The Spectrum of Neuro-AIDS Disorders: Pathophysiology, Diagnosis, and Treatment

Early in the HIV/AIDS epidemic, the deleterious consequences of HIV-1 infection in the central and peripheral nervous system were described. They were considered to be due to severe immunosuppression, and encephalitis was considered predominantly attributable to concomitant cytomegalovirus (CMV) infection. Antiretroviral agents (ARVs) was further noted that patients with HIV-1-associated neurocognitive disorders would initially improve but later progress despite the continued use of zidovudine (ZDV). In December 1995, the highly active antiretroviral therapy (HAART) era began when the protease inhibitors (PIs) were introduced into practice with the FDA approval of saquinavir. A number of changes have occurred across the spectrum of HIV-1-associated neurocognitive disorders since the introduction of HAART. The incidence of HIV-1-associated dementia (HAD) is widely reported to have decreased following the introduction of HAART; however, the incidence of HIV-1 encephalopathy (as defined neuropathologically) appears to have increased, although interestingly, both the neuropathological and the clinical aspects of the syndrome seem to be less severe than those observed in the pre-HAART era. In addition to the above-mentioned changes in clinical manifestations of HIV-1-associated neurocognitive disorders, their underlying pathophysiology has also evolved. Aside from the original focus on virologic (pathogen), inflammatory/immunologic (host response), and comorbid infection factors, there are now three additional categories of pathogenic factors that demand attention. These are the vascular, medication toxicity, and genetic factors. Molecular investigations of multidrug resistance (MDR) resulted in the isolation and characterization of genes coding for several associated proteins, including P-glycoprotein and the MDR-associated protein MRP1.

This chapter summarizes the neuropsychological (NP) findings from the highly active antiretroviral therapy (HAART), and pre-HAART eras, including a discussion of the impact that impairment has on “real-world” functioning. Reports from a number of cohorts suggest that, in the HAART era, a subset of individuals transition in and out of impairment over time, raising the possibility that neurocognitive dysfunction in HIV-1 infection may be neither static nor chronically progressive but in the mildest forms may exhibit a fluctuating, relapsing/remitting course, similar to demyelinating disorders. HIV-1 infection of the brain is characterized by HIV encephalitis (HIVE), or the presence of multinucleated giant cells, microglial nodules, astrocytosis, and myelin pallor. Importantly, in the Heaton and coworkers study, both the NP and functional batteries were independent predictors of “real-world” functional status, based on complaints of cognitive difficulties, level of dependence/independence in instrumental activities of daily living, and employment status. Several brief cognitive screening techniques have been developed for situations in which a full or focused NP evaluation is not indicated or not feasible. Most research studies of NP function in HIV-1 infection utilize between-group mean comparisons of test scores on individual measures. Some controversy still exists regarding whether affective/ mood disorders, such as major depression and anxiety, interact with neurocognitive impairment. Ivnik and coworkers showed that large positive and negative test score changes were not uncommon for individuals across time, even though test-retest means stay relatively stable across the entire sample.

The reporting of stroke in HIV-infected subjects has faced several challenges that have limited one's ability to determine whether a direct association between cerebrovascular disease and HIV infection exists. With increased survival, aging of the HIV-infected cohorts is accompanied not infrequently by metabolic and lipid disorders, which are observed often in subjects on highly active antiretroviral therapy (HAART). Recent evidence for the development of premature atherosclerotic disease in this population calls for a revision of the association between stroke and HIV infection. The majority of strokes reported in the clinical and postmortem series were associated with underlying diseases. Intracranial hemorrhage was usually associated with underlying thrombocytopenia, primary central nervous system (CNS) lymphoma, or metastatic Kaposi’s sarcoma. The chapter discusses potential mechanisms of ischemic stroke in HIV-infected patients, and presents new insights into the mechanisms of stroke in HIV-infected patients. Pathological studies of a different vascular bed provide support for the possibility of an HIV-related vasculopathy inducing endothelial cell disturbance. Future studies will be required to better assess the macrovascular and microvascular complications that may result from HIV infection, the metabolic derangements induced by HAART, or both, as well as to determine the optimal treatment and prevention for this specific patient population.

This chapter discusses the complications arising from involvement of the meninges, spinal cord, and muscles by the virus. Clinical features, diagnostic tests, and management of HIV-associated myelopathy, myopathy, and meningitis are discussed. The incidence of clinical HIV-associated myopathy has not been established in prospective studies, although on the whole it appears to be relatively uncommon. In contrast, electromyography is sensitive and specific in the diagnosis of myopathy. Early reports described two histological patterns of HIV-associated myopathy prior to the availability of antiretroviral agents. The percentage of ragged red fibers was reported to be correlated with the severity of clinical myopathy. The conclusion was that mitochondrial abnormalities were not specific to ZDV-associated myopathy. Corticosteroids may provide benefit in HIV-associated myopathy. While intravenous immunoglobulins may be an alternative option without risk of immunosuppression, there is only limited reported experience with their use in HIV-associated myopathy. Spinal cord dysfunction, muscle disease, and meningitis may occur associated with HIV infection. The precise pathogenic mechanisms are unclear, but in myelopathy and myopathy, indirect mechanisms are believed to be responsible. In HIV-associated myelopathy, symptomatic treatment is the mainstay of management. Corticosteroids and intravenous immunoglobulin therapy are used for the treatment of HIV-associated myopathy; the initiation of HAART without myotoxic agents may also provide benefit in those who are untreated.

The autonomic nervous system is a complex and widespread neuronal network with multiple functions. Autonomic dysfunction predisposing to orthostatic hypotension may be quite common in HIV infection, as several studies have shown impaired ability to maintain blood pressure. Autonomic testing is used both to confirm that autonomic dysfunction is present and to delineate the anatomical and physiological distribution of the deficit. This chapter reviews the ways in which these tests have been used to evaluate autonomic dysfunction in human immunodeficiency virus (HIV) infection. Although, in general, the severity of autonomic dysfunction correlates with advancing HIV infection, the progression in individual patients is less clear and appears slow. The transient appearance of hyperactive autonomic function may occur for a limited period over weeks to months in patients with autonomic nervous system degeneration, probably secondary to denervation supersensitivity. The exaggerated normal response observed in the early stages of HIV infection may reflect this phenomenon. The peripheral nervous system is involved in up to 80% of patients with AIDS, with 95% involvement noted postmortem. Although it may present at any stage of HIV infection, the distal sensory polyneuropathy is relatively uncommon early in the course of HIV disease and becomes more prevalent in immunologically compromised HIV-infected persons. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and mononeuritis multiplex, two other neuropathic accompaniments of HIV infection, are not likely to cause autonomic dysfunction.

This chapter discusses the clinical features, diagnosis, and management of HIV distal sensory polyneuropathy (DSP); toxic neuropathies, with emphasis on the antiretroviral (ARV)-associated neuropathies; and other neuropathies found in HIV-infected individuals. Subjects were classified as having asymptomatic DSP if they only had neurologic signs or as having symptomatic DSP if they also had paresthesias or pain in a study by Schifitto and coworkers. The study showed that use of these drugs was not a significant risk factor for incident symptomatic DSP. Such an effect may be related to preservation of immune function, forestalling the potential occurrence of neurotoxicity. This study also addressed the important issue of whether the presence of asymptomatic DSP is a risk factor for incident symptomatic DSP. Thus, it is not surprising that patients with advanced HIV infection and severe immunosuppression remain at the greatest risk of neurotoxicity due to ARV agents. The incidence, severity, progression, and reversibility of peripheral neuropathy from zalcitabine (ddC), as with other toxic neuropathies, are dose dependent. Unlike other toxic neuropathies, dapsone-induced peripheral neuropathy involves primarily motor nerves. Mononeuropathy multiplex (MM) is an infrequent manifestation of HIV infection. A reduced number of oxytocin neurons in the paraventricular nucleus of the hypothalamus have also been described, although the clinical significance of this is unclear. It has been suggested that the pathophysiological mechanism may be due to HIV infection itself as well as an autoimmune mechanism. It may arise from HIV itself or from medications used to treat HIV infection and other concomitant infections.

Mitochondria differ from other subcellular organelles in that they contain their own DNA (mitochondrial DNA [mtDNA]). In mitochondrial disorders, not only does energy failure in tissues and organs result, with a variety of clinical symptoms, but the metabolic block at the end of the anaerobic glycolysis can also lead to excessive pyruvate and lactate accumulation. Lactic acidosis, therefore, can be a manifestation of mitochondrial dysfunction. Symptomatic hyperlactatemia associated with antiretroviral therapy is linked to the mitochondrial respiratory-chain impairment in HIV disease. The recent availability of antiretroviral drugs has substantially reduced HIV-associated mortality and morbidity through decreased viral burden and immune restoration. Mitochondria are the site of generation of most of the cellular ATP pool. The conversion of one molecule of glucose to pyruvate or lactate is associated with the net formation of two molecules of ATP. Nucleoside analog reverse transcriptase inhibitors (NRTI)-related mitochondrial toxicity appears to be the major factor responsible for hyperlactatemia and lactic acidosis in patients with HIV disease. All metabolic acidoses have profound effects on the respiratory, cardiac, and nervous system. It seems essential to discontinue all antiretroviral drugs at the time of NRTI-associated lactic acidosis (NALA) diagnosis; however, surviving patients often need to continue antiretroviral therapy.

This chapter provides a review of the methodology and selection criteria that might be employed in order to identify and validate candidate measures as surrogates of clinical outcome. The analytical procedures outlined here are applicable to a wide range of HIV neurological research but are broad enough to be helpful in general medical investigation. In HIV infection, monitoring of CD4+ T-lymphocyte counts and plasma HIV RNA levels (viral load) is routinely used, rather than observing the occurrence of new opportunistic infections or death. The ability to include uncontrolled studies in meta-analyses evaluating surrogate markers is extremely significant, especially in neuro-AIDS, because the majority of studies that have assessed neurological surrogate markers in HIV have included only a single treatment regimen. The authors simulated a validation study of the screening test in which it was assumed that the true sensitivity and specificity of the screening instrument were at the midpoints of the reported intervals (i.e., 93% and 77%). An overall prevalence of 30% for HIV-associated peripheral neuropathy in the patient population was also assumed. Increasing availability of treatment options in HIV infection has improved the prognosis of many patients infected with HIV. The chapter presents the essential elements for identification and validation of a candidate measure as a surrogate marker. These are distilled into two criteria related to the prognostic ability of the marker for the event of interest and its ability to adequately summarize the treatment effect on the clinical event.

The majority of HIV subunit vaccines are based on the envelope proteins of HIV, namely, gp120 and gp 41, which form the gp160 glycoprotein complex, or on selected epitopes (immunogenic peptides) identified within these proteins. The focus of this chapter is to describe a novel strategy using comparative genomics to select a potential HIV-1 antigen (gp120). This novel approach has proven most promising for the subsequent screening of short peptides from HIV-1 gp120 antigen that are predicted to bind to a wide array of HLA alleles with a view toward the design of cocktail peptide vaccines. In the experimental model described in this chapter, the authors chopped the 510-residue segments of the gp120 envelope protein sequence into overlapping 9-residue-long peptides and then predicted the binding of all the peptides to 295 HLA-A alleles and 540 HLA-B alleles using T-Epitope Designer. The study model presented allowed the comparison of nine HIV-1 protein sequences with the protein sequences from the human genome, which showed that almost all HIV-1 proteins have some degree of sequence similarity to one or more human proteins. The viral diversity, together with host HLA variation in ethnic groups, sets the limit for peptide vaccine progress. The authors have outlined possible solutions to the issues using methods to predict appropriate T-cell epitopes and the rational design and synthesis of a highly conserved antigenic region of gp120. The experimental model described in the chapter serves as a framework for HIV-1 peptide vaccine design.

The National Institute of Mental Health (NIMH) of the U.S. National Institutes of Health (NIH) organized a meeting to discuss clinical and basic research priorities on CNS-related comorbidities and complications in HIV-1-infected older populations. Of interest is a study in which it was demonstrated that HIV-1 RNA in cerebrospinal fl uid (CSF) is produced both from the peripheral blood and from the brain parenchyma in infected individuals. This study supports the notion that the remission of HAART-associated neurological disorders might be relevant to the decrease in peripheral viral load. The study involved comparison of viral env and pol gene sequences from viral genomic DNA isolated either directly from tissues or coculturing methodology for retrieval of viral quasispecies. Other important findings of this study were that during antiretroviral therapy the virus present in the CSF declined rapidly, with an estimated half-life of 1 to 3 days. Viral genome dynamics also play an important role in immune evasion as well as emergence of drug-resistant quasispecies. Changes in the expression of various genes might provide an environment conducive to viral persistence in the brain. Technological strategies used in this study provide a paradigm to isolate HIV-1 from individual cell types and its characterization. Several studies in the past and long-term experience with HAART suggest that the HIV-1-associated severe neurological disorder, HIV-1-associated dementia (HAD), has been significantly reduced in countries where the health care infrastructure could afford this costly treatment.

In 1991, a revision of the terminology was made by the American Academy of Neurology AIDS Task Force, which developed the term human immunodeficiency virus (HIV)-1-associated cognitive motor complex (HIV-CMC), to encompass both the milder HIV-1- associated minor cognitive motor disorder (HIV-MCMD) and the more severe HIV-1-associated dementia complex (HIV-DC) (American Academy of Neurology AIDS Task Force, 1991). Although the advent of highly active antiretroviral therapies (HAART) has made great strides in extending life for AIDS patients, this longer life span may present increasing opportunity for HIV dementia (or HAD) to develop. HIV-1 encephalitis, the histo- and neuropathological correlate of central nervous system (CNS) HIV infection and HAD, occurs in most but not all cases of HAD. Infiltration of infected and/or activated immune cells from the periphery is increased with HIV infection and likely to be essential for development of HAD. Passage of infected cells or virus across the blood-brain barrier (BBB) results in the presence of activated immune cells in the brain, primarily macrophages and microglia but also astrocytes, which are thought to be directly causal to developing HAD. Continuous exposure to these noxious molecules is not necessary for progressive neuronal dysfunction and death. As a consequence of these generalized pathogenic mechanisms, numerous molecules and signaling pathways are secreted and activated that are thought to be involved in precipitating the pathophysiology of HAD, many of which share functions in both normal cellular signaling and other neurodegenerative diseases.

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) is commonly associated with a multinucleated giant cell (MNGC) encephalitis termed HIV encephalitis (HIVE). Importantly, it occurs in most, but not all, cases of dementia related to HIV-1 infection. This chapter strives to describe what is known about multinuclear phagocytes (MP) activation and neuronal dysfunction with a focus on chemokines. Mounting evidence suggests that chemokines affect the pathogenesis of HAND. First, there is a state of “immune privilege” within the central nervous system (CNS) that is, in part, an evolutionary adaptation for which increasing evidence suggests that functional immunity is quite operative in the brain. Second, the maintenance of nervous system function requires protection from a variety of environmental insults occurring during inflammatory activities, such as HIVE. Third, chemokines (chemotactic cytokines) and chemokine receptors are an important part of the immune response that affects cell migration, activation, and tissue homeostasis. Fourth, following local production, chemokines induce leukocyte cytoskeletal changes, for example, actin polymerization, optimizing cell migration to areas of microbial infection or degeneration. Chemokine receptors are critical for the infection of perivascular macrophages and microglia. It has also been shown that chemokines and their receptors play a more direct role in the neuropathogenesis of HIV-1 infection. The neuropathogenesis of HIV-1 infection revolves around inflammatory factors secreted from virus-infected and immunocompetent brain MP. Chemokines and their chemokine receptors are expressed in the nervous system, and their engagement affects neuronal and glial function.

The major clinical and pathological features of the AIDS dementia complex (ADC), or synonymously, AIDS dementia, HIV-associated dementia, and minor cognitive motor disorder, were characterized almost 20 years ago. The fundamental difficulty is that although ADC is caused by HIV itself, the presence of HIV in cerebrospinal fluid (CSF) has little diagnostic specificity. The authors describe a pathogenetically based approach using a combination of CSF markers. In simple terms, ADC pathogenesis can be considered to result from the evolving interactions of three factors: the driving force, HIV; the modulating influence, immune dys-regulation; and the target, central nervous system (CNS). Importantly, alteration of the immune system is likely important in permitting progressive HIV infection of the CNS and in determining its pathogenic character. In the immunological marker category, the most promising measurements are those of CSF neopterin and monocyte chemotactic protein 1 (MCP-1). The uncertainty of ADC diagnosis more than 20 years after its initial characterization remains a conspicuous shortcoming both in the clinic and in clinical trials. There is still a pressing need to develop objective, laboratory-based markers to aid in predicting development of ADC, establishing ADC diagnosis, and appraising disease activity, including treatment responses. While it is likely that the foundation has been laid with a number of exploratory studies already published, these have fallen short of practical clinical application.

This chapter presents (i) unifying neuropathological criteria for diagnosing HIV encephalopathy to decrease variability in diagnostic terms and criteria, (ii) an overview of the neuropathology of HIV infection, and (iii) data to show that highly active antiretroviral therapy (HAART) can reduce the severity of HIV encephalopathy but does not prevent monocyte trafficking to the brain. To determine the prevalence of HIV encephalopathy in autopsies before and after the introduction of HAART in 1995-1996, a group of physicians in Frankfurt, Germany, reevaluated neuropathology reports of autopsies performed on 436 HIV-infected patients between 1985 and 1999 at the Edinger Institute. Throughout the study period, HIV encephalopathy was the most common histological finding and the only neuro-AIDS complication that increased over time; the prevalence of cytomegalovirus (CMV), toxoplasmosis, cryptococcosis, and central nervous system (CNS) lymphoma decreased. The diagnosis of CMV infection of the brain required the identification of cells with the characteristic cytoplasmic and intranuclear inclusions of CMV. Gross examination of the brain and spinal cord at autopsy may reveal no lesions specific for HIV encephalopathy. Brain atrophy is present in severe cases and can be mild to marked, with hydrocephalus ex vacuo. New neuropsychological impairment was twice as common in the pre-HAART group as in the post-HAART group and occurred sooner in the course of HIV. The treatment of choice for HIV dementia and HIV-associated neurocognitive decline is HAART.

This chapter talks about the neuro-AIDS epidemic. Recent decreases in the heterogeneity of HIV sequences for many strains that have occurred in several places in the world including Southeast Asia are described, and their possible association with human behaviors such as drug abuse is considered. Genetic variability and sequence heterogeneity are key features of HIV. Its enzyme, reverse transcriptase (RT), exhibits the ability to jump between nucleic acid strands during replication, resulting in recombination of different types of HIV that infect the same cell. The basic risks for HIV infection are no mystery. Sexual activity, drug abuse (injection), transfusion, needle-sticks, and transplacental transmission are primary risks. It has been hypothesized that there are long-term viral reservoirs of HIV-1. These can exist in the context of T-cell latency as well as highly active antiretroviral therapy (HAART). HIV-associated neurocognitive disorders (HAND) recognized a spectrum of neurocognitive impairments ranging from asymptomatic neurocognitive impairment to HIV-1- associated mild neurocognitive disorder to full-blown HAD. HIV viral isolates and strains with different sequences appear to be important for the pathogenesis of brain disease in neuro-AIDS, and early studies identified HIV-1 isolates related to neuro-AIDS. Genetic recombination is a highly significant and effective mechanism associated with this genetic hypervariability that protects HIV-1 from immunity and eventually leads to profound immunosuppression and demise of AIDS patients.

Impaired neuroprotection, due to increased oxidative stress, has been implicated as a factor affecting neuronal degeneration in HIV/AIDS. This chapter reviews the role of biological antioxidants in maintaining adequate brain function in HIV-1 disease. Cognitive impairment is the major neurological complication of HIV-1 infection, ranging in severity from a mild subclinical cognitive deficit to a dementing illness (HIV-1- associated dementia [HAD]). The advent of protease inhibitors has raised the possibility of HIV-1 suppression and potential eradication, as well as potential neuropsychological benefit. Treatment with highly active antiretroviral therapy (HAART) appears to produce a beneficial effect on neurocognitive functioning. Microglial activation, through the mediation of oxidative stress, appears to play a major role in neuronal apoptosis and consequent neuronal loss in HIV-1-infected individuals. Antioxidants may also decrease neuropathogenesis through regulation of specific proinflammatory cytokines that contribute to neurodegenerative changes and are evident in HIV-1 disease. Alterations in nutritional status have long been acknowledged in various HIV-1-infected cohorts, including men who have sex with men, drug users, heterosexual adults, and children. Antioxidative treatment (daily intake of selenium, vitamin E, and vitamin C) has been reported to inhibit progression of mental deterioration in patients with multiple sclerosis. Moreover, antioxidant therapies have been reported to slow the progression of Alzheimer’s disease and improve cognitive function in late life for those without dementia.

This chapter discusses the known mechanisms by which cell cycle proteins regulate viability, which of these mechanisms are at play in regulating neuronal viability, evidence that cell cycle regulators are stimulated in HIV encephalitis, the implications of these findings in the post-HAART era, and their potential for additional therapy. The three cell cycle proteins implicated in regulating cell viability are retinoblastoma (pRb), E2F1, and p53. pRb and p53 are the two key targets of signaling pathways that regulate cellular decisions to divide, differentiate, or die. Phosphorylation of pRb has been observed in several in vitro models of neuronal apoptosis including trophic factor withdrawal, DNA damage, low potassium levels, beta-amyloid treatment, and oxidative stress. Further investigation is necessary to determine if they are the ultimate targets for deciding between life and death in neurons for the subset of toxins associated with neurodegeneration in response to HIV encephalitis (HIVE). Investigation into cell cycle proteins in HIVE is still in its early days; however, research thus far indicates that mechanisms of neuronal response to the degenerative stimuli in HIVE are similar to those seen in other neurodegenerative diseases. By understanding the impact of macrophage-secreted factors such as cytokines, chemokines, neurotrophic factors (NTF), and reactive oxygen species (ROS) on modulation of cell cycle regulatory proteins in neurons, a greater insight into neurodegenerative processes in HIVE and neurodegeneration as a whole can be gained and hopefully potential therapeutic targets for treatment of these devastating diseases can be identified.

As the HIV/AIDS epidemic approaches the 20th anniversary of the first mysterious reports of people with the syndrome, researchers and clinicians continue to grapple with the complexities of the virus. HIV has been detected in the brain as early as 15 days after accidental intravenous inoculation. However, the mechanism of HIV-related brain injury remains poorly understood. This review attempts to describe the imaging findings associated with brain disorders in HIV-seropositive patients and the rationales for integrating neuroradiological techniques, including radionuclide techniques. HIV has nine genes and belongs to the lentivirus genus of retroviruses. HIV-associated dementia (HAD) is now probably the most common cause of dementia worldwide among people aged 40 or less. The histopathological marker of the HIV-infected brain is the presence of multinucleated giant cells (MGC). Several authors have claimed that neuroimaging studies are relatively insensitive in the detection of early changes in the brain due to HIV infection. Future diffusion tensor imaging (DTI) studies comparing diffusion changes with MRS and virological and immunological parameters will be helpful in further understanding the alterations in the HIV-infected brain. Retinitis is one of the most common manifestations of cytomegalovirus (CMV) infection. In one study, MRS was used to distinguish HIV from CMV encephalitis. The findings suggest that a larger choline signal and a smaller N-acetylaspartate (NAA) signal could be inferred within the white-matter abnormalities due to HIV encephalitis/encephalopathy than in those due to CMV encephalitis.

Neuroimaging studies can aid in the diagnosis of HIV-related brain diseases, as well as improve our understanding of the pathophysiology of HIV dementia. The ultimate goal of "functional" neuroimaging studies is to improve the understanding of common cognitive deficits in HIV patients, such as decreased sustained attention, mental flexibility, general motor speed, and short-term and working memory. To date, only three studies have used perfusion magnetic resonance imagery (pMRI) to evaluate cerebral perfusion in patients with HIV dementia. This chapter reviews some of the technical aspects of pMRI and blood oxygenation level-dependent (BOLD) functional MRI (fMRI), as well as the results of published studies of patients with HIV. Few fMRI or pMRI studies in patients with HIV brain injury have been published. The major findings from pMRI include frontal hypoperfusion, as well as subcortical gray-matter and parietal white-matter hyperperfusion. These regional perfusion abnormalities may reflect neuronal dysfunction or inflammatory changes. Finally, due to the highly reproducible intrasubject patterns of brain activation, fMRI holds great promise, not only for evaluating the extent of brain injury, but also for longitudinal clinical trials to monitor treatment effects in HIV-associated brain injury.

This chapter describes the different methods used to perform magnetic resonance spectroscopy (MRS) studies of patients with HIV infection, reviews the major findings from the studies, and identifies future directions for clinical studies that may further elucidate the pathophysiology of HIV-associated brain injury, as well as discusses issues to consider in treatment monitoring. MRS studies have been performed in both adult and pediatric patients with HIV infection, using localized MRS and MRS imaging (MRSI) techniques and long TEs and short TEs, and before or after antiretroviral treatment. The majority of the studies used localized spectroscopy techniques (either point resolved spectroscopy (PRESS) technique or the stimulated echo acquisition method) and evaluated one to three brain regions. Limited by magnetic-susceptibility problems in evaluating the frontal brain regions, many of the earlier localized MRS studies evaluated the parietal or the occipital brain regions. Improvements in MRS techniques, such as adjustments of the slice order, allow the assessment of the frontal lobe and subcortical brain regions. Prior to highly active antiretroviral therapy (HAART), several longitudinal MRS studies reported changes in metabolite ratios or levels in HIV patients during antiretroviral treatment. Levels of inflammatory markers, such as the chemokine macrophage chemoattractant protein 1 (MCP-1), were found to be higher in patients with HIV-associated dementia than in those who were neuroasymptomatic. Additionally, both in vivo and ex vivo MRS studies in animal models of AIDS (e.g., simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV)) should provide additional insights into the pathophysiology of HIV-associated dementia.

Recent studies focusing on Hepatitis C virus (HCV) survival strategies revealed that viral proteins may interfere with pathways of retinoid-acid-inducible gene I and Toll-like receptor 3, which constitute two major pathways of host defense triggered by viral nucleic acids. In particular, HCV seems to interfere at several different points with interferon (IFN) and IFN-stimulated gene signaling. A powerful strategy employed by the virus is genetic variability resulting in the constant and dynamic development of variants capable of avoiding eradication by host defenses. Several studies have reported that transmission of infection may be limited to a few variants present within the quasispecies population. Thus, viral populations found in children infected at birth were found to be more homogeneous than those in mothers. HCV infection is common among HIV-positive patients, as the two pathogens share similar routes of transmission. HCV is a positive-strand RNA virus, which replicates through negative-strand RNA, the presence of which could be regarded as direct evidence of ongoing replication. HCV RNA-negative strand was detected only in a minority of cases; however, it is likely that the strand-specific assays are not sensitive enough to detect low-level extra hepatic replication. Infected macrophages and microglia cells could release proinflammatory cytokines, such as tumor necrosis factor (TNF)- α, interleukin-1 (IL-1), and IL-6, neurotoxins such as nitric oxide, and viral proteins, which could induce alteration in brain function leading in turn to neurocognitive dysfunction and depression.

This chapter focuses on the pathogenesis, diagnosis, and management of central nervous system (CNS) toxoplasmosis. The latest epidemiological trends are discussed, and special attention is given to recently developed diagnostic modalities including laboratory techniques and newer neuroimaging modalities. The lesions associated with toxoplasmosis vary in size, characteristics, and location. Typical lesions of toxoplasmosis are characterized histopathologically by three zones. In patients with AIDS, toxoplasmosis is almost always due to reactivation of previously acquired infection. Manifestations of toxoplasmosis in the AIDS population are primarily those of CNS dysfunction and usually reflect the multiple abscesses that are present. Given the high seroprevalence of toxoplasmosis, positive serology is not helpful in distinguishing reactivation from quiescent infection and is not very useful in ruling in active Toxoplasma infection. The locations of lesions adjacent to cerebrospinal fluid (CSF) pathways, e.g., periventricular as well as subependymal spread or ventricular encasement, are characteristic of primary CNS lymphoma (PCNSL), rather than toxoplasmosis. Thallium-201 single photon emission computed tomography (Tl-SPECT), fluorodeoxyglucose positron emission tomography (FDG-PET), and magnetic resonance spectroscopy have all been studied as methods to differentiate PCNSL from other causes of focal brain lesions, specifically toxoplasmosis. For patients who have not received HAART, primary prophylaxis and maintenance therapy need to be continued indefinitely due to the high risk of acute toxoplasmic encephalitis (TE) and relapse of TE, respectively.

The 1980s brought a story in the setting of the emerging disease AIDS. Here, retinitis, gastrointestinal disease, and nervous system infection predominated. Cytomegalovirus (CMV) is an enveloped double-stranded DNA virus in the beta subgroup of the herpesvirus family. Well-documented shedding of virus in human breast milk, urine, saliva, tears, semen, and cervical secretions, some of which occurs in healthy hosts, suggests that epithelial cells may harbor latent but reactivatable virus. Autopsy studies of homosexual men with AIDS have shown that multiple strains of CMV can infect different tissues. Longitudinal serial isolates from homosexual men show that 29% have two or more strains and semen was the most common site of viral shedding (40%). The pathology of CMV radiculomyelitis usually consists of inflammation and necrosis, with typical cytomegalic inclusion cells in the lumbosacral roots. The broad spectrum of observed central nervous system (CNS) disease in AIDS is likely related to a broader range of viral load secondary to the immunodeficiency. The hematogenous-endothelial mode of entry is postulated to lead to diffuse disease. There is one report of its successful use in AIDS-associated ventriculoencephalitis with both clinical improvement and reversion of CSF to CMV negative by PCR.

Fungal infections of the central nervous system (CNS) are an important cause of morbidity and mortality in HIV-infected patients. Cryptococcus neoformans is the most important fungal pathogen in AIDS patients throughout the world. Other important but less frequent fungal pathogens include Histoplasma capsulatum, Coccidioides immitis, Aspergillus spp., the zygomyces, Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Candida spp. Histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and blastomycosis are limited to certain geographic areas, whereas the other pathogens are relatively ubiquitous. In the developed world the incidence of invasive fungal infections has declined with the widespread use of highly active antiretroviral therapy (HAART); however, in the developing world, where the vast majority of HIV-infected individuals are not receiving HAART, these pathogens, especially C. neoformans, continue to cause significant morbidity and mortality. Major advances in the management of cryptococcosis in the past few years have led to significant improvements in mortality, but morbidity remains elevated. The optimal management of other, less common CNS fungal infections in AIDS is less well defined due to the paucity of controlled trials. The advent of the worldwide AIDS pandemic led to a sharp increase in the number of cases of cryptococcosis. Further decreases in cryptococcosis have paralleled the decline in other opportunistic complications observed in the HAART era. In much of the developing world C. neoformans remains an important cause of morbidity and mortality and is one of the most common AIDS-defining conditions.

The presence of cerebrospinal fluid (CSF) abnormalities does not necessarily predict the development of neurosyphilis. The characteristic spinal cord syndrome associated with parenchymatous neurosyphilis is tabes dorsalis. A more rapid development of neurosyphilis in HIV-infected individuals than would otherwise be expected may result from the impairment of delayed hypersensitivity. Despite the associated immunosuppression, serum nontreponemal titers at the time of presentation of neurosyphilis in the HIV-infected individual are typically high, averaging 1:128. In general, those neurologic manifestations occurring early in syphilis, namely, asymptomatic neurosyphilis and syphilitic meningitis, are readily treatable and typically resolve without neurologic sequelae. Dependence on the CSF for determining the adequacy of treatment for neurosyphilis in HIV-infected individuals often yields inaccurate results, due to the frequency with which CSF abnormalities are detected with HIV infection alone. Neurosyphilis is broadly defined as the occurrence of neurological complications due to infection with Treponema pallidum. While the diagnosis of syphilis is relatively straightforward with serum tests for demonstration of treponeme or immune response to this pathogen, the diagnosis of neurosyphilis is more complicated. The goal of neurosyphilis treatment is to reach treponemicidal levels of penicillin in the CSF. The best determinant of treatment adequacy for neurosyphilis is the resolution of CSF abnormalities, although it often yields inaccurate results in HIV patients because of irregularities due to HIV infection alone. HIV-seropositive patients should be monitored for neurosyphilis relapse for at least 2 years following treatment.

Progressive multifocal leukoencephalopathy (PML) is an important viral infection of the central nervous system that has attracted increasing attention in recent years because of the surge in incidence accompanying the epidemic of the human immunodeficiency virus (HIV). An interesting problem raising concern among neuro-AIDS experts has been the development of an increasing number of serious, undiagnosed white matter conditions in the setting of highly active antiretroviral therapy (HAART). Clinical presentations of PML are also helpful in suggesting the diagnosis. While the disease is often pathologically multifocal, it is most commonly clinically characteristic of a progressive focal disease. Analysis of the cerebrospinal fluid (CSF) has been complementary to examination and magnetic resonance (MR) scanning and has improved the sensitivity and specificity to the point that in most cases, even for research purposes, a brain biopsy does not appear to be necessary. Numerous case reports of cytosine arabinoside (cytarabine) treatment associated with disease arrest were included in the literature through the years. PML remains an important challenge for clinicians and researchers. Increasing ability to detect and tract the activity of this ubiquitous virus will enhance our understanding of its pathobiology.

Epstein-Barr virus (EBV) is a double-stranded DNA virus of 172 kbp. It is classified as a lymphocryptovirus in the gammaherpesvirus group. Infection with EBV is very common, usually occurring early in life, and is endemic in all human populations. There are two main types of EBV infection, lytic and latent. The infection occurs even in populations that are geographically isolated, thus indicating that EBV is a fairly ancient virus. Encephalitis is an uncommon manifestation of acute EBV infection but is well described. The diagnosis of EBV-related disease must be planned thoughtfully, choosing appropriate methods to answer well-defined questions. Primary central nervous system (CNS) lymphomas (PCNSL) is an EBV-associated opportunistic neoplasm of the brain found in patients with very advanced HIV disease, having very low CD4+ T-cell counts. This is the most common CNS manifestation of EBV infection in AIDS patients, although with the advent of highly effective combination antiretroviral therapy, the disease has become quite uncommon. Infection with EBV is common and lifelong in humans and rarely results in severe disease. Treatment of opportunistic neoplasms is difficult, and the prognosis is still not very good despite the progress that has been made in understanding these tumors. On the other hand, recent basic research has suggested a number of new approaches, and much clinical trial work remains to be done.

This chapter reviews of the epidemiology, diagnosis, and treatment of the major psychiatric aspects of HIV infection, in addition to somatic symptoms such as sleep disorder, fatigue, sexual dysfunction, and HIV-associated lipodystrophy, all of which have substantial quality of life impact. Benzodiazepines should be avoided in patients with cognitive impairment and delirium. Delirium is common among hospitalized HIV/AIDS patients. Most studies documenting rates of delirium were conducted in the pre-highly active antiretroviral therapy (HAART) era and were restricted to subsets of patients seen in psychiatric consultation. Sleep disorders, primarily insomnia disorders, are prevalent in the HIV-infected population. Hepatitis C virus (HCV) infection is increasingly recognized as a significant comorbid condition that affects the clinical outcome of patients with substance abuse disorders and HIV disease. Fatigue is common among patients with HIV/AIDS and may contribute to impairment in physical function and disability. With the advent of nucleoside analog reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine), nonnucleoside analog reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz), and PIs (e.g., indinavir) as part of HAART, there has been heightened interest in the issue of drug interactions in the context of HIV psychopharmacology. HIV-associated lipodystrophy is an increasingly recognized complication of prolonged treatment with HAART that may have significant impact on the psychological well-being and quality of life of those affected.

This chapter reviews the studies which provide evidence for a synergistic effect of drugs of abuse and human immunodeficiency virus (HIV) infection on brain function. Understanding the interactive mechanisms of this neurodegeneration is critical to our ability to optimize therapy for drug-abusing HIV-infected populations. The chapter discusses the proposed underlying mechanisms of this combined neurotoxicity, the current state of knowledge about the role of highly active antiretroviral therapy (HAART) in this interaction, and implications for future research and therapeutic development. It discusses the evidence that each of the drugs of abuse interacts with HIV infection through influences on the dopaminergic system and by other mechanisms as well. A recent study showed that morphine inhibits CD8-positive T-cell-mediated noncytotoxic anti-HIV activity in latently infected human immune cells, largely by interfering with a gamma interferon signaling pathway. Naltrexone blocked this morphine-induced inhibition. This study suggests that morphine impairs the anti-HIV function of the immune system. In injection drug users, HAART utilization decreases mortality compared to nonutilization, though all injection drug users, with or without HAART utilization, have better survival in the HAART era than in the pre-HAART era. By stopping the interactive mechanisms discussed in this chapter, it would seem reasonable that drug abstinence would halt or potentially reverse the synergistic progression of HIV-associated dementia in drug-abusing individuals. Further work is needed to optimize and develop new strategies for the benefit of the drug-abusing population.

The nature of neurocognitve impairment associated with HIV has changed, after the introduction of highly active antiretroviral therapy (HAART), to more subtle forms, requiring the establishment of new definitional criteria. Recently, the neurological spectrum of HIV-1 infection has been divided into the eras before and after HAART. Antiretroviral (ARV) therapy has had a direct impact on patient survival and the clinical manifestations of neurological complications. In the pre-HAART era, the most common neurological complications were HIV encephalitis, cytomegalovirus infection, toxoplasmosis, cryptococcus infection, and progressive multifocal leukoencephalopathy. The role of host factors in HIV-1-associated dementia (HAD) has been illustrated by finding genetic mutations associated with the disease. The presence of neurocognitive impairment in HIV-1-infected individuals, which varies from subtle, mild deficits (e.g., asymptomatic with subclinical neuropsychological deficits) to minor cognitive-motor disorder (MCMD) to HAD, is one of the common neurological, neuropsychological, and neuropsychiatric complications of HIV-1 infection. There is limited literature regarding neuro-AIDS complications in ethnic groups and special populations. Assessing for neurocognitive performance in ethnic groups is critical to establish population-specific normative standards and culturally valid tests. Ethnic, gender, education or literacy, genetic, and age factors may contribute to different manifestations of HIV-1 cognitive impairment; consequently, they should be considered in research design. It is possible that the different scales used for HIV-1 cognitive function (Memorial Sloan Kettering, HDS, and AAN criteria) may fail to correctly identify cognitive impairment in different ethnic groups.

Generally, HIV-1-positive women start highly active antiretroviral therapy (HAART) more rarely and later than men. HIV can affect the central and peripheral nervous system directly, provoking neurological signs and symptoms, and indirectly by causing immunodeficiency and thus susceptibility to infections with opportunistic infectious bodies. The incidence of HIV-1-associated dementia (HAD) has declined in the era of HAART, but in 2002, prevalence rates began to rise again due to the longer survival time of HIV-1-positive patients. On the whole, studies of neuro-AIDS conditions in women and how they possibly differ from men are scarce. There have been two studies analyzing the effect of HAART on neurocognitive performance in HIV-1-positive women. However, it is interesting that there are large cohort studies that analyze neurological disorders in homosexual and bisexual men, but even large studies like the Women's Interagency HIV Study do not automatically examine neuro-AIDS conditions but leave them to surprisingly small substudies. The HIV-1/AIDS-associated neurological manifestations increase with more intensive use of HAART and longer survival of affected people, including women. Thus, it is mandatory to gather more details on women developing neurological complications due to the virus itself or to HAART. The chapter talks about sex- and gender-specific data analysis in a German cohort of women living with HIV/AIDS.

This chapter reviews the clinical, neuroimaging, and neuropathological features of pediatric neuro-AIDS (prior to the use of antiretroviral (ARV) agents) and the changing neuroepidemiology in the highly active ARV therapy (HAART) era. Salient features of pediatric HIV/AIDS and its epidemiology are briefly summarized, since there are major differences between adult and pediatric HIV/AIDS, and neurological aspects need to be viewed in the context of this complex and progressive illness for which the epidemiology is diverse and changing, as are treatment protocols and their availabilities. Among adolescents, intravenous drug use and sexual exposure are the most common risk factors for acquiring HIV-1 infection. Some children develop progressive and disabling motor deficits yet maintain relatively stable (albeit impaired) cognitive and adaptive social skills, whereas others have more impaired cognitive than motor function. Some children can also have relatively stable minor motor and cognitive findings. Host genetic factors are relevant as well (e.g., CCR5 and CXCR4 polymorphisms, virus-host interactions affecting genes and gene products, and as-yet-undefined virus-host interactions). Secondary central nervous system (CNS) complications should be considered in the differential diagnosis of the HIV-1-infected child who presents with new onset of mental status changes, headache, seizures, or focal neurological deficits. The most effective way to prevent pediatric HIV-1-associated neurological syndromes is to prevent vertically acquired HIV-1 infection. Clearly the most effective strategy to achieve this goal is to prevent HIV-1 infection in all women of childbearing age.

The foregoing introduction to the epidemiology of aging in HIV-1 infection leads us to an important preliminary conclusion. That is, the study of older age in HIV-1 infection is more properly considered as (i) the study of a population of newly infected older individuals and (ii) the study of a separate group of long-term HIV-1-infected patients successfully treated with highly active antiretroviral (ARV) therapy (HAART). The authors used a generalized linear models approach with age category, HIV-1 disease category (HIV-1 seronegative, CDC stage B/early symptomatic HIV-1 infection, and CDC stage C/AIDS), and their interaction as predictors of the total number of MCMD symptoms (zero to six) defined by the American Academy of Neurology. Given the hypercortisolemia-induced neuronal cellular toxicity associated with major depressive disorder and with chronic stressor exposure, both of these conditions may enhance the likelihood of neurocognitive impairment (NCI) and neurocognitive disorder when superimposed upon the toxicities associated with the aging process and HIV-1 infection of the brain. In addition to the consideration of how aging might interact with HIV-1 infection in specific neuro-AIDS conditions, an overarching issue exists. That issue is related to how an increased frequency of medical comorbidities might interact with aging in the likelihood of expression of neuro-AIDS conditions.

This chapter attempts to address the palliative-care issues that currently affect patients with HIV/AIDS and neurologic disease in many developed countries that have moved into the chronic-disease phase of the epidemic. The spectrum of morbidity and mortality in patients with AIDS has changed dramatically in recent years, following the advent of highly active antiretroviral therapy (HAART) in the mid-1990s. The chapter discusses the issues and the importance of incorporating a palliative care approach with respect to specific HIV-related neurologic conditions and symptoms. The current environment requires not only individual clinicians' sensitivity and expertise in dealing with the chronic symptom syndromes but also the institutional and programmatic response of the care delivery system in order to meet the needs effectively. While the chapter focuses on the palliative and supportive management of patients with HIV/AIDS with chronic neurologic disabilities and symptoms, it is important also to focus on care needs at the end of life for patients who die either of AIDS-related causes, of incurable comorbidities, or of other etiologies. In closing, it must be mentioned that the stresses and cumulative burden of caring for patients with AIDS in this chronic disease phase of the epidemic are also different from what they were earlier, when patients did not survive as long and there was a shorter shared history with their caregivers than is now the case.

This chapter focuses on some of the key legal elements relating to human immunodeficiency virus (HIV) infection and AIDS. The AIDS Drug Assistance Program is one of the key government-funded programs that provide AIDS-related drugs to those who could otherwise not afford them. A recent study found that HIV therapies reduce infectivity by 60%. Access to HIV therapies reduces the viral load (or the amount of HIV present in a person’s bloodstream)—a key factor in curbing infectivity and in reducing the ability to transmit HIV. There is now evidence that AIDS, if untreated, affects the cognitive functioning of patients, sometimes quite early in the disease process. AIDS patients should be educated about the common neurological complications of HIV infection, including peripheral neuropathy as well as neurocognitive disorder. The American Medical Association has stated that physicians have an ethical obligation to provide care for patients with HIV infection and AIDS. AIDS has affected all aspects of family life. Injection drug use is responsible for over 30% of the transmission of HIV/AIDS in certain parts of this country, like New York City. It emphasized the need to protect human rights and human dignity in the context of the HIV/AIDS pandemic. Efforts to prevent the spread of HIV have helped decrease the transmission in developed countries. It is learned from experience that coercion in the form of threats, penalty, and discrimination is not an effective tool to prevent the spread of an epidemic such as AIDS.

In developed countries the effect of highly active antiretroviral therapy (HAART) on the neurological complications in the short term has been well described, but the long-term effects are only just starting to be clarified. These issues are best discussed within a framework that structures the complications according to whether they are direct or indirect. Within this framework this chapter deals briefly with the more significant aspects of nervous system involvement in HIV infection emphasizing three points: possible new complications in developing countries, new complications in HAART-treated patients as well as complications such as progressive multifocal leukoencephalopathy (PML) that have only marginally changed with HAART, and future directions. The direct complications such as dementia and neuropathy are organized according to the degree of advancement of HIV disease and anatomical region involved. With the introduction of HAART, some aspects of investigations have changed; however, this is an evolving area that still needs clarification. There are several myopathies that have been linked to HIV disease. The association seems to be at least in part causal rather than just associative. The two most important are polymyositis and inclusion body myositis. The indirect neurological complications related to HIV disease are many. Only the more important are discussed in the chapter. The most significant aspects of these disorders in the era of HAART are that the incidence of opportunistic infections has significantly declined with HAART and that HAART may induce the clinical expression of previously subclinical disease through the immune reconstitution syndrome.