Chapter 19 Primary neurological manifestation of HIV/AIDS
Introduction
NeuroAIDS issues may be considered as primary complications, including conditions that are in some way the direct consequence of the HIV infection, or secondary complications (Box 19.1). The primary complications include a spectrum of HIV-associated neurocognitive disorders (HAND), HIV-associated myelopathy, and HIV-associated peripheral neuropathy. Secondary complications result as a consequence of the immunodeficient state of the host (Box 19.1). Neurological infections that fall into this category include cryptococcal meningitis, toxoplasmic encephalitis, cytomegalovirus encephalitis and radiculomyelitis, progressive multifocal leukoencephalopathy, and varicella zoster complications. This chapter will focus on the primary neuroAIDS complications while many of the secondary complications are described elsewhere in the text.
Box 19.1 HIV-associated neurological complications
Epidemiology
Neurological complications of HIV infection are common manifestations of the AIDS illness [1]. Pre-combination antiretroviral therapy (cART) era investigations documented that two-thirds of patients with AIDS developed HAD. Although, after successful introduction of antiretroviral therapy, the incidence of frank dementia declined significantly, milder cognitive difficulties and HIV-associated peripheral neuropathies have persisted. The CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, a multicenter NIH study, evaluated over 1,500 HIV-infected individuals in the USA and found 53% had cognitive impairment [2]. The risk of impairment was higher in those with co-morbidities. The same study also found evidence of peripheral neuropathy in more than half of the subjects. Early studies in Uganda support the prevalence of neurologic impairment in less developed settings [3]. A recent report found HAND in 23.5% of HIV-infected patients seen at HIV care centers in South Africa [4].
Pathophysiology, Pathogenesis, and Genetics
Primary HIV-associated complications result from infection in the nervous system, and respond to antiretroviral therapy. The mechanism by which HIV infection leads to HAD is likely multifactorial. HIV enters the brain and CSF almost immediately after systemic infection, probably via HIV-infected monocytes, which then differentiate into macrophages. The virus can be recovered from the nervous system throughout the illness. However, productive infection is almost exclusively localized in monocytes and macrophages and mainly occurs late in the disease. Neurons are rarely if ever infected, and astroglial cells, while they may be infected, do not seem to support replication. The consequences of astroglial infection remain uncertain. However, recent research supports an association of HAD with astrocyte infection, suggesting that these cells controlling the environment in the brain could be critical and require further study [5]. It seems likely that much of the pathological consequence of the HIV infection in the brain is driven by immune response to infection rather than directly correlated to the viral load in the CNS. Cytokine production is more closely linked with the degree of HAD than the viral load. However, replicative HIV infection in the CNS, reflected by increasing HIV RNA viral loads in the CSF, has been loosely associated with primary HAD prior to the cART era [6]. Pathologic changes are found in the deep gray matter of the brain, in white matter, and eventually in the cortex, resulting in loss of neurons and simplified dendritic structures [7].
While most people are susceptible to HIV, infection requires both CD4 receptors and chemokine receptors. Viral isolates may evolve in a host from CCR5 receptor dependent (R5) to viral tropism using the CXCR4 (X4) co-receptors. Generally, primary brain isolates are of the R5 class consistent with the fact that CCR5 is the predominant receptor on monocytes and macrophages, the primary cells with replicative infection in the brain. It is interesting that some people are protected from HIV infection by a genetic mutation in the CCR5 chemokine receptor that prevents it from participating as a co-receptor for cellular infection. A leukemia patient who received a bone marrow transplant from a donor with a non-binding CCR5 cell surface protein has been reported as showing evidence of a cure of HIV infection 3 years after receiving the transplant, including no evidence of the virus on brain biopsy [8].
HIV-Associated Neurocognitive Disorders (HAND)
Clinical features
HIV-associated neurocognitive disorders (HAND) include a spectrum of cognitive impairments that range from asymptomatic neurocognitive impairment (ANI) to a severe form, HAD. Early on, it had been noted that HAND varied in severity and affected different domains of brain function, resulting in a variety of cognitive, motor, and behavioral manifestations. A consensus nomenclature for study of HAND was developed in 2007 by experts who presented a modified comprehensive classification of HAND [9]. In this classification, three HAND conditions are characterized: ANI, HIV-associated mild neurocognitive impairment (MND), and HAD. The work group emphasized the possibility of bidirectional temporal changes in diagnosis. These conditions should be classified using a variety of specific clinical and laboratory-based methods, depending upon the resources available where the patients are being evaluated. Ideally, baseline neuropsychological (NP) assessment should be part of the clinical evaluation. Where NP testing is not available, presence of cognitive impairment involving two or more ability domains may be suggested by quantitative neuropsychological testing using demographically appropriate normative cutoffs. Tools of value for screening include the HIV Dementia Scale, the International HIV Dementia Scale, Mattis Dementia Rating Scale, and the Montreal Cognitive Assessment (MoCA). Recent interest in use of the MoCA includes availability in multiple languages, balanced simple assessment of several domains, and low cost (free access at http://www.mocatest.org).
ANI and MND must both have documented neurocognitive impairment, but only in the case of MND does this impact on activities of daily living. The Frascati-proposed diagnostic criteria defines ANI and MND by performance at least 1 standard deviation (SD) below the mean of demographically adjusted normative scores in at least two cognitive areas (attention-information processing, language, abstraction-executive, complex perceptual motor skills, memory, including learning and recall, simple motor skills, or sensory perceptual abilities), with MND having evidence of functional impairment in daily living. HAD has a more profound impact on motor, cognitive, and behavioral problems that develop in advancing HIV infection (Box 19.2). Early signs and symptoms of HAND may be subtle, but evolution to HAD occurs mainly in untreated HIV. Before cART, patients often presented with insidious onset of reduced work productivity, poor concentration, mental slowing, and forgetfulness. The cognitive decline was often characterized by slowed thought and speech, which the patient as well as examiners may recognize. Habits of reading and recreation are impacted early, while productivity drops. Apathy and withdrawal from hobbies and social activities are common and must be differentiated from depression. Motor slowing is also typical, and has provided convenient means of documenting advancing neurological involvement. Imbalance, clumsiness, and weakness are common motor complaints. Behavioral changes are less common, but may be dramatic manifestations of the neurological involvement. Flattened affect is typical, and develops even without overt affective disorder. Other manifestations include sleep disturbance, psychosis, and seizures. Occasional frank psychotic episodes develop.
