HIV (human immunodeficiency virus) is the virus that causes AIDS (acquired immune deficiency syndrome). HIV attacks the immune system by destroying specific white blood cells called CD4 positive (CD4+) T cells that are vital to fighting off infection. The resulting shortage of these cells leaves people infected with HIV vulnerable to other infections and diseases, and additional complications.
AIDS is the final stage of HIV infection. A person infected with HIV is diagnosed with AIDS when he or she has a dangerously low number of CD4+ T cells as well as one or more “opportunistic” infections, such as some types of pneumonia or tuberculosis, that do not typically affect people with healthy immune systems.
Although HIV infection and AIDS primarily affect the immune system, they also disturb the nervous system and can lead to a wide range of severe neurological disorders, particularly if HIV goes untreated and progresses to AIDS. Many of the most severe neurological conditions can be prevented with antiretroviral therapy. However, even individuals who receive this treatment can develop less severe neurological and cognitive difficulties.
How do HIV/AIDS affect the nervous system?
HIV does not directly invade nerve cells (neurons) but puts their function at risk by infecting cells called glia that support and protect neurons. HIV also triggers inflammation that may damage the brain and spinal cord (central nervous system) and cause symptoms such as:
- confusion and forgetfulness
- inability to concentrate
- behavioral changes
- mood disorders (anxiety disorder and depression)
- movement problems (loss of movement control) including a lack of coordination and difficulty walking.
Damage to the peripheral nerves can cause progressive weakness and loss of sensation in the arms and legs. Research has shown that HIV infection can cause shrinking of brain structures involved in learning and information processing.
Other nervous system complications that can occur as a result of HIV infection or the drugs used to treat it include:
- difficulty swallowing
- vision loss
- coma, and
- problems with bladder control or sexual function.
These symptoms may be mild in the early stages of AIDS but can become increasingly severe.
In children, the disease can cause:
- developmental delays
- loss of previously achieved milestones
- brain lesions
- nerve pain
- smaller than normal skull size
- slow growth
- eye problems, and
- recurring infections.
Can neurological complications develop in individuals treated with antiretroviral therapy (ART)?
Even when HIV is well controlled with ART, many infected individuals still develop HIV-associated neurological and cognitive difficulties. This is because many drugs used to combat HIV cannot cross the protective layer called the blood-brain barrier and enter the brain, and even those that can may not completely control the virus in the brain. Antiretroviral drugs can also become toxic after long-term use and cause neurological side effects.
What are some of the neurological complications that are associated with HIV infection?
AIDS-related disorders of the nervous system may be caused directly by the HIV virus, by certain cancers and opportunistic infections (illnesses caused by bacteria, fungi, and other viruses that would not otherwise affect people with healthy immune systems), or by toxic effects of the drugs used to treat symptoms. Other neuro-AIDS disorders of unknown origin may be influenced by but are not caused directly by the virus.
AIDS dementia complex (ADC), or HIV-associated dementia (HAD), occurs primarily in persons with more advanced HIV infection. Symptoms include encephalitis (inflammation of the brain), behavioral changes, and a gradual decline in cognitive function, including trouble with concentration, memory, and attention. Persons with ADC also show progressive slowing of motor function and loss of dexterity and coordination. When left untreated, ADC can be fatal. It is rare when anti-retroviral therapy is used. Milder cognitive complaints are common and are termed HIV-associated neurocognitive disorder (HAND). Neuropsychologic testing can reveal subtle deficits even in the absence of symptoms.
Central nervous system (CNS) lymphomas are cancerous tumors that either begin in the brain or result from a cancer that has spread from another site in the body. CNS lymphomas are almost always associated with the Epstein-Barr virus (a common human virus in the herpes family). Symptoms include headache, seizures, vision problems, dizziness, speech disturbance, paralysis, and mental deterioration. Individuals may develop one or more CNS lymphomas. Prognosis is poor due to advanced and increasing immunodeficiency, but is better with successful HIV therapy.
Cryptococcal meningitis is seen in about 10 percent of untreated individuals with AIDS and in other persons whose immune systems have been severely suppressed by disease or drugs. It is caused by the fungus Cryptococcus neoformans, which is commonly found in dirt and bird droppings. The fungus first invades the lungs and spreads to the covering of the brain and spinal cord, causing inflammation. Symptoms include fatigue, fever, headache, nausea, memory loss, confusion, drowsiness, and vomiting. If left untreated, patients with cryptococcal meningitis may lapse into a coma and die.
Cytomegalovirus (CMV) infections can occur concurrently with other infections. Symptoms of CMV encephalitis include weakness in the arms and legs, problems with hearing and balance, altered mental states, dementia, peripheral neuropathy, coma, and retinal disease that may lead to blindness. CMV infection of the spinal cord and nerves can result in weakness in the lower limbs and some paralysis, severe lower back pain, and loss of bladder function. It can also cause pneumonia and gastrointestinal disease. This is rarely seen in HIV-treated individuals since advanced immunity is required for CMV to emerge.
Herpes virus infections are often seen in people with AIDS. The herpes zoster virus, which causes chickenpox and shingles, can infect the brain and produce encephalitis and myelitis (inflammation of the spinal cord). It commonly produces shingles, which is an eruption of blisters and intense pain along an area of skin supplied by an infected nerve. In people exposed to herpes zoster, the virus can lay dormant in the nerve tissue for years until it is reactivated as shingles. This reactivation is common in persons with AIDS because of their weakened immune systems. Signs of shingles include painful blisters (like those seen in chickenpox), itching, tingling, and pain in the nerves.
People with AIDS may suffer from several different forms of neuropathy, or nerve pain, each strongly associated with a specific stage of active immunodeficiency disease. Peripheral neuropathy describes damage to the peripheral nerves, the vast communications network that transmits information between the brain and spinal cord to every other part of the body. Peripheral nerves also send sensory information back to the brain and spinal cord. HIV damages the nerve fibers that help conduct signals and can cause several different forms of neuropathy. Distal sensory polyneuropathy causes either a numbing feeling or a mild to painful burning or tingling sensation that normally begins in the legs and feet. These sensations may be particularly strong at night and may spread to the hands. Affected persons have a heightened sensitivity to pain, touch, or other stimuli. Onset usually occurs in the later stages of the HIV infection and may affect the majority of advanced-stage HIV patients.
Neurosyphilis, the result of an insufficiently treated syphilis infection, seems more frequent and more rapidly progressive in people with HIV infection. It may cause slow degeneration of the nerve cells and nerve fibers that carry sensory information to the brain. Symptoms, which may not appear for some decades after the initial infection and vary from person to person, include weakness, diminished reflexes, unsteady gait, progressive degeneration of the joints, loss of coordination, episodes of intense pain and disturbed sensation, personality changes, dementia, deafness, visual impairment, and impaired response to light. The disease is more frequent in men than in women. Onset is common during mid-life.
Progressive multifocal leukoencephalopathy (PML) primarily affects individuals with suppressed immune systems (including nearly 5 percent of people with AIDS). PML is caused by the JC virus, which travels to the brain, infects multiple sites, and destroys the cells that make myelin – the fatty protective covering for many of the body’s nerve and brain cells. Symptoms include various types of mental deterioration, vision loss, speech disturbances, ataxia (inability to coordinate movements), paralysis, brain lesions, and, ultimately, coma. Some individuals may also have compromised memory and cognition, and seizures may occur. PML is relentlessly progressive and death usually occurs within 6 months of initial symptoms. However, immune reconstitution with highly active antiretroviral therapy allows survival of more than half of HIV-associated PML cases in the current treatment era.
Psychological and neuropsychiatric disorders can occur in different phases of the HIV infection and AIDS and may take various and complex forms. Some illnesses, such as AIDS dementia complex, are caused directly by HIV infection of the brain, while other conditions may be triggered by the drugs used to combat the infection. Individuals may experience anxiety disorder, depressive disorders, increased thoughts of suicide, paranoia, dementia, delirium, cognitive impairment, confusion, hallucinations, behavioral abnormalities, malaise, and acute mania.
Toxoplasma encephalitis, also called cerebral toxoplasmosis, occurs in about 10 percent of untreated AIDS patients. It is caused by the parasite Toxoplasma gondii, which is carried by cats, birds, and other animals and can be found in soil contaminated by cat feces and sometimes in raw or undercooked meat. Once the parasite invades the immune system, it remains there; however, the immune system in a healthy person can fight off the parasite, preventing disease. Symptoms include encephalitis, fever, severe headache that does not respond to treatment, weakness on one side of the body, seizures, lethargy, increased confusion, vision problems, dizziness, problems with speaking and walking, vomiting, and personality changes. Not all patients show signs of the infection. Antibiotic therapy, if used early, will generally control the complication.
Vacuolar myelopathy causes the protective myelin sheath to pull away from nerve cells of the spinal cord, forming small holes called vacuoles in nerve fibers. Symptoms include weak and stiff legs and unsteadiness when walking. Walking becomes more difficult as the disease progresses and many patients eventually require a wheelchair. Some people also develop AIDS dementia. Vacuolar myelopathy may affect up to 30 percent of untreated adults with AIDS and its incidence may be even higher in HIV-infected children.
How are these disorders diagnosed?
Based on an individual’s medical history and findings from a general physical exam, a physician will conduct a thorough neurological exam to assess various functions: motor and sensory skills, nerve function, hearing and speech, vision, coordination and balance, mental status, and changes in mood or behavior. The physician may order laboratory tests and one or more of the following procedures to help diagnose neurological complications of AIDS. (See the NINDS publication, Neurological Diagnostic Tests and Procedures, for a comprehensive review of the tests used in diagnosing neurological and other disorders: http://www.ninds.nih.gov/disorders/misc/diagnostic_tests.htm.)
Brain imaging can reveal signs of brain inflammation, tumors and CNS lymphomas, nerve damage, bleeding, white matter irregularities, and other abnormalities. Several painless imaging procedures are used to help diagnose neurological complications of AIDS.
- Computed tomography (also called a CT scan) uses x-rays and a computer to produce two-dimensional images of bone and tissue to show inflammation, certain brain tumors and cysts, brain damage from head injury, and other abnormalities. It provides more details than an x-ray alone.
- Magnetic resonance imaging (MRI) uses a computer-generated radio waves, and a powerful magnetic field to produce either a detailed three-dimensional picture or a two-dimensional “slice” of body structures, including tissues, organs, bones, and nerves. It does not use the ionizing radiation that an x-ray does and provides a better look at tissue located near bone.
Functional MRI (fMRI) uses the blood’s magnetic properties to map areas of the brain that are active and to note how long they stay active. It can assess brain damage from head injury or degenerative disorders such as Alzheimer’s disease and identify and monitor other neurological disorders, including AIDS dementia complex.
- Magnetic resonance spectroscopy (MRS) uses a strong magnetic field to study the biochemical composition and concentration of hydrogen-based molecules, some of which are very specific to nerve cells, in various brain regions. MRS can show decreases in chemicals related to nerve cells and increases in chemicals related to inflammation in patients with HAND.
Electromyography, or EMG, is used to diagnose nerve and muscle dysfunction, including spinal cord disease, nerve fiber damage, and other nerve problems caused by the HIV virus. It records spontaneous muscle activity and muscle activity driven by the peripheral nerves.
Biopsy is the removal of tissue from the body for examination. A brain biopsy, which involves the surgical removal of a small piece of the brain or tumor, is used to diagnose a tumor, inflammation, or another brain irregularity. Unlike most other biopsies, it requires hospitalization and carries its own risks. Muscle or nerve biopsies can help diagnose neuromuscular problems.
Cerebrospinal fluid analysis can detect bleeding in the brain, infections of the brain or spinal cord such as neurosyphilis, and any harmful buildup of fluid. It can also be used to sample viruses that may be affecting the brain. A sample of the fluid is removed by needle under local anesthesia and studied to detect any irregularities.
How are these disorders treated?
No single treatment can cure the neurological complications of HIV/AIDS. Some disorders require aggressive therapy while others are treated as symptoms arise.
Neuropathic pain—chronic pain caused by damage to the nervous system—is often difficult to control. Medicines range from over-the-counter pain killers to anticonvulsant drugs, opiates, and some classes of antidepressants. Inflamed tissue caused by autoimmune or other conditions can press on nerves, causing pain. Such illnesses may be treated with corticosteroids or procedures such as plasma exchange, formally known as plasmapheresis, that clear the blood of harmful substances that cause inflammation.
Treatment options for AIDS- and HIV-related neuropsychiatric or psychotic disorders include antidepressants and anticonvulsants. Psychostimulants may also improve depression and reduce fatigue. Drugs such as cholinesterase inhibitors, which can temporarily improve or stabilize memory and thinking skills in people with dementia, may relieve confusion and slow mental decline. Benzodiazepines may be prescribed to treat anxiety. Psychotherapy may also help some individuals.
Aggressive antiretroviral therapy is used to treat AIDS dementia complex or HAND, vacuolar myopathy, progressive multifocal leukoencephalopathy, and cytomegalovirus encephalitis. Combined antiretroviral therapy (cART) uses at least three drugs to reduce the amount of virus circulating in the blood and may also delay the start of some infections. The goal is to use those agents that have good penetration into the brain.
Other treatments may include physical therapy and rehabilitation, radiation therapy and/or chemotherapy to shrink cancerous brain tumors that may be related to HIV, antifungal or antimalarial drugs to combat certain bacterial infections associated with the disorder, and penicillin to treat neurosyphilis.
What research is being done?
Within the Federal government, the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), supports research on the neurological consequences of HIV and AIDS. NINDS works closely with its sister agencies, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Mental Health (NIMH), to fund research related to HIV and AIDS. The Office of AIDS Research (OAR) coordinates AIDS research across NIH.
NINDS conducts research into how the weakened immune systems of individuals with AIDS lead to neurological illnesses. NINDS investigators are studying the JC virus, which can reproduce in the brains of people with impaired immune systems and cause progressive multifocal leukoencephalopathy (PML). In one small NINDS study, the anti-cancer drug pembrolizumab showed promise in slowing or stopping the progression of PML. Additional research is needed to confirm results, which could lead to new investigations that help revolutionize treatment for similar chronic infections in immune compromised individuals.
Many NINDS-funded projects are investigating how the HIV virus damages the brain and the reason for continued neurological injury even in individuals whose illness is well-controlled with combined antiretroviral therapy (cART). Some of this research focuses on the contributions of immune cells in the brain called microglia that are sent into overdrive by HIV infection and may be harmful to neurons as a result. Other experiments are attempting to determine how the HIV virus damages the blood-brain barrier and are investigating new formulations of cART as well as drug delivery methods that are better able to cross into the brain.
Many individuals whose infection is successfully suppressed with cART experience a reactivation of the virus upon stopping treatment. Researchers are studying how a reservoir of inactive HIV is maintained in the brain. This research is a first step toward developing a means to render the virus permanently dormant or even to rid the brain of all traces of the virus.
Several researchers are studying AIDS dementia complex and cognitive dysfunction in HIV to better understand how the death of neurons contributes to these conditions. Investigators are also studying inflammatory mechanisms associated with HIV-1 dementia and how early proteins produced by HIV-1 alter cellular signaling mechanisms in a manner that contributes to the loss of cognitive functions in infected individuals. Other researchers hope to identify HIV mutant strains that will help develop vaccines that may have the potential to prevent HIV-1 brain infection and HIV-associated neurocognitive disorders with HIV-associated dementia.
Aging is consistently identified as a risk factor for HIV-associated cognitive impairment. Older adults infected with HIV are more likely to develop these neurocognitive disorders than their younger counterparts. Scientists are examining how the HIV virus accelerates brain aging and how natural aging affects the development and symptoms of HAND.
Several studies are aimed at understanding the role of genetics in HAND. Other researchers hope to identify how genetic differences in the HIV virus modify its impact on the brain.
Researchers are also investigating how HIV affects not only the brain but also the peripheral nervous system, where it causes peripheral neuropathy. Some of these studies focus on determining how HIV causes that condition, while others aim to develop new treatments for neuropathic pain or examine how brain activity differs in HIV-positive individuals with and without pain.