In 1981, a mysterious disease was discovered to be infecting men—the disease leading to odd patterns of deadly infections and diseases

. The diseases that ultimately killed the patients were known, but usually only afflicted those whose immune systems were compromised for some reason. Blood testing revealed that these patients had low levels of T4 cells (T helper lymphocytes). These cells help fight off disease-causing microorganisms. Researchers discovered that a retrovirus was killing these T4 cells—the human immunodeficiency virus (HIV). The virus manufactures its DNA in host cells. AIDS is diagnosed when a patient has HIV, has an opportunistic infection (or Kaposi’s sarcoma), and has a low number of T4 cells or low ratio of T4 cells to T8 cells (T helper cells to T suppressor cells or CD4+ cells to CD8+ cells) (Flanders et al.). Short Case Study (I) In 2004, a young boy of middle-school age was admitted to the hospital, his mother complaining that his cognitive function and academic ability had been declining in the past year. Both legs had become weak months before his admission to the facility, and the boy had been bedridden for eight weeks. His short-term memory capacity was declining. Diagnostic tests led to many possible diagnoses, but during his hospitalization his cognitive abilities declined even further. The child’s father had died at a young age, from tuberculosis; upon finding this out, the doctors added HIV to their possible diagnoses. Through a battery of testing, it was determined that the boy had antibodies to HIV, and also

2 determined that his mother (who showed no symptoms) also had HIV (John et al.). By early January of 1985, there were scientific studies showing that the AIDS virus resided in brain tissue of AIDS patients who suffered from dementia and cognitive impairment. Macrophages get infected by HIV, making them unable to fight infection, even if T4 cells give them the signal to do so. The infection of macrophages is believed to contribute to symptoms of dementia due to brain cells being destroyed (Flanders et al.). The purpose of this paper is to explore and explain AIDS Dementia Complex (ADC). Symptoms of ADC and Stages of Progression The most common cause of dementia in adults (adults forty years of age or less) is HIV infection. In those patients with dementia, the untreated condition worsens quickly in just months. The incidences of ADC would more than likely be rising now, because of improved rates of survival of HIV patients; some data shows that 20% of AIDS patients still develop some level of ADC today (Mattson et al.). The number of ADC incidences was as high as 40-70% in AIDS patients just a decade ago, when patients had no treatment before dementia set in (which may prevent the dementia from even beginning) (Bartlett). The stages of ADC and its progress range from normal functioning to very severe/end stages. The earliest complaints of patients suffering from ADC are difficulty thinking and paying attention. Their motor and cognitive skills progressively decline; they become slow mentally, forgetful, physically weak and

3 unsteady. They may also develop tremors. Their behavior may change to become agitated and hallucinatory, and they cannot move their limbs and eyes rapidly. They also have a “loss of will” (Portegies et al.). As the dementia progresses to later stages, patients may be unresponsive, unaware, severely confused, unable to be coordinated, and involuntarily jerking and convulsing (DeVita et al.). (Table 1 outlines major symptoms of all stages.) Uncommon occurrences in ADC are agnosia, aphasia, and mania in late stages.

4 Figure 1 (bottom of previous page): Deficiencies in areas of ability of AIDS patients that had neurological impairment, indicating a “subcortical pattern.” Source: Gendelman, Howard E. et al., eds. The Neurology of AIDS. London: Oxford University Press, 2005. The system used to clinically determine the progression of dementia in patients ranges from Stage 0 to Stage 4 (see table below). (Fanning) Table 1: Staging Scheme for the AIDS Dementia Complex (ADC) Stage Stage 0 (normal) Stage 0.5 (Equivocal/Subclinical) Characteristics ▪ Normal mental and motor function ▪ Either minimal or equivocal symptoms of cognitive or motor dysfunction characteristic of ADC, or mild signs (snout response, slowed extremity movements), but without impairment of work or capacity to perform activities of daily living (ADL). ▪Gait and strength are normal ▪ Unequivocal evidence (symptoms, signs, neuropsychological test performance) of functional intellectual or motor impairment characteristic of ADC, but able to perform all but the more demanding aspects of work or ADL ▪ Can walk without assistance ▪ Cannot work or maintain the more demanding aspects of work or ADL, but able to perform basic activities of selfcare ▪ Ambulatory, but may require a single prop ▪ Major intellectual incapacity (cannot follow news or personal events, cannot

Stage 1 (Mild)

Stage 2 (Moderate)

Stage 3 (Severe)

5 sustain complex conversation, considerable slowing of all output) or motor disability (cannot walk unassisted, requires walker or personal support, usually with slowing and clumsiness of arms as well) Stage 4 (End Stage) ▪ Almost vegetative ▪ Intellectual and social comprehension and responses are at a rudimentary level. ▪ Mute or almost mute ▪ Paraparetic or paraplegic with double incontinence

Source: DeVita Jr., Vincent T. et al. AIDS: Etiology, Diagnosis, Treatment and Prevention. Philadelphia, Pennsylvania: Lippincott-Raven Publishers, 1997.

6 Figure 2 (bottom of previous page): “Prevalence of cognitive, affective, and neuromotor symptoms at different stages of HIV disease. Controls are HIVnegative ‘at risk’ controls.” (1996 data) Source: Gendelman, Howard E. et al., eds. The Neurology of AIDS. London: Oxford University Press, 2005. Laboratory Testing, Clinical Examination Procedure and Neuroimaging When attempting to make a diagnosis, testing and neuroimaging are essential to rule out other diseases and disorders. These tests cannot pinpoint ADC as a diagnosis, but they are characteristic in nature. MRI and CT scans almost always show atrophy of the cerebrum in these patients. The MRI scans of some patients show abnormal white matter, basal ganglia or thalamus. Pediatric ADC patients may have brain atrophy with calcification in the basal ganglia.

Figure 3: MRI of an ADC patient showing abnormality in the white matter near the lateral ventricles; the sulci of the cortex are also “prominent,” which is characteristic of atrophy.

7 Source: Sakaie, K. E. et al. “Imaging of Neuroaids.” NeuroAids. August 1999: 2, issue 7. 18 January 2008.

Figure 4: An MRI of a healthy brain is on the left; on the right is the brain of a patient with ADC. The white areas are indicative of cell loss.

Source: FoxNews.com. “Scientists Testing Drugs to Block AIDS Dementia.” 3 October 2006. 17 January 2008.

Examination of the cerebrospinal fluid (CSF) is also characteristic, not diagnostic. Doctors and researchers look for differences between those of most AIDS patients and those they suspect have ADC. In about half patients in the latter stages of ADC, the HIV p24 antigen is detected; in patients in early stages, this antigen is rarely present. This finding is not really of much help, simply because by the time a patient is in the latter stages, the ADC is very apparent. If the patient has no opportunistic infections or lymphoma in the central nervous

8 system (CNS), then high levels of quinolinic acid, neopterin, and β2-microglobulin may be helpful in diagnosing ADC in early stages. The levels of these chemicals in the CSF show direct correlation to the severity of the dementia. Cytokines are involved in these chemical markers, suggesting that the effect on the CNS may be related to cytokine-based reactions. Interleukin-6, prostaglandins, tumor necrosis factor-α, and interleukin-1β may also be elevated because they share the same pathways as the aforementioned chemicals, but are of less clinical importance. These chemical upregulations are immune responses that happen as the ADC progresses, even though AIDS patients generally are immunosuppressed (DeVita et al.). ADC has to be “differentiated” from other disorders that may have similar cognitive symptoms, and, in some patients, these other disorders may accompany the ADC. These other causes of ADC-like cognitive symptoms may be trauma to the head, seizure or drug-related disorders (including drug withdrawal and medication-induced side effects), masses in the brain, and psychiatric, infectious, vascular and metabolic disorders. Depression many times coexists with ADC (Fanning). Epidemiology ADC develops in the latter stages of HIV infections and in settings of severe immunosuppression; it is also associated with “limited survival times.” There was a 67% mortality rate (over a six-moth period for ninety-seven patients) for those patients in stages 2, 3 or 4. This rate was three times greater than the mortality rate of AIDS patients with PCP (pneumocystis pneumonia—an

9 opportunistic infection). Low hemoglobin levels in some AIDS patients suggest that these individuals are more likely to develop ADC. Older patients with high levels of neopterin and β2-microglobulin in their CSF are found to develop ADC more readily than others, but hemoglobin levels are seemingly not a factor in these patients (DeVita et al.).

Figure 5 Source: Gendelman, Howard E. et al., eds. The Neurology of AIDS. London: Oxford University Press, 2005. Neuropathy Multi-nucleated cell encephalitis, paleness of white matter, excess astrocytes in the brain, and vacuolar myelopathy are found in most ADC patients. Neurons in the brain die and there is localized death in the basal ganglia, spinal cord, thalamus, brain stem and white matter—subcortical structures (DeVita, et al.). Dendrites may shrink, and there is a loss of synapses in the neurons; this

10 damage is suspected to be indirect, because the neurons themselves are not usually infected (Mattson et al.).

Figure 6: A section of white matter taken from an ADC patient. Note the giant cells and “inflammatory infiltrate.” Source: Bell, Jeanne E. “HIV Infection of the Nervous System.” Neuropathology Laboratory, Department of Pathology, The University of Edinburgh. 7 May 2004. 20 January 2008.

Etiology/Pathogenesis It is hypothesized that ADC is a direct result of HIV, as suggested by observation, studies of the brain, and animal models. The mechanism by which HIV affects the brain is still somewhat unknown however. Southern blot analyses

11 have shown CNS infection by HIV; those show high proviral DNA and high numbers of copies of that DNA in some patients with the complex. Viral DNA and RNA, viral antigens, and HIV virions are also present in the brain tissue. The macrophage and microgliocyte have been shown to promote HIV brain infection; the macrophage is the main culprit however. The macrophage actually maintains the infection and stimulates the cytokine pathways. Multinucleated cells more than likely result from the fusion of macrophages and microglia, which is caused by HIV (DeVita et al.). HIV also infects the astrocytes (Mattson et al.). Limited productive infection in some patients suggests that there are indirect mechanisms by which the infection affects the brain. Toxic cytokines, viral gene products, and neurotoxic pathways are all involved in these indirect mechanisms (DeVita et al.).

Figure 7: Computer enhanced electron micrograph of “viral products budding from an infected cell.”

Source: Gabuzda, Dana. “Nerve Cell ‘Suicide’ in AIDS Dementia.” The Harvard Mahoney Neuroscience Institute Letter On the Brain. Winter 1996: 5, number 1. 17 January 2008.

12 In 2004, researchers at the University of Minnesota discovered that HIV may stop cells from differentiating into neurons, by binding onto receptors on the cells. The neural progenitor cells may actually be “stunted” by proteins that are on the outside of the virus. In 2005, a new study documented that the HIV virus can multiply one hundred times faster in the temporal lobe than anywhere else in the body. This fast replication of the virus causes white blood cells to flood the area, which can cause inflammation. The dementia could be caused or worsened by this “overcrowding” (National Science Foundation).

Figure 8: “White blood cells swarming to attack HIV in the brain.” Source: “Autoimmune Overload May Damage HIV-Infected Brain.” National Science Foundation. 27 September 2005. 20 January 2008.

13 Treatment Studies show that antiretroviral drugs may prevent and treat ADC; this therapy is called highly active antiretroviral therapy (HAART) (DeVita , et al.). Trials on ADC are difficult to perform, making it difficult to determine the best way to approach treatment (Dolin, et al.). When both adults and children were given zidovudine (500-600 mg doses), their neuropsychological status improved (when compared to those given placebo). If their status worsened despite the dosage, the dosage was increased, but the risk of toxicity was greater (DeVita et al.). Zidovudine has the ability to penetrate the blood-brain barrier well—something most other antiretroviral drugs cannot do (Fanning). The effect of dideoxyinosine (ddI--also an antiretroviral agent) is under investigation as a drug to treat ADC if zidovudine cannot be used. Doctors usually use a combination of these drugs to treat ADC. Neurotoxic reaction inhibitors are being studied now, since neurotoxins are thought to be underlying causes of ADC (DeVita et al.). Table 2: CSF penetration of antiretroviral drugs and their efficacy in patients with AIDS dementia complex Clinical CSF CSF:serum Efficacy Efficacy ratio Nucleoside Reverse Transcriptionase Inhibitors Zidovudine Positive Positive 0.6 Didanosine Conflicting No Data 0.2 (dideoxyinosine) Available Zalcitabine Positive No Data 0.2 Available Lamivudine No Data No Data 0.1 Available Available Stavudine No Data No Data 0.3-0.4 Available Available Drug

14 No Data No Data 0.2 Available Available Protease Inhibitors Indinavir No Data No Data 0.18 Available Available Nelfinavir No Data No Data No Data Available Available Available Saqinavir No Data No Data No Data Available Available Available Ritonavir No Data No Data No Data Available Available Available VX-478 No Data No Data No Data Available Available Available Non-nucleoside reverse transcriptionase inhibitors Delaviricine No Data No Data No Data mesylate Available Available Available Loviride No Data No Data No Data Available Available Available Nevirapine No Data No Data 0.45 Available Available Modified from: Portegies, Peter et al. “AIDS Dementia Complex.” CNS Drugs. 1998: 9, issue 1. Academic Search Premier. Samford University Library, Birmingham, AL. 7 January 2008. Abacavir

It is also shown that agents that protect the neurons may be effective (neuroprotectants). Nimodipine (a Ca2+ channel blocker) and memantine (NMDAglutamate antagonist) are being studied as possible treatment options (Fanning).

15 Figure 9 (bottom of previous page): In the image on the left (brain section of an untreated ADC patient), there are macrophages and multi-nucleated giant cells present with inflammation. The image on the right is a section from a patient who has been treated with neuroprotective therapy. Source: “Neuroprotective and Anti–Human Immunodeficiency Virus Activity.” The Journal of the American Medical Association. 27 April 2005: 293, number 16. 20 January 2008.

Short Case Study (II) A sixty-nine year old man in Britain presented with “dizziness, confusion and reduced conversation.” He had been this way for two months; he had a lesion in his left frontal lobe that was indicative of tissue death due to loss of blood supply. Doctors diagnosed him with “left-sided cerebrovascular accident.” He was given aspirin and sent home. He returned two months later in a worsening condition; he was falling, incontinent (urinary), bedridden, and almost completely mute. He had a seizure sometime before he was readmitted also. He now had a tremor and was “rigid.” By this time, the lesion had disappeared, but there was atrophy in the cerebrum. Further tests led them to the presence of characteristics of encephalopathy; they diagnosed him with “multi-infarct dementia.” The patient’s wife informed the neurologist that, in the past, her husband had an affair while living in Zambia over a decade before these symptoms appeared. His tests showed antibodies to HIV, and his CSF HIV viral load was in excess of 1,000,000 copies/ml. He was treated with HAART and

16 made a vast improvement within six weeks of beginning treatment. By then he was walking, independent, and his mental status had improved greatly (Parsonage et al.). Conclusion . Replication of HIV in the brain may be controlled before immunodeficiency starts, but when control is lost, the virus replicates and spreads rapidly. HIV may be inactive in the brain for years, since its host cells (macrophages and microglia) live long, and retroviruses integrate themselves into the genome of those host cells (Gartner). Before HAART was introduced as a treatment, between 30%-70% of AIDS patients had some kind of cognitive impairment by the time they died (Bartlett); and children with ADC often became severely mentally retarded (Harvard Mental Health Letter).

17

Figure 10 (bottom of previous page): Incidence rates (per 1000 people) of ADC since HAART was begun. Source: Gendelman, Howard E. et al., eds. The Neurology of AIDS. London: Oxford University Press, 2005.

18 Sources

“AIDS and Mental Health—Part II.” Harvard Mental Health Letter. 1999: 15, issue 10. Academic Search Premier. Samford University Library, Birmingham, AL. 7 January 2008. “Autoimmune Overload May Damage HIV-Infected Brain.” National Science Foundation. 27 September 2005. 20 January 2008. Bartlett, John G. The Johns Hopkins Hospital 200-2001 Guide to Medical Care of Patients with HIV Infection (Ninth Edition). Baltimore, Maryland: Lippincott Williams & Wilkins Publishing, 2000. Bell, Jeanne E. “HIV Infection of the Nervous System.” Neuropathology Laboratory, Department of Pathology, The University of Edinburgh. 7 May 2004. 20 January 2008. DeVita, Jr., Vincent T, Samuel Hellman, and Steven A. Rosenberg. AIDS: Etiology, Diagnosis, Treatment and Prevention. Philadelphia, Pennsylvania: Lippincott-Raven Publishers, 1997. Dolin, Raphael, Henry Masur, and Michael S. Saag. AIDS Therapy. Philadelphia, Pennsylvania: Churchill Livingstone Publishing, 1999. Fanning, Mary M. HIV Infection: A Clinical Approach. Philadelphia, Pennsylvania: W. B. Saunders Company, 1997. Flanders, Carl N., and Stephen A. Flanders. Library in a Book: AIDS. New York, New York: Facts On File, Inc., 1991. FoxNews.com. “Scientists Testing Drugs to Block AIDS Dementia.” 3

19 October 2006. 17 January 2008. Gabuzda, Dana. “Nerve Cell ‘Suicide’ in AIDS Dementia.” The Harvard Mahoney Neuroscience Institute Letter On the Brain. Winter 1996: 5, number 1. 17 January 2008. Gartner, Suzanne. “HIV Infection and Dementia.” Science. 1 January 2000: 287, issue 5453. Academic Search Premier. Samford University Library, Birmingham, AL. 7 January 2008. Gendelman, Howard E., Igor Grant, Ian Paul Everall, Stuart A. Lipton, and Susan Swindells, eds. The Neurology of AIDS. London: Oxford University Press, 2005. “HIV Dementia Mechanism Found.” United Press International. The University of Minnesota. 28 June 2008. John, Binu V., S. Subramanian, Dhanya Mohan, Ankamma Rao, and Kurien Thomas “A Hint from the Past.” Lancet. 16 October 2004: 364, issue 9443. Academic Search Premier. Samford University Library, Birmingham, AL. 7 January 2008. Mattson, M.P., N.J. Haughey, and A. Nath. “Cell Death in HIV Dementia.” Cell Death and Differentiation. 2005: 12. Academic Search Premier. Samford University Library, Birmingham, AL. 9 January 2008. “Neuroprotective and Anti–Human Immunodeficiency Virus Activity.” The Journal of the American Medical Association. 27 April 2005: 293, number 16. 20 January 2008. Parsonage, Mirella Jane, Elizabeth Hart, Edmund G.L. Wilkins, and Richard Paul

20 Talbot. “Lesson of the Week: A New Cause of Treatable Dementia.” Age of Aging. 8 March 2204: 33, issue 3. Academic Search Premier. Samford University Library, Birmingham, AL. 13 January 2008. Portegies, Peter and Nathalie R. Rosenberg. “AIDS Dementia Complex.” CNS Drugs. 1998: 9, issue 1. Academic Search Premier. Samford University Library, Birmingham, AL. 7 January 2008. Sakaie, K. E. and R. G. Gonzalez. “Imaging of Neuroaids.” NeuroAids. August 1999: 2, issue 7. 18 January 2008.

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