The Gay Men's Health Crisis Newsletter of Experimental Therapies - Volume 6, Number 2 - February 1992
Derek Link

ADC consists of many progressive conditions which can be mistaken for other problems, such as depression, drug-induced side effects, or specific opportunistic infections which affect the brain, like toxoplasmosis or lymphoma. Symptoms of ADC may include: poor concentration, forgetfulness, loss of short- or long-term memory, social withdrawal, slowed thinking, short attention span, irritability, apathy, weakness, poor coordination, impaired judgement, and personality change, to name a few. Because there are many different manifestations of ADC, the syndrome is poorly understand poorly understood and has been reported and described in a variety of conflicting ways. This article will attempt to illuminate some of the complicated issues surrounding AIDS-related dementia in adults, as well as the treatment options which are available.

BACKGROUND AND SYMPTOMS

Nervous system and mental diseases thought to be associated with, or caused by, HIV have been reported since the earliest days of the epidemic. Such manifestations were given a variety of names and descriptions by many different researchers. "HIV encephalopathy or encephalitis," "multifocal giant-cell encephalitis," "subacute encephalitis," and "progressive dementia" are all names once used to describe this syndrome. In 1985, Drs. Navia and Price coined the name"AIDS dementia complex."[3] Since that time, the condition has been added to the list of AIDS-defining illnesses and has been further refined for surveillance purposes by the Centers for Disease Control (CDC). In May, 1991, Dr. Janssen and colleagues published the most recent working definition of ADC,[4] which includes only the most debilitating manifestations and leaves out some of the more common, but harder to detect symptoms, such as irritability and moodiness.

AIDS dementia complex consists of many progressive conditions, which can include poor concentration and coordination... impaired judgement, and personality change.

As an AIDS-defining condition, ADC is characterized by severe changes in cognition, behavior, motor coordination, or mood that are directly attributable to HIV.s Cognition is the process of acquiring knowledge. It is defined as awareness, perception, judgement, and memory. In ADC, "cognitive impairment" is often characterized by memory loss, speech problems, inability to concentrate, and poor judgement. Behavioral changes in ADC are the least understood and least defined. They can best be characterized as impairments in the ability to perform common tasks and activities of daily living. Such changes are found in 30%-40% of patients with early ADC.[6] Motor impairment is often characterized by incontinence, paralysis and loss of control of the legs, and stiff, awkward, or markedly slow movements. Mood (also called affect) impairments are defined as changes in emotional responses to experiences. In ADC, affect impairment is characterized by severe mental conditions, such as depression, psychosis, and mania.

Although the definition of ADC has been refined over the last few years, diagnosing the illness is still dependent on the keen judgement of doctors. It is easy to imagine how difficult it might be to determine impairments in mood and behavior. Consequently, the debate about the categories and usefulness of the ADC definition remains vigorous.

Incidence

At present, there is no reliable data concerning the percentage of people with AIDS who may eventually develop ADC. Several studies were conducted in the mid-1980s, but together they found that between 10%-70% of people with AIDS may develop ADC.[7] The reason for this wide range in percentage is two-fold: These studies were conducted 1) without a uniform definition of ADC, and 2) prior to the availability of AZT treatment for a-symptomatic HIV-positive people.

Anecdotal reports indicate that there are fewer patients with ADC since AZT therapy has become standard, and that patients who do have the syndrome tend to be sicker. One scientific study from England corroborates this theory. The British study found that only 2% of patients with AIDS taking AZT developed ADC between 1982 and 1988, compared to 20% of patients not taking AZT. The incidence of ADC has dropped from 53% in 1987 (prior to the introduction of AZT) to 3% in 1988 (after the introduction of AZT).[8] Early in the epidemic, a significant percentage of new AIDS diagnoses were attributed to ADC.[9] These newly-diagnosed people often had ADC, but no other AIDS-related condition. Many clinicians report that they are no longer seeing people who have just ADC. ADC has increasingly become a disease of late stage AIDS where people suffer from multiple infections.

Natural history and epidemiological studies are needed now to confirm the observations of clinicians. These studies are necessary not only to define the rate of ADC among people with AIDS, but also to define what factors, if any, correlate with progression.

Diagnosis

The main way to detect and evaluate ADC is a test called the mental status examination. The examination is designed to reveal problems such as short- or long-term memory loss, problems with orientation, concentration, and abstract thinking, as well as swings in mood. In addition, certain laboratory tests can be useful. These include examination of cerebrospinal fluid (CSF) which is obtained by a spinal tap. Research shows that most patients with ADC have mild elevations of certain proteins and of white blood cells, which are detected by CSF examination.[10] Additionally, the amount of HIV in CSF seems to correlate with progressive dementia in children.[11]

Other tests which may help in the detection of ADC are CT scans, MRI scans and SPECT scans. CT scans are x-rays which use special beams to produce detailed images of organs and structures within the body. In ADC-affected patients these scans usually show signs of atrophy of brain tissue. MRI, or Magnetic Resonance Imaging, is an expensive sensitive brain scan that is used when CT findings are inconclusive. MRIs usually detect white matter disease in the brain. SPECT scars (single photon emission computed tomograms) are the latest technology in the diagnosis of ADC. SPECT uses a radioactive material to measure blood flow in the brain, and may be useful to detect early HIV dementia.[12] SPECT scans can also follow response of senses to antiviral therapy. The scan is able to show if anti-HIV therapy improves the blood flow of the brain.

In order to diagnose ADC accurately, mental status exams, a spinal tap and one of the standard scans are required (CT, MRI, or SPECT). These tests may also help differentiate ADC from other brain disorders such as cryptococcal meningitis, toxoplasmosis, lymphoma, or PML.

How Does HIV Cause ADC?

While it is clear that HIV can cause serious nervous system disease in people with AIDS, the direct role of the virus in causing AIDS-related dementia is unclear.[13] In general, such central nervous system and mental disorders as described above are caused by the death of nerve cells. While it has been demonstrated that HIV does not directly infect nerve cells, it is thought that the virus is somehow able to kill them indirectly.

To date, AZT is the best understood and perhaps most effective treatment available for ADC

Macrophages, white cells which are prevalent in the brain and act as HIV reservoirs, appear to be HIV's primary cell target in the central nervous system. HIV-infected macrophages can transport HIV into the brain from the blood stream. These macrophages then harbor large amounts of virus in the brain, where they are the primary source of indirect injury to nerve cells.[14] Test tube studies offer the following three hypotheses about the way in which macrophages may cause nerve cell destruction:

1.) A particle on HIV's outer coat, called gp120, may be shed by an infected macrophage in the brain, causing damage to nerve cells.[15]

2.) The HIV TAT gene, a protein that helps in the production of new virus, detaches from HIV and circulates in the blood, causing toxic effects in nerve cells.[16]

3.) The macrophage itself releases a toxic substance called quinolinic acid into the brain.[17] The substance binds to nerve cells and causes cell death. Recent research has found elevated levels of quinolinic acid in the spinal and brain fluid of persons with ADC.[18]

More research is needed to further characterize the role of HIV in ADC. Such research is critical to the future success of efforts to develop treatments for AIDS dementia complex.

AIDS Dementia in Early HIV?

Recent reports of subtle nervous system symptoms in persons with early HIV-illness have understandably caused a great amount of concern. Several small, scientifically-questionable studies indicated that asymptomatic HIV infected people had subtle neurologic deficits.[19] While it is important to note that mild neurologic deficits are distinct and possibly unrelated to ADC, such findings are disturbing. However, these studies have been forcefully refuted by the work of many other researchers. Data from several large studies of persons with asymptomatic HIV have found no neurological deficits.[20]

AZT, ddI & ddC as Treatment for ADC

Treatments for ADC have been extremely slow in coming, especially compared to treatments for other AIDS-related conditions. The reasons for this include: a lack of understanding of the cause of ADC; a lack of reliable data on the incidence of ADC; and, not insignificantly, a dearth of research funding and initiative in this area. Despite these obstacles several agents have been identified as useful in treating ADC.

The best therapies to treat ADC seem to be anti-HIV drugs. To date, AZT is the best understood and, perhaps, most effective treatment available for ADC. Several groups have reported an improvement in cognitive functioning with AZT.[21] Larger doses (1,000 mg compared to the now standard 600 mg per day) of AZT appear to be necessary for treatment of ADC. The high dose of AZT may present problems, since many people with AIDS, particularly those who are the sickest, are often unable to tolerate the high doses of the drug. Another approach to treatment is direct injections of AZT into the spinal canal. One study found that of eight patients receiving AZT injections, five showed neurological improvements.[22]

ddI and ddC (both drugs work in ways similar to AZT) have not been studied sufficiently for the treatment of ADC. Several small studies[23] and numerous anecdotal reports from clinicians suggest that ddI and ddC are less effective than AZT for treating AIDS dementia. It seems that ddI and ddC do not penetrate into the brain and spinal fluid as well as AZT does. In fact, it is estimated that only about 20% of ddI crosses the blood/brain barrier. However, ddI and ddC should be studied and considered for people who are unable to tolerate high doses of AZT.

Many people with AIDS have begun to use ddI or ddC in combination with AZT for the treatment of overall HIV infection. While the results are highly promising at this time for the treatment of overall HIV infections, nothing is known about their usefulness in treating ADC. This question needs to be rigorously addressed by pharmaceutical and government researchers.

Treating the Symptoms of ADC

The full range of psychoactive drugs is often used to treat the signs and symptoms of persons with ADC. These drugs include: antipsychotics, antidepressants, anxiolytics, psychostimulants, antimanics, and anticonvulsants.[24] These drugs do not affect the underlying cause of ADC, or stop its progression. However, they may well alleviate some of its symptoms. Haloperidol (Haldol), an effective drug for Alzheimer's Disease, is often indicated for alleviating ADC symptoms. It should be noted that the drug, however, has many side effects. Patients with ADC are extremely sensitive to Haldol. Small doses (0.5 -1 mg) should be used to avoid severe side effects.

Ritalin (methylphenidate) has been used with success in patients with ADC to alleviate apathy and to increase energy, concentration, and appetite. Doses of 5 -10 mg per day are often sufficient.[25]

In cases of severe behavior disorders, antipsychotics such as thorazine and mellaril can be used to control agitation. Ativan and Valium may also be used for sedation and anxiety-control. Other psychiatric drugs which are used include: perphenazine (Trilafon); thiothixene (Navane); molindole (Moban); and fluoxetine (Prozac) with bupropion (Wellbutrin).

Promising New Treatments

Nimodipine, a calcium blocker, is one of the few agents under development specifically for treating ADC. Nimodipine is commercially available as a pill, manufactured by Miles Pharmaceuticals under the brand name Nimotop. The drug is prescribed for treatment of cerebral hemorrhages. In test tube studies, nimodipine counteracts the toxic effects of the HIV protein gp120.[26] Testing of nimodipine in persons with ADC has been delayed for over a year because of various bureaucratic problems. However, because of its potential, some people with ADC have been prescribed nimodipine by their doctors. Since there is no data, it is impossible to recommend an appropriate dose level. It is notable that physicians prescribing the drug use 30-120 mg per day. There is no scientific basis, however, to support choosing these doses. Nimodipine can cause hypotension (lowered blood pressure) and careful monitoring is required.

A note of caution is warranted: the drug verapamil, a compound closely related to nimodipine, has been shown to increase HIV replication in test tube studies.[27] It is not known whether nimodipine increases HIV replication in the test tube or in humans.

Additionally, Peptide T, a very non-toxic drug made up of amino acids, has demonstrated ability to improve neuropsychologic symptoms in persons with AIDS.[28] Peptide T is believed to block the toxic effect of gp120 in brain cells. Evidence from a small study of 15 AIDS and ARC patients, reported in Florence, suggest that Peptide T protects brain cells from the effects of gp 120 and helps nerve cells survive.[29]

Conclusion

Scientific research of new treatments for ADC is desperately needed. It is important that new anti-HIV drugs, like ddI and ddC, be thoroughly evaluated for their usefulness in treating ADC. At the same time, other promising drugs which may work to treat the underlying causes of ADC need investigation.

Footnotes ---------

1. Goethe KE et al. Neuropsychological and neurological function of the human immunodeficiency virus seropositive asymptomatic individuals. Arch Neurol 46:129-33, 1989.

2. Grant I et al. Evidence for early central nervous system involvement in AIDS and other HIV infections. Studies with neuropsychologic testing and magnetic resonance imaging. Ann Intern Med 107:828-36, 1987.

3. Navia BA and Price RW. AIDS Dementia Complex I. Clinical Features. Ann Neurol 19:517-24, 1986.

4. American Academy of Neurology. Nomenclature and research case definition for neurologic manifestations of HIV-1 infection. 41:778-785, 1991.

5. Navia BA and Price RW. The AIDS dementia complex as the presenting or sole manifestation of HIV infection. 44:65-69, 1988.

6. Barlow 1. Dementing illness in HIV. BETA, May 1991.

7. Navia BA et al. The AIDS Dementia Complex. Clinical Features. Annals of Neurology 19:525-530, 1986; and Navia BA and Price RW The AIDS dementia complex as the presenting or sole manifestation of HIV infection. 44: 65-69, 1988.

8. Portegies P et al. Declining evidence of ADC after introduction of zidovudine therapy. Br Med Journ 299:819-22, 1989.

9. Navia BA and Price RW. The AIDS dementia complex as the presenting or sole manifestation of HIV infection. 44: 65-69, 1988.

10. Ho D et al. The AIDS dementia complex. Ann Intern Med 111:400-410, 1989.

11. Epstein LG et al. Expression of HIV in CSE of children with progressive encephalopathy. Ann Neurol 21 (4):397-401,1987.

12. Masdeo I et al. SPECT in HIV encephalopathy. Journ Nucl Med 32:1471-75, 1991.

13. Tillman M, Wigdahl B. Neuropathogenesis of HIV infection. Seminars in the Neurosciences 3:131-139, 1991.

14. Koenig S et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1098-1093, 1987.

15. Kaiser PK et al. Neruonal injury due to HIV-1 envelope protein is blocked by anti-gp120 antibodies but not by anti-CD4 antibodies. Neurology 40:1757-1761, 1990.

16. Sabatier lM et al. Evidence for neurotoxic activity of tat from HIV-1. Journal of Virology 65:961-967, 1991.

17. Giulian D et al. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 250:1593-1596, 1990.

18. Heyes MP et al. Quinolinic acid in cerebrospinal fluid and serum in HIVC-1 infection: relationship to clinical and neurological status. Neural 29:202-209, 1991.

19. Grant I et al. Evidence for early CNS involvement in AIDS and other HIV infections. Ann Intern Med 107:828-836, 1987.

20. Miller et al. Neuropsychological performance in HIV-1 infected homosexual men. Neurology 40:197-203, 1990; Miller et al. Computerized and conventional neuropsychological assessment of HIV-1-infected homosexual men. Neurology 41:1608-1616, 1991; and Seline OA et al. HIV-1 infection: no evidence of cognitive decline during the asymptomatic stages. 40:204-208, 1990.

21. Price RW et al. Zidovudine treatment of the AIDS dementia complex: results of a placebo controlled, multicentered therapeutic trial.

22. VIIth Int'l Conf on AIDS, abstract # MB 2050, Florence, June 1991.

23. Yarchoan. R. Long-term toxicity/activity profile of 2/, -dideoxyinosine in AIDS or AIDS-related complex. Lancet 336(8714):526-9, 1990.

24. Barlow I. Dementing illness in HIV. BETA, May 1991.

25. VIIth Int'l Conf on AIDS, abstract # MB 2053, Florence, June 1991.

26. Dreyer EB et al. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248:364-7, 1990; and Lipton SA. Calcium channel antagonists and HIV coat protein mediated neruonal injury. Ann of Neur 30:110-114, 1991.

27. Harbison MA et al. Effect of the calcium channel blocker verapamil on HIV-1 replication in lymphoid cells. Journ of Infect Dis 164: tk-tk, 1991.

28. VIIth Int'l Conf on AIDS, abstract # TH.B. 90, Florence, June 1991.

29. VIIth Int'l Conf on AIDS, abstract # M.B. 2049, Florence, June 1991.

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