and quickly to neurosyphilis [163, 166]. These considerations lead to the need for aggressive treatment and follow-up of syphilis in patients with HIV infection. Neurosyphilis is treated with high doses of aqueous penicillin G (12 to 24 million U/d) for 10 days, with probenecid added to increase serum and cerebrospinal fluid levels [163]. Serum and cerebrospinal fluid should be followed for at least 2 years to monitor response to therapy. Although the goal is normalization of cerebrospinal fluid values and VDRL titers, the presence of concurrent HIV infection may cause persistent cerebrospinal fluid abnormalities.

                Other less common central nervous system infections in AIDS include Candida albicans infection [1], coccidioidomycosis [2], histoplasmosis [167], Mycobacterium tuberculosis infection [168], Herpes zoster infection [2, 169], Herpes simplex infection [2, 170, 171], aspergillosis [2, 3], amoebiasis [172], Trypanosoma cruzi infection [173], and nocardia [174].

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                Myelopathy

                Patients with myelopathy (spinal cord dysfunction) develop slowly progressive painless gait disturbance, lower extremity sensory complaints, and sphincter abnormalities. Neurologic signs include spastic paraparesis, hyper-reflexia, extensor plantar responses, and mild sensory impairment. The most common cause of myelopathy in AIDS is vacuolar myelopathy [175, 176], which is detected in as many as 40% of cases at autopsy [176]. Other causes of myelopathy in AIDS include toxoplasmosis [177], lymphoma [1], varicella zoster granulomatous myelitis [178], herpetic necrotizing myelitis [179], cytomegalovirus [2, 180], and vitamin B12 deficiency [181]. Radiologic studies of the spinal cord and cerebrospinal fluid examination are helpful to exclude treatable infections or neoplasms.

                The pathologic findings of vacuolar myelopathy include vacuolization of myelin sheaths due to the accumulation of foamy macrophages and microglia, with relative preservation of axons Figure 6 B. No evidence shows that the pathogenesis of vacuolar myelopathy is related to a direct effect of HIV infection [182]. The myelin damage may be the result of indirect mechanisms such as the release of toxic cytokines, particularly tumor necrosis factor [183]. Vitamin B12 deficiency may play a role in a few patients with AIDS-associated myelopathy [181, 184]. No information exists about the efficacy of antiretroviral agents in vacuolar myelopathy. Symptomatic therapy includes antispasticity agents (baclofen, for example), management of sphincter dysfunction, and physical therapy.

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                Peripheral Neuropathies

                Distal Symmetrical Polyneuropathy

                Distal symmetrical polyneuropathy (DSP) is the most common form of neuropathy in HIV infection. The most frequent complaints in DSP are numbness, burning, and paresthesias in the feet. These symptoms are typically symmetrical and often so severe that patients have contact hypersensitivity and difficulty in walking. Involvement of the upper extremities and distal weakness may occur later in the course of DSP. Neurologic examination shows sensory loss to pain and temperature in a stocking and glove distribution, increased vibratory thresholds, and diminished ankle reflexes compared with knee reflexes. Patients with AIDS frequently have concurrent central nervous system disorders and neuropathy, characterized by hyperactive knee reflexes and depressed ankle reflexes.

                Although DSP is relatively uncommon early in the course of HIV disease, the incidence of DSP increases with advancing immunosuppression, in parallel with decreasing CD4 cell counts. In our series of 165 persons with HIV infection and DSP, the frequency of DSP was inversely correlated with the CD4 count [185]. Clinical or electrophysiologic abnormalities consistent with DSP may be detected in approximately 35% of patients with AIDS [186]. In addition, pathologic evidence of DSP is present in almost all patients who die of AIDS [187]. The mechanism of DSP in AIDS is unknown. Although early reports proposed a direct effect of HIV [188-190], most investigators have found that primary HIV infection of the peripheral nerve does not cause DSP [191-193]. A “dying back” neuropathy affecting all fiber types, with prominent macrophage infiltration of the peripheral nerve has been described [187, 190, 192]. Tumor necrosis factor-α, interleukin-1, and other cytokines have been identified in peripheral nerves of patients with AIDS [194, 195]. Griffin and colleagues [195] suggest that cytokines may interact with nerve growth factors. These findings provide a rationale for the investigation of therapeutic agents such as nerve growth factors and anticytokines in DSP.

                Toxic Neuropathy

                Many conditions other than HIV infection may cause DSP, including vitamin deficiencies (that is, of pyridoxine, vitamin B12), diabetes mellitus, and alcoholism. Peripheral neurotoxins such as dapsone, vincristine, isoniazid, and particularly the antiretroviral nucleoside analogs didanosine [196-198], zalcitabine [199, 200], and stavudine [201] may cause DSP. Persons with a history of subclinical neuropathy before initiation of neurotoxic therapy are more susceptible to the development of symptomatic neuropathy after drug administration [202, 203].

                It is difficult to clinically differentiate nucleoside-related neuropathy from that resulting from HIV alone. Numbness, tingling, and pain occur in AIDS neuropathy and in nucleoside analog-associated neuropathy. Similarly, both toxic and HIV-related neuropathy predominantly affect the distal extremities, most severely in the lower limbs, whereas the upper extremities may be relatively spared until late stages of disease. The onset of symptoms may provide useful information because AIDS-related DSP may take weeks to months to develop, whereas nucleoside analog-associated neuropathy tends to evolve more rapidly [204]. Ultimately, a beneficial response to drug withdrawal will determine if the neuropathy is drug related, although a “coasting period” of symptom intensification, lasting 4 to 8 weeks, may occur before improvement after drug cessation [200]. Patients often tolerate drug rechallenge at lower doses. Symptomatic therapy for DSP includes analgesics, tricyclic antidepressants, anticonvulsants, and topical capsaicin [205]. Simpson and colleagues [206] reported the results of a randomized, placebo-controlled trial in which they found that intranasal peptide T was ineffective in treating painful DSP. Amitriptyline, mexiletine, nerve growth factor, and acupuncture are being evaluated in controlled clinical trials involving patients with painful AIDS-associated neuropathy.

                Inflammatory Demyelinating Polyneuropathy

                Inflammatory demyelinating polyneuropathy (IDP) in patients with HIV infection is associated with acute or chronic progressive weakness, areflexia, and minor sensory complaints, similar to the Guillain-Barre syndrome or chronic IDP observed in patients with negative HIV serum test results [207]. The condition generally occurs early in the course of HIV disease and may be the initial clinical disorder when seroconversion occurs [208]. Cerebrospinal fluid pleocytosis is commonly found in patients with HIV infection and IDP [209], whereas those who are HIV negative tend to have acellular cerebrospinal fluid. Inflammatory demyelinating polyneuropathy is probably mediated by autoimmune mechanisms and has responded, in series with no control group, to immunomodulating treatment, including corticosteroids, plasmapheresis, and intravenous immunoglobulin [209-212]. Prospective trials are needed to determine if persons with HIV infection and IDP respond to therapy as do patients with negative HIV serum tests. When IDP occurs late in the course of HIV disease, in association with a low CD4 count, cytomegalovirus may be the primary etiologic agent [213].

                Progressive Polyradiculopathy

                The clinical features of progressive polyradiculopathy are rapidly progressive lower extremity and sacral paresthesias, flaccid paraparesis, areflexia, sensory loss, and urinary retention [214, 215]. Cerebrospinal fluid examination shows marked pleocytosis, containing hundreds to thousands of polymorphonuclear leukocytes [215, 216]. Although cerebrospinal fluid culture results are positive in only approximately 50% of these patients [135, 215], considerable clinical and pathologic evidence suggests that most cases of AIDS-associated progressive polyradiculopathy result from primary cytomegalovirus infection of nerve roots [135, 193, 214, 217, 218]. Approximately 50% of patients with progressive polyradiculopathy have neurologic improvement or stabilization after therapy with ganciclovir or foscarnet [135]. Progressive polyradiculopathy must be treated with antiviral therapy early in the course of the disease before irreversible nerve root necrosis occurs [135, 216-218]. Less common causes of AIDS-associated progressive polyradiculopathy are neurosyphilis [219], leptomeningeal lymphoma [215, 220], and tuberculosis [221].

                Mononeuropathy Multiplex

                Multifocal, asymmetric, cranial, or peripheral nerve lesions, including facial or laryngeal palsy, wrist or foot drop, and other neuropathic symptoms develop in patients with mononeuropathy mulitplex [222]. In the early stages of HIV infection, it is usually limited to one or a few nerves and resolves spontaneously without treatment [223]. In advanced HIV disease, particularly when CD4 counts decrease to less than 50 cells/mm3, this neuropathy may progress rapidly to quadriparesis [223-225]. When the neurologic deficits are diffuse and confluent, mononeuropathy multiplex may be mistaken for IDP, DSP, or progressive polyradiculopathy [223-225]. Said and associates [224] have reported that the extensive form of mononeuropathy multiplex results from primary cytomegalovirus infection Figure 6 C and that these patients improve with ganciclovir therapy.

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                Myopathy

                Myopathy may occur at all stages of HIV infection [226]. Proximal muscle weakness, manifested by difficulty in rising from a chair or climbing stairs, is the predominant symptom. Myalgia occurs in 25% to 50% of affected patients, although this is a nonspecific symptom with HIV infection [226, 227]. Weight loss commonly accompanies myopathy, and, in some patents, myopathy is the underlying cause of the HIV wasting syndrome [228].

                The most sensitive serologic test for HIV-associated myopathy, as in other primary muscle diseases, is creatine kinase measurement. Simpson and coworkers [227] reported that creatine kinase is elevated in 92% of patients with myopathy, with a median of 478 U/L. However, an elevated creatine kinase level with or without myalgia is not by itself diagnostic of myopathy [229]. Proximal muscle weakness, preferably with supportive electrophysiologic and pathologic data, is necessary to diagnose myopathy specifically, particularly if therapeutic intervention is planned. Electromyography is a sensitive diagnostic test for HIV-associated myopathy [227] and is particularly helpful in challenging cases.

                The most common finding in muscle biopsy specimens in HIV-associated myopathy is scattered myofiber degeneration Figure 6 D, with occasional associated inflammatory infiltrates. In general, muscle biopsy specimens from patients with HIV infection show less interstitial inflammation than do specimens from patients with HIV-negative polymyositis [230], with which HIV-associated myopathy shares many features. Other pathologic findings in HIV-associated myopathy include myofiber inclusions such as nemaline rod bodies [226, 231], cytoplasmic bodies [230], and various mitochondrial abnormalities [227, 232, 233].

                The pathogenesis of HIV-associated myopathy is unknown, although immune mechanisms are likely, as in HIV-negative polymyositis [227, 234]. Although HIV may infect infiltrating cells of the monocyte-macrophage lineage [235], current techniques have not detected myofiber infection [226, 231]. Rarely, other opportunistic organisms infect muscle of patients with AIDS; these include Toxoplasma gondii[236], cytomegalovirus [237], microsporidia [238], Cryptococcus neoformans[239], Mycobacterium avium intracellulare [239] and Staphylococcus aureus[240].

                Many authors have implicated zidovudine as a cause of myopathy [232, 241, 242]. The degree to which zidovudine toxicity contributes to underlying HIV-associated myopathy and whether certain features distinguish these disorders has been debated [227, 243, 244]. Dalakas and colleagues [232] reported that “ragged-red fibers” in muscle biopsy specimens, a histologic feature of mitochondrial dysfunction, indicate zidovudine-induced myopathy. However, the specificity of these histologic abnormalities and their clinical significance have varied among series [227, 232, 243-246]. Investigators have reported other evidence of zidovudine-induced mitochondrial dysfunction, supported by magnetic resonance spectroscopy [247], cytochrome C oxidase deficiency [248], mitochondrial DNA abnormalities [233], and findings in animal models [249]. However, other studies using similar techniques have not confirmed these results [250-252].

                The importance of these investigations extends beyond the role of zidovudine in myopathy. For example, mitochondrial toxicity has been implicated as a possible mechanism of hepatic failure and death in several patients given fiurilidine, an experimental nucleoside analog tested to treat viral hepatitis [253]. The extent to which different nucleoside analogs share the potential of mitochondrial toxicity and its relevance to clinical findings are active areas of investigation.

                Because it may be difficult to prospectively identify patients with zidovudine myotoxicity, initial management of patients with considerable limb weakness and objective evidence of myopathy includes zidovudine dose reduction or withdrawal. The percentage of patients given zidovudine who show objective improvement in muscle strength after therapy with zidovudine is discontinued has varied among series from 18% to 100% [227, 241, 243, 246, 254]. In our experience, only a few patients with myopathy improve with zidovudine withdrawal, suggesting that in most patients, HIV rather than zidovudine causes myopathy [227].

                In several retrospective series, prednisone therapy improved strength in most patients with HIV-associated myopathy, with tolerable adverse effects [228, 232, 242, 243, 254]. These results were supported by our prospective, placebo-controlled study of prednisone in HIV-associated myopathy [255]. In patients with functionally significant limb weakness and objective evidence of myopathy, we generally begin with prednisone at a dose of 60 mg/d and modify the dose to alternate-day therapy and taper it as rapidly as possible. Patients with or without inflammatory infiltrates in muscle may respond to steroid therapy. We are conducting placebo-controlled studies of zidovudine withdrawal and oxandralone (anabolic steroid) therapy in patients with HIV-associated myopathy [256].

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                Conclusions

                HIV infection is associated with various central and peripheral nervous system disorders. Multiple levels of the nervous system may be affected simultaneously, further complicating their diagnosis. The prevalence of neurologic disorders probably will increase as more effective treatments of HIV and opportunistic infections extend the lives of patients with AIDS. Recognition and early diagnosis of these disorders is crucial because the institution of therapy may dramatically change patients' quality of life and survival time. Basic research advances will further elucidate pathogenetic mechanisms of neurologic manifestations of AIDS and should provide a foundation for controlled clinical research trials of new therapeutic agents.

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