AIDS Dementia Complex (ADC)

What is it?

AIDS dementia complex (ADC), sometimes called HIV-associated dementia (HAD),

is different than other types of AIDS-related illnesses. Most AIDS-related illnesses
are caused by other infections (such as bacteria, fungi, and other viruses). ADC is one
of the only illnesses that can be caused directly by HIV.

HIV can pass into the brain. In fact, some studies show that HIV enters the brain in as
few as two days after the virus first enters the body. HIV can damage nerve cells in
the brain, although researchers don't totally understand how this happens.

ADC can happen at any T-cell count. However, it is much more likely to occur when
the T-cell count falls below 200. This is because the immune system plays a major
role in protecting nerves in the brain. If the immune system becomes suppressed, HIV
and other organisms can damage these nerves and affect the way the brain works.

It has been estimated that between 20% and 35% of all HIV-positive people will
eventually develop some symptoms of ADC. However, the number of HIV-positive
people with ADC is much lower today, thanks to the availability of powerful anti-HIV
drug therapy.

What are the symptoms?

The symptoms of early dementia include:

• Trouble learning new things

• Difficulty remembering things that happened in the past
• Changes in behavior
• Confusion
• Depression

If dementia progresses, it can cause the following symptoms:

• Speech problems
• Balance problems
• Vision problems
• Problems walking
• Loss of bladder control
• Mania (an exaggerated feeling of well-being) or psychosis (a loss of contact
with reality)

It is important to remember that many of these symptoms can have many different
causes, not just ADC. Depression, for example, can develop in anyone – not just HIV-
positive people with suppressed immune systems. Thus, it is important to discuss any
changes in your mood, concentration, or behavior with a healthcare provider to figure
out what might be going on.
How is it diagnosed?

Because there are several AIDS-related diseases that can cause symptoms similar to
those of ADC, it is often necessary to conduct different tests to determine the actual
causes of the symptoms. Toxoplasmosis, lymphoma, and PML have many of the same
symptoms as ADC.

The most common tests are:

A mental status exam: This includes game-like tests to check memory and
concentration abilities.

X-rays, CT scans, and MRI: All of these are painless and provide doctors with
images of the brain and spinal column. Different diseases cause different types of
damage to the brain and/or spinal column. Examining these images can help doctors
determine what is going on.

A spinal tap: A needle is inserted into the spinal column to drain a small amount of
cerebrospinal fluid – the liquid that surrounds the brain and spinal column. A
laboratory can examine this fluid to look for organisms that might be causing
symptoms, including HIV.

How is it treated?

Just as anti-HIV medications are the best tools to keep viral load undetectable and to
keep the immune system healthy, they are also the most effective treatments for ADC.
However, some anti-HIV drugs are more effective than others. Not all of the anti-HIV
drugs are able to cross from the bloodstream into the brain. This is because the brain
is protected by the "blood-brain barrier" – a tight mesh of cells that prevent many
organisms and chemicals (including medications) from entering into the brain.

This is a list of anti-HIV drugs that do cross the blood-brain barrier and may help stop
or slow HIV damage in the brain:

Anti-HIV Drugs That Cross the Blood-Brain Barrier

Nucleoside Reverse Transcriptase Inhibitors (NRTIs):

• Retrovir® (AZT)
• Zerit® (d4T)
• Epivir® (3TC)

• Ziagen® (abacavir)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
 • Viramune® (nevirapine) - high levels of this drug can cross into the brain

• Sustiva® (efavirenz)
Protease Inhibitors (PIs):

• Agenerase® (amprenavir)

Retrovir® (AZT) was one of the first drugs studied for the treatment of ADC. Clinical
trials found that it was helpful for patients with ADC. Based on these results, experts
agree that other drugs that cross the blood-brain barrier – especially if they are used in
combination – can help halt or reverse many of the symptoms associated with ADC.

While anti-HIV drugs can treat the underlying cause of ADC, they may not
effectively treat the symptoms. Some people may see their symptoms disappear
slowly. Others may simply not get any worse. Sometimes, symptoms of ADC can
actually become worse. Thus, it might be necessary to use additional treatments to
help manage these symptoms.

Some of the drugs that have been shown to be effective include:

Possible Treatments for the Symptoms of ADC

Haloperidol (Haldol®): Is used to treat a variety of symptoms frequently seen in
dementia.

Methylphenidate (Ritalin®): Most commonly used to treat attention deficit

disorder in children. It can also be used to help people with dementia to maintain
their concentration.

Chlorpromazine (Thorazine®) and thioridazine (Mellaril®): These are anti-

psychotic drugs and can be used to control agitation and to stabilize severe behavior
problems.

Lorazepam (Ativan®) and diazepam (Valium®): Anti-anxiety/sedative drugs.

Antidepressants: These include fluoxetine (Prozac®) and bupropion

(Wellbutrin®). Antidepressants can help boost (or prevent) important electrical
impulses in the brain. This may help alleviate behavioral and emotional symptoms
of ADC.

Can it be prevented?

ADC is the result of two situations: immune suppression caused by HIV and the direct
effects of HIV in the brain. Anti-HIV drugs, particularly those discussed in the last
section of this lesson, can help prevent ADC, provided that treatment is started before
immune suppression occurs (less than 200 T-cells).
Peripheral Neuropathy

What is it?

Peripheral neuropathy results from injury to the peripheral nerves in the body. These
nerves carry signals between the central nervous system (the brain and spinal column)
and the muscles, skin, and internal organs. When peripheral neuropathy first develops,
people often report a tingling or prickling in the toes, although it can also start in the
fingers. Over time, the tingling gradually spreads up the feet or hands and worsens
into a burning, shooting, and/or throbbing pain. People who have severe peripheral
neuropathy may experience extreme pain and may have difficulty walking, sometimes
requiring the assistance of a cane or wheelchair to move around.

People who have peripheral neuropathy usually experience symptoms on both sides of
their bodies. In other words, peripheral neuropathy almost always occurs in both feet
and/or both hands. The sensations can be either constant or periodic. Sometimes they
may not be noticeable, while at other times they may be extremely bothersome.

Not only can peripheral neuropathy be physically painful, it can also have a profound
effect on quality of life. The natural instinct to avoid or reduce pain can prevent
people from going about their regular day-to-day activities, whether it be going up
and down stairs, visiting with family or friends, or going to work. This can cause a
great deal of anxiety and can lead to serious depression—serious emotional problems
that can make life seem altogether frustrating.

What causes peripheral neuropathy?

There are several possible causes of peripheral neuropathy. Direct injury, such as a
broken bone or a severe burn, can cause damage to peripheral nerves. Certain
diseases, such as diabetes, arthritis, or lupus, can also result in nerve damage. A lack
of essential vitamins and minerals, particular vitamins B12 and E, can contribute to
nerve damage. Conversely, taking too much vitamin B6 (more than 200 mg a day) can
actually cause this condition.

HIV itself has also been shown to cause nerve damage, usually in people with
seriously suppressed immune systems. In most HIV-positive people, however,
peripheral neuropathy is a side effect of the medicines they use—certain drugs,
including those used to treat HIV and certain AIDS-related infections, can damage
peripheral nerves and eventually lead to symptoms of neuropathy.

The most likely reason why certain HIV drugs cause peripheral neuropathy is that
they can damage mitochondria—the genetic powerhouses inside cells that help
convert nutrients into energy that our cells need. Too much mitochondrial damage,
researchers believe, can lead to nerve damage and peripheral neuropathy.
Some of the HIV/AIDS drugs that can cause peripheral neuropathy include:
Hivid (zalcitabine) - sales are to be discontinued before the end of 2006.
Videx; Videx EC (didanosine)
Zerit (stavudine)
isoniazid (INH; Nydrazid; Tubizid) - for the prevention and treatment of
tuberculosis (TB)
vincristine (Oncovin; Vincasar) or vinblastine (Velban) - for the treatment of
Kaposi's sarcoma (KS)
ethambutol (Myambutol) - for the treatment of MAC and other bacterial infections
metronidazole (Flagyl) - for the treatment of amoebas and parasitic infections
linezolid (Zyvox) - for the treatment of bacterial infections
dapsone - for the treatment of Pneumocystis carinii pneumonia (PCP) and other
infections

While peripheral neuropathy is a common side effect of these drugs, this does not
mean that all people who take them will experience nerve damage or develop
symptoms of neuropathy. It's possible that people who combine these drugs—such as
Zerit and Videx, two nucleoside reverse transcriptase inhibitors (NRTIs) that are no
longer routinely used together—are at a greater risk of experiencing neuropathy or
developing more severe and painful symptoms. Similarly, people who use these HIV
medications with other drugs known to cause peripheral neuropathy may also be at an
increased risk of this side effect. The risk of peripheral neuropathy may be higher still
if these medications are used in people with a history of neuropathy, diabetes, heavy
alcohol consumption, poor nutrition, and/or older age.

What are the symptoms of peripheral neuropathy?

Because peripheral neuropathy is not the only nerve-related problem that can occur in
HIV-positive people, it's important that you report any noticeable symptoms to your
healthcare provider. Once you and your doctor have determined the source of these
symptoms, you can work together to figure out what to do about it.

The symptoms of peripheral neuropathy usually occur in the feet and/or hands:
Numbness/insensitivity to pain or temperature
Extreme sensitivity to touch
Tingling, prickling, or burning sensation
Sharp pain/cramping
Loss of balance/coordination
Loss of reflexes (your doctor can check these)
Muscle weakness
Noticeable changes in the way you walk
Other symptoms of nerve damage that you'll want to report to your doctor
include:
Noticeable increase in the number of times you need to urinate during the day and
at night
 Difficulty walking up and down stairs
Frequent stumbling or falls
Erectile dysfunction

Should I stop my medicines that are causing the neuropathy?

Generally speaking, the best way to manage peripheral neuropathy is to stop (or
switch) any medications that may be causing the problem. For example, if you are
taking an anti-HIV drug regimen that contains Zerit, the first approach should be to
switch the Zerit for another NRTI that is less likely to cause peripheral neuropathy
(options might include Retrovir [zidovudine], Viread [tenofovir], or Ziagen
[abacavir]). Of course, you should discuss this option with your healthcare provider—
do not attempt to stop any of your medications or to switch them without first
checking in with your doctor.

It can sometimes take a few weeks or months for symptoms of peripheral neuropathy
to improve after stopping an offending drug. In some cases, symptoms can worsen
before they get better.

What about medications to treat peripheral neuropathy?

Other than stopping neuropathy-causing drugs—which isn't always possible for

people with limited HIV treatment options or in need of other medications for certain
illnesses—managing peripheral neuropathy can be a challenge. A number of
treatments have been used over the years, and are still prescribed, to treat the painful
symptoms of peripheral neuropathy (reviewed in the next section). What has been
missing, however, are treatments that reverse the underlying cause of neuropathy
symptoms, notably the mitochondrial damage that can lead to nerve problems.
Fortunately, some research progress has been made in recent years.

To reverse mitochondrial damage caused by NRTIs in people with peripheral

neuropathy, at least two widely available supplements are being studied in clinical
trials. The first is acetyl-L-carnitine, believed to improve the function of cellular
mitochondria through its ability to transport fatty acids. In a study conducted at the
Royal Free and University College Medical School in London and published in 2004,
21 HIV-positive people with NRTI-associated peripheral neuropathy were treated
with 1,500mg twice-daily doses of acetyl-L-carnitine for up to 33 months. After six
months of treatment, biopsies taken from the patients—and compared to those taken
from HIV-negative study volunteers—found significant regrowth in nerves of the
skin. Sixteen (76%) patients also reported symptom improvements during the study
period.

In another study, reported in 1997, 500 to 1,000mg daily acetyl-L-carnitine reduce

neuropathy symptoms in 10 of 16 (63%) HIV-positive patients with peripheral
neuropathy. Unfortunately, biopsies were not conducted to measure nerve growth in
this study. A third study using a combination of supplements that included acetyl-L-
carnitine did not appear to reverse symptoms of peripheral neuropathy or improve
neurological tests in HIV-positive people with this side effect.

Uridine, sold in the U.S. as NucleomaxX and in Europe as Mitocnol, is another

supplement that may help improve mitochondrial function. Encouraging data using
uridine in clinical trials involving people with diabetic neuropathy have been reported.
Studies of uridine involving HIV-positive people with neuropathy are being
conducted.

What about medications to reduce the symptoms of neuropathy?

Non-narcotic pain relievers. These include aspirin, acetaminophen (e.g., Tylenol),

ibuprofen (e.g., Advil), and naproxen (e.g., Aleve). All of these are available over-
the-counter at pharmacies and grocery stores. These medicines are often quite
effective in handling mild pain associated with peripheral neuropathy. While they
can irritate the stomach, they are not addictive and can be taken regularly to
maintain comfort. Prescription versions of these drugs—which are reimbursed by
most private and public health-insurance policies—are available for pain that is
slightly more severe.

Topical medications. 5% lidocaine gel (Lidoderm), an anesthetic gel applied

directly to the skin, is now available with a doctor's prescription in the United
States. However, a clinical trial involving 65 HIV-positive people failed to
demonstrate significant reductions in pain caused by peripheral neuropathy.

Another topical medication being studied is capsaicin, the spicy chemical in chili
peppers. Patches containing 8% capsaicin—applied directly to the feet for 30 to 90
minutes at a time—moderately reduced pain, compared to placebo, in a clinical trial
involving 307 HIV-positive people with peripheral neuropathy.

Tricyclic antidepressants. These drugs work by reducing certain chemicals in the

brain, called "neurotransmitters," that are associated with pain and emotional
distress. They are often combined with non-narcotic pain relievers (see above) and
are usually recommended for the treatment of mild-to-moderate pain. They are also
prescribed, in combination with narcotic painkillers, to help manage severe pain.
While anecdotal (word-of-mouth) reports from HIV-positive patients and doctors
suggest that tricyclic antidepressants are sometimes helpful in managing symptoms
of peripheral neuropathy, data from clinical trials are either limited or have not
shown that these drugs are, in fact, effective.

The two most common tricyclic antidepressants are amitriptyline (Elavil) and
nortriptyline (Pamelor). It is important that low doses of these drugs be used at first,
with a slow buildup to the recommended daily doses. Amitriptyline should be
started using a dose of 25 mg or less, usually at bedtime. Over time, the dose may
be increased to 75 mg a day. With nortriptyline, the recommended starting dose is
10 mg three times a day, building up gradually to 30 mg three times a day.
Increasing the dose gradually is necessary to prevent certain side effects, such as
dry mouth, problems urinating, and sleepiness, that can occur with both of these
drugs. Note: Some anti-HIV protease inhibitors and non-nucleoside reverse
transcriptase inhibitors (NNRTIs) can either increase or decrease blood levels of
tricyclic antidepressants. As a result, your doctor may want to regularly check the
amount of these drugs in your bloodstream. Be sure to discuss the possibility of
drug interactions with your doctor.

Anticonvulsants. Anticonvulsants are normally used to treat epilepsy, another

neurological disorder. These drugs help calm the central nervous system, including
the part of the nervous system responsible for processing pain. There have been
some data from clinical trials, as well as many anecdotal (word-of-mouth) reports
from HIV-positive patients and doctors, suggesting that anticonvulsants are
sometimes helpful in managing symptoms of peripheral neuropathy.

Pregabalin (Lyrica), gabapentin (Neurontin), lamotrigine (Lamictal), carbamazepine

(Epitol; Tegretol), phenytoin (Dilantin), and topiramate (Topamax) are six
anticonvulsants that can be used for pain associated with peripheral neuropathy. As
with the tricyclic antidepressants, it might be necessary to increase the doses of
these drugs (particularly gabapentin and lamotrigine) over the first few weeks of
treatment, and to alter your dose of these drugs if side effects occur. Some of the
side effects of anticonvulsants include loss of muscle control, rash, and decreased
blood pressure. Note: Some anti-HIV protease inhibitors and non-nucleoside
analogues can either increase or decrease blood levels of anticonvulsants. As a
result, your doctor may want to regularly check the amount of these drugs in your
bloodstream. Be sure to discuss the possibility of drug interactions with your doctor.

Narcotic pain relievers. When the symptoms of peripheral neuropathy get to be

too much and don't subside with the use of the medications discussed above, it
might be necessary to use some of the more powerful narcotic drugs to manage the
pain. These drugs are usually used in combination with non-narcotic pain relievers,
along with tricyclic antidepressants or anticonvulsants. While it's certainly safe to
use narcotic pain relievers to manage pain over the short term—even for HIV-
positive people with a history of drug addiction—they can become addictive if used
on a long-term basis. Narcotic medications can also cause nausea, vomiting, and
sleepiness. Thus, it's important to work closely with your doctor to find a dose that
helps control the pain without the addition of unwanted side effects.

For moderate pain, the recommended narcotic pain relievers include morphine,
oxycodone, codeine, and meperidine. For severe pain requiring heavy-duty relief,
the options are usually sustained-release morphine, methadone, and fentanyl
patches. Low doses of these drugs should be started at first and then gradually
increased until the pain is more manageable without additional side effects. Note:
Some anti-HIV protease inhibitors and non-nucleoside analogues can either
increase or decrease blood levels of narcotic pain relievers. As a result, your doctor
may want to regularly check the amount of these drugs in your bloodstream. Be
sure to discuss the possibility of drug interactions with your doctor.