NEUROLOGICAL MANIFESTATIONS OF HIV AND AIDS IN MINORITIES AND WOMEN

H. Aaron Aronow, MD Associate Clinical Professor of Neurology and Internal Medicine University of Southern California School of Medicine

Elyse J Singer, MD Associate Professor of Neurology University of California Los Angeles School of Medicine

As the world enters the third decade of the AIDS epidemic, it is inexcusable that so little is known about the neurological manifestations of HIV and AIDS among minorities and women. Why is this issue so important? Currently, women make up 30% of all cases of HIV infections in the US, and over 50% of new HIV cases occur in members of racial or ethnic minority groups.

Research has indicated that in other neurological diseases significant differences can be found in the incidence, manifestations, and response to treatment of patients when comparisons are made by gender and among racial and ethnic groups. Some data indicate that this is likely to be true in neuro-AIDS as well.

One of the most important reasons for the lack of knowledge about the effects of gender and ethnicity on the neurological aspects of HIV and AIDS is the under-recruitment or the frank exclusion of women and minorities from HIV research, particularly during the early years of the epidemic.^1,2 Another factor that has contributed to the failure to study the neurology of AIDS in women and minorities is delayed diagnosis of HIV infection, so that patients are often too moribund to participate in most neurological studies.³ Women and racial and ethnic minorities are more likely to be uninsured or under-insured.⁴ They are also more likely to be diagnosed at the onset of their first AIDS-defining opportunistic condition, which is often a neurological disease. The reasons for delay in diagnosis and treatment are multiple, and include a lack of access to medical care, the mistrust many African Americans and Latinos feel toward the largely white, male-dominated medical profession and toward government, and concerns over confidentiality issues. In addition, neurological care is a sub-specialty and access to neurologists with HIV/AIDS expertise may be restricted even in the best of circumstances. Also, these inequalities in care may confound comparisons to groups who receive more optimal treatment.

The Changing Nature of the AIDS Epidemic

As early as 1987, Mays and Cochran published the first major review of AIDS in the African American community that concentrated on psychosocial issues.⁵ Their findings predicted the current state of the epidemic. They predicted that heterosexual transmission and the subsequent infection of women would become paramount in African- American communities. The most recent statistics from the Centers for Disease Control and Prevention (CDC) confirm that women constitute approximately 30% of all new infections each year in the US and that the majority of these women are African American and Latina. As of 1998, African Americans comprised 13% of the total US population, yet accounted for 50% of all new cases of HIV infection among men and 64% of new cases among women. Latinos comprised 12% of the US population, but accounted for 20% of all new infections in men and 18% of all new infections in women. Cumulatively, African Americans comprised 45% and Latinos comprised 20% of all AIDS cases. African American women and Latinas comprise less than 25% of all women in the US, but they account for almost 80% of all cumulative AIDS cases among women in the United States.

Many HIV-infected women, African Americans, and Latinos are uninsured and have lower overall income, often below the poverty line. As a result, they more frequently receive care from public health clinics and hospitals, often by medical house staff and other inexperienced providers. This, coupled with a late treatment and a general mistrust of the medical profession, has led to disastrous results in both clinical care and clinical research.

Differences in HIV-associated neurological illnesses among women, racial, and ethnic groups

Neuro-AIDS and Women

Many HIV providers are aware that the manifestations of HIV and AIDS appear to vary by gender. For example, HIV- infected women as a group are reported to become ill at lower viral loads than do HIV-infected men.⁶ However, HIV providers may not be aware that the incidence and clinical features of many neurological diseases, such as Alzheimer's disease⁷ Parkinson's disease⁸ schizophrenia⁹ and pain syndromes^10,11 also differ between men and women. Even the process of normal aging of the brain has been reported to differ significantly between women and men.^12,13

Some of these differences are associated with unique female physiology and the effect of sex hormones, such as estrogen, on the brain. Curiously, the effect of estrogen in HIV-associated dementia (HAD) has not yet been examined in a controlled fashion. Women also metabolize many drugs differently than do men.^14,15 This may contribute to a differential effect of drug treatment on HIV and on the nervous system.

There are strong socio-economic factors that appear to affect women as well. As mentioned above, women are often diagnosed with late-stage AIDS. Gail Wyatt, PhD, and her colleagues have reported that this delayed diagnosis occurs in middle-class Caucasian and Asian women, as well as in economically deprived minorities, because women's physicians typically do not consider them to be at risk for HIV.15 Many HIV-infected women patients are caregivers for infected men and children, and ignore their own health. They do not have the time to participate in research studies. These problems make HIV neurological disease in women more difficult to study, because they preclude easy access to participation in clinical studies.

Neuro-AIDS in Minorities

An increasing proportion of AIDS cases in the US occur among members of racial and ethnic minority groups, especially African Americans, Hispanics, and Native Americans. Differences in the incidence and manifestations of nonHIV related neurological illnesses among various ethnic and racial groups, such as stroke, infectious diseases, and hereditary illnesses, are well known.¹⁶ These differences can be traced to genetics, culture, and exposure to different pathogens that are prevalent in different geographical areas and climates, as well as to lower socio-economic status and resultant lack of access to quality health care.

There has been great and understandable mistrust among African Americans of the predominantly white, male-dominated medical profession. This distrust is traceable in part to the pre-War Tuskegee experiments, during which African American men infected with syphilis were used as guinea pigs by white researchers supported by the US government.¹⁷ These men, who were research volunteers, were provided with no treatment for syphilis even though penicillin was available. These patients were allowed to progress to the most severe forms of neurosyphilis, including development of strokes from meningovascular syphilis, brain mass lesions known as gummas, and a severe neurocognitive dementia known as GPI or generalized paresis of the insane. Tuskegee is frequently cited as a reason why African Americans are reluctant to trust the medical establishment and/or participate in clinical research studies.¹⁷

Hu et al reported that minorities are more likely to have a delayed AIDS diagnosis and attributed this to lack of exposure to prevention efforts and lack of access to medical care, among other factors.¹⁸ Factors that may contribute to a delay in seeking medical care for HIV/AIDS among African American and Latino males often include denial of illness. Religious convictions that chastise bisexual and gay African American and Latino males may also cause them to remain closeted about their sexual orientation and risk factors for HIV infection. Cultural differences in some Latino male populations can allow for male-to-male risk of transmission without self-identification as being gay or bisexual.¹⁹ A disproportionately high number of African American and Latino males are incarcerated in prisons where high risk sexual behavior is the norm, and injection drug use is common. Formerly incarcerated minority individuals may hesitate to come forward and be tested for HIV because of fears of reincarceration, especially if they are on parole. Needle exchange and IDU education programs are not plentiful in minority communities, despite evidence that these programs are successful in lowering the transmission rates of both HIV and Hepatitis C. In areas with large immigrant populations such as California and New York, and with a substantial number of undocumented persons, the fear of mandatory reporting of HIV infection may also be a deterrent to getting early diagnosis and treatment. Nakashima and colleagues in a 1998 study showed no added benefit to public health from mandatory names reporting.²⁰ However, the study was performed in states where there are relatively few undocumented immigrants. We are years behind in sending out a culturally sensitive educational message geared to specific racial, ethnic, and socioeconomic communities.

Studies of Neurological Disease in Minorities and Women:

HIVassociated dementia (HAD)

Historically, HAD has been shown to affect between 30 and 60 percent of all people with HIV infection. These statistics were generated from groups of patients who were untreated and in the later stages of disease; in such groups, HIV viral load is likely to be high and CD4+ cell are low (below 200/mm3).²¹ Likewise, most opportunistic conditions that affect the nervous system such as toxoplasmosis, primary brain lymphoma, progressive multifocal leukoencephalopathy (PML), CMV encephalitis, and cryptococcal meningitis, tend to occur in very advanced HIV disease.

HAD is the most advanced form of neurological infection by HIV. It is characterized by a subcortical dementia, with memory loss, decreased attention and concentration, and psychomotor slowing, among other cognitive abnormalities.²¹ By definition, the cognitive abnormalities in a dementia must be acquired (not congenital) and be severe enough to impair the activities of daily living. In addition to dementia, many HAD patients develop central nervous system motor problems that interfere with activities such as hand coordination and ambulation. They may also develop changes in behavior, such as irritability and withdrawal. HAD must be distinguished from a myriad of other problems that can contribute to poor cognitive performance, such as low levels of education, head trauma, other infections, and drug abuse.

HAD must also be distinguished from less severe forms of HIV-associated cognitive dysfunction. Both the bedside mental status examination and neuropsychological testing play an important role in detecting and quantifying HAD, and in measuring its progression or improvement. It is well known that neuropsychological test performance is affected by the patient's age, education, culture, gender, and socio-economic status. However, the norms or normal values for cognative performance have largely been developed and tested primarily in samples of white, middle-class, male subjects who are part of the mainstream culture. Thus, it is possible that these tools can give an inaccurate picture of the true cognitive capabilities of minority individuals.

In order to test women and minority subjects in a fair and accurate manner, it is important to restandardize such testing to adjust for gender, educational, and cultural differences. Even in simple bedside mental status testing, which is the first part of the general neurological examination, one must pay attention to educational and cultural differences. For example, some individuals may never know the current and past Presidents of the United States, but they can tell you current and past baseball rankings and players. If a person is functionally illiterate or poorly educated, they may not be able to spell a five-letter word forward, let alone backward, nor will they be able to perform the standard test of repeatedly subtracting seven from one hundred (serial sevens). If such tests fail to account for these differences, they may give a false picture of dementia. Pittman, et al reported the results of a study that evaluated dementia in a large, racially and ethnically heterogeneous sample.²² Both a semi-structured neurological examination performed by a physician, and a battery of neuropsychological tests were used to characterize the subject as normal, cognitively impaired, or demented. The neurological and neuropsychological results were evaluated separately and in combination. Physicians were more likely to diagnose dementia in persons with low levels of education, based on the results of a clinical mental status examination and assessment of functioning. These results reinforce the need for testing methods that are educationally and culturally sensitive and appropriate.

Women and HIVassociated dementia

To date, there have been very few neurological studies that have examined differences in gender with regard to HAD. Three of these studies were retrospective reviews that included data from early years of the epidemic. They may be confounded by the tendency for women to be diagnosed later in the course of HIV and AIDS (when neurological disease is more common) than are men. In 1992, Janssen et al reported on a series of initial AIDS-defining diagnoses from the CDC general statistics.²³ He found no significant difference between men and women in the likelihood of HAD as an initial AIDS-defining diagnosis. Fleming et al in 1993 also reported on a retrospective analysis of CDC index AIDS-defining diagnoses.²⁴ No significant differences were found between women and men. Chiesi published a retrospective review of HAD in European patients. He reported that in a population of 5729 men and 575 women, the risk of HAD at the time of the first AIDS-defining diagnosis was almost two times as common among women than men. However, in persons whose index diagnosis was not HAD, there were no gender-related differences in the occurrence of HAD after the first AIDS diagnosis.²⁵ The only prospective longitudinal study that compared men and women was reported by Marder in 1995.²⁶ The study followed a cohort of HIV infected and HIV seronegative IDUs over a three and a half-year period. The HIV infected group, included 85 men and 39 women. Marder found that overall, HIV-infected women had fewer abnormal neurological signs on physical examination than HIV-infected men. In addition, the HIV-infected women often presented with such abnormal signs at a higher CD4+ cell count than did HIV-infected men. The incidence of neuropsychological decline was comparable between HIV-infected women and men. However, this report was confounded by the low number of women followed and the restriction to an injection drug user (IDU) population.

The few studies that have examined the neuropsychological aspects of HIV in women indicate that the qualitative types of abnormalities seen, such as decreased psychomotor speed, verbal memory, and attention, are similar to those that have been reported in men.²⁷ Studies examining the impact of neuropsychological abnormalities on the lives of HIV-infected women have reported that these deficits are associated with problems with employment and medication adherence. Further investigation of the pathogenesis of HAD in women may be warranted because of the observations of researchers studying other neurological diseases in women. Since the 1970s, investigators have reported that in animal models, estrogen increased learning. Although a recent study found that estrogen had no significant therapeutic benefit on cognitive impairment in women already diagnosed with Alzheimer's disease,²⁸ numerous other studies suggest that estrogen replacement may prevent or delay the development of Alzheimer's disease.²⁹ The effect of estrogen on HAD is unknown.

Minorities and HIVassociated dementia

Overall, there are no significant differences in neuropsychological test performance in HIV-infected subjects based on race when one adjusts for IQ, cultural, and age differences. Becker et al studied subjects in a well-balanced series of 200 HIV-positive subjects that included women and minorities, including those with lesser degrees of cognitive-motor dysfunction not meeting criteria for HAD. He reported that, when level of education, age, and handedness were taken into account, there were no significant differences in neuropsychological performance among all groups.³⁰ Furthermore, there were no race-based differences in HIV-infected children in cognitive performance, indicating that, because children have been studied from neonatal life on, there are no major differences between races with regard to HIV and neurocognitive performance when people are treated early or matched for the same stage of disease at time of first treatment.³¹

Other Neurological conditions

There are other specific disease syndromes that complicate HIV infection and that have been shown to disproportionately affect minority populations. Many of these illnesses are infections that vary geographically in distribution, or are related to the exposure to infectious agents via the dietary habits of a particular culture. Patients may be initially exposed to these infectious agents during childhood. A latent infection may reactivate during AIDS-related immunosuppression. An example of the latter is central nervous system toxoplasmosis, a disease that is more common in Hispanics, among persons from the tropics, and among those who consume under-cooked meat.¹⁶ Extra-pulmonary tuberculosis, including meningitis and brain abscesses (tuberculomas) is more prevalent among African Americans, Hispanics, Asians, Native Americans, and in persons born outside the US.^16,32 Neurocysticercosis is a parasitic disease that is more prevalent in individuals from Mexico, Central America, and South America. Persons with symptomatic neurocysticercosis typically experience seizures, and in severe cases can develop stroke, hydrocephalus, and other complications. In the authors' personal experience, neurocysticercosis is less responsive to treatment with either praziquantel or albendazole in the setting of HIV infection. HTLV-1associated myelopathy (HAM) infection (also referred to as tropical spastic paraparesis) can occur in HIV-infected patients. It is more prevalent among people of African descent and among those who live in endemic areas in South America. Individuals who are co-infected with both HIV and HTLV-1 have a higher incidence of this myelopathy than those infected with HIV alone.³³ Among HTLV-I infected persons, women are more likely to develop neurological disease and myelopathy than are men.

An important and well-documented difference is that, as a group, HIV-infected women, IDUs, and African Americans statistically are undertreated for HIV-associated pain.^34,35 The two most frequent pain complaints among all HIV-infected patients are headache and painful feet (usually due to painful sensory neuropathy). In 1996 Breitbart et al studied 438 ambulatory AIDS patients with regard to pain and found that females and non-Caucasians reported significantly more pain than white males. Hewett and colleagues (1997) studied 274 ambulatory AIDS patients and found that women in particular had a higher incidence of headaches and radiculopathy than HIV-infected men, although even men with AIDS had a higher incidence of headaches than non-infected men.³⁶ Likewise, Kelleher et al studied individuals receiving care in a London hospice and confirmed a disproportionately high rate of headache and musculoskeletal pain in women versus men with AIDS.³⁷

Conclusion

Certain specific neurological illnesses endemic to minority populations, gender differences with regard to pain syndromes and management, and possible gender differences involving a hypothesized neuroprotective role of estrogen are potentially important areas of future Neuro-AIDS research. Other differences in the neurological manifestations of HIV and AIDS between men and women and among minorities are probably not related to the natural history of AIDS. These differences are likely to be associated with the social and economic factors that predispose women and minorities to obtain medical help late in the course of infection. These factors also contribute to under-representation of women and minorities in clinical research trials, patient distrust of the heathcare system, lack of access to appropriate heath care, and cultural and ethnic belief systems. These problems can only be solved when we provide real outreach to the impoverished and into communities of color. This will require educated professionals and paraprofessionals who represent their communities and can speak to and educate their patients in a cultural- and language-specific manner. True outreach will involve providing confidential free HIV counseling and testing to all poorly insured or uninsured people when they present to clinics or emergency rooms, with appropriate referral to healthcare providers if patients test HIV-positive. It must also include prison reform that ranges from providing condoms to providing full HIV care services. And it must include needle-exchange programs, education about available rehabilitation programs, and referral for HIV and Hepatitis C testing and comprehensive healthcare treatment. Finally, all healthcare providers must be attentive to possible neurocognitive deficits in their patients. In addition to performing the appropriate medical workup and possibly providing referral for neurological consultation, the healthcare provider must enlist significant others, family members, and friends to ensure the best compliance and response to treatment for cognitively impaired patients.

All of these problems are changing, however, and in our current research at the Los Angelesbased National Neurological AIDS Bank, our demographics closely match the current face of the epidemic in our geographic area.

1. Stone V, Mauch M, Steger K, Janas S, Craven D. Race, gender, drug use, and participation in AIDS clinical trials. Lessons from a municipal hospital cohort [see comments]. Journal of General Internal Medicine. 1997, Vol. 12, Pages 150157.

2. Fox R, Ethier K, Cerreta C, Ickovics J. Women and HIV/AIDS: Representation in neurological and neuropsychological research. HIV Infection in Women: Setting a New Agenda, Washington, DC, February 2224, 1995.

3. Schoenbaum E, Webber M. The underrecognition of HIV infection in women in an inner-city emergency room. American Journal of Public Health. 1993, Vol. 83, Pages 363368.

4. Bastian L, Bennett C, Sloane R. Sex differences in quality of care and outcomes among patients hospitalizd with AIDS-related PCP. Annual AHSR/FHSR Meeting, San Diego, CA, 1994.

5. Mays V, Cochran S. Acquired immunodeficiency syndrome and black Americans: Special psychosocial issues. Public Health Reports. 1987, Vol. 102, Pages 224231.

6. Farzadegan H, Hoover D, Astemborski J, et al. Sex differences in HIV-1 viral load and progression to AIDS [see comments]. Lancet. 1998, Vol. 352, Pages 15101514.

7. Ott B, Tate C, Gordon N, Heindel W. Gender differences in the behavioral manifestations of Alzheimer's disease. Journal of the American Geriatrics Society. 1996, Vol. 44, Pages 583587.

8. Lyons K, Hubble J, Troster A, Pahwa R, Koller W. Gender differences in Parkinson's disease. Clinical Neuropharmacology. 1998, Vol. 21, Pages 118121.

9. Andia A, Zisook S, Heaton R, et al. Gender differences in schizophrenia. Journal of Nervous and Mental Disease. 1995, Vol. 183, Pages 522528.

10. Gear R, Gordon N, Heller P, Paul S, Miaskowski C, Levine J. Gender difference in analgesic response to the kappa-opioid pentazocine. Neuroscience Letters. 1996, Vol. 205, Pages 207209.

11. Coyle D, Sehlhorst C, Mascari C. Female rats are more susceptible to the development of neuropathic pain using the partial sciatic nerve ligation (PSNL) model. Neuroscience Letters. 1995, Vol. 186, Pages 135138.

12. Xu J, Kobayashi S, Yamaguchi S, Iijima K, Okada K, Yamashita K. Gender effects on age-related changes in brain structure. American Journal of Neuroradiology. 2000, Vol. 21, Pages 112118.

13. Meyer J, Rauch G, Crawford K, et al. Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia. International Journal of Geriatric Psychiatry. 1999, Vol. 14, Pages 10501061.

14. Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. Journal of Clinical Pharmacy and Therapeutics. 1999, Vol. 24, Pages 339346.

15. Wyatt G, Moe A, Guthrie D. The gynecological, reproductive, and sexual health of HIV-positive women. Cultural Diversity and Ethnic Minority Psychology. 1999, Vol. 5, Pages 183196.

16. Hu D, Fleming P, Castro K, et al. How important is race/ethnicity as an indicator of risk for specific AIDS-defining conditions. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1995, Vol. 10, Pages 374380.

17. CorbieSmith G. The continuing legacy of the Tuskegee Syphilis Study: Considerations for clinical investigation [see comments]. American Journal of the Medical Sciences. 1999, Vol. 317, Pages 58.

18. Hu D, Byers RJ, Fleming P, Ward J. Characteristics of persons with late AIDS diagnosis in the United States. American Journal of Preventive Medicine. 1995, Vol. 11, Pages 114119.

19. Mason H, Marks G, Simoni J, Ruiz M, Richardson J. Culturally sanctioned secrets? Latino men's nondisclosure of HIV infection to family, friends, and lovers [see comments]. Health Psychology. 1995, Vol. 14, Pages 612.

20. Nakashima A, Horsley R, Frey R, Sweeney P, Weber J, Fleming P. Effect of HIV reporting by name on use of HIV testing in publicly funded counseling and testing programs [see comments]. Journal of the American Medical Society. 1998, Vol. 280, Pages 14211426.

21. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Annals of Neurology. 1986, Vol. 19, Pages 517524.

22. Pittman J, Andrews H, Tatemichi T, et al. Diagnosis of dementia in a heterogeneous population. A comparison of paradigm-based diagnosis and physician's diagnosis. Archives of Neurology. 1992, Vol. 49, Pages 461467.

23. Janssen RS, Nwanyanwu OC, Selik RM, StehrGreen JK. Epidemiology of human immunodeficiency virus encephalopathy in the United States. Neurology. 1992, Vol. 42, Pages 14721476.

24. Fleming P, Ciesielski C, Byers R, Castro K, Berkelman R. Gender differences in reported AIDS-indicative diagnoses. Journal of Infectious Diseases. 1993, Vol. 168, Pages 17.

25. Chiesi A, Vella S, Dally L, et al. Epidemiology of AIDS dementia complex in Europe. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1995, Vol. 11, Pages 3944.

26. Marder K, Liu X, Stern Y, et al. The risk of human immunodeficiency virus type 1related neurologic disease in a cohort of intravenous drug users. Archives of Neurology. 1995, Vol. 52, Pages 11741182.

27. Mason K, Campbell A, Hawkins P, Madhere S, Johnson K, TakushiChinen R. Neuropsychological functioning in HIV-positive African American women with a history of drug use. Journal of the National Medical Association. 1998, Vol. 90, Pages 665674.

28. Mulnard R, Cotman C, Kawas C, et al. Estrogen Replacement Therapy for treatment of Mild to Moderate Alzheimer Disease . A Randomized Controlled Trial. Journal of the National Medical Association. 2000, Vol. 283, Pages 10071015.

29. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: The Baltimore Longitudinal Study of Aging. Neurology. 1997, Vol. 48, Pages 15171521.

30. Becker J, Sanchez J, Dew M, Lopez O, Dorst S, Banks G. Neuropsychological abnormalities among HIV-infected individuals in a community-based sample. Neuropsychology. 1997, Vol. 11, Pages 592601.

31. Cohen S, Mundy T, Karassick B, Lieb L, Ludwig D, Ward J. neuropsychological functioning in human immunodeficiency virus type 1 seropositive children infected through neonatal blood transfusion. Pediatrics. 1991, Vol. 88, Pages 5868.

32. Trujillo J, GarciaRamos G, Novak I, Rivera V, Huerta E, Essex M. Neurologic manifestations of AIDS: A comparative study of two populations from Mexico and the United States. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1995, Vol. 8, Pages 2329.

33. Harrison L, Vaz B, Taveira D, et al. Myelopathy among Brazilians coinfected with human T-cell lymphotropic virus type I and HIV [see comments]. Neurology. 1997, Vol. 48, Pages 1318.

34. Breitbart W, McDonald M, Rosenfeld B, et al. Pain in ambulatory AIDS patients. I: Pain characteristics and medical correlates. Pain. 1996, Vol. 68, Pages 315321.

35. Breitbart W, Rosenfeld B, Passik S, McDonald M, Thaler H, Portenoy R. The undertreatment of pain in ambulatory AIDS patients. Pain. 1996, Vol. 65, Pages 243249.

36. Hewitt D, McDonald M, Portenoy R, Rosenfeld B, Passik S, Breitbart W. Pain syndromes and etiologies in ambulatory AIDS patients. Pain. 1997, Vol. 70, Pages 117123.

37. Kelleher P, Cox S, McKeogh M. HIV infection: The spectrum of symptoms and disease in male and female patients attending a London hospice. Palliative Medicine. 1997, Vol. 11, Pages 152158.