IMAGING AND HAD
Imaging techniques that may be useful in establishing a diagnosis of HAD include CT and MRI.8 Use of single photon emission CT (SPECT), which may be more sensitive than either CT or MRI, often demonstrates multifocal cortical and subcortical areas of hypoper-fusion.9 Positron emission tomography, which demonstrates areas of hypometabolism in the basal ganglia shown to correlate with HAD severity, also has been found useful in establishing a diagnosis.10 Magnetic resonance spectroscopy also has proved useful in identifying reduced levels of N-acetylaspartate, which is a marker of neuronal function in the frontal cortex and basal ganglia.11
"We have found that diffusion tensor imaging techniques, which are not routinely available in most institutions, may be even more sensitive than the MRI. Furthermore, the SPECT scan has been especially useful in identifying those patients in whom a lumbar puncture should be performed every 6 months." Crystal added.
"No single combination of antiretroviral agents has been shown to improve HAD," remarked Crystal. "Experts in the field always recommend those agents that have the highest CNS penetration. In the case of psychiatric symptoms, such as severe agitation, delusions, and hallucinations, antipsychotic agents such as olanzapine(Drug information on olanzapine) [Zyprexa] and risperidone(Drug information on risperidone) [Risperdal] have been shown to be effective. In many patients who suffer from depression or apathy, selective serotonergic reuptake inhibitors have been helpful. In my opinion, the use of stimulants such as amphetamines for patients with HAD who exhibit severe apathy may not be helpful."
Treatment for HAD should begin by controlling the underlying infection using HAART. Current HAART regimens are routinely made of 2 nucleoside analog reverse transcriptase inhibitors combined with either a potent protease inhibitor or a nonnucleoside analog reverse transcriptase inhibitor.6
"Improvement of HAD with HAART regimens is inferential and based predominantly on cohort trials in which MRI studies have demonstrated improvement with HAART," explained David M. Simpson, professor of neurology and director of the Clinical Neurophysiology Laboratories and the Neuro-AIDS program at Mount Sinai Medical Center in New York City. "At this point, it would be safe to say that HAART is associated with an overall improvement in AIDS dementia, but if one tries to get placebo-controlled trials as a standard of evidence, there are remarkably few available."
When asked about the future of treatments for HAD, Crystal commented that the only modality that seems to show promise is HAART. Simpson, however, explained that he and his colleagues are in the process of developing new treatments and are engaged in on-going clinical trials.
"The types of treatments that are being pursued fall into 2 main categories. The first category is new antiretroviral therapy. Data to date suggest that the antiretroviral agents that have optimal penetration of the blood-brain barrier are most likely to be the most effective for the treatment of dementia," said Simpson. The second category concerns understanding and attacking "secondary mechanisms beyond direct viral infection that drive dementia," Simpson continued.
Simpson explained that the HIV-1 viral load in the brain is relatively modest in relation to the degree of dementia seen in patients with HIV infection. "In fact, primary neurons are not infected by HIV even though they do degenerate. Secondary mechanisms related to dementia pathogenesis are likely involved," he said. "So there is a large effort being made to study agents that target these secondary mechanisms." Agents that have been studied in placebo-controlled trials include the calcium channel blocker nimodipine (Nimotop), the N-methyl-d-aspartate antagonist memantine (Namenda), the tetracycline(Drug information on tetracycline) antibiotic minocycline(Drug information on minocycline), and the monoamine oxidase-B inhibitor selegiline(Drug information on selegiline), Simpson explained.
"Before HAART, the prognosis of an HAD diagnosis was 6 to 7 months, after which the patient usually died," commented Crystal. "With HAART, life can now be extended for many months to years."
In terms of risk factors in HIV-infected patients, a low CD4 count is probably the best indicator of progression to HAD, said Crystal. "Other risk factors include coinfection with hepatitis C, intravenous drug use, concomitant diabetes and hypertension, or low cognitive reserve."