What Is AIDS Dementia Complex?

An AID-Defining Condition Affecting the Brain

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AIDS dementia complex (ADC), also known as HIV encephalopathy and HIV-associated neurocognitive disorder (HAND), is a complication of advanced HIV infection characterized by a significant loss of memory, cognitive function, judgment, and verbal fluency. It typically occurs when a person with HIV is severely immunocompromised (as measured by the loss of CD4 T-cells).

Mature man looking depressed and confused staring out a window
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ADC is among the list of AIDS-defining conditions classified by the Centers for Disease Control and Prevention (CDC). It is less commonly seen today than it was during the height of the AIDS pandemic of the 1980s and 1990s due to the advent of combination antiretroviral therapy.

Even so, between 4% and 15% of people with living HIV will experience some form of neurocognitive impairment as a direct result of HIV infection. This not only includes people with an untreated infection but also those on long-term HIV therapy.

Symptoms

The symptoms of ADC are similar to those of other types of dementia. By definition, dementia is a chronic disorder caused by brain disease or injury that manifests with memory problems, personality changes, and impaired reasoning.

Symptoms of ADC can vary from one person to the next but may include:

  • Forgetfulness
  • Memory loss
  • Mood changes
  • Personality changes
  • Apathy
  • Difficulty concentrating
  • Impaired reasoning and judgment 
  • Confused thinking
  • Difficulty following instructions
  • Difficulty generating or communicating ideas
  • Inability to describe or recognize emotions
  • Delayed or absent verbal responses
  • Reduced awareness of one's surroundings
  • Mutism and catatonia

The hallmark of later-stage ADC (or any form of advanced dementia) is the inability to recognize one's own symptoms.

With that said, the symptoms of ADC can often fluctuate, particularly in response to a person's immune status and an HIV-associated illness. This makes it different from neurodegenerative forms of dementia in which the decline tends to be constant and irreversible.

Complications

In addition to cognitive impairment (the loss of one's conscious intellectual capacity), ADC commonly manifests with psychological problems, particularly as the neurological symptoms become more profound.

A 2016 study from Brazil concluded that over 50% of adults with ADC experience clinical depression. While a person's emotional response to ADC can contribute to depression, global changes to the brain factor in significantly. Mania and psychosis are also sometimes seen.

Changes to the neural network of the brain can manifest with physical symptoms as always, particularly in people with severe ADC. These include:

  • Paraparesis (partial paralysis of the lower extremity)
  • Ataxia (characterized by slurred speech, stumbling, falling, and clumsiness)
  • Hyperreflexia (overresponsive reflexes)
  • Extensor-plantar response (the abnormal curving of the toes and feet when stroked)

Causes

AIDS dementia complex is associated with advanced HIV infection. It tends to affect people whose CD4 count is below 200 cells per microliter (cells/mL)—the CDC definition of AIDS.

A CD4 count of 200 increases a person's risk of ADC by three-fold, while a CD4 count under 100 elevates the risk by seven-fold.

ADC is primarily seen with untreated HIV infection. People over 50 are most commonly affected. Some studies have shown that women with HIV are at greater risk than men, although it is unclear why.

The relationship between HIV infection and ADC is not well understood, but it is thought that HIV affects the brain directly and indirectly in several ways.

Viral Infiltration

From the earliest stages of infection, HIV is able to cross the blood-brain barrier that separates the brain from the rest of the body. Once the virus enters the brain, it immediately establishes hidden reservoirs in a type of nerve cell called a microglia.

However, rather than generating new viruses, this hidden virus (called a provirus) will replicate silently alongside the host cell, unseen by the immune system and largely untouched by antiretroviral therapy.

Even so, toxic proteins produced by the virus can start to damage microglia and nearby cells called astrocytes. These are the cells in the central nervous system that regulate nerve signaling and transmission (synapsis), protect nerve cells from oxidative damage, and maintain the integrity of the blood-brain barrier.

Beyond the toxic effect that HIV has on these cells, the increased permeability of the blood-brain barrier leaves the brain exposed to the indirect ravages of HIV infection.

Immune Activation and Inflammation

The direct damage caused by HIV only plays a part in the onset of ADC. It is, in fact, the indirect mechanisms triggered by HIV that appears to play the bigger role.

When HIV infection occurs, the immune system will activate and release inflammatory proteins called cytokines that trigger a defensive inflammatory response. Even during the latent stage of infection when the disease largely asymptomatic, chronic inflammation will persist, causing ongoing injury to nerve cells and the axons that connect them.

This is evidenced by structural changes to the brain in people with long-term HIV infection. Even those on effective antiretroviral therapy will often experience changes in the subcortical parts of the brain (including the basal ganglia and hippocampus) that regulate emotions, learning, and memory formation.

Under the burden of untreated HIV, the increased circulation of cytokines—paired with the destruction of the blood-brain barrier—can compound the damage to these parts of the brain, often irreversibly.

The incidence of ADC has declined by more than half since the introduction of combination antiretroviral therapy in the 1990s. Even so, a study published in Neurology reported that no less than 12% of people living with HIV today experience mild cognitive dysfunction, while 1.2% meet the clinical definition of ADC.

Diagnosis

AIDS dementia complex is diagnosed by the characteristic symptoms and features of the disorder as well as the exclusion of all other possible causes.

The diagnostic process can be complicated since most people will present with mild cognitive dysfunction rather than the catastrophic loss of memory and executive function.

There are no lab tests or imaging studies that can definitively diagnose ADC; rather it is diagnosed based on clinical criteria and an expert review of evidence.

Physical Examination

The diagnosis of neurological disorders in people with HIV typically starts with a physical exam.

In addition to reviewing a person's symptoms, medical history, and treatment status, the doctor will perform a hands-on evaluation to check for tell-tale signs of neurological dysfunction. These may include an unsteady gait, lack of coordination, hyperreflexia, rapid eye movements, and the extensor flexor response.

Mental Status Exam (MSE)

The mental status exam (MSE) is the psychological equivalent of a physical exam. It assesses a person's mental status by looking objectively at a variety of components, including:

  • A person's appearance
  • Behavior
  • Speech
  • Mood
  • Thought processes
  • Thought content
  • Judgment and insights

Key findings suggestive of ADC may include inattention, impaired concentration, memory loss, slowed verbal response, and emotional blunting (the inability to express or convey emotion).

Lab Tests

The doctor will also order lab tests to check your immune status and viral load. This is especially important if you have only recently been diagnosed or have not yet started treatment.

This is especially important because ADC is more common in people with a low CD4 nadir (the lowest point the CD4 count has dropped). As such, someone with a CD4 nadir of 50 is more likely to have ADC than someone with a CD4 nadir of 250.

In addition, a lumbar puncture ("spinal tap") may be ordered to check for any abnormalities in the cerebrospinal fluid. It can exclude other neurological conditions that commonly affect people with advanced HIV, including opportunistic infections like cryptococcosis or toxoplasmosis that can manifest with confusion and personality changes.

As opposed to opportunistic infections that cause the sudden onset of neurological symptoms, ADC is characterized by the gradual development of symptoms, often over the course of years.

Other lab tests may be ordered, including a liver function test, syphilis test, and thyroid hormone test, to see if any other abnormalities can account for your symptoms. A drug screen may also be requested if substance abuse is suspected.

Other Procedures

In addition to lab tests, imaging studies may be ordered to not only look for characteristic changes in the brain but to also check if other conditions, such as s cerebrovascular or neurodegenerative disorder, are the cause of your symptoms.

A magnetic resonance imaging (MRI) scan is typically the procedure of choice since it is better able to image soft tissue. With ADC, the doctor would expect to see areas of brain atrophy (death) in the subcortical region as well as in the white matter of the brain where nerve cells and axons reside.

The MRI may be accompanied by an electroencephalogram (EEG) which measures the electrical activity in the brain. With ADC, those signals would be expected to be slowed.

Diagnostic Criteria

Over the years, several guidelines have been issued outlining the diagnostic criteria for ADC. One of the more recent adapted guidelines issued by the American Academy of Neurology back in 1991.

The updated guidelines, coordinated by the National Institute of Mental Health in 2007, requires that the following criteria be met in order for ADC to be diagnosed:

  1. There must be the marked impairment of cognitive function involving at least two characteristic features, most notably slowed response, inattention, and difficulty learning new information.
  2. A person's daily functioning must be significantly impaired.
  3. The symptoms cannot meet the criteria for delirium.

Staging

Based on the cumulative findings, the doctor can stage ADC based on a system developed by Memorial-Sloan Kettering Hospital back in the 1980s. The system is categorized on a scale of 0 to 4, with 0 being the least severe and 4 being the most severe.

Stage Definition Characteristics
0 Normal There is evidence of cerebral atrophy but no signs of cognitive dysfunction.
1 Mild The person can work and performmore demanding aspects of life but has neurcognitive deficits when tested.
2 Moderate The person is able to care for themselves but is unable to work or maintain the more demanding aspects of their life.
3 Severe The person has a severe intellectual incapacity and can no longer walk without assistance.
4 End-Stage The severe loss of cognitive and motor skills leaves a person in a near-vegetative state. Stage 4 is highly predictive of early death.

The staging of ADC only has limited application since it doesn't alter the course of treatment. It can, however, inform the prognosis, including a person's estimated survival time.

Differential Diagnosis

One of the challenges of ADC is that it occurs at a time in life when other causes of dementia, namely Alzheimer's disease (AD), may develop. As such, any signs of dementia may have little or nothing to do with HIV, even in someone with a low CD4 count.

With that said, there are several key differences between ADC and AD.

AIDS Dementia
  • More likely to have difficulty remembering recent events

  • Characterized by the slowing of movement and thought

  • Symptoms can fluctuate and vary

  • Characteristically affects subcortical parts of the brain

  • Low levels of a protein called tau are found in cerebrospinal fluid

Alzheimer's Disease
  • More likely to have difficulty remember events from the past

  • Motor slowing is less characteristic, and muscle tone often increases

  • The decline is invariably progressive

  • Brain atrophy tends to be more global and often occurs at the back of the brain

  • High levels of a protein called tau are found in cerebrospinal fluid

In addition to Alzheimer's disease, the doctor will explore other conditions in the differential diagnosis, including:

Treatment

The frontline treatment of AIDS dementia complex is antiretroviral therapy. The combination of drugs blocks multiple stages in the life cycle of HIV, preventing the replication of the virus.

The resulting drop in the viral load, ideally to undetectable levels, alleviates the inflammatory burden on the body while allowing the immune system to rebuild itself.

The combination typically involves three different drugs taken daily to maintain a consistently high concentration in the blood.

Although there are no guidelines directing the choice of drug in people with ADC, certain antiretrovirals—like Tivicay (dolutegravir)—are better able to penetrate the blood-brain barrier and are typically used in first-line therapy.

Treatments Under Investigation

In addition to antiretrovirals, a number of adjunctive therapies have been explored to treat or prevent ADC. While none have yet proved strongly effective, there three agents under investigation thought to have neuroprotective effects:

Prognosis

Although the damage caused to nerve cells is often irreversible, the symptoms of ADC often are. It depends largely on how advanced ADC was at the time of diagnosis, the CD4 nadir, and other factors.

The recovery of cognitive and motor skills generally corresponds to increases in the CD4 count, the recovery of which can often take time. A lower CD4 nadir at the start of therapy almost invariably results in slower recovery times. In fact, some people with extremely low CD4 counts may never get to normal levels (defined as 500 and above).

Even so, studies suggest that with optional HIV therapy, many people with ADC will usually achieve better concentration, processing speed, and executive function. Others may not.

The failure to recover cognitive and motor functions is generally predictive of a poor outcome.

A Word From Verywell

Although the more severe manifestations of ADC are less common today than they once were, people with long-term HIV infection can still experience mild cognitive deficits. While most cases won't lead to dementia per se, some do—particularly in the absence of HIV therapy.

While there is no evidence that early treatment can outright prevent neurological changes to the brain, by maintaining a high CD4 count and low viral load, you are less likely to experience notable signs of impairment over the long-term.

Antiretroviral therapy is today recommended at the time of diagnosis. The early treatment of HIV not only confers to near-normal life expectancy but also reduces the risk of serious HIV-associated and non-HIV associated illnesses by 61%.

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