Neurological defects secondary to HIV infection may be due to the direct effects of the retroviruses on the nervous system or to secondary infections after significant immune-system compromise. The dementias are often classified in two ways: according to the underlying pathophysiology and according to the neurological location of injury. HIV-1 passes the blood-brain barrier easily, resulting in a greater concentration of the virus in the brain than in other organs of the body (67). It is replicated in the monocytes and multinucleated macrophages within the brain (68). The primary site of destruction is in the subcortical regions of the brain. There is now evidence that the excitatory N-methyl D-aspartate (NMDA) receptors may be sensitized by the HIV-1 coat protein gp120, resulting in neurotoxic elevations of calcium (69). A great deal of work is being carried out in an attempt at retarding this neurotoxicity, but to date there are no clearly effective clinical treatments.
Minor cognitive impairment not meeting the criteria for a diagnosis of dementia is detectable in 0.4% of patients in the asymptomatic period (70). Rarely, there may be an early-phase dementia, which occurs soon after infection with HIV and reflects an encephalopathy (70). There may also be an uncommonly reported middle-phase dementia, which presents similarly to multiple sclerosis after what appears to be an autoimmune reaction affecting the white matter of the brain (71).
The third phase of HIV-associated dementia, initially classified as AIDS dementia complex, is now referred to as HIV-1-associated cognitive/motor complex. The etiology of this disorder is associated with either diffuse HIV pathology or focal lesions secondary to OIs. This complex was once thought to involve approximately 40% of AIDS patients, but this is now thought to have been an overestimate. One study by the World Health Organization
(WHO) showed a point prevalence of between 8 and 16% of patients with AIDS. Estimates of annual incidence have approximated 7.0% (72,73). In patients in the late stage of disease, it has been estimated that 27% may have diagnosable dementia (74). The true incidence secondary to cerebral HIV infections is difficult to determine. It may be overestimated secondary to the high prevalence of pre-existing cognitive difficulties seen in many patients at risk for HIV-1 infection, and the uncertainty in determining the related contributions of AIDS-related secondary encephalopathies and chronic substance abuse (75).
A decline in the CD4 cell count is associated with a dramatic increase in the prevalence of neurological involvement, including dementia (76). Of note, dementia is associated with poor prognosis (75). The Multicenter AIDS Cohort Study (72) demonstrated a median survival of 6 months after diagnosis, although the potential impact of combination antiretroviral therapy has yet to be assessed.
Neurocognitively, the HIV dementia complex has many similarities to that seen with chronic substance abuse, including problems with attention, concentration, cognitive flexibility, verbal memory, and psychomotor speed (77,78). There is also evidence of an escalation in appearance of symptoms of cognitive decline in the chronic substance-abusing HIV-positive patient over that seen in non-substance-abusing HIV-positive patients (79). In this and other studies there is generally, although not invariably, evidence that substance abuse patients with concurrent HIV-seropositive status have a more prominent decline in neurocognitive abilities than those who are seronegative (80). Age and educational background are also important factors in the decline of cognitive abilities in these patients (81,82). Clearly, continued substance dependence negatively effects the status of the already cognitively impaired HIV-positive patient.
Assessment of cognitive impairments in HIV-infected patients is critical both to initiate treatments for the underlying cause of the neurological decline and because cognitive impairments may adversely affect compliance with complicated medication regimens. The Mini Mental Status Exam is a rapid, easily preformed assessment tool to evaluate for possible dementia or evidence of a variety of neurological deficits. However, it may not be sufficiently sensitive to pick up subtle early changes, especially in patients with premorbid levels of functioning. The Neuropsychological Impairment Scale (NIS) is a self-assessment scale that has shown greater sensitivity in evaluating these patients. It can assist the clinician in following the potential development of cognitive difficulties during the course of a patient's illness (83). More complete neuropsychological testing, including the Rey Verbal Memory Task for detection of cortical abnormalities, and Trailmaking B, symbol digit, and nonverbal memory tests may be needed for identification of subcortical dementias (84,85).
Specialized approaches may be beneficial in improving compliance with complex medication schedules in patients with cognitive impairments. Information can be presented in simple language and repeated format, making use of written, verbal, and illustrated materials. One multimodal approach incorporating cognitive remediation strategies such as behavioral games, role playing, quizzes, memory books, large-format presentations, and frequent feedback has been found effective in reducing high-risk behavior in a small sample of opiate- and cocaine-dependent, HIV-seropositive patients (86).
Zidovudine (AZT) may be helpful in the treatment of HIV dementia. A randomized, double-blind, placebo-controlled study provided evidence that HIV dementia patients have improvement of neuropsychological performance following administration of high-dose (2000 mg/day) of AZT (87). There is evidence that the incidence of HIV dementia and opportunistic brain disease can be reduced after the administration of AZT if started not only before but also after the onset of AIDS dementia (88). Unfortunately, there was no evidence that AZT was protective against HIV dementia complex when a large cohort of these patients were followed over time (72). No clear evidence exists that other antiviral therapies effectively reduce the incidence of brain disease in the HIV-positive patient (89). However, an open-label trial of the nonnucleoside reverse transcriptase inhibitor atevirdine has shown preliminary favorable results (90). Unfortunately, it is lack of compliance with difficult drug regimens in the substance-use-disordered population that remains the barrier to their benefiting from effective preventive treatment for HIV-related dementia.
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