// HIV

Dementia Due To HIV Disease

Human immunodeficiency virus (HIV) was first identified in 1983, although associated complications had been described two years prior to that time. HIV is a devastating disease that affects more than 36 million people worldwide. It has several neurological complications that are a result of both the virus itself, and multiple opportunistic infections. Encephalopathy in HIV infection is associated with dementia, and is termed AIDS dementia complex.

Epidemiology

AIDS dementia complex is primarily seen in patients with advanced immunodeficiency. Increased viral load predisposes patients to developing dementia. The introduction of highly active antiretroviral therapies (HAART) has reduced the incidence of dementia to less than 10 percent of patients with AIDS. Before effective antiretroviral treatments were developed, AIDS dementia complex developed in approximately 60 percent of patients. HIV is also associated with many opportunistic infections that cause neurological complications, the most common of which are cryptococcal meningitis, toxoplasmosis, cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, neurosyphilis, and central nervous system lymphoma. The primary neurological conditions seen with HIV infection are peripheral neuropathy, myelopathy, and encephalopathy.

Etiology

AIDS dementia complex is probably related to neuronal loss and changes in synaptic architecture. Infected astrocytes and multinucleated macrophages may be partially responsible for the neuronal damage. Recent evidence supports the roles of envelope glycoprotein gp120, Tat, and cytokines such as tumor necrosis factor in causing neurotoxicity and resultant cellular and cognitive dysfunction. There remains a debate, however, as to whether AIDS dementia complex is a result of migration of infected peripheral cells into the CNS, or whether it represents a primary CNS infection site.

Clinical Features and Diagnosis

Cognitive decline and motor slowing are the predominant characteristics of AIDS dementia complex. Cognitive changes tend to occur gradually over an approximate six-month period, and patients often maintain insight into the nature of the decline. Concentration problems and memory impairment are frequent complaints, and typically interfere with daily activities. Motor deficits are usually symmetric, affecting the extremities, and may include ataxia, weakness, tremor, and loss of fine motor coordination. Behavioral changes and depressed mood may also occur, although with less certainty. Psychotic symptoms are rare, and typically transient if present. In late stages of the disease, AIDS dementia complex may progress to mutism, incontinence, and paraplegia. Many patients with HIV also develop a mild cognitive disorder that does not meet criteria for frank dementia but may be a precursor to AIDS dementia complex.

The diagnosis of AIDS dementia complex is made by confirmation of HIV infection and exclusion of alternative pathology to explain cognitive impairment. The American Academy of Neurology AIDS Task Force developed research criteria for the clinical diagnosis of central nervous system disorders in adults and adolescents. The AIDS Task Force criteria for AIDS dementia complex require laboratory evidence for systemic HIV, at least two cognitive deficits, and the presence of motor abnormalities or personality changes. Personality changes may be manifested by apathy, emotional lability, or behavioral disinhibtion. Like the DSM-IV-TR, the AIDS Task Force criteria also require the absence of clouding of consciousness or evidence of another etiology that could produce the cognitive impairment. Cognitive, motor, and behavioral changes are assessed using physical, neurological and psychiatric examinations, in addition to neuropsychological testing. Neuroimaging studies and cerebrospinal fluid (CSF) evaluation are useful in ruling out other possible etiologies including opportunistic infections and CNS neoplasms.

Pathology and Laboratory Examination

Neuropathological findings associated with HIV are termed HIV leukoencephalopathy. These are diffuse inflammatory changes with microscopic foamy macrophages and multinucleated giant cells that invade subcortical white matter. In addition to routine laboratory examinations, CSF evaluation may reveal mononuclear cells, oligoclonal bands, and elevated protein. However, these latter findings are nonspecific and not limited to patients with AIDS dementia complex. Specific correlates of AIDS dementia complex in the CSF include elevated levels of b2-microglobulin, neopterin, quinolinic acid, and Fas, all of which were shown to decline with antiviral treatment and decreasing viral loads. Cerebrospinal fluid is also useful to rule out the presence of cryptococcal antigen, neurosyphilis, and CMV. Neuroimaging is not diagnostic, but instead may reveal pathological changes consistent with other primary diseases, such as CNS lymphoma, toxoplasma encephalitis, or progressive multifocal leukoencephalopathy. Research is focused on improving techniques, such as MR diffusion tensor imaging, to better detect subtle white matter changes in HIV. In the future, magnetic resonance spectroscopy (MRS) may reliably monitor HIV brain involvement by measuring metabolites that reflect loss of neurons and glia.

Treatment

Because it is clear that AIDS dementia complex is caused by HIV in the CNS, and that increased viral load is associated with a greater risk of developing AIDS dementia complex. The primary goal of treatment in HIV and AIDS dementia is to control the viral load. There is a current trend to delay treatment of HIV because of concern about the inevitable evolution of the virus to become resistant over the long term, and the risk of potential toxicity. The initiation of treatment is usually recommended for symptomatic infection, high viral loads (>55,000 copies per millimeter), or when the CD4 count falls below 350 cells per cubic millimeter. Today, most patients are expected to reach undetectable levels of plasma virus with HAART. Current research is focused on testing resistance to improve drug selection. Scientists are also focusing on monitoring therapeutic drug levels to aid in dose selection and prevent toxicity. There are a total of 15 approved antiretroviral medications that fall within three main classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Special attention may be paid to choosing regimens that maximize the potential to cross the blood brain barrier.