Definitions And History

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In 1981, the Centers for Disease Control and Prevention (CDC) reported the occurrence of Pneumocystis carinii pneumonia (PCP) in five Los Angeles homosexual men. Within months of this report, clusters of similar cases of young, previously healthy homosexual men, who had developed unusual neoplasms and unexplained opportunistic infections (OIs), were reported in New York and California. The disorder, which had the clinical and immunological hallmarks of a cell-mediated immunodeficiency (development of Ols, depressed numbers of circulating T-helper cells, with "reversed T4/T8 ratios"), was termed the gay related immune deficiency (GRID) syndrome. By the following year, the same syndrome complex was recognized in recipients of blood or blood products (mostly hemophiliacs) and in Haitians. Shortly thereafter, other high-risk groups were identified, namely men and women intravenous drug users and women whose only risk factor was sexual contact with men who were intravenous drug users, bisexuals, or both. These women's children were also a high-risk group. The disorder was renamed the acquired immunodeficiency syndrome (AIDS). Its epidemic nature was appreciated as increased numbers of cases were identified from specific geographic regions in the United States, Europe, and Africa. It was also appreciated that transmission of the disorder was from sexual contact, via mother to infant, or through bloodborne mechanisms. The agent, at that time, was thought to be most likely a virus that could survive the processing of blood factor VIII.

The etiological agent of AIDS, a retrovirus, was isolated in 1983 y y y and named the human immunodeficiency virus (HIV) in 1986.[4 Once the agent was identified, studies confirmed the presence of HIV in sera that had been collected in central Africa in 1959 and the United States in 1968. It was not, however, until the early 1980s that HIV-1 infection began to reach epidemic proportions. Since then the epidemic has expanded relentlessly. From its beginning until January 1, 1996, an estimated 30.6 million people worldwide have been infected with HIV-1.

As a matter of definition, all individuals with AIDS are necessarily infected by the HIV virus. However, patients with HIV infection do not qualify for classification as having AIDS unless certain criteria are fulfilled (..Tabje 44.-1 , see later discussion). In certain settings (pediatric cases), the actual demonstration of HIV infection per CDC definition, however, is not required for the diagnosis of AIDS (see Ta.b.!§...4.4.-1).

Nervous system involvement complicating the course of AIDS was recognized in the very early years of the epidemic. In fact, the first reports of neurological complications appeared when the disorder was still termed GRID and thought to be restricted to homosexual males. Initially, in adults, neurological complications were believed to be caused strictly by central nervous system (CNS) OIs and neoplasms as a consequence of the immunodeficiency. [5 However, in 1985 distinct primary HIV-1-associated neurological disorders, unrelated to secondary infections or neoplasms, were described. In that same year HIV-1 was isolated from brain, spinal cord, cerebrospinal fluid, and peripheral nerves. y , y Between 1985 and 1988, further evidence from clinical, virological, and neuropathological studies indicated that neurological impairment in HIV- 1-infected patients, referred to as AIDS-dementia complex

TABLE 44-1 -- CDC CLASSIFICATION FOR HIV-1 INFECTION AND EXPANDED AIDS SURVEILLANCE CASE DEFINITION FOR ADOLESCENTS AND ADULTS

CD4+ Cell Categories

Clinical Categories

(A)

(B)

(C)

Asymptomatic or PGL

Symptomatic Not (A) or (C) Conditions

AIDS-Indicator Conditions

(1)

A1

B1

C1

500/mm3

(2) 200 to 499/mm3

A2

B2

C2

(3) <200/mm3 AIDS-indicator cell count

A3

B3

C3

PGL persistent generalized lymphadenopathy Category A

Acute retroviral syndrome Generalized lymphadenopathy Asymptomatic disease Pneumocystis carinii infection Pneumonia, bacterial

Progressive multifocal leukoencephalopathy

Salmonellosis

Category B

Bacterial endocarditis, meningitis, pneumonia, or sepsis

Candidiasis, vulvovaginal: persisting (>1 month duration) or poorly responsive to therapy Candidiasis, oropharyngeal (thrush) Cervical dysplasia

Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting >1 month Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Nocardiosis

Pelvic inflammatory disease

Peripheral neuropathy

Category C

CD4 count >200/mm3

Bacterial pneumonia, recurrent

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) HIV-1 encephalopathy

Herpes simplex: chronic ulcer(s) (>1 month duration) or bronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month duration) Kaposi's sarcoma

Lymphoma, Burkitt's (or equivalent term) Mycobacterial disease in adults^ and AIDS encephalopathy/shprogressive encephalopathy in children, '91 was associated with primary HIV-1 CNS infection. These studies included the following: (1) recovery of RNA and DNA in brain; (2) demonstration of intrathecal synthesis of anti-HIV antibodies; (3) localization of HIV-1 antigen in brain macrophages and monocytes by immunocytochemistry; (4) identification of viral particles within multinucleated giant cells and macrophages by electron microscopy; and (5) demonstration of increased levels of HIV-1 DNA in the brain compared with other organs by Southern blot analysis. y y '121 '131 '141 '151 HIV-1 was also shown to belong to the lentivirus subfamily of retoviruses. In 1987, HIV/AIDS encephalopathy was recognized by the CDC as a major complication of HIV-1 infection and designated as one of the AIDS-defining conditions, that is a condition that is specific enough to diagnose AIDS in the context of documented HIV infection (see Table

It is now well recognized that neurological disease at every anatomic level is a common complication of HIV-1 infection and neurological symptoms and signs may be the initial manifestation of HIV/AIDS. y , y Primary HIV- 1-associated clinical syndromes are diverse and can occur not only at the onset but at different times during the course of infection. For example, a self-limited "aseptic meningitis" y may occur soon after initial infection as may an acute encephalopathy, y myelopathy,^1 or neuropathy. During the next stage of HIV-1 disease (mild immune dysfunction), neurological complications such as "aseptic" meningitis, inflammatory demyelinating polyradiculopathy, myopathy, or zoster radiculitis may occur. With advancing HIV-1 disease (moderate to severe immunodeficiency), signs and symptoms of cognitive dysfunction, dementia, myelopathy, sensory neuropathy, and myopathy become more prevalent, as do nervous system OIs and neoplasms. y

In general, neurological involvement becomes increasingly more frequent with progression of HIV-1 disease

and as the immunodeficiency worsens, the prevalence of associated neurological disorders increases. In 1992, it was estimated that 37 to 77 percent of the approximately 154,000 persons alive with AIDS in the United States had an associated neurological condition. y As the number of patients with AIDS increases and as medical therapies for primary HIV-1 disease and its complications lengthen survival, it can be anticipated that HIV-1-associated neurological disorders will be among the commonest neurological conditions seen by neurologists. These grim statistics also unfortunately apply to children. It is estimated that there are 15,000 to 20,000 HIV-1-infected children in the United States. It can be anticipated that HIV-1-associated CNS disease will become one of the leading causes of mental deficiency and developmental disabilities among infants and children in some areas of our country. This chapter first presents a review of the HIV virus, an overview of its general role in disease and the clinical criteria for AIDS. This is followed by a detailed account of HIV- 1-related neurological disorders and a brief summary of the neurological malignancies and OIs that occur in the setting of AIDS.

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