HIV AIDS

Introduction
Background

Neurologic complications from the human immunodeficiency virus (HIV) may arise from HIV itself, opportunistic infections, tumors, or drug-related complications. HIV encephalopathy and AIDS dementia complex (ADC) are the neurologic complications that arise from primary HIV infection, others include vacuolar myelopathy, peripheral neuropathies, and polymyositis.

Several important terms exist concerning CNS conditions caused by HIV. HIV encephalopathy is part of the acute HIV syndrome during seroconversion. HIV-associated progressive encephalopathy (HPE) is a syndrome complex with cognitive, motor, and behavioral features seen in children. ADC, also known as HIV-associated dementia complex (HAD), is characterized by cognitive, motor, and behavioral features in adults, which usually develops in advanced AIDS when CD4+ lymphocyte counts fall below 200 cells/mm3. With the advent of highly active antiretroviral therapy (HAART), a less severe dysfunction, minor cognitive motor disorder (MCMD), has become more common than ADC.

ADC is more frequently associated with advanced age and lowCD4+ counts.
Pathophysiology

The mechanism by which HIV infection leads to ADC is likely multifactorial and is the subject of intense research. The following paradigms are supported by multiple studies.

* HIV neuroinvasion: HIV is thought to enter the brain via HIV-infected monocytes and other infected CD4+ cells, which then differentiate into macrophages. The virus replicates in these cells and can then, in theory, infect other cells, such as microglia, oligodendrocytes, astrocytes, and neurons; macrophages and microglia are the most common. In vitro models have shown that HIV may enter the CNS by transcytosis of endothelial cells.
* Cellular proteins: The widespread pathologic damage may occur via indirect cellular responses with the secretion of chemokines, proinflammatory cytokines, nitrous oxide, and other neurotoxic factors. These products are produced not only from the infected cells (macrophages, astrocytes, microglia), but also from noninfected activated cells. Recently, much attention has been placed on chemokines, such as CCL4 and CXCL12, and their respective chemokine receptors, CCR5 and CXCR4, which may affect many cellular processes including neuronal migration, apoptosis, and neurotransmitter regulation.
* HIV proteins (virotoxins): Damage to neurons may occur through the actions of specific HIV proteins, including gp120, gp41, Tat, Nef, Vpr, and Rev. These viral proteins may be directly toxic to neuronal cells or may cause damage by activating astrocytes, microglia and macrophages to release cytokines, chemokines, or neurotoxic substances. Studies in several transgenic mouse models indicate that expression of a single or multiple HIV genes leads to clinical and histologic abnormalities. By initiating feedback loops, virotoxins may amplify their toxicity and cause widespread damage.
* Autoimmune disease: CNS damage by humoral immune mechanisms, as evidenced by the presence of anti-CNS antibodies in AIDS patients with dementia, but not in those without dementia.
* Altered neurotransmitter release
* Increases in excitatory amino acids and free intracellular calcium

Frequency
United States

The Multicenter AIDS cohort Study prospectively followed 2734 American men with HIV. Before HAART (1990-1992), the incidence of HIV dementia was 21 cases per 1000 person-years; after the advent of HAART (1996-1998), this value decreased to 10.5 cases per 1000 person-years.

The frequency of HPE as an initial AIDS-defining illness in children is 12-67%. In untreated children, the prevalence of HPE is about 50%. In a recent study of HIV encephalopathy in children with HIV infection who are receiving HAART, the rate of active HPE in 2000 was 1.6% and the prevalence of arrested HPE was 10%. HPE relapse occurred in 23% of the sample group with previously arrested HPE.
International

The Australian AIDS surveillance data demonstrate a pre- to post-HAART decline in the incidence of ADC of 135 reported cases in 1993-1995 to 119 cases in 1996-2000. In the same intervals, its prevalence increased from 5.2% to 6.8% because ADC patients live longer with HAART. Not surprisingly, survival of those with ADC and advanced AIDS (CD4 count <100) increased from 5 months pre-HAART to 38.5 months post-HAART.

In a study of patients with HIV in a Ugandan clinic, the prevalence of ADC was 31%. If extrapolated to sub-Saharan Africa (26 million people with HIV out of 40.3 million people infected worldwide), ADC would be the most important cause of dementia under age 40.
Mortality/Morbidity

In one study (pre-HAART), the median survival after diagnosis of ADC was 6 months, or about 2 months less than the survival in AIDS patients without dementia. However, the advent of HAART has not only improved the prognosis of AIDS in general but may also reduce the incidence of ADC and lead to improvement in cognitive function in patients who already have ADC. About 10% of HIV-infected adults have ADC and 30% have MCMD. In children treated with HAART, HPE may be thought of as an infrequent and reversible complication of HIV.
Race

In a large US cohort, the likelihood of ADC was similar in white and nonwhite patients.
Sex

The sex distribution of ADC reflects that of HIV infection.
Age

Older patients have a higher likelihood of having ADC.

Drug use: Viral proteins Tat and gp120 have been shown to have synergistic neurotoxicity with cocaine and methamphetamine. IV drug users may have a higher likelihood of developing ADC.

Other: Poorer prognosis has been associated in patients with lower educational levels, lower CD4 counts and higher HIV RNA levels, anemia, low body mass index, and more constitutional symptoms.
Clinical
History

ADC and HPE affect cognitive, behavioral, and motor function.

* Patients often present with the insidious onset of reduced work productivity, poor concentration, mental slowness, decreased libido, and forgetfulness.
* Apathy and withdrawal from hobbies or social activities are common and must be differentiated from depression.
* Rare features include sleep disturbances, psychosis (with mania), and seizures.
* Motor problems include imbalance, clumsiness, and weakness.
* Early signs and symptoms are subtle and may be overlooked.
* Later, these symptoms evolve into a global dementia with memory loss and language impairment. This can lead to a vegetative state.
* In MCMD, activities of daily living are only mildly impaired unlike ADC.
* Regarding HPE, in infants, characteristic features include decline in intellectual and motor milestones. In young children, the rate of acquisition of new skills decreases and impairment of fine motor ability and dexterity may be associated; they may also have feeding difficulties. In older children and adolescents, the presentation is similar to that of ADC in adults.

Physical

* The neuropsychological examination reveals features more suggestive of subcortical dementia, as seen in Parkinson disease, than of cortical dementia of the Alzheimer type.
o Early on, neuropsychological examination reveals psychomotor slowing, memory loss, and word-finding difficulties. Subcortical involvement with impaired retrieval and manipulation of acquired knowledge is prominent.
o Later, severe psychomotor retardation and language impairment become obvious, leading to akinetic mutism.
* Neurologic examination in adults
o Early on, the neurologic examination may be normal or reveal subtle impairment of rapid limb and eye movements.
o Later, frontal lobe release signs, tremor, hyperreflexia, clonus, spasticity, weakness, and poor coordination develop. These signs may reflect a concomitant vacuolar myelopathy.
o The terminal stage of ADC, after progression over several months, includes severe psychomotor retardation and dementia, apraxia, paraparesis, and akinetic mutism. Death ensues within a few months of reaching this stage.
o Seizures are rare and warrant exclusion of other conditions.
* Price and Brew in 1988 outlined a clinical staging of ADC, summarized by the following:
o Stage 0 (normal): Mental and motor functions are normal.
o Stage 0.5 (equivocal/subclinical): Symptoms may be absent, minimal, or equivocal, with no impairment of work or performance of activities of daily living (ADL). Mild signs (snout response, slowed ocular or extremity movements) may be present. Gait and strength are normal.
o Stage 1 (mild): The patient is able to perform all but the more demanding aspects of work or ADL but has unequivocal evidence of functional, intellectual, or motor impairment. Signs or symptoms may include diminished performance on neuropsychological testing. Patient can walk without assistance.
o Stage 2 (moderate): The patient is able to perform basic activities of self-care but cannot work or maintain the more demanding aspects of daily life. The patient is ambulatory but may require a single prop.
o Stage 3 (severe): The patient has major intellectual incapacity (cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all outputs). Motor disability precludes walking unassisted (ie, without walker or personal support); walking usually slowed and accompanied by clumsiness of arms.
o Stage 4 (end stage): The patient is in a nearly vegetative state. Intellectual and social comprehension and output are at a rudimentary level. The patient is nearly or absolutely mute. The patient is paraparetic or paraplegic with urinary and fecal incontinence.
* Neurologic examination in pediatric populations
o In neonates, the physical examination findings are often normal.
o Although the age of onset is usually in the first year of life, manifestations may not be noticeable until age 2-3 years. At this time, children may present with cognitive impairment, maskedlike facies, acquired microcephaly, and pseudobulbar and corticospinal tract signs.
o Common findings in older children and adolescents are impaired attention, decreased linguistic and scholastic performance, psychomotor slowing, emotional lability, and social withdrawal. Examination findings are similar to those in adults with ADC.