HIV-associated neurocognitive disorder

HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. HAND may include neurological disorders of various severity such as AIDS dementia complex (ADC) also known as HIV dementia and HIV-associated dementia (HAD), HIV encephalopathy, and Mild Neurocognitive Disorder (MND). HIV-associated neurocognitive disorders are associated with a metabolic encephalopathy induced by HIV infection and fueled by immune activation of macrophages and microglia.^[1] These cells are actively infected with HIV and secrete neurotoxins of both host and viral origin. The essential features of ADC are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change. Cognitive impairment is characterised by mental slowness, trouble with memory and poor concentration. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include apathy, lethargy and diminished emotional responses and spontaneity. Histopathologically, it is identified by the infiltration of monocytes and macrophages into the central nervous system (CNS), gliosis, pallor of myelin sheaths, abnormalities of dendritic processes and neuronal loss.^[1][2]

ADC typically occurs after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. It is sometimes seen as the first sign of the onset of AIDS. Prevalence is between 10-24% in Western countries^[3] and has only been seen in 1-2% of India-based infections.^[4][5] With the advent of highly active antiretroviral therapy (HAART), the incidence of ADC has declined in developed countries, although its prevalence is increasing.^[6][7] HAART may prevent or delay the onset of ADC in people with HIV infection, and may also improve mental function in people who already have ADC.

Dementia only exists when neurocognitive impairment in the patient is severe enough to interfere markedly with day-to-day function. That is, the patient is typically unable to work and may not be able to take care of him or herself. Before this, the patient is said to have a mild neurocognitive disorder.

Diagnostic criteria

1. Marked acquired impairment of at least two ability domains of cognitive function (e.g. memory, attention): typically, the impairment is in multiple domains, especially in learning, information processing and concentration/attention. The cognitive impairment is ascertained by medical history, mental status examination or neuropsychological testing.
2. Cognitive impairments identified in 1 interfere markedly with day-to-day functioning.
3. Cognitive impairments identified in 1 are present for at least one month.
4. Cognitive impairments identified in 1 do not meet the criteria for delirium, or if delirium is present, dementia was diagnosed when delirium was not present.
5. No evidence of another, pre-existing aetiology that could explain the dementia (e.g. another CNS infection, CNS neoplasm, cerebrovascular disease, pre-existing neurological disease, severe substance abuse compatible with CNS disorder.^[8]

While the progression of dysfunction is variable, it is regarded as a serious complication and untreated can progress to a fatal outcome. Diagnosis is made by neurologists who carefully rule out alternative diagnoses. This routinely requires a careful neurological examination, brain scans (MRI or CT scan) and a lumbar puncture to evaluate the cerebrospinal fluid. No single test is available to confirm the diagnosis, but the constellation of history, laboratory findings and examination can reliably establish the diagnosis when performed by experienced clinicians. The amount of virus in the brain does not correlate well with the degree of dementia, suggesting that secondary mechanisms are also important in the manifestation of ADC.

Research

AIDS Dementia Complex (ADC) is not a true opportunistic infection; it is one of the few conditions caused directly by HIV itself. However, the etiology of ADC can be difficult to discern because the central nervous system can be damaged by a number of other causes related to HIV infection:

• opportunistic infections
• Primary cerebral lymphoma or metastasis of other AIDS-related cancers
• direct effects of HIV in the brain
• toxic effects of drug treatments
• malnutrition

Many researchers believe that HIV damages the vital brain cells, neurons, indirectly. According to one theory, HIV either infects or activates cells that nurture and maintain the brain, known as macrophages and microglia. These cells then produce toxins that can set off a series of reactions that instruct neurons to kill themselves. The infected macrophages and microglia also appear to produce additional factors such as chemokines and cytokines that can affect neurons as well as other brain cells known as astrocytes. The affected astrocytes, which normally nurture and protect neurons, also may now end up harming neurons. HIV protein gp120 inhibits the stem cells in the brain from producing new nerve cells.^[9] In the neuronal cells, the HIV gp120 induces mitochondrial-death proteins like caspases, which may influence the upregulation of the death receptor Fas leading to apoptosis.^[10] Researchers hope that new drugs under investigation will interfere with the detrimental cycle and prevent neuron death.

ADC stage characteristics

• Stage 0 (Normal) Normal Mental and Motor Function
• Stage 0.5 (Subclinical) Minimal symptoms of cognitive or motor dysfunction characteristic of ADC, or mild signs (snout response, slowed extremity movements), but without impairment of work or capacity to perform activities of daily living (ADL). Gait and strength are normal.
• Stage 1 (Mild) Evidence of functional intellectual or motor impairment characteristic of ADC, but able to perform all but the more demanding aspects of work or ADL. Can walk without assistance.
• Stage 2 (Moderate) Cannot work or maintain the more demanding aspects of daily life, but able to perform basic activities of self care. Ambulatory, but may require a single prop.
• Stage 3 (Severe) Major intellectual incapacity - cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all output. And/or motor disability - cannot walk unassisted, requiring walker or personal support, usually with slowing and clumsiness of arms as well.
• Stage 4 (End Stage) Nearly vegetative. Intellectual and social comprehension and responses are at a rudimentary level. Nearly or absolutely mute. Paraparetic or paraplegic with urinary incontinence and fecal incontinence.

See also

• Cognitive effects of HIV
• Shityakov, S., Dandekar, T., Förster, C. Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia. HIV AIDS (Auckl). 2015, 7, 265-276. (doi: 10.2147/HIV.S88438)

References