CHAPTER 93 NEUROLOGICAL DISORDERS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Neurological disorders caused by the retrolentivirus human immunodeficiency virus (HIV), occur at all levels of the neural axis, including the central (CNS) and peripheral (PNS) nervous systems throughout the entire course of HIV infection.1 Indeed, the prevalence of neurological syndromes during HIV infection is high, affecting up to 90% of untreated patients with the acquired immunodeficiency syndrome (AIDS).2–4 Approximately 55 million people worldwide have been infected with HIV since it was first identified in the early 1980s. With the advent of highly active antiretroviral therapy (HAART) in the mid 1990s, many individuals infected with HIV are living more than 20 years after their initial infection in industrialized countries.5 Nonetheless, despite the availability of HAART, HIV-related neurological disease continues to represent substantial personal, economic, and societal burdens.
In developed countries, conversion to AIDS usually occurs approximately 10 years after initial infection (Fig. 93-1). It is defined by the Centers for Disease Control and Prevention as either a decline in CD4+ T lymphocyte levels below 200 cells/μL or an AIDS-defining illness, such as Pneumocystis carinii pneumonia, cryptococcal meningitis, or toxoplasmosis encephalitis. There are also infection-driven malignancies, such as Kaposi’s sarcoma and primary CNS lymphoma, that are commonly associated with progression to AIDS. There are two major strains of HIV: type 1 (HIV-1), which predominates globally, and type 2 (HIV-2), which is limited largely to West Africa and is less virulent. Because of HIV’s remarkable capacity for replication and subsequent mutation, significant viral molecular and antigenic diversity has occurred, which has precluded the development of an effective vaccine to date. In the industrialized world, HIV-1 B subtype (also termed B clade) predominates and is the source of most of the current understanding of HIV-related neurological disease.
NEUROLOGICAL DISORDERS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Early in the HIV epidemic, two groups of neurological disorders arising as consequences of HIV infection were recognized. The first group of neurological syndromes includes the primary HIV-induced disorders, which reflect HIV’s immediate deleterious effects on neural cells and result in damage to the brain, spinal cord, and peripheral nerves. These primary HIV-associated illnesses include HIV-associated dementia (HAD) (also termed AIDS dementia complex and HIV encephalopathy) and its antecedent syndrome, minor cognitive and motor deficit (MCMD); vacuolar myelopathy; and several types of peripheral neuropathy6 (Fig. 93-2). Indeed, other neurological disorders, including entrapment neuropathies, headache, seizures, and myopathy, appear to be more frequently encountered among patients with HIV or AIDS than noninfected persons, although these conditions are not necessarily linked to the direct effects of virus (HIV) infection. The second group is composed of the opportunistic infections of the CNS and PNS, which arise as direct consequences of HIV-induced immunosuppression. These include toxoplasmosis encephalitis, cryptococcal meningitis, cytomegalovirus encephalitis and radiculitis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, and neurotuberculosis (meningitis and tuberculoma) and are dealt with in detail in other publications.7,8
HUMAN IMMUNODEFICIENCY VIRUS NEUROPATHOGENESIS AND NEUROPATHOLOGY
Under healthy conditions, the CNS and PNS are well protected by the blood-brain barrier or blood-nerve barrier from toxins and infectious pathogens circulating in the blood (Fig. 93-3). However, HIV is able to traverse the blood-brain barrier, and probably the blood-nerve barrier, soon after primary infection via circulating HIV-infected (and activated) leukocytes, including macrophages and lymphocytes, which adhere to endothelia within the neural compartment and subsequently enter the parenchyma. On entry, HIV establishes infection of perivascular macrophages, resident microglia, and to a lesser extent, astrocytes or Schwann cells. In contrast HIV infection of neurons is minimal or nonexistent. This process by which HIV enters the CNS or PNS is termed the “Trojan Horse” hypothesis. HIV infects macrophages and microglia through binding to the CD4+ molecule, which acts as the primary receptor in association with the chemokine receptors (CCR5 and CXCR4) as co-receptors for infection. HIV-1 exerts its neuropathogenic effects through two principal mechanisms; one is stimulation of neuroimmune cells within the CNS or PNS to produce host proinflammatory molecules, such as cytokines, chemokines, prostaglandins, redox reactants, excitotoxic amino acids or derivatives thereof, and enzymes, which damage neurons and the proximate astrocytes that support them. The alternative mechanism by which neural cells are injured is through direct (neurotoxic) interactions between HIV-encoded proteins (including glycoprotein 120, glycoprotein 41, Tat, and Vpr) and the target cell (including neurons or astrocytes). In fact, these mechanisms overlap in a complementary manner, inasmuch as perivascular macrophages and microglia are the chief sources of both the host neuropathogenic molecules and the secreted neurotoxic viral proteins; whereas some of the host molecules activate viral replication, most of the viral proteins can also activate neuropathogenic host gene responses.
The CNS pathological hallmarks of HIV infection include multinucleated giant cells, diffuse white matter pallor, perivascular cuffs composed of monocytes and lymphocytes, microglial nodules, and the presence of HIV-1 antigens9–11 (Fig. 93-4). The diffuse white matter pallor exhibits preserved myelin protein expression but concurrent deposition of serum proteins in white matter, which implies that altered permeability of the blood-brain barrier rather than frank demyelination underlies diffuse myelin pallor.12,13 Neuronal and astrocyte injury and death are defined by dendritic “pruning,” together with cell death involving both necrotic and apoptotic mechanisms, depending on the effector molecule and the selective vulnerability of the target cell (Fig. 93-5). For example, neurons in the basal ganglia represent a highly susceptible population, in part because of the high density of microglia in this region of the CNS but also because of the intrinsic properties of this group of neurons. In the PNS, infiltrating macrophages and lymphocytes are present during HIV infection and often exhibit HIV antigens and genome. Damage to dorsal root ganglia neurons and a dying-back (wallerian) pattern of axonal injury, chiefly affecting small-diameter axons, is apparent.14,15
A limited correlation exists between the clinical entity HAD and the pathological entity HIV encephalitis, defined by the presence of multinucleated giant cells or the presence of viral antigens.9,16,17 There may also be a correlation between HIV antigen load and HAD,18 although other studies have suggested that macrophage and microglia presence and activation in the basal ganglia are better predictive markers for HAD.19 Although neuronal injury and death in the frontal cortex and deep gray matter occur in the brains of patients with AIDS,20–22 the degree of neuronal loss is correlated with the severity of HAD. Results of a 2001 study also imply that the astrocyte death is associated with rapidly progressive HAD.23
NEUROCOGNITIVE SYNDROMES IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Unlike acute viral infections of the CNS, the pathogenic effects of HIV usually manifest long after initial infection, with ensuing cognitive, motor, and behavioral dysfunction among affected patients. Nevertheless, rare cases of acute encephalopathy have been reported during HIV seroconversion. HAD represents a constellation of progressive symptoms and signs associated that usually begin once an individual’s CD4+ T cell counts dips below 200 cells/μL of blood; not surprisingly, HAD is an AIDS-defining illness (Table 93-1). With the availability of HAART, HAD is now manifesting with CD4+ cell levels exceeding 200 cells/μL. Of most importance, the diagnosis of HAD heralds a worsened survival prognosis with or without HAART.24 Before the era of HAART, the annual incidence of HAD was 53%, although the overall prevalence was only 6%,24 probably a consequence of the high mortality rate after HAD onset, as survival time after diagnosis was only 5.1 months.25,26 With the advent of HAART, the incidence of HAD has fallen to less than 10%, survival time after diagnosis has leapt to 38.5 months, and longer survival times have resulted in overall higher prevalence rates. Risk factors for HAD include low CD4+ levels, high viral loads in cerebrospinal fluid or plasma, anemia, extremes of age, and intravenous drug use (Table 93-2). Also, patients with marked immunosuppression who have no experience with antiretroviral therapy may experience an exaggerated immune response, the immune reconstitution inflammatory syndrome (IRIS), after HAART introduction.27 Indeed, IRIS occasionally manifests as transient cognitive dysfunction together with signs and symptoms of acute meningoencephalitis, although preexisting neurological complications of AIDS may also be exacerbated with IRIS.28,29
TABLE 93-1 Clinical Features of HIV-Associated Dementia (Typical of a Subcortical Dementia)
HIV, human immunodeficiency virus.
TABLE 93-2 Risk Factors for HIV-Associated Dementia
HIV, human immunodeficiency virus.
It has also been postulated that MCMD is a risk factor for progression to HAD.30 MCMD is a syndrome exhibiting many clinical aspects of HAD, although the signs and symptoms are less severe. Because MCMD has been identified in patients with higher CD4+ counts, there is some suggestion that it may be the precursor to HAD.31 MCMD may affect as many as 30% of patients with HIV or AIDS in North American clinics.32 Nonetheless, comorbid conditions, including chronic drug abuse, head injury, and other risk factors for neurocognitive impairments, may contribute to the diagnosis of MCMD. Because HIV preferentially affects the basal ganglia and deep white matter, HAD predictably manifests with many of the features of a subcortical dementia (Table 93-3). Affected patients typically display neurocognitive impairment, emotional disturbances, and progressive motor decline,33 although HAD has remarkably diverse clinical phenotypes that may include movement disorders.34–36
TABLE 93-3 Radiological, CSF, and Neuropathological Features of HIV-Associated Dementia
CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IgG, immunoglobulin G; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; PCR, polymerase chain reaction.
Of importance is that HAD is difficult to detect with the Mini-Mental Status Examination unless the patient is severely demented, most likely because HAD is a subcortical dementia. If there is a suspicion that an HIV-seropositive patient is suffering from HAD, more useful screening tools are applicable, including the HIV Dementia Scale,40 the Mental Alteration Test,41 the Executive Interview,42 and the HIV Dementia Assessment.43 A widely accepted tool for clinical staging of HAD is the Memorial Sloan-Kettering Scale, which provides a qualitative measure of dementia severity, allowing the physician to track progression of the dementia over time.44
Radiological features accompanying HAD (Fig. 93-6) include cerebral and basal ganglia atrophy and diffuse periventricular white matter hyperintensities on T2-weighted MRI (Fig. 93-7).45,46 Unfortunately, it is difficult to correlate the presence of these radiological changes with the presence of HAD, as nondemented patients with HIV infection or AIDS also display these changes on neuroimaging.47 Magnetic resonance spectroscopy studies show diminished N-acetyl aspartate levels in the brain, which imply neuronal injury or loss.48 Other critical investigations include cerebrospinal fluid analyses, chiefly to exclude opportunistic processes and also to assess the levels of viral replication in the neural compartment.
The course of the dementia is variable; some individuals experience an abrupt decline in function over weeks, whereas others display a protracted course over several years that culminates in death.49 The most effective management of HAD is treatment of the underlying cause. HAART routinely consists of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and either a potent protease inhibitor (PI) or a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI). Clinical trials have shown that neuropsychological testing scores improve in patients with HIV or AIDS who are treated with two NRTIs and the NNRTI nevirapine,50 as well as with two NRTIs and a protease inhibitor.51,52
