Physicians' Column

Dr. Daniel Malone Addresses Association

(excerpted from the Fall 1998 issue of the WI - CFS Association "Lifeline" newsletter)

Dr. Malone, a rheumatologist on the staff of the University of Wisconsin Hospital and Clinics, discussed chronic fatigue syndrome and fibromyalgia syndrome at Spring Seminar '98 on March 21 at the University of Wisconsin Hospital.

Dr. Malone began his remarks by stating, "Of course, you can't treat a disease intelligently unless you understand it. In order to treat this disease, we have to try to figure out what could be causing it."

"I'm privileged to be privy to information that's pretty new as a result to having been invited to a couple of conferences over the past several years that have been held on the west coast. The point of these conferences was to bring together people who would have something to contribute to this subject. I'm going to share with you some of the new things that are going on."

"The definitions of chronic fatigue syndrome and fibromyalgia syndrome differ. If you look at it in the political sense, it may not be advantageous to separate the two entities in terms of funding, foundations, etc. Clinically, the two conditions are probably more similar than they are different."

Dr. Malone then projected a slide that depicts symptoms of fibromyalgia. The definition of fibromyalgia is 'pain all over, without other explanation, that lasts 6 months or more, with 11 of 18 tender points that measure four kilograms or less in their pain threshold.' In chronic fatigue syndrome, the clinical definition is a little more detailed. It includes symptoms not included in the fibromyalgia description -- fever and immune dysfunction. Slide two is a continuation of the list of symptoms (see Table 1).

"There is a huge overlap between fibromyalgia and chronic fatigue syndrome in the sense that they so many of these clinical manifestations," continued Dr. Malone. "There are some differences. In my experience with about 300 patients, the main differences appear to be that chronic fatigue syndrome patients have fatigue as a more disabling or prominent symptom. They appear to have more immune dysfunction as evidenced by frequent infections, fever and swollen lymph nodes -- called lymph adenopathy in 'medicalese.' Other than that, the two conditions are quite similar. I look at this as one might look at diabetes. In diabetes, you have a wide variety of clinical manifestations. It's the same basic problem which is lack of control of blood sugar, but some patients have significant amounts of kidney disease; other patients have a significant amount of arterial blockages; other patients have nervous system problems with the peripheral nerves - the nerves of the fingers and feet that aren't working properly. They're all called diabetics."

"You can look at this group of chronic fatigue syndrome and fibromyalgia patients, and I include post-traumatic stress disorder and Persian Gulf illness, because if you look at the symptoms from those other two illnesses you find the same list that I just showed you. (See Table 1) I look at these as basically a central nervous system disorder with different subsets. We don't understand what causes these subsets and why they differ. Until we know what the nature of the basic disorder is, we are not going to know the rationale behind the clinical separations."

Dr. Malone posed the question, "How do you make meaning of the 30 or 40 different symptoms I showed you? There are symptoms that involve the gastrointestinal tract (GI tract), immunological-related symptoms, symptoms of psychiatric disease like depression, sexual malfunction, plenty of endocrine dysfunction. We are talking about basically every system in the body. How do you conceptualize an illness that has so many manifestations? People have recognized this illness since the mid-1800s and have been biopsy-ing muscles since the early 1900s and looking at the tissue under microscopes and haven't been able to find much wrong with the muscles. They've done nerve conduction velocity studies on the tingling nerves of such patients and find that the nerves conduct electricity just fine. They've biopsied bowels with fiber optic instruments that can take little biopsies of the bowel wall of people who have irritable bowel syndrome and they find no abnormalities. How do you justify disabling symptoms and not be able to see anything under the microscope?"

"I think that the problem is not in the peripheral organs; the problem is not in the bowel or the muscles or the peripheral nerves. The problem is in the control center. The metaphor I use is of a building, an Ameritech (telephone company) building. All of the wiring comes into the building where they have their computers and their switching controls. The wires go out to your house and my house where there's a telephone. If your telephone's not working, something's has malfunctioned at the control center. You can take the telephone apart and try to figure what's wrong, and what are you going to find? Nothing. You can look at the telephone wire and try to figure out if there's something wrong and you won't find anything wrong with the wire. You can go to each person's house and do the same thing. But you won't find anything because the problem is in the control center."

"If you invoke the problem in the control center of all these physical symptoms (of CFS and FMS) you could explain how it would all malfunction. What system contacts every other part of the body? The nervous system and the blood vessels. Which system is easier to study? The blood vessels -- you can biopsy those. Their function is to form a tube that carries a fluid. We have biopsied the blood vessels and have found no problem there. So that leaves the nervous system. And that is a problem because the nervous system's control center is not as accessible as the blood vessels are. Our nervous system's control center is the brain which is encased in a very impenetrable skull. Furthermore, it has all the functions of a three-story control center in a very small area, which means that everything is very compact. It's like trying to diagnose what's wrong with a computer chip by looking at it."

"We have an input plug and an output plug to our brain. If we do an MRI scan of that brain, what are we going to see? Nothing, most of the time. We have to go at the problem indirectly. Most researchers recognize that the problem with chronic fatigue syndrome and fibromyalgia is in the control center."

"In what part of the brain do these problems exist? We know that it's not the outer part. We all know that the brain has control over virtually every system. We think that the problem in CFS and FMS is in a dysfunction in one or more of the control centers. What I'm going to do is take an example of a manifestation and show you how we have come to think that one of the control centers is probably responsible."

"For the first example, let's take the GI tract. How can the intestines and the stomach be controlled by the brain? Anyone who has taken a test or given a talk and gotten nervous standing up in front of a group of people knows that the brain has control over the rest of the body. Some people get diarrhea or nausea or sweat before a performance. This is central nervous system emotion control of peripheral organs. That tells you right there that there has to be a connection. Of course, it works both ways. The spinal cord has plenty of signals coming down from the brain, but you have to remember that the brain can only do what it's told. It can only react to what's going on peripherally down in the organs. So there's also a traffic of information coming up. And that becomes very important when we talk about pain. Irritable bowel syndrome is a common complaint in fibromyalgia and pretty common in chronic fatigue syndrome. Therefore there is a control center that is very closely wired to the emotional system called the limbic system."

"In the brain, each of the thousands of functions is wired to each of the others. It involves, movement, sight, coordination, memory, etc. In chronic fatigue syndrome, fibromyalgia and chronic pain syndromes, many systems can be messed up. It could be that there is a problem in that particular system or that the input from several other systems is not correct. In any case, multiple systems are going to malfunction - the GI tract, blood pressure control systems, temperature controls systems, weight control systems. That's the way most researchers are thinking about these illnesses, and that's the way they are approaching the study. Is there a single problem that has a ripple effect that affects everything else? Is there a set of problems that affect the control centers? Is it the cross talk? We have very limited knowledge about these questions at this point. In the future, as we get better neuroimaging techniques and better electrophysiological techniques, we can start to figure these things out."

Dr. Malone continued by posing the question, "Now, what about pain? Certainly, in fibromyalgia, pain is the overriding clinical manifestation. All incoming signals have to travel through the thalamus to the cortex of the brain, and one of the jobs of the thalamus is to act as a filter. It's thought that, in fibromyalgia, the thalamic filter is not working correctly. It is constantly being bombarded by sensory input, light touch input and temperature input, all the time, most of which is filtered out. But if I step on a tack while I am walking up here to talk to you, that becomes very important -- it is traveling with all the other information, but it is more important to my survival. The thalamus has to be able to push that up to my consciousness and say, 'Hey, you just stepped on a tack. Pull your foot away and react.' The thalamus has to be able to send up that message and filter everything else out."

"In fibromyalgia, that filter isn't working, and it's not working to the degree that non-noxious stimuli get transmitted up to the cortex as being painful. It's not too difficult to understand how a person with fibromyalgia can have total-body pain without even being touched. I have patients where I can press on their shoulder muscle with one kilogram of pressure, and they have major pain. (Four kilograms of pressure is enough to turn your finger tip white when you press on a table.) In fact, this is pain. If you think it hurts, it hurts. In 97% of the female population of North America, one kilogram of pressure is not enough to cause pain, but in 3% of the population, who have fibromyalgia, one kilogram of pressure can cause pain. It's a central nervous system malfunction."

"All of these central control centers are in the same region of the brain. Why is depression so common in fibromyalgia and chronic fatigue syndrome? The limbic system is very close by and is closely wired to the sensory systems. Whatever parts of that central nervous system are not working correctly are going to cause clinical manifestations. Why is this so difficult for most of the medical community to accept than other neurologic diseases? Probably because the output is subjective. It is hard to measure. 'I'm fatigued.' 'I hurt.' How do you measure these? It's very easy to measure the neurological malfunction if you have Parkinson's Disease because it affects one of the motor control centers. The tremor can be measured. Fibromyalgia and chronic fatigue are also control center malfunctions, just a different one -- a much more difficult one to measure."

"If you do an MRI on someone with Parkinson's Disease, do you know what you find? No abnormality. So when someone tells you that your head MRI is normal and there can't be anything wrong with you, that's nonsense. All that tells you is that the test we have used is not sensitive enough to detect an abnormality or is not the right test."

"Nerve cells talk to each other electrochemically. At the junction, called a synapse, there is set of electrochemical reactions that allows the current to go from one nerve cell to another nerve cell. That's how the whole nervous system works. Anything that disrupts this function could result in a malfunction of the circuit. It will appear normal microscopically and normal on the MRI. And since we can't stick probes into peoples' brain stems to measure current flow along these circuits, we have a poor way of evaluating the function other than to note what the output is."

"What are some of the things that have been found? The research really started in earnest when people realized that this must be a brain disease. So they started looking at the endocrine. What are some of the hard evidences that have been found to mobilize these lesions or malfunctions to the brain stem? We know that in 2/3 of fibromyalgia patients (and I have no doubt that if we looked at CFS patients we would find a high percentage as well), have low growth hormone. Growth hormone is important for bone mineral density -- how much calcium you have in your bones. It has many other functions as well. It promotes muscle development; it protects against the development of coronary atherosclerosis. And growth hormone secretion is completely controlled by the central nervous system."

"We've studied a lot of endocrine hormones involved with the stress system. That involves cortisol and its control hormones. Again, what causes the secretion of cortisol, which actually comes from the adrenal gland, are signals from the pituitary gland. The pituitary gland gets its signals from the hypothalamus. The endocrine system has most of its control centers up in the central nervous system. We know that the secretion of cortisol, if you look at it over a whole day, isn't different from normal. But cortisol isn't secreted in a constant fashion. It goes up and down and has close ties with circadian rhythms which are the biorhythms that govern sleep, wakefulness, menstrual cycles and many other things. So the nature of cortisol secretion has been found to be quite abnormal in patients with chronic fatigue syndrome and fibromyalgia."

"If you look at the makeup of this audience, you will see that it's four-or-five-to-one, females to males. That's because there are that many more females than males who have the disease. Obviously, there must be some role of the sex hormones in this whole thing, which are controlled by the brain. The testes and ovaries that secrete these hormones are peripheral, and when you biopsy test them, there is nothing wrong with them. It's the control center that isn't working. This has all been shown to be true."

"What about sleep? If you take a rat, and you deprive a rat of sleep for a long time, the rat begins to lose its hair, get infected and behave in a very different fashion, and within several weeks, the rat is dead. That proves that sleep, in higher organisms, is a very important thing. Unless this brain of ours gets proper sleep, it malfunctions in a major way. It also tells you that bad things happen peripherally -- hair falls out, infections appear, etc. We have some understanding of what controls sleep. Most of the controls of sleep rhythms are in the central nervous system. Other areas of the brain open what is called, sleep gates. In normal people, sleep gates open between nine and midnight and about four in the afternoon, which explains why even people without CFS or FMS get a little sleepy at that time. People who take siestas are just succumbing to their biorhythms."

"When you go to sleep, you go into stage 1 pretty quickly, and then stages 2, 3, 4 and REM, and then you come back up and spend some time in stage 3 or 4. Stages 3 and 4 are considered to be restorative phases of sleep -- very deep sleep. It's the lack of these two stages that appears to kill the rats. Fibromyalgia and CFS patients spend virtually no time in stage 3 or 4 sleep. They bounce up and down between stage 1 and 2 and REM and wakefulness. Every two hours, you wake up, and you can't get back to sleep. The biorhythms that control sleep are messed up. We don't have the chemical knowledge of how it's messed up."

"The immune system is an area that is exploding in terms of its importance and its breadth of knowledge in the research community. There is an emerging of neuroimmunology founded on certain facts. There is clearly a connection between the central nervous system and the immune system. What's the evidence? First of all, certain neurotransmitters (chemical signals which allow current to flow between nerves) such as dopamine and seratonin have receptors on lymphocytes. There are receptors for those neurotransmitters in lymph nodes and in the spleen. Those are immuno-competent organs -- organs that are very important in the immune system function. It is clear that interleukin-1, a cytokine, causes fever. When you get an infection, the immune cells get activated and start secreting all these different chemical messengers to elicit a body-wide response, one of which is fever. Where is fever generated? In the central nervous system. That's just one of hundreds of examples of a cytokine that can act as a neurotransmitter."

"Do I see chronic fatigue syndrome or fibromyalgia as a static or dynamic disorder? Do we experience differing plateaus that change over the years? Certainly. I view it as a dynamic process in that symptoms wax and wane depending on a lot of factors -- stressors, the weather, menstrual cycles, etc. In some people, it gets worse with time, and in others it seems to plateau and remain about the same. Dr. Jay Goldstein tries one medicine after another to try to affect neurotransmitters. If one works, you stay with that one."

"What about weight gain? In the brain stem, there appears to be a set of weight control centers that, as a thermostat acts, they act. Everybody has a thermostat that governs how they handle calories. You can handle calories one of two ways. You can make heat or you can make fat. There appears to b a center in the brain that, probably chemically, affects what the balance is swinging toward -- heat or fat. Some of these chemicals are starting to be identified now. That's why phen-fen worked -- because it affected dopamine and seratonin. Along with improving fibromyalgia, it also had an effect on that weight control center that shifted it from fat toward heat. So, weight came tumbling off of people as fast as if they had not eaten at all. It wasn't necessarily related to appetite suppression. The average weight loss continued for about six months." Ì