Cheney lecture, Feb. 6, 1999, Orlando, Florida - part 2, pages 5 - 8

[Guest guest]

Cheney lecture, Feb. 6, 1999, Orlando, Florida - part 2, pages 5 - 8

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HHV-6

Also, in addition to activation of the immune system, particularly this

RNaseL pathway, evidence of common and ubiquitous human herpes viruses,

ranging from EBV to CMV to HHV-6 and to other viruses were frequent. This

is a study out of the NIH showing white cells in culture. These are normal

white cells, the small ones. These are large giant cells infected with

HHV6. The HHV6 strain a is a lytic virus. It replicates rapidly within the

white cell. The white cell expands and then it explodes, releasing

thousands of virions into the blood that then move out and infect other

cells. This is basically a fluorescent microscopy stain using antibody tags

to identify them. In fact these large cells are infected with HHV6

HHV6 was first discovered in HIV disease. In fact HIV and HHV-6a seem to be

an important dual combo in generating the disease we now know as AIDS. If

there is any relationship between HIV disease and chronic fatigue syndrome

it's most acutely HHV6. This is a virus they share in common, with a

frequent culture positivity rate of about 70% in these cases.

BRAIN DISORDER

In addition to immune activation, particularly this RNaseL pathway, and

also evidence of activation of common human herpes viruses, brain disorder

is impressive in this disease, and it comes in different forms in terms of

clinical presentation. They say, " I've lost my mind, I can't think very

well, I can't process information, my memory is shot, I can't think very

quickly, I'm overwhelmed. " It may come emotionally as molehills become

mountains. " I'm depressed, I'm irritated, I don't know what's wrong with

me, I'm not myself. " And it comes in other soft neurologic findings of

balance disturbances, and hyperreflexia and disorders of locomotion and

it's really quite an impressive disease from the brain standpoint.

This is a nice study out of Harvard which looked at functional scans of the

brain using a SPECT scan that measures blood flow and they compared chronic

fatigue syndrome with AIDS dementia complex and with depression. They

wanted to see if the disorder of brain dysfunction was more like AIDS

dementia complex or if it was more like depression or maybe it wasn't even

there at all.

They took scans of the deep brain that sliced through the thalamus, as

against scans to the cerebellum, and they took these ratios of one cut to

another cut to factor out natural variations in blood flow, which occur in

all of us from moment to moment and from time to time. By taking a ratio

they factored out these natural variations in bloodflow and got lower

variances. What they found essentially was that CFIDS and AIDS dementia

complex cannot be distinguished. They look identical by this cut analysis,

as opposed to depression and normal people, which look identical by this

particular analysis.

What's interesting about this of course is that HHV-6, which is a virus

shared in common, attacks the brain, and specifically likes the central

brain region. Also seen are MRI (?) scan lesions, most commonly these

punctate lesions. I guess you can see them here. In the high cerebral

convexity they are seen in about 80% of cases, also seen in older people so

they're not necessarily abnormal except by age. But in some cases there are

far more significant types of lesions really more reminiscent of multiple

sclerosis. There's a lot of relationship clinically in some cases between

MS and chronic fatigue syndrome, although they're differentiated clinically

as well.

You can examine the brain more carefully using a dual chromatography

technique on cerebral spinal fluid, which we did some years ago in Boston,

and you can separate out the chronic fatigue syndrome patients due to

metabolic aberrations in the cerebral spinal fluid quite readily from the

normal population, suggesting that this is severe metabolic disturbance in

the brains of these patients.

Perhaps one of the more important publications out of the National

Institutes of Health in this disease has to do with aberration of the

hypothalamic-pituitary-adrenal axis. This particular study was launched

initially to prove that this was depression because the HPA axis is

deranged in a certain way in depressed people. Instead what they found was

that the axis was in fact deranged, but was the opposite of depression.

Rather than activated, which it is in depression, these patients had a

suppression of this axis, indeed a suppression of the adrenal axis,

localized to an injury to the hypothalamus, as proven by this paper.

We've extended this study a little bit by looking at cortisol response to

stress. It is known that the stress hormone system responds significantly

to a defined stressor, in this case, exercise. In the case of CFIDS versus

control groups where the cortisol typically doubles, depending how sick

they are--the walking wounded, or can't work but can take care of

themselves--versus having trouble taking care of themselves--these are

different functional categorizations kps (Karnofsky?) scores. The cortisol

level dropped and dropped and actually reversed in the more significantly

ill, meaning that rather than having an augmented adrenal response to

stress they actually had a reversed adrenal response to stress, which is

the fundamental reason they cannot work, because you cannot work if your

cortisol axis goes south instead of north in response to a stress

situation, you simply can't function in the workplace.

NARCOTIC ANTAGONISTS AND AGONISTS

This slide is a pathophysiologic summary of all that i've said before. This

disease begins as an immune activation state--could be a toxin, a viral

trigger or some other process, initiating alpha interferon, which then

activates the 2-5a RNaseL pathway. This RNaseL pathway really disrupts cell

metabolism. It can affect every single enzyme system and every single

hormone and every single structure in the cell. It has a devastating

effect. I think the center of focus for this metabolic derangement is in

the area of detoxification defects. The alpha interferon can also injure

the central nervous system directly through the opium receptor, because in

rat studies it's been observed that alpha interferon's injury to the deep

brain can be blocked by narcotics or narcotic antagonists.

Let me explain why some of the patients respond well to narcotic

antagonists and agonists. The neurotoxicity seems to be centered at the

hypothalamus, which can downregulate the cortisol access, and if that

happens you're in a positive feedback loop. As you downregulate the HPA

axis you upregulate the immune system and you're kind of in a vicious cycle

and it can go on and on and on for years.

ENERGY PRODUCTION

To look specifically at energy production, since this is a fatiguing

illness, we elicited the support of a group at U.N.C. Chapel Hill to look

at mitochondria, using a very interesting laser scanning microscopy that

allows you to look at a single mitochondria in a living cell, and measure

its energy production.

This is actually what it looks like under fluorescent (fluorescence?)

conditions and in a computer-generated coloremetry (?) and essentially the

reddish areas are hot energy generation of a single mitochondria in a

single white cell--see this round structure here?--it's a lymphocyte stuck

on a glass, and the little dots of light that you see are the actual

mitochondria, making energy, making ATP, and the intensity of this

fluorescense (?) light is proportional to the inner membrane mitochondrial

potential, which is proportional to ATP generation. So you're actually

looking, in this coloremetry model, at the actual energy production of the

cell.

If you plot the different mitochondrial distributions of energy production,

this is a normal map--most of the mitochondria operate at a very high

energetic level with inner membrane potentials of 180 to 240 milligalls

(?), but a subset of mitochondria operate somewhat lower. I don't have the

slide to show this, but chronic fatigue syndrome patients are the exact

opposite of this, they're the mirror image. Most of their mitochondria are

operating down here; very few are operating up here. Indeed there is a

significant derangement in mitochondrial function. They're essentially

browned out--almost like a rheostat (?) tuning down their mitochondrial

energy production. And it's quite generalized, suggesting a metabolic

origin as opposed to a point mitochondrial problem or a cell-specific

mitochondrial problem.

Which brings me to a generalized concept, and we'll conclude here in just a

few minutes, and that is what about chronic fatigue syndrome as a

xenobiotic toxicity disorder. As I said before, the RNase activity

significantly disrupts cell enzyme function, and if you were to disrupt

cell enzyme function across all organ systems you might ask the question,

what would make you feel the worst? if your brain was downregulated

energetically, functionally. how would you feel? If your heart was

downregulated energetically or functionally how would you feel?

(to be continued)