Excerpt from Dementia Due to HIV Disease

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Background

Physicians frequently encounter neurologic and psychiatric complications in patients with human immunodeficiency virus (HIV) infection. This is not surprising since the HIV virus enters the central nervous system (CNS) early in the course of the infection. Prior to the advent of highly active antiretroviral therapy (HAART), dementia was a common source of morbidity and mortality, usually observed in the late stages of AIDS, and was seen in up to 50% of patients prior to their death.¹ In 1986, the term AIDS dementia complex (ADC) was introduced to describe a unique constellation of neurobehavioral findings. ADC is now considered a single entity with a broad and varied spectrum of clinical manifestations and severity.

Globally, 33.2 million people were estimated to be living with HIV/AIDS in 2007.² Of those people, only 2 million have access to HAART because they live in developed countries.

In the United States, 1 million people are estimated to live with HIV.¹ With the changing face of AIDS and HIV infection, a geographical difference in how ADC presents is now clear. HAART has brought dramatic changes in the lives of patients and divided the disease into "have" and "have nots." On one hand, in developed countries like the United States, having an HIV-infected patient present for the first time with a full-blown ADC picture is rare; on the other hand, in countries like Africa where HAART is not available, this scenario is still the norm.

Pathophysiology

The HIV virus enters the CNS by infecting macrophages and monocytes that then cross the blood brain barrier, carrying the virus with them. Immunohistochemistry studies show that the virus is most densely located in the basal ganglia, subcortical regions, and frontal cortex. Pathological changes at autopsy are also predominantly subcortical, involving the deep gray (ie, basal ganglia, thalamus) and white matter regions. Infected macrophages or microglial cells then elaborate proinflammatory diffusable cellular neurotoxins, including tumor necrosis factor-alpha (TNF-alpha), cytokines, interleukins, chemokines, nitric oxide, and excitatory amino acids. These neurotoxic agents create an inflammatory environment by activating uninfected microglia and then proceed to injure surrounding astrocytes and neurons. HIV does not directly infect the neuron, but the neuron is damaged by the effects of various proinflammatory neurotoxins.

Using immunohistochemical techniques, many HIV viral products have been implicated in HIV dementia. The basal ganglia show the highest immunostaining by the HIV p24 antigen. Some studies show that gp41 expression in the basal ganglia and frontal lobes correlates significantly with the severity of dementia. Other viral proteins, including tat and gp120, are present in abundance in the brains of patients with HIV dementia. gp120 causes neuronal death in vitro and is accompanied by the opening of calcium channels in the neuronal membrane.

A lot of research and interest has been generated in the role of p53 (tumor suppressor transcription factor), which appears to have multiple roles in the pathogenesis of the disease. HIV proteins tat and gp120 cause microglia to release factors that promote neuronal p53 activation. All 3 cell types in the brain (microglia, astrocytes, and neurons) accumulate p53, causing cell cycle arrest; in neurons, this ultimately induces apoptosis and cell death by oxidative injury and DNA damage.

In summary, both viral (eg, gp120, gp41, tat) and host cell products (eg, TNF-alpha, cytokines, interleukins, quinolates, nitric oxide, platelet-activating factors) can either amplify or directly contribute to neuronal injury. However, the presence of macrophages and microglia correlate better with clinical dementia than with the amount of HIV-infected cells in the brain, as determined by gp41-positive cells.

See Medscape's HIV Pathogenesis Resource Center.

Frequency

United States

The annual incidence of HIV dementia in the Western world prior to HAART was 7%, with a cumulative risk of 5-20%.³ With HAART, the incidence of HIV dementia started declining initially, but has begun increasing again. The prevalence of the disorder is now increasing; the cumulative incidence is 25-38% and the prevalence is around 37%.³ Milder forms of ADC affect an additional 30-40% of patients. In 4-15% of patients, ADC is the presenting clinical manifestation of HIV disease.³ The multicenter AIDS cohort study found a rate of HIV dementia of less than 1% in asymptomatic seropositive patients.⁴

Mortality/Morbidity

ADC causes a significant increase in the overall morbidity due to AIDS.

• The increase in morbidity results from a combination of factors, including the increased number of hospitalizations, increased duration of hospital stays, and decreased life expectancy compared with AIDS patients who do not have dementia. In the pre-HAART era, AIDS patients who had untreated ADC had an average life span of 6 months, which was significantly less than that for AIDS patients without dementia. This has now increased to 38 months for ADC patients in the Western hemisphere who have been on a stable regimen of HAART.³
• The overall psychosocial and emotional burden on the family and friends of such patients is tremendous, far beyond that of a cognitively intact patient with AIDS.
• Patients with cognitive difficulties have problems with compliance and adherence to their medication regimen. Because of their neuropsychiatric problems, these patients are likely to be less inhibited and are more prone to HIV-related risk behavior like unprotected intercourse, and they therefore pose a greater risk of transmission of the virus.  

Race

HIV has a high incidence and prevalence in the African-American community, which is reflected in the race distribution of ADC.

Sex

Some data suggest that female sex may be a risk factor of HIV dementia.⁵ Some studies have found that women with HIV may have a more rapid progression of neurologic symptoms and signs.^{6, 3}

Age

The Multicenter AIDS Cohort Study reported that older age was associated with more rapid progression to dementia and death.⁷ Becker et al reported that the prevalence of cognitive disorders in those who are HIV positive and older than 50 years was significantly greater than in younger patients.⁸

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