Author:
Elyse J Singer, MD, and H. Aaron Aronow, MD,
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Date Posted: Thu, October 18 2001, 18:41:23 PDT
In reply to:
H. Aaron Aronow,MD Neurology and Internal Medicine USC ..
's message, "Neurological manifestation of HCV" on Sat, May 19 2001, 10:27:06 PDT
HIV-BRAIN DISEASE: THE ROLE OF DRUG ABUSE
Elyse J Singer, MD, Associate Professor of Neurology UCLA School of Medicine and Principal Investigator National Neurological AIDS Bank and H. Aaron Aronow, MD, Associate Professor of Neurology and Internal Medicine USC School of Medicine and Co-Investigator National Neurological AIDS Bank
People with AIDS and their healthcare providers have clearly seen the benefits of highly active anti-retroviral therapy (HAART) and prophylaxis against opportunistic conditions. Many people infected with HIV are living fuller, more productive lives without frequent, prolonged life-threatening illnesses. Both doctors and patients do not have to deal as often with the constant stresses of death and dying. As people infected with HIV are living longer, both doctors and patients have to face chronic problems such as alcoholism and drug abuse and deal with these problems effectively. People affected by HIV and hepatitis C usually appreciate the role that intravenous drug use (IDU) plays in the spread of infection. Despite endless public-service announcements: ("This is your brain on drugs," accompanied by a picture of an egg being cracked into a frying pan), what many people do not appreciate is the role drug use plays in causing or worsening neurological diseases (diseases of the brain, spinal cord, and peripheral nerves). However, new findings strongly suggest that many drugs accelerate the damage caused by HIV in the nervous system.
In previous articles in Numedx (see Vol. 1 Issue 2)(all previous issues of Numedx can be accessed by visiting Numedx.com) we discussed how the brain may be a reservoir for persistent HIV infection, due to the ability of the blood—brain barrier to limit the penetration of many antiretroviral drugs. One result of HIV brain infection is HIV Cognitive-Motor Complex (HIVCMC, sometimes-called "AIDS Dementia Complex" or "HIV Associated Dementia"). The symptoms of HIVCMC include cognitive dysfunction (decreased memory, attention, concentration, and mental slowing), impairment of central motor function (weakness, spasticity, hyperreflexia, uncoordination), and abnormalities in behavior (apathy, psychomotor retardation). Even in the era of HAART, HIVCMC is diagnosed in about 15% of AIDS patients before death. Autopsy studies indicate that HIV encephalitis (infection and inflammation of the brain caused by HIV) is found at autopsy in at 25% to 40% of AIDS patients,1 indicating that HIVCMC may be underdiagnosed during life. This condition and others appear to be more common and severe in persons who use some recreational drugs.
Drug Abuse and Neurological Disease
Drug abuse was known to cause neurological problems for years before the HIV epidemic. Neurological diseases were often caused by unsterile injection techniques and needle sharing, leading to infections of the brain and spinal cord. In addition, poor hygiene, malnutrition, concurrent alcohol abuse, and other aspects of the drug-using lifestyle are not compatible with optimal brain function. Compared to the general population, intravenous drug users (IDUs) tend to be less educated, poorer, and have a history of multiple head injuries, major psychiatric diseases, and systemic illnesses such as hepatitis C virus infection (HCV) that can affect the nervous system [see Numedx Vol. 3 Issue 2)]. These factors tend to complicate the evaluation of neurological and neuropsychological problems in IDUs, even in the absence of HIV infection.2 Drugs of abuse can also be toxic to neurons, the primary cells in the nervous system. In the 1980s, young, HIV-negative IDUs in northern California developed neurological symptoms such as stiffness, tremor, and loss of voluntary movements, symptoms that closely resembled Parkinson’s disease. This is unusual because Parkinsonism typically occurs in elderly persons. Investigative work by neurologists uncovered the fact that all these patients injected a synthetic narcotic derived from meperidine (Demerol). This narcotic contained a neurotoxin (a substance that kills neurons, or nerve cells) called 1—Methyl—4— phenyl—1,2,3,6— tetrahydropyridine or MPTP. MPTP selectively poisoned the cells of the substantia nigra in the addicts’ brains, causing loss of the neurons that produce the neurotransmitter dopamine. Neurotransmitters are chemicals that are used by neurons to communicate, and dopamine is essential for normal control of movement. MPTP was found to be such a reliable neurotoxin that it was used to produce the animal model for Parkinson’s disease,3 and neurologists began to study the long-term effects of other drugs of abuse on the brain.
Researchers using neuropsychological tests (paper and pencil tests that carefully measure memory, speed, concentration, and attention) and neuroimaging techniques (such as brain scans) have determined that many recreational drugs cause long-lasting damage to the brain in HIV-negative users. Animal experiments have also been very helpful in showing the effects of drugs on the brain, because animals can be protected from the negative effects of the drug-users lifestyle–such as malnutrition and head injury–that can also cause brain damage. Animals can be exposed to measured amounts of drugs, alone and in combination with animal retroviruses such as Simian Immunodeficiency Virus (SIV), a virus that resembles HIV and allows us to study monkeys as animal models for AIDS.
The Role of Drugs in HIV
Drug use is a factor in HIV transmission because users share needles and trade sex for drugs or for money to buy drugs, and because some drugs loosen inhibitions and promote unsafe sex.4 In addition, some drugs such as cocaine impair the immune system, independently of HIV. For example, cocaine appears to increase the susceptibility of drug users to HIV infection. What is the evidence that drug abuse increases HIV dementia? Initial studies performed early in the epidemic failed to demonstrate that HIV-infected drug users had higher rates of neuropsychological abnormalities, or neuroimaging abnormalities, than HIV-negative drug users.5,6 These studies, however, had certain deficiencies. First, many studies examined persons in the early stages of HIV infection, when HIV neurological disease is uncommon, and not persons with advanced AIDS, among whom neurological problems are common. Further, HIV-infected drug users were compared with HIV-negative drug users, who have a higher rate of neurological problems of many types (including neuropathy and cognitive dysfunction) than the non—drug-using population. The neuroimaging techniques that were used could detect structural problems (such as strokes and tumors), but were not sensitive to abnormalities in brain function (such as how the brain uses substances like blood, oxygen, and glucose).
Recent studies of large groups of persons with AIDS indicate that there is an increased incidence of neurological and neuropsychological abnormalities in IDUs. An Italian study of 1600 AIDS patients found a higher incidence of HIVCMC diagnosis in IDUs than in other risk groups.7 Likewise, a French study of over 1200 persons who died of AIDS,8 a European study of over 6,000 persons,9 and an American study of over 400 persons with AIDS in San Francisco10 found significantly more HIV dementia in IDUs than in other risk groups. Autopsy studies of HIV-infected persons are especially useful because the interpretation of brain pathology is not likely to be influenced by the patient’s cultural and educational history. Several large neuropathology studies reported that HIV encephalitis is significantly more common at autopsy in IDU AIDS patients than in non-IDU AIDS patients. HIV encephalitis is a form of brain inflammation due to HIV infection, and is strongly associated with HIVCMC during life. A German study of over 200 AIDS patients11 found significantly more HIV-related encephalitis in drug abusers (59.5%) versus gay men (28%). A study from the United Kingdom also confirmed that HIV encephalitis is more common among IDUs.12 Note that the type and quantity of drug use was not well defined in most of these studies, so that the effects of various drugs on the brain of HIV patients could not be differentiated.
Effects of Specific Drugs–Cocaine
Cocaine (coke, blow) is a powerfully addictive drug that stimulates the nervous system. Studies indicate that cocaine instigates a stress response by the immune system, increasing inflammation and impairing the function of the body defenses, such as natural killer cells, T cells, neutrophils and macrophages.13,14 In experimental situations, cocaine-induced stress results in increased infection and increased replication of HIV in human cells.
Cocaine and the Brain
Cocaine affects the release and breakdown of the neurotransmitter dopamine. Neurotransmitters are chemicals that are released from one neuron and attach to another neuron by binding to a receptor site (like a key is inserted into a lock). This process carries a chemical message from one neuron to another, and allows the two brain cells to communicate. Neurotransmitters play an essential role in all cognitive (thought), motor (movement), and behavioral (emotional and mood) processes. In the healthy brain, dopamine is released by a neurons into the synapse (a space between two neurons), where it can bind with dopamine receptors on neighboring neurons. Under normal circumstances, dopamine is then recycled back into the transmitting neuron. If cocaine is present, it blocks the normal recycling process, resulting in a buildup of dopamine in the synapse. This excess dopamine contributes to the pleasurable effects of cocaine. Dopamine is a part of the brain’s chemical reward system, and is involved in the addictive properties of every major drug of abuse. Loss of dopamine-producing neurons in the brain is associated with symptoms of Parkinson’s disease, such as tremor and stiffness.
Chronic cocaine use in HIV-negative persons is associated with long-lasting problems with attention and concentration, learning and verbal memory, information processing speed (e.g., reaction time), visuo-spatial skills, ability to perform calculations, and abstraction. These deficits can be measured in a quantitative way by administering neuropsychological tests.15,16 One group examined HIV-negative, cocaine-dependent patients who had abstained from cocaine use at the time of testing. They found that these abstinent cocaine users had abnormalities such as hand tremor, slow reaction times, and electroencephalogram (EEG) brain-wave abnormalities, indicating that cocaine use alone can cause significant neurological impairment.17 Cocaine use in HIV-negative persons is a cause of brain vasculitis (inflammation and spasm of the arteries, causing lack of blood flow and stroke).
Researchers who compared neurologically asymptomatic cocaine users to normal, age-matched controls who did not use drugs found significantly more abnormalities on magnetic resonance imaging (MRI) brain scans in the cocaine users than in controls.18 These abnormalities appeared to be silent, stroke-like events in the brain. Asymptomatic, HIV-negative, cocaine users also have subtle brain abnormalities that can be detected by techniques such as magnetic resonance spectroscopy (MRS), a special brain scan that is used to detect changes in chemical balance in specific areas of the brain. Investigators have found that these specific chemical imbalances correlate with an overall loss of brain cells.19 Further, combined use of cocaine and alcohol can lead to the formation of a cocaine metabolite called cocaethylene, which is more toxic than cocaine itself.
Cocaine Use and HIV Encephalitis
Cocaine is known to cause brain injury in HIV-negative persons. Cocaine exerts its effect on dopamine, a neurotransmitter that is believed to be depleted in advanced HIVCMC.20 Therefore, researchers felt that cocaine was a good candidate drug to study to see if it accelerated the development of dementia in people with AIDS. Single-photon—emission computed tomography (SPECT) is a neuroimaging technique that is used to monitor brain function and brain perfusion (circulation) and is used to evaluate a variety of dementing diseases. One SPECT study compared the brain scans of patients with HIVCMC to subjects with cocaine polydrug abuse and with normal, non—drug using controls. They reported that 100% of the HIVCMC subjects and 90% of the cocaine-polydrug abuse subjects had cortical perfusion defects, significantly more than noted in the controls.21 These researchers concluded that the brain perfusion pattern visualized on SPECT, while a sensitive indicator of HIVCMC, could not be distinguished from chronic cocaine polydrug use.
Another group of researchers examined the effect of cocaine on the blood—brain barrier, which protects the brain and separates it from the blood stream.22 In their experiment, they found that cocaine increases the permeability of the blood—brain barrier, making it more porous and thus increasing the ability of HIV to cross from the blood to the brain. Cocaine caused this increased permeability in several ways. First, cocaine caused apoptosis (cell death) of the capillary endothelial cells (cells that line the blood vessels of the brain and help make up part of the blood—brain barrier). Second, cocaine increased the secretion of inflammation-causing chemicals such as tumor necrosis factor (TNF), which also enhances the invasion of the CNS by HIV. In addition, other scientists have found that cocaine increases the migration of monocytes (white blood cells) across the blood—brain barrier.23 These cells can be HIV-infected and carry HIV into the brain. Cocaine stimulates the production of adhesion molecules, chemicals that increase the stickiness of monocytes to the blood vessels of the brain. Cocaine also increased the chemicals that opened the brain blood vessels to HIV-infected cells.24 In summary, cocaine may increase the risk of HIV neurological disease by causing small strokes, neuronal death, and by opening the blood—brain barrier to HIV. Chronic cocaine use may also damage dopamine-producing neurons, which may exacerbate the symptoms of HIVCMC.
Methamphetamine
Methamphetamine (speed, meth, or crystal) is a highly addictive stimulant drug that is particularly popular among young gay men on the West Coast. Methamphetamine use is strongly associated with high-risk sexual behaviors that result in infection with HIV and other sexually transmitted diseases.25 In laboratory experiments, methamphetamine use appears to suppress the immune system,26 but this has not yet been confirmed in humans.
Methamphetamine and the Brain
Methamphetamine use is a well-known cause of chronic neurological problems, such as strokes and memory loss, and behavioral changes, such as decreased decision-making ability, psychosis with hallucinations, paranoia, and flashbacks. These problems occur in both active users and in persons who used in the past but were abstinent when tested, indicating that methamphetamine has a long-lasting effect on the brain. Brain MRS has been used to detect neuronal cell damage in abstinent methamphetamine abusers.27 Methamphetamine, like cocaine, causes a massive release of dopamine within the brain. This corresponds to the sensation of the "rush." This is followed by constriction of blood vessels, hypertension, and, if enough blood cannot get through the constricted blood vessels, a stroke or a heart attack. Methamphetamine is also known to be a neurotoxin. Animal research shows that methamphetamine damages the nerve-cell endings of both dopamine- and serotonin-containing neurons. (Serotonin is a neurotransmitter that is essential in maintaining normal appetite, mood, sexuality, and memory.) Re-growth of these nerve endings appears to be very limited. Baboons given methamphetamine in doses comparable to those used by humans who abuse drugs developed long-term reductions in brain dopamine, as shown by positron emission tomography (PET) brain scans.28
Methamphetamine and HIV Encephalitis
The interactions between methamphetamine and HIV are important because neurologists have found that HIV itself also can cause damage to dopamine-containing neurons.20 HIV infection is known to cause decreased levels of serotonin and its metabolites in the brain and spinal fluid.29 Therefore, the two factors (HIV and methamphetamine) may be synergistic. Because methamphetamine is a likely candidate to accelerate HIV neurological diseases, studies that examine the effect of methamphetamine use in HIV-infected persons are warranted.
Heroin
Prior to the AIDS epidemic, the chronic use of opiates (such as heroin) was associated with increased susceptibility to many infectious diseases, such as bacterial pneumonia, tuberculosis, diarrhea, abscesses, endocarditis (heart infection), viral infections, malaria, and hepatitis.30 However, it was not clear if these infections were due to suppression of the immune system by heroin, the poor lifestyle changes that often accompanied heroin abuse, or lack of hygiene in IDU. Heroin IDU was associated with HIV infection from the beginning of the epidemic. Heroin, and other opiate drugs such as morphine, has been reported to cause immune suppression in some laboratory studies, independent of the effect of HIV infection.31,32 However, other researchers have observed both positive and negative effects of opiates on the immune system. Further, no human study has been able to show in a clear and convincing manner that chronic opiate abuse accelerates the progression to AIDS, as measured by CD4+ cell count. The effect of opiates on other aspects of AIDS (such as opportunistic infections) has not been well-studied.33
Heroin and the Brain
The medical literature is full of reports of the dangerous effects of chronic heroin use on the nervous system. HIV-negative, chronic heroin users have been reported to have deficits in learning and memory.34 On CT brain scans, chronic opiate abuse is associated with brain atrophy (shrinkage), independent of HIV infection.35 However, it is not clear whether this brain atrophy is due to long-term opiate-induced neurotoxicity or to the effects of drug overdose, which can kill neurons due to ischemia (lack of blood and oxygen to the brain). Autopsy studies of HIV-seronegative heroin users demonstrate both acute and chronic ischemic damage, brain nerve-cell loss, and reactive changes.36 Thus, it is possible that chronic heroin use could deplete the brain’s functional reserve and lower the threshold for the development of HIVCMC. Smoking heroin vapor is a well-described cause of a potentially fatal leukoencephalopathy (disease of the brain’s white matter) that is also seen independently of HIV infection.37 The author has seen at least one case where this was confused with HIV neurological disease.
Heroin and HIV Encephalitis
HIV activates immune cells in the brain and elsewhere to make cytokines (chemicals that allow immune cells to communicate with each other and that regulate immune functions). Studies have shown that opiate drugs such as morphine may increase the ability of these cytokines to damage neurons. Researchers in Edinburgh, Scotland have carefully studied a group of IDUs since the 1980s. These IDU subjects mostly used heroin, although in recent years amphetamine use has become popular as well. They became infected with HIV (as well as hepatitis B, C, and D) during a very short period in the early 1980s, by sharing needles. In many cases, the seroconversion dates of these patients were known. The IDUs in Edinburgh have been examined regularly with CD4 cell counts and neurological and neuropsychological tests. As they died, of AIDS or of drug overdose, a large number of them have been autopsied. As a group, they have been compared to local gay/bisexual men who seroconverted at the same time. This Edinburgh cohort of IDU subjects had a very high incidence of HIV encephalitis at autopsy, despite access to good medical care and antiretroviral treatment. Approximately 56% of IDUs were found to have HIV encephalitis in their brains at autopsy, versus only 17% of gay/bisexual men.38 Further, IDUs with HIV encephalitis had greater quantities of HIV and more diffuse HIV infection in their brain tissue. The presence of HIV encephalitis at death closely correlated with a history of HIV dementia during life. Researchers also compared the brains of both HIV-negative and HIV-infected IDUs to the brains of non—drug using persons who died of other causes. Both the HIV-positive and HIV-negative IDU brains had evidence of activated microglial cells (immune cells found in the brain); however, only the HIV-IDU group had elevated numbers of white blood cells infiltrating the brain and the cerebral blood vessels. This suggests that some, though clearly not all, of the abnormalities seen in HIV-infected brains can be associated with drug abuse.39 Of interest, the same group of researchers also examined the spinal cords of AIDS patients. They found that HIV myelitis (inflammation of the spinal cord caused by HIV) was far more common in persons who used IV drugs than in gay/bisexual men.40
Ketamine
Ketamine, (Special K) is a popular party drug. Ketamine has many legitimate uses in medicine as an anesthetic and pain reliever, and is under study as a potential treatment for epilepsy and certain brain injuries. Its medical utility is based on the fact that it is an N—Methy l—D—Aspartate (NMDA) receptor blocker. NMDA receptors are activated by any brain insult, and their activation results in nerve-cell damage and death. Ketamine has been postulated, therefore, to have neuro-protective properties. However, ketamine has also been used to produce an experimental model of psychosis. It can induce hallucinations, dissociation, and a state that resembles schizophrenia, along with the related street drug phencyclidine (PCP, or angel dust). Use of ketamine as a party drug produces a dissociative state that can be correlated with increased brain metabolism in the pre-frontal portion of the brain, as demonstrated on positron emission tomography or PET scans in human volunteers.41 In addition to an ketamine-induced thought disorder, users may experience a decrease in several different types of memory function.42 Chronic ketamine users have been reported to develop persistent memory deficits. Given how many patients I have spoken to who are HIV+ and who use ketamine, we were surprised to find so little in the medical literature about its possible long-term neurological effects on HIV-infected people.
Ecstasy
Ecstasy (also called XTC) is the common name for methylene— dioymethamphetamine (MDMA}, a synthetic drug with both amphetamine-like and hallucinogenic properties. Ecstasy use is common at rave parties and among teenagers. Its use has been reported to cause suppression of the CD4/CD8 ratio in a very small study.43 Ecstasy is a potent and selective brain neurotoxin that targets and kills the serotonin-containing neurons.44,45 Animal studies show that brief exposure to Ecstasy can cause brain problems that last for years. Studies that compare current and past users of Ecstasy to healthy non—drug using controls report that both past and current Ecstasy users have significantly more memory deficits.46 Ecstasy users have reduced memory for new information, and tend to be more impulsive than nonusers. This pattern of cognitive and personality changes is consistent with reports on Ecstasy-treated animals, showing damage to the frontal part of the brain (impassivity), and the hippocampus (memory deficits).47 Positron Emission Tomography (PET) scans confirm abnormalities in the brains of current and recently abstinent Ecstasy users, compatible with a toxic effect on serotonin-containing pathways.48 Spinal taps were performed on Ecstasy users and confirmed low levels of serotonin metabolites in their spinal fluids. The literature on the effects of Ecstasy on HIV-infected persons is sparse, considering how popular this drug is among high-risk teenagers and young adults, and the possibility of synergistic damage to serotonergic brain pathways by Ecstasy and HIV. The antiretroviral drug ritonavir (Norvir) is known to inhibit the metabolism of Ecstasy49 and is sometime used deliberately for this purpose to prolong the high.
Summary
Drugs of abuse may accelerate the brain damage caused by HIV, both by damaging neurons independently of HIV infection, and by opening the door to HIV. Researchers need to study the biological consequences of drug abuse in the brain, such as acceleration of HIV CMC. There is a need to understand the effects of specific drugs of abuse on the brains of HIV-infected persons. In our current longitudinal study at the National Neurological AIDS Bank, we are obtaining detailed drug histories and toxicology panels in our subjects; the plan is to correlate drug use with the results of neurological, neuropsychological, and eventually, autopsy findings. Recreational drug use and substance abuse in general is a reality that faces much of the HIV-infected population. It is our hope that over time, our collaborative research will reveal the specific effects that drugs have on the nervous systems in HIV-infected individuals. Only then will healthcare providers be able to educate the HIV-affected population fully about the exact inherent risks of drug use and abuse.
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