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AIDS Dementia Complex

HIV/CNS infections: it appears that infections of the nervous system - we see this particularly in the spinal fluid but probably the same thing is true in the brain - that it’s an intrinsic part of the ecology of HIV. One of the things that is puzzling about that is that early infection for a protracted period of time, despite this infection or exposure to the nervous system, it is entirely asymptomatic, even though we might find abnormalities in the spinal fluid. Only under certain conditions late in AIDS dementia complex.

There are two variants that we encompass within the definition of AIDS dementia complex, and sometimes they are separated out. One is the dementia or the brain problem, the cerebral problem, which is a combination really of cognitive.

Myelopathy. This syndrome is a coherent syndrome that has a hierarchy of symptoms and signs, although with some variability. Early on patients, the major problem is slowing of both cognitive and motor spheres. So patients complain of some difficulty with concentration, focusing on things and so forth, and they may also have mild motor slowing. Later on, that is those that progress - and they don’t all progress - other domains are involved cognitively.

Then there’s a sub-group within this pathology of patients who have true HIV infection or HIV encephalitis. In this case marked by macrophage infiltration and you probably can’t see but a number of these macrophages are multinucleated and that’s the so-called multinucleated-cell encephalitis, which is true HIV encephalitis. These are HIV-infected macrophages. The major cell that is productively infected in the brain, which has been known for some time, is the macrophage or microglial cell. Subsequently more recently it has been shown that other cells can be infected.

So we always have the problem of: how do you explain dysfunction if the cells infected are just macrophages? They are not the functional elements of the brain. At times the neural imaging will be normal. But the characteristic findings are brain atrophy, so clearly this process affects the brain. The brain shrinks and sometimes we see white matter abnormalities of the diffuse variety. At times these will be misread as PML, but the appearance really isn’t the same as that of PML. It tends to be a diffuse and fluffy white matter involvement and if you had PML this extensive, the patient would be virtually vegetative and these patients don’t have.

Now the vacuolar myelopathy: let me just dwell a moment on that. A variety of myelopathies can occur in HIV infection but the vacuolar myelopathy is what we call a non-segmental or non-focal myelopathy. That is, there is not a level on the body where it changes from abnormal to normal, but rather it’s a myelopathy that seems to shade toward the chordal end so that the legs are more affected. They are hyperreflexic, spastic.

This is the vacuole myelopathy. This is a severe case. This bubbly appearance is edema within the myelin sheath and we still don’t know the pathogenesis. It’s not straightforward HIV infection of the spinal cord.

What’s happened to dementia in the era of HAART? The disorder, the more severe dementia, is a disorder that occurs in individuals with low CD4 count, with a high systemic viral burden and systemic immune activation. So it’s an any-stage HIV complication. Very much following the profile of the major opportunistic infections. Although we don’t have clear data, I think anecdotal data and emerging information - and even extrapolation from information earlier in therapy with AZT monotherapy - all suggest together that HAART has a protective effect against the dementia just like it does with opportunistic infections.

Pathogenesis: the way we think, or the general thought about the pathogenesis of the disease is that the virus drives the process. It’s the major prime mover of the process but that there are these secondary events which we can encompass under what we call neuropathogenic pathways that then lead to the disease phenotype. In terms of the infection, just to reiterate a bit, the important part of the infection, or the aspects that have been identified, is that this occurs in a setting usually of poor control of systemic infection. There is CNS invasion of the virus.

Very briefly, the general idea just to represent another way is that the infection initiates the process. Various viral products probably trigger other events involving whole expression of toxic host genes that then target.

Let me talk a little about CSF studies that relate to the nature of the infection. And this simple cartoon is just a reminder that the brain and the CSF are separate. They are not the same thing, so when we look at CSF there’s always the caveat that we are looking at something that is a little bit different than looking at the brain itself. Of course we look at CSF because we are able to relatively non-invasively sample it, whereas obviously we can’t sample the brain and particularly sample the brain over time. Both the CSF and the brain have barriers that separate them from the blood so there’s a selection of what goes into the brain and what goes into the CSF. These barriers are somewhat different but many of the properties are sufficiently similar that we think that this can be looked at as a parallel compartment. There also is an element of interchange between the brain and CSF so certain things can leak in different directions. Particularly leak out of the brain into the CSF. So the importance is that when we look at the CSF we can look at virus, we can look at virus sub-types, we can look at infection and we can look at immune activation molecules and so forth, and, at least hypothetically, see that they may reflect the same kind of things that are going on in the brain. But we always have the reservation that they may not be identical.

Let me just go on to describe some general things about the CSF in HIV. First of all, is a CSF examination worthwhile in demented patients? I think that the bottom line is generally no. In terms of routine studies, both the protein and the cell count are variable. These are old data but actually they are good data since there was a larger series that could be collected. And the general thing that Harry said is true, that later in infection, and in the case of demented patients the more severe the dementia, there is a tendency for these things to actually be more normal. That is, the protein to be more in the normal range rather than elevated, which it characteristically is in early HIV infection, and the cell count to actually go down. This is true in demented and non-demented patients. Late HIV infection, the cell count tends to normalize if