Your Family Physician

Introduction

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.^2,3 ADC is now considered a single entity with a broad and varied spectrum of clinical manifestations and severity.⁴

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, more than 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.

Nosology

Cognitive impairment associated with HIV disease is widely called AIDS dementia complex (ADC). This term encompasses cognitive deficits, behavioral changes, and motor involvement. Those affected may manifest deficits in each of the 3 aspects at varying severity. Some may present primarily with cognitive changes such as slowed processing of information captured by neuropsychological testing. Others may present to the psychiatrist for behavioral management. Others may be affected by motor symptoms such as unsteady gait, tremor, or weakness.

In 1991, the AmericanAcademy of Neurology defined neurocognitive deficits seen with HIV as HIV-associated dementia (HAD) and minor cognitive motor disorder (MCMD). Criteria for diagnosis of HAD included cognitive deficits in 2 or more cognitive domains causing impairment in activities of daily living (ADL) and an abnormality in either motor or neurobehavioral function. Patients with MCMD had decreased function in 2 cognitive or behavioral domains but were not impaired severely enough to meet criteria for HAD.

In 2007, Antinori et al proposed more refined criteria for diagnosing cognitive impairment associated with HIV. They proposed 3 entities: asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). Standardized neuropsychological testing was required to assess the following domains of cognition: language, attention, executive function, memory, speed of information processing, and perceptual and motor skills. In order to make one of the above diagnoses, patients have to have no other etiology of dementia and not have the confounding effect of substance use or psychiatric illness.⁵

ANI was proposed based on the experience with patients who declined in their performance on formal neuropsychological testing but had no functional impairment in daily activities. One standard deviation (SD) below the mean for age and education appropriate norms in at least 2 of at least 5 tested domains in formal testing is diagnostic of ANI. Patients with MND meet the criteria for ANI, except they also have impairment with activities of daily living as reported by patient or by a corroborator. HAD can be diagnosed if patients score 2 SD below the mean in at least 2 cognitive domains and have marked impairment in ADLs as a result of cognitive decline.

This proposed change in nosology improves the sensitivity of diagnosis of cognitive decline in HIV; however, the term most widely used in literature is ADC and that term will be used in throughout this article.

Pathophysiology

HIV 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 proinflammatory⁶ 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)⁷ , 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.⁸

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.^9,10 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.¹¹

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%.¹² With HAART, the incidence of HIV dementia started declining initially, but has begun increasing again. The incidence of HIV-1 encephalopathy has been increasing in the post–HAART era. The prevalence of the disorder is now increasing; the cumulative incidence is 25-38% and the prevalence is around 37%.¹² Milder forms of ADC affect an additional 30-40% of patients. In the post-HAART period, rapidly progressive dementia is less commonly a presentation, and chronic and fluctuating forms of HIV dementia are more common.

In 4-15% of patients, ADC is the presenting clinical manifestation of HIV disease.¹² The multicenter AIDS cohort study found a rate of HIV dementia of less than 1% in asymptomatic seropositive patients.¹³

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.¹²
• 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.

Comorbidities

• Hepatitis C virus: HIV infection and hepatitis C virus infection affect disease progression of each other. HIV-1 infection accelerates the progression of HCV-associated liver fibrosis. Infection with multiple genotypes of HCV can accelerate the progression of HIV disease.¹⁴
• CMV: This virus is the most commonly found co-infection in HIV-1 infected patients at autopsy. Wohl et al studied CMV-seropositive patients and concluded that CMV DNA was an independent predictor of death, aside from the well-known predictors, CD-4 count and HIV-plasma load. In the HAART era, CMV encephalopathy has decreased in incidence.¹⁵
• Neurosyphilis: The course of neurosyphilis is shortened, and it is more aggressive and difficult to treat in HIV patients.

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 gender may be a risk factor of HIV dementia.¹⁶ Some studies have found that women with HIV may have a more rapid progression of neurologic symptoms and signs.^17,12

Age

The Multicenter AIDS Cohort Study reported that older age was associated with more rapid progression to dementia and death.¹⁸ 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.¹⁹

Clinical

History

See Nosology in Background.

Physical

The examination includes a full Mental Status Examination (MSE), a general neurologic examination, and a general physical examination. The patient should then be referred to a neuropsychologist for complete neuropsychological testing addressing specific domains as suggested above.

• Some patients with HIV can become depressed, suicidal, and homicidal. Therefore, a thorough psychiatric assessment should also be performed at each visit.
• In the early stage, findings from the MSE and the general neurologic examination are normal. MSE findings are abnormal if the patient exhibits inattention, impaired concentration (eg, digit span, serial 7' s), memory loss (eg, recalling 3 objects at 5 min), slowed verbal responses, and a blunted affect.
• In the more severe form of HIV-associated dementia complex, the neurologic examination shows frontal release signs, slowed rapid movements, antisaccadic eye movements, incoordination, abnormal gait, hyperreflexia, hypertonia, extensor-plantar response weakness, and peripheral neuropathy.³ Cortical signs, including apraxia, aphasia, and agnosia, typically are absent.
• In the late stages of the disease, patients also may have quadriparesis or paraparesis, myoclonus, and incontinence.²⁰

Causes

• Several risk factors for ADC have been identified, including low weight, anemia, constitutional symptoms, low CD4 count, and high plasma HIV-RNA load.
• The prevalence of ADC increases 3-fold with a CD4 count of less than 200/µL and increases 7-fold with a CD4 count of less than 100/µL.
• Patients with concomitant hepatitis C virus (HCV) have a worse cognitive status than those without.
• A recent report implicated apolipoprotein E4 as a risk factor for the development of dementia.

Source : http://emedicine.medscape.com/article/292225-overview