AIDS dementia complex
Synonyms and keywords:  Major or mild neurocognitive disorder due to HIV infection
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# Overview
AIDS dementia complex (ADC; also known as HIV dementia, HIV encephalopathy and HIV-associated dementia) has become a common neurological disorder associated with HIV infection and AIDS. It is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of brain macrophages and microglia. 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 apoptosis.
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 10-20% in Western countries and has only been seen in 1-2% of India based infections. This has to due to with differences in diets, such as consumption of curcumin (in curry) and EGCG or Theaflavins (in teas), both which can pass the blood brain barrier and have neuroprotective effects.  With the advent of highly active antiretroviral therapy (HAART), the frequency of ADC has declined in developed countries. HAART may not only prevent or delay the onset of ADC in people with HIV infection, it can 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.

# Anatomical Areas Involved
- HIV is associated with pathological changes in mainly subcortical and fronto-striatal areas of the brain, including the basal ganglia, deep white matter, and hippocampal regions.
- Neuroimaging studies of HIV patients indicate that significant volume reductions are apparent in the frontal white matter, whereas subcortically, hypertrophy is apparent in the basal ganglia, especially the putamen.
- Some studies suggest loss of brain volume in cortical and subcortical regions even in asymptomatic HIV patients and patients who were on stable treatment.  Cerebral brain volume is associated with factors related to duration of the disease and CD4 nadir; patients with a longer history of chronic HIV and higher CD4 nadir present with greater cerebral atrophy.
- CD4 lymphocyte counts have also been related to greater rates of brain tissue loss.
- Current factors, such as plasma HIV RNA, have been found to be associated with brain volumes as well, especially with regards to basal ganglia volume and total white matter.
- Changes in the brain may be ongoing but asymptomatic, that is with minimal interference in functioning, making it difficult to diagnose HIV-associated neurocognitive disorders in the early stages.

# Behavioral Aspects of Neurocognitive Impairments

## Cognitive Impairments
- Cognitive impairments associated with HIV occur in the domains of attention, memory, verbal fluency, and visuospatial construction. Specifically for memory, the lowered activity of the hippocampus changes the basis for memory encoding and affects mechanisms such as long-term potentiation.
- Severity of impairment in different domains varies depending on whether or not a patient is being treated with HAART or monotherapy.
- Studies have shown that patients exhibit cognitive deficits consistent with dysfunction of fronto-striatal circuits including associated parietal areas, the latter of which may account for observed deficits in visuospatial function.

## Psychological Dysfunction
- In addition to cognitive impairments, psychological dysfunction is also noted. For example, patients with HIV have higher rates of clinical depression and alexithymia, i.e., difficulty processing or recognizing ones own emotions.  Patients also have more difficulty recognizing facial emotions.
- Without combination antiretroviral therapy, cognitive impairments increase with successive stages of HIV.  HIV patients in early stages show mild difficulties in concentration and attention.  In advanced cases of HIV-associated dementia, speech delay, motor dysfunction, and impaired thought and behavior are observed. Specifically, lower motor speeds were found to correlate with hypertrophy of the right putamen.
- The diagnosis of HIV-associated neurocognitive impairment is made using clinical criteria after considering and ruling out other possible causes.  The severity of neurocognitive impairment is associated with nadir CD4, suggesting that earlier treatment to prevent immunosuppression due to HIV may help prevent HIV-associated neurocognitive disorders.

# Differential Diagnosis
- CNS lymphoma
- Cryptococcosis
- Drug abuse
- Hepatitis C virus
- Neurocognitive decline related to cerebrovascular disease
- Neurodegeneration
- Alzheimer's disease
- Syphilis
- Toxoplasmosis

# Epidemiology and Demographics

## Prevalence
The prevalence of major or mild neurocognitive disorder due to HIV infection is :
25,000 per 100,000 (25%) for mild neurocognitive disorder
5,000 per 100,000 (5%) for major neurocognitive disorder

# Risk Factors
- Aging
- Co-infections,with hepatitis C virus
- Chronic exposure to antiretroviral drugs
- Drug-resistant viral strains
- Drug abuse
- Inadequate control of HIV in the central nervous system
- Long-term systemic and brain inflammation
- Past history of CNS trauma

# Diagnostic criteria
- 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.
- Cognitive impairments identified in 1. interfere markedly with day-to-day functioning.
- Cognitive impairments identified in 1. are present for at least one month.
- 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.
- 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.
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.

## DSM-V Diagnostic Criteria for Major or Mild Neurocognitive Disorder Due to HIV Infection 

# 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 double incontinence

# 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 - there are many
- 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. The HIV virus protein gp120 inhibits the stem cells in the brain from producing new nerve cells. Researchers hope that new drugs under investigation will interfere with the detrimental cycle and prevent neuron death.