Keywords
HIV/AIDS, HIV-associated neurocognitive disorder, HIV-associated dementia, antiretroviral therapy, primary HIV infection, opportunistic infection, HIV-associated myelopathy, HTLV, HTLV-associated myelopathy, tropical spastic paraparesis, peripheral neuropathy, cerebrospinal fluid
Human immunodeficiency virus type 1 (HIV-1) infection involves the central nervous system (CNS) beginning during primary viremia and continuing over the course of untreated infection. Although the majority of patients with HIV infection do not present with neurologic symptoms, HIV disease has protean manifestations in the CNS determined largely by host characteristics such as immune status, treatment history, and access and adherence to antiretroviral therapy (ART).
Thirty Years Later: HIV Beyond the Immune System
Thirty years after the report of five unexplained cases of Pneumocystis carinii pneumonia in men suffering from what would eventually become recognized as the acquired immunodeficiency syndrome (AIDS), HIV infection remains the subject of intense biochemical, molecular, clinical, and epidemiologic investigation. HIV infection is a blood-borne and sexually transmitted disease that impacts both individual and public health and has disproportionately affected vulnerable and marginalized individuals and populations including the poor and underserved, injection drug users, commercial sex workers, and men who have sex with men. The epidemic has also changed in the last decades. What once was largely a disease of young men who have sex with men in urban centers has expanded to affect all populations; the highest route of overall transmission of HIV is currently through heterosexual contact, often in rural areas in individuals unaware of their risk of HIV acquisition.
It is estimated that there are currently 34 million people infected with HIV worldwide and 2.5 million new infections annually. Around 1.7 million individuals die from the disease and its sequelae each year. Although the greatest number of new infections and the worst outcomes occur in the lowest-resource settings in sub-Saharan Africa and Southeast Asia, nearly 50,000 individuals are newly infected in the United States each year, reflecting little change over the course of the epidemic.
A better understanding of the virus’s characteristics, including its pathogenesis and transmission patterns, has led to both prophylactic and therapeutic interventions, but many questions about the pathogenesis of HIV infection remain unanswered. An increased focus on the effects of HIV infection beyond the immune system has emerged, including its end-organ effects on the nervous system.
HIV in the Nervous System
HIV is a single-stranded, positive-sense retrovirus of the genus Lentivirus . Once transmitted to a new host, the virus uses a reverse transcriptase to transcribe viral RNA into DNA. This DNA is, in turn, integrated into the genome of the host. The stages of HIV infection are divided into the acute phase that immediately follows transmission and includes the CD4 + T-cell nadir, the asymptomatic latent phase characterized by a slow decline in CD4 + T cells, and the symptomatic phase of chronic AIDS. In antiretroviral-naïve patients, it takes approximately 10 years to develop AIDS, although this time may be extended indefinitely with combination ART (cART; Fig. 44-1 ). Following the development of AIDS, median survival is typically between 1 and 4 years.
It is increasingly recognized that the body’s reaction to HIV infection can be as damaging as the activity of the virus itself, and this is particularly true in the nervous system. The inflammatory milieu that is induced by the activity of HIV in invading cells and triggers an immune response has important implications throughout the time course of infection. It is thought that HIV pathogenesis within the CNS is mediated primarily by inflammation induced by both systemic immune activation as well as HIV infection of macrophages, microglia, and astrocytes. It is hypothesized that an indirect toxic injury to neurons results from a cascade of chronic and persistent neuroinflammation, in part fostered by cytokines produced by infected or activated cells within the brain. In the earliest stages of infection, the virus crosses the blood–brain barrier for the first time and initiates cytokine release that contributes to breakdown of that barrier. Other effects include a cerebrospinal fluid (CSF) pleocytosis, macrophage and lymphocyte activation, interference with neuronal synthesis and maintenance pathways, and ultimately neuronal injury that can be detected through biomarkers and neuroimaging. Although control of the virus through the initiation of cART can decrease the viral load and supppress the immune response, the CNS remains particularly vulnerable to further insult and may not normalize as well as systemic compartments.
Recent studies of the end-organ effects of HIV beyond the immune system have led to the recognition of a biologic compartmentalization that allows for infection and injury of target tissue, independent evolution of the virus from its counterparts in the plasma, and protection of the virus from systemic therapy. The development of these distinct biologic compartments, such as those in the breast and genital tract, facilitates viral replication, complicates viral eradication, and leads to organ-specific effects. Chronic HIV infection is associated with the establishment of a CNS reservoir of infection, as evidenced by the detection of HIV DNA in perivascular brain macrophages, microglial cells, and astrocytes, compartmentalization of HIV quasi-species in CNS tissues, and clinical cases of isolated CNS “escape” from antiretroviral therapy. Targeting treatments and strategies towards CNS reservoirs of HIV has become an important aspect of recent efforts to achieve a cure for HIV infection.
Neurologic Dysfunction in the Setting of Antiretroviral Therapy
The introduction of cART in the mid-1990s fundamentally altered the landscape of both systemic and neurologic HIV disease. The profound immunodeficiency associated with HIV/AIDS that acted as the substrate for the “classic” neurologic manifestations of the disease itself and the opportunistic infections with which it was associated can now be significantly delayed or prevented, transforming the disease from one that was uniformly fatal into a manageable chronic illness.
In general, antiretroviral therapy suppresses both plasma and CSF viral levels and improves neurologic outcomes in patients with HIV infection. Typically, plasma HIV RNA suppression is paralleled by suppression in the CSF, and the initiation of cART also limits the extent of immune activation in the CSF, as measured by white blood cell count and immunologic markers. With systemic control of the virus and improved immune status has come a striking decline in the occurrence of neurologic opportunistic infections over the last two decades, while the attenuation of viral replication and immune activation in the CNS has resulted in a decline in the incidence of the most dramatic forms of HIV-associated neurologic disease. Nevertheless, even individuals with well-controlled HIV infection continue to experience neurologic dysfunction which, although often less pronounced than the illnesses experienced 30 years ago by many patients with AIDS, has the potential to seriously impact productivity and quality of life.
HIV-Associated Neurocognitive Disorder
What was previously defined in its most severe form as the AIDS-dementia complex is now represented by a spectrum of disorders reflecting the variability in presentation, outcome, and impact of neurologic disease.
HIV-associated neurocognitive disorder (HAND) comprises a diverse set of neurocognitive diseases, ranging from clinically asymptomatic impairment to severe dementia. HAND is a clinical diagnosis defined by abnormalities identified through neuropsychologic testing and is subdivided into three categories of increasing severity: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (HAD) ( Table 44-1 ). These diagnoses require the administration of a specific neuropsychologic test battery assessing language, attention, executive functioning, memory (learning and recall), processing speed, visuospatial abilities, and motor skills. While the incidence of the most severe manifestations of HAND has decreased in the setting of widespread access to cART, mild-to-moderate HAND has persisted and has become the most prevalent primary CNS complication of HIV infection.
| Asymptomatic Neurocognitive Impairment (ANI) | Mild Neurocognitive Disorder (MND) | HIV-Associated Dementia (HAD) | |
|---|---|---|---|
| Neuropsychological Testing Abnormalities | One standard deviation below the age- and education-adjusted mean on two cognitive domains | One standard deviation below the age- and education-adjusted mean on two cognitive domains | Two standard deviations below the age- and education-adjusted mean on two cognitive domains, especially learning, information processing, and attention/concentration |
| Effect on Everyday Function | None | Mild | Marked |
| Absent | Absent | May be present, but must be absent on at least one prior occasion where dementia was present | |
| Dementia | Absent | Absent | Present |
| Other causes such as opportunistic infection, vascular dementia, severe active drug use must be absent |
Asymptomatic Neurocognitive Impairment
The most benign and most common manifestation of HAND is asymptomatic neurocognitive impairment, which has been identified in approximately one-third of HIV-infected patients. It is characterized as a subclinical cognitive decline with decreased performance on neuropsychologic testing in two or more domains not attributable to comorbid conditions (e.g., mood disorders, substance abuse). It specifically requires that no negative impact on everyday functioning is present, distinguishing it from mild neurocognitive disorder.
It is unclear whether asymptomatic neurocognitive impairment predicts more severe neurologic impairment later in the course of HIV, whether it contributes to neuropathologic vulnerability, and whether early intervention with cART at this stage might prevent ongoing deterioration.
Mild Neurocognitive Disorder
A form of mild cognitive impairment is being recognized increasingly in individuals treated with cART, who typically have a relatively reconstituted immune system characterized by high CD4 + T-cell counts and suppressed or undetectable viral loads. As the population of patients with chronic, well-controlled HIV infection continues to grow, so too does the overall prevalence of mild neurocognitive disorder, which may approach 12 percent in some studies.
The diagnosis of mild neurocognitive disorder depends on the detection of abnormalities in neuropsychologic testing in attention, processing speed, memory, and executive function domains. In contrast to those with asymptomatic neurocognitive impairment, patients typically are aware of a subtle impairment in cognitive ability and increased difficulty carrying out activities of daily living. Mild neurocognitive disorder can also affect both pyramidal and extrapyramidal motor systems, producing symptoms such as ataxia, tremor, and incoordination that may worsen over time. It can lead to behavioral symptoms that are independent of those associated with mood disorders concomitant with HIV infection.
HIV-Associated Dementia
The disorder initially described 25 years ago as the AIDS-dementia complex is now known as HIV-associated dementia (HAD), the most dramatic manifestation of HAND. The diagnosis remains a challenge, as there are no diagnostic studies or laboratory tests that are specific for HAD.
The diagnosis of HAD is based on progressive neurocognitive impairment and the exclusion of other conditions that can mimic these symptoms including CNS opportunistic infections and mass lesions such as tumors. HAD is still identified most commonly in patients not taking antiretroviral therapy; the prevalence in treated patients may be as low as 2 percent. HAD most typically occurs in patients with slowed cognitive processing in the context of long-standing HIV infection and is often accompanied by motor abnormalities such as slowed movement and spastic gait along with hyperactive muscle stretch reflexes. Evaluation with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain is used to exclude other AIDS-related neurologic conditions, including opportunistic infections and CNS lymphoma. With these diagnoses excluded, diffuse cerebral atrophy and subcortical or periventricular white matter changes are consistent with, although not specific for, HAD.
Etiology
Although the biologic substrate of HAND in the setting of antiretroviral therapy is unknown, one potential mechanism involves injury occurring in the earliest stages of HIV infection. Such injury would begin before treatment is initiated and would continue along a trajectory that may or may not be mitigated by initiation of cART. After several years, a combination of host susceptibility and disease factors may result in the development of symptomatic neurologic disease.
Another possibility is that, due to the compartment-specific nature of CNS HIV infection, neurologic injury is incurred despite the initiation and continuation of systemically suppressive treatment. Even in individuals with no overt signs or symptoms of neurocognitive impairment, the presence of HIV in the CNS may result in constant low-level inflammation and immune activation that may lead to ongoing brain injury. CSF immune activation, brain inflammation detected by magnetic resonance spectroscopy, and microglial activation persist in patients on long-term suppressive antiretroviral therapy.
Diagnosis and Management
Because HAND has no specific diagnostic markers, it is necessary to exclude CNS opportunistic infections, delirium, toxic-metabolic disorders, psychiatric disease, and other neurodegenerative conditions before making the diagnosis. Although traditional neuroimaging is useful in excluding other HIV-associated disease processes, including CNS lymphoma, infections, and inflammatory processes, there are no findings on standard imaging that are specific for HAND ( Fig. 44-2 ). Efforts to use more advanced neuroimaging techniques to identify mild HAND have included brain mapping, high-field structural imaging, functional MRI, and magnetic resonance spectroscopy. The utility of these new modalities remains to be determined. Figure 44-3 provides an algorithm for the identification and management of HAND.
Performance on neuropsychologic tests in severe forms of HAND improves with the initiation of cART. The introduction of cART has been associated with decreased incidence and prevalence of HAD despite increases in the prevalence of milder forms of HAND. While initiation of cART significantly improves cognitive performance and neurologic function in antiretroviral naïve patients with HAD, this improvement is frequently incomplete. Furthermore, many patients already taking cART also have HAND.
Treatment
Adjunctive therapies that target the CNS have been studied in an attempt to attenuate the inflammatory events that are postulated in the pathogenesis of HAND. Adjunctive therapies other than with antiretroviral agents, including with memantine, selegiline, and nimodipine, have not been successful. Valproic acid and lithium have been hypothesized to decrease HIV replication and neuroinflammation through their glycogen synthase kinase-3β activity, as have serotonin reuptake inhibitors such as citalopram and paroxetine through an unknown mechanism; no clear improvement in HAND has been demonstrated with these agents. Due to its anti-inflammatory and antiviral effects, the antibiotic minocycline has also been suggested as a potential therapy, but randomized trials have been unsuccessful. Statins, which have widespread anti-inflammatory effects, are under study. Methylphenidate successfully treats fatigue and psychomotor slowing in patients with HAND, but does not alter the course of the disease. An alternate treatment strategy using antiretroviral drugs that penetrate into the CNS is discussed later.
Targeted Treatment of CNS HIV Infection
By separating the CNS from the systemic circulation, the blood–brain and blood–CSF barriers affect the ability of antiretroviral agents to access the CNS compartment. In addition, local spontaneous replication of HIV within this viral sanctuary may allow for independent mutations of HIV virions. While the response of CSF HIV RNA levels to cART parallels that in the plasma, the rate of decay in the CSF may be more gradual in some patients, suggesting a compartmentalization characterized by slower cell turnover, extended macrophage release, or attenuated drug entry.
Because of the blood–brain barrier, HIV in the CNS may be protected from the full effect of antiretroviral agents, especially those drugs that are large or hydrophilic. The CNS penetration-effectiveness (CPE) index represents an effort to estimate quantitatively the relative ability of each antiretroviral agent to penetrate the CNS and interfere with CSF HIV replication. Each agent is assigned a CPE score based on presumed CNS exposure and efficacy of the drug in relation to others in its class ( Table 44-2 ).
| Drug Class | CNS Penetration-Effectiveness Score | |||
|---|---|---|---|---|
| 4 | 3 | 2 | 1 | |
| NRT Inhibitor | Zidovudine | Abacavir Emtricitabine | Lamivudine Stavudine | Didanosine Tenofovir Zalcitabine |
| NNRT Inhibitor | Nevirapine | Delavirdine Efavirenz | Etravirine | – |
| Protease Inhibitor | Indinavir/r | Darunavir/r Fosamprenavir/r Indinavir Lopinavir/r | Atazanavir Atazanavir/r Fosamprenavir | Nelfinavir Ritonavir Saquinavir Saquinavir/r Tipranavir/r |
| Entry Inhibitor | Vicriviroc | Maraviroc | – | Enfurvirtide |
| Integrase Inhibitor | – | Raltegravir | – | – |
Some studies have shown that antiretroviral regimens with higher CPE scores tend to be more successful at achieving HIV RNA suppression in the CNS. While more potent HIV RNA suppression in this compartment might be expected to lead to better neurocognitive outcomes, results have been mixed, with some studies showing that regimens with higher CPE scores actually lead to poorer neurocognitive performance or only benefit patients treated with more than the standard cART regimen of three drugs.
The inability of antiretroviral therapy to control the potential reservoir of HIV that exists in monocytes has been proposed as one possible explanation for continued neurocognitive impairment in the setting of cART. As a result, a monocyte efficacy (ME) score has been proposed as an alternative means of quantifying the ability of antiretroviral agents to affect neurologic outcomes. Preliminary work has suggested that that the ME score correlates with neurocognitive performance even when CPE score does not.
Progressive Disease Despite Systemic Response
Several new clinical syndromes have been recognized in patients taking systemically suppressive cART, often after a long period of apparently successful treatment. A phenomenon of CSF/plasma viral load discordance in the setting of new neurologic symptoms has been identified in some patients with a well-controlled plasma viral load. This discordance syndrome is also known as symptomatic CSF escape . Although the virus is controlled or suppressed in the plasma, it is present at a concentration of 1 log greater in the CSF. Patients with symptomatic CSF escape include a broad spectrum of individuals with cART-managed HIV including those persistently suppressed or well-controlled for many years, as well as those with recent spikes in viral load and those beginning to achieve viral control.
The pathogenesis of symptomatic CSF escape is related to the failure of cART to suppress local CNS infection despite peripheral CD4 + T-cell reconstitution. Although detectable CSF HIV in the context of cART is required, it is not sufficient, since asymptomatic CSF escape has been identified as a frequent finding (up to 10%) in asymptomatic individuals undergoing lumbar puncture in the context of HIV research studies. A moderately reconstituted immune system may actually contribute to the symptomatic syndrome by eliciting a symptomatic inflammatory response and providing a substrate for ongoing discordant HIV replication within the CNS. This process may lie on the spectrum of the immune reconstitution inflammatory syndrome (IRIS), but may represent a stable state of antigen and immune response within the CNS, rather than the exaggerated response upon immune reconstitution that occurs in IRIS. Low CD4 + T-cell nadir (i.e.,<250 cells/mm 3 ) may be a risk factor for CSF “escape,” suggesting that a history of advanced immunosuppression may confer increased risk of the syndrome. In addition to resistance and poor penetration, poor medication adherence might also contribute by leading to insufficient drug concentrations in the CSF and thus to the selection of resistant virus within the CSF.
The clinical features of symptomatic CSF escape include a variety of subacute to acute, progressive neurologic symptoms including cognitive, sensory, and motor impairment resulting in significant debilitation. Diagnosis is achieved through the recognition of plasma/CSF discordance and the exclusion of opportunistic infections including progressive multifocal leukoencephalopathy (PML). Imaging may show white matter hyperintensities on T2-weighted MRI sequences. Resistance genotyping of CSF HIV may demonstrate mutations in the CSF viral subpopulation. The CSF typically shows elevated protein level and white blood cell counts consistent with an inflammatory response beyond that seen in healthy controls without HIV infection and neurologically asymptomatic HIV-infected subjects taking cART. Elevated CSF neopterin and pronounced inflammation with CD8 + T-lymphocyte infiltration are seen on brain biopsy. Some patients with CSF escape demonstrate improvement when the antiretroviral therapy regimen is optimized based upon the results of genotyping and CPE score of the current cART regimen.
Reports of a CD8 T-cell encephalitis in subjects taking cART probably reflect a disorder on a similar spectrum. This disorder has been considered a form of CNS IRIS related to HIV itself although, as in symptomatic CSF escape, many of these patients developed the syndrome while apparently immunologically stable on cART. Several reports have demonstrated perivascular inflammation and leukoencephalopathy following initiation of cART, which is consistent with previous descriptions of IRIS relating to other pathogens.
Emerging Issues in Neurologic HIV Infection
A number of new concerns regarding neurologic manifestations of HIV have arisen in the era of widespread access to cART; epidemiologic shifts in HIV disease incidence, prevalence, and course; and demographic changes in individuals infected with the virus.
HIV and Hepatitis C Coinfection
HIV and hepatitis C virus (HCV) coinfection occurs in up to 40 percent of individuals, due in many cases to similar routes of transmission. Intravenous drug users are more likely to be coinfected with both pathogens. Patients coinfected with HIV and HCV have more rapid progression of both diseases and worse overall clinical and survival outcomes.
HCV has been detected both in brain tissue and in CSF of HIV and HCV coinfected patients, and HCV core protein has been demonstrated to induce neuronal injury. MR spectroscopy has detected reduced cerebral N -acetylaspartate in these patients, further suggesting neuronal injury. HIV and HCV coinfected individuals may exhibit a higher prevalence of multiple neurologic disorders than patients infected with HIV alone, including an elevated risk of seizures.
Some studies have indicated that coinfection with HIV and HCV leads to more severe cognitive effects than infection with HIV alone. Others have suggested that while the overall level of neurocognitive deficits is similar, specific impaired cognitive domains may differ.
There are many confounding factors related to combined HIV and HCV disease including mood disorders, substance abuse, and socioeconomic influences. HCV management with interferon-α, itself known to cause cognitive abnormalities in uninfected individuals, may result in improved cognitive profiles in the coinfected population.
Aging with HIV Infection
With widespread access to cART has come a dramatic increase in life expectancy for people living with HIV infection, with some living with the disease for over 20 years. HIV-associated cognitive deficits, particularly mild HAND, therefore have the opportunity to evolve over time and become confounded by typical age-associated neurocognitive disorders. At the same time, some individuals are beginning to acquire HIV infection at older ages, perhaps resulting in host factors that are different from those that characterized the initial epidemic. By the year 2015, half of the global HIV-infected population will be older than 50 years, and in sub-Saharan Africa nearly 14 percent of the HIV-infected population is already over 50 years old.
The normal process of aging involves the development of subtle deficits in neuropsychologic domains that parallel those affected by HAND, including processing speed, memory, and attention. Studies have suggested that age has an effect on cognitive impairment in patients infected with HIV and that older age at seroconversion and duration of infection may increase the risk of HAD. It is unclear whether there is an additive effect, in which HIV-related cognitive impairment directly compounds age-related impairment, or whether the effect is accelerated, with the combination of age-related and HIV-related impairment resulting in an overall level of impairment significantly worse than the combination.
More recent models suggest that HAND in cART-treated patients may reflect premature aging and an increased likelihood of neurodegeneration. This model takes into consideration the growing evidence for persistent neurodegeneration in patients treated with cART as well as the facilitated expression of separate (i.e., non-HAD) neurodegenerative processes identified through CSF and neuropathologic markers of neurodegeneration.
Imaging studies of HIV-infected individuals older than 60 years have shown disruptions in structural networks that exceed that expected with normal aging, even in the setting of access to cART. Individuals predisposed to neurodegeneration by the apolipoprotein E4 allele exhibit even worse neural network disruption. Aging patients with HIV infection display a diminished utilization of brain reserve; while patients without HAND are able to compensate for age-related declines in attention through utilization of brain reserve, individuals with HAND may be unable to do so, leading to worsening cognitive decline. These changes are possibly related to a combination of declines in dopaminergic function and glial activation in the setting of neuronal injury.
Stroke
Stroke is under-reported in the HIV-infected population ; during the cART era, rates of hospitalization for ischemic stroke in patients with HIV have increased dramatically, whereas those in non-HIV infected persons have declined. In the context of HIV infection, ischemic stroke affects patients who are more likely female, younger, and lack traditional risk factors for cerebrovascular disease. HIV infection is an important risk factor for stroke in the developing world as well.
In the pre-cART era, most cases of stroke in HIV-infected patients were attributed to the intracranial opportunistic infections and tumors associated with advanced immunosuppresion. In the cART era, the pathogenesis of stroke in HIV-infected persons is likely to be due to a multifactorial combination of HIV infection itself and side effects from the activity of antiretroviral agents including dyslipidemia.
HIV itself induces endothelial activation, which can lead to ischemic vascular events in the heart and brain. Cardiac disease has been increasingly recognized in the HIV-infected population and cardioembolic causes of cerebral ischemia are more common than in the pre-cART era. Especially in the late stages of the disease, HIV-infected patients have diastolic dysfunction and HIV-associated dilated cardiomyopathy, which was identified as the cause of stroke in 20 percent of patients in one series. While opportunistic vasculitis was commonly implicated in ischemic stroke in the pre-cART era, a small-vessel vasculopathy related to the virus is increasingly common. Hypercoagulability and intracranial aneurysms occur more frequently in this population than the general population and can lead to stroke.
Although cART increases life expectancy, it also may allow patients to develop age-related atherosclerotic disease. Longer exposure to the virus itself may exacerbate stroke risk through mechanisms described earlier. In addition, the protease inhibitors used in cART regimens contribute to numerous metabolic abnormalities including lipodystrophy, dyslipidemia, and insulin resistance. However, an uncontrolled HIV viremia may be a greater risk factor for stroke than antiretroviral medications, as suggested by the results of a study in which participants who interrupted therapy to reduce their overall exposure to antiretroviral drugs actually demonstrated increased cardiovascular-related morbidity and death.
Metabolic disorders also worsen neurologic performance outside the context of clinically detectable stroke in patients with HIV infection. Insulin resistance and poor glucose control have been associated with poorer neurocognitive performance. Clinical or subclinical carotid artery disease is also significantly associated with neurocognitive decline, and central obesity contributes to worse neurocognitive performance in HIV-infected patients.
Central Neurotoxicity of Antiretroviral Agents
The tissue-specific adverse effects of antiretroviral agents outside the nervous system include pancreatitis, lactic acidosis, ototoxicity, and lipodystrophy. In addition to controlling systemic HIV levels, a goal of therapy is to protect the brain from damage related to viral pathogenesis and to eliminate the CNS reservoir of the virus. Although antiretroviral therapy that achieves sufficient penetration into the CSF can successfully control CNS viral replication, there has been growing concern that the therapeutic concentrations needed to achieve effective viral suppression are associated with a risk of neurotoxic adverse effects.
Recent in vitro work has suggested that abacavir, efavirenz, etravirine, nevaripine, and atazanavir have the most neurotoxic potential. The mechanism of antiretroviral toxicity outside the nervous system may relate to inhibition of mitochondrial DNA production, but it is unclear whether this occurs in the CNS. Neurotoxicity may be related not to cell death, but rather associated with reversible dendritic changes.
The adverse reactions associated with efavirenz are the most common and include sleep disturbances (e.g., abnormal dreams, nocturnal awakening, and insomnia), mood disorders, impaired concentration, and, in some cases, suicidal ideation. These reactions typically occur in the days following initiation of treatment and are most common during the first 4 weeks; nearly half of all subjects will experience some form of reaction and the effects can persist for months or years. The incidence of these side effects may be related to drug concentration, which demonstrates significant variability between individuals, possibly related to differences in liver metabolism. Although the adverse effects of efavirenz have typically been considered mild, they can also manifest as severe depression, mania, and aggression. Neuropsychiatric effects are the primary reason for efavirenz discontinuation, suggesting that they might also have an impact on medication adherence. Abacavir, etravirine, nevaripine, and atazanavir have fewer clinical reports of neurotoxicity but each has been associated with dizziness, fatigue, and rare instances of peripheral neuropathy, although the latter is difficult to separate from the effects of HIV itself, as discussed later.
Neurologic Dysfunction in Antiretroviral-Naive Patients
The advent of antiretroviral therapy has led to a 10-fold decrease in CNS disease. However, in the United States, an estimated 34 percent of patients reach a CD4 + count below 200 cells/µl by the time they are diagnosed with HIV infection. Therefore, some patients still present with the classic complications of AIDS. This decline of neurologic complications in the developed world has not been paralleled in resource-poor settings internationally, where the diagnosis and management of neurologic disease are complicated by a lack of access to HIV diagnostic and neurologic imaging technology, limited treatment programs that often begin late in the disease course, and neurologic coinfections with endemic pathogens including malaria and tuberculosis.
Effects of Primary HIV in the Central Nervous System
The study of neurologic disease in HIV infection has traditionally focused on chronic and late-stage neurocognitive manifestations, but recent work has shown effects of HIV on the CNS much earlier in the disease course, including during primary HIV infection (defined as the first year following transmission of the virus). Primary HIV infection is characterized by a rapid and dramatic rise of HIV RNA levels in the plasma, accompanied by an increase in HIV antibody levels that are detectable within 2 weeks of transmission by fourth-generation enzyme immunosorbent assay (EIA) tests. In at least two-thirds of individuals, the period of seroconversion is accompanied by the acute retroviral syndrome, characterized by vague symptoms of fatigue, malaise, fever, and anorexia. Within a few months of seroconversion, a partially effective immune response causes HIV RNA to stabilize at a reduced, chronic, individual-specific level. This plateau is a result of the increased activity of CD8 + T cells in conjunction with a decreased reservoir of CD4 + T cells available for infection by the virus.
In addition to the acute retroviral syndrome, a subgroup of individuals newly infected with HIV develop neurologic symptoms and signs around the time of seroconversion. HIV can be found in the CSF and brain tissue of patients during the earliest stages of infection, in the weeks to months following viral transmission. Indeed, HIV has been identified in the CSF as early as 8 days after transmission. Immune activation accompanies the presence of HIV virions in the CSF during primary infection, and the elevation in CSF leukocyte count, neopterin, and inflammatory cytokines during the first months of infection suggests that CNS injury can take place during this period. Biomarkers of neuronal injury are elevated in patients with primary HIV infection and correlate with both neuroinflammatory markers and MR spectroscopic evidence of neuronal dysfunction.
One of the first syndromes to be linked with primary HIV infection was aseptic meningitis, characterized by a CSF lymphocytosis with or without clinical signs of meningitis. Other individuals experience varying degrees of encephalopathy in the setting of meningoencephalitis, encephalitis, or encephalomyelitis. Acute neuropathies, including facial nerve paralysis and optic neuritis, also occur frequently with seroconversion and are common in acute HIV infection. Although clinically heterogeneous, these neurologic syndromes associated with primary HIV infection share several common features, including onset 2 to 3 weeks after the symptomatic manifestations of the acute retroviral syndrome, a self-limited course, and evidence of temporally associated HIV seroconversion. The pathogenesis of these syndromes is therefore probably due to a host-mediated autoimmune response in the setting of massive systemic immune activation. Evaluation of patients with these acute neurologic syndromes should include not only HIV antibody testing but also nucleic acid testing for the presence of HIV by polymerase chain reaction (PCR) since antibody responses may be absent or indeterminate during the earliest stages of infection.
Symptomatic seroconversion, also characterized by a variety of non-neurologic symptoms, has been associated with more rapid disease progression. It appears that these early signs of neuroinflammation are related to objective neuronal injury, but it is unclear whether inflammation or injury at this early time-point predicts neurologic outcomes in later stages of the disease, and whether the early initiation of antiretroviral therapy can ameliorate these processes before systemic immunosuppression occurs.
CNS Complications of Longstanding Untreated HIV Infection
Classic HIV-Associated Dementia
The disorder now called HAD was initially described as the AIDS-dementia complex. There are no individual diagnostic studies or laboratory tests that are specific for HAD. Identification of this disorder depends on the recognition of the clinical syndrome and the exclusion of alternative diagnoses. Diagnostic criteria and approach to treatment were described earlier and in Table 44-1 . Initiation of antiretroviral therapy is associated in the majority of patients with a dramatic improvement of clinical signs and symptoms over the early weeks to months of treatment. More gradual improvement may be detectable up to 18 months later.
Opportunistic Infections
For the first two decades following the discovery of HIV infection, opportunistic infections were among the most dramatic and dreaded complications of the disease ( Table 44-3 ). The incidence of these complications has declined with the widespread use of cART in the developed world, but HIV-associated opportunistic infections remain a significant cause of morbidity and mortality worldwide, particularly in areas where access and adherence to antiretroviral therapy are limited.
| Cerebral Toxoplasmosis | Primary CNS Lymphoma | Progressive Multifocal Leukoencephalopathy | Cytomegalovirus Encephalitis | Cryptococcal Meningitis | Tuberculous Meningitis | |
|---|---|---|---|---|---|---|
| Disease Characteristics | ||||||
| CD4 Count | <200 | <100 | <100 | <50 | <50 | Variable |
| Time Scale | Days | Weeks to months | Weeks to months | Days to weeks | Days to weeks | Days to weeks |
| Signs/Symptoms | ||||||
| Alertness | Reduced | Variable | Preserved | Reduced | Variable | Reduced |
| Fever | +/− | − | − | +/− | +/− | + |
| Seizures | + | + | − | + | − | − |
| Headache | + | + | − | − | + | + |
| Focal Deficits | + | + | + | − | − | +/− |
| CSF Studies | ||||||
| WBC | Increased | Increased | Unchanged | Increased | Unchanged | Increased |
| Protein | Increased | Unchanged/increased | Unchanged/increased | Increased | Increased | Increased |
| Glucose | Decreased | Unchanged | Unchanged | Unchanged | Decreased | Decreased |
| Other Tests | Toxoplasma PCR | Epstein–Barr virus PCR | JC virus PCR | Cytomegalovirus PCR | Increased opening pressure; antigen test | Acid-fast bacilli stain; M. tuberculosis PCR |
| Imaging Findings | ||||||
| Focal Lesions | + | + | + | − | − | − |
| Number | Multiple | One or few | One or multiple | n/a | n/a | n/a |
| Mass Effect | + | + | − | − | − | − |
| Enhancement | +(ring) | +(ring or complete) | − | +(periventricular) | +(meningeal) | +(basilar) |
| Location | Basal ganglia, cortex | Periventricular, subependymal | Subcortical white matter; brainstem | Periventricular | Basal ganglia | Basal ganglia |
| Special Features | Eccentric target sign | Ring- or completely enhancing | Dark on T1, bright on T2 | n/a | Gelatinous pseudocysts | Tuberculomas, abscesses |
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