PHOENIX RISING

Why is this update important? Since many if not most CFS patients already know of or have tried Isoprinosine it’s efficacy (or lack thereof) is not news to CFS patients. What is news is the commitment of a company that to go through the rigors of the testing process to get approval of this drug for CFS. The official approval of any non-psychiatric drug for CFS is big news for CFS patients; these drugs help to chip away at the paradigm of CFS as a psychological disorder and make it more difficult for advocates of that theory to state (falsely) that only CBT therapy has been proven to help CFS patients. They also give normal doctors an ‘in’ to CFS treatment that involves immunology not psychology. In short they help to begin to turn around the medical thinking on CFS.

Diaz-Mitoma, F., Turgonyi, E., Kumar, A. Lim, W., Larocque, L. and B. Hyde. 2003. Clinical Improvement in Chronic Fatigue Syndrome is associated with enhanced natural killer cell-mediated cytotoxicity: the results of a pilot study with Isoprinosine. Journal of Chronic Fatigue Syndrome 11.

"Project Day Lily tells the story of the discovery that men and women of our Armed Forces were actually exposed to chemical and biological mixtures from missiles and sprayers during the Gulf War that were supplied, in part, by a sinister network using a group of rogue bureaucrats, intelligence operatives and scientists. (Strong Words!). Project Day Lily presents the story of how one of these biological agents was found by two American scientists in veterans of the Gulf War and in civilians as part of a massive testing program and how various academic and governmental employees did everything in their power to prevent this information from being released to the American public."

"The Nicolsons are great storytellers of intrigue and menace in the scientific research world. Breaking the mold of traditional suspense novels, Project Day Lily is based on fact ….It is a fascinating, absorbing, eye-opening page-turner. Project Day Lily has alerted me of the danger that public policy could easily become the captive of the scientific technologically elite….And God help those of us who are unsuspecting victims!"

Sharon Briggs, M.S.N., R.N., Mycoplasma Support, Shasta CFIDS - "I received the very first draft and read it with increasing amazement as I was going along. I knew Garth Nicolson from his days at the Salk Institute and knew he was (is) of sound mind. The implications, medical and political, of what is revealed in "Project Day Lily" are major. If you are interested in Chronic Fatigue Syndrome, Fibromyalgia, or the problems of our Veterans with Gulf War Syndrome, you will want to read this book, think, and wonder.

Gerald Schumacher, Colonel, U.S. Army Special Forces (ret) "….I dismissed the reports of Gulf War Illness. That is, until soldiers in my command and their families developed illnesses that could only be attributed to their service in the Gulf or their association with people and material that had been returned from Iraq. In my search for the truth, I met Dr. Garth Nicolson. He was a lone, and much maligned, voice in the quest for a cure. Project Day Lily is a riveting and profound essay on what really happened.  It’s time the public knew."

To read an excerpt from the first chapter click here. Website: http://www.projectdaylily.com/

A – several difference making papers on CFS pathophysiology

D – 1 or no important papers on CFS pathophysiology but several on other aspects of CFS

F – no important papers on CFS

This important paper begins to explain one of the more paradoxical aspects of postural tachycardia (POTS) and CFS patients – how they could have both low blood volume and low renin and low aldersterone levels. The renin-aldosterone-angiotensin system (RAS), one of the fundamental regulators of blood volume, is usually activated when blood volume falls below a certain point. In POTS and therefore some CFS patients renin and aldosterone not only are not increased, they are actually lower than normal. These are findings indicative of people who have high not low blood volume.

These studies involve a subset of POTS patients called ‘low-flow’. Low flow POTS patients have increased vasoconstriction (narrowed blood vessels), reduced blood flows to the extremities and low blood volume. Like all POTS patients they become particularly symptomatic upon standing but in the laboratory exhibit vascular abnormalities even when lying down.

POTS and perhaps CFS is all about blood flow and circulation; research into POTS circles around the questions of why some POTS patients have low blood volume (and thus blood flow) and why all POTS patient have problems with circulation. The inability of the blood vessels of low-flow POTS patients to open wide enough results in poor circulation to the legs leaving them often cool to the touch and with a mottled appearance.

The renin-aldosterone-angiotensin system - Reduced blood volume usually stimulates the kidneys to produce an enzyme called renin which induces angiotensinogen to produce angiotensin I. Angiotensin I is then converted by an angiotensin converting enzyme (ACE) to angiotensin II, which prompts the adrenal glands to produce a hormone called aldosterone. Aldosterone increases blood volume by increasing sodium retention in the blood.

Study Findings - This study found that low-flow POTS patients had significantly (P<.01) increased angiotensin levels and significantly decreased blood volume. One would, in fact, expect this to be the case – low blood flows to the kidneys should have prompted, as noted above, a process leading to increased angiotensin II levels. The problem was that both renin – the putative upregulator of angiotensin - and aldosterone - the actual agent that increases blood volume - levels were low. The two questions Stewart was faced with were (1) how did Ang II levels get so high in the face of normal levels of renin and (2) why did Ang II not prompt the adrenals to produce aldosterone?

Stewart dispatches the first question fairly quickly; athough increased renin levels usually drive and are correlated with increased Ang II levels, they can also, in a negative internal feedback loop, end up inhibiting renin production. This perhaps suggests that chronically elevated renin levels result in a chronic down regulation of renin. But then how did Ang II get high?

The more important question is why increased Ang II levels do not result in increased aldosterone production and increased blood volume. Stewart suggests one of two problems could be involved; (1) decreased or improperly functioning angiotensin I receptors (AT 1) may be inhibiting Ang II’s message from getting through or (2) that there is a problem with ‘sodium loading’. He speculates that chronically elevated Ang II levels may have resulted in a down regulation of the angiotensin receptors (AT-1) receptors on the adrenal glands.

The process of receptor down regulation in response to chronically high levels of its activator, or the obverse, receptor up regulation in response to low levels of its activator, is a commonly occurring process in the body. No explanations are given regarding ‘sodium loading’ but this presumably refers to increased sodium intake or levels that in a negative feedback loop inhibit aldosterone production in order to ward off further sodium loading. Since aldosterone achieves increased blood volume by increasing sodium retention it makes sense it would be sensitive to sodium levels. Stewart does not believe sodium loading plays a role but acknowledges the need to control for sodium intake in further studies.

This study examined five different aspects of blood vessel vasodilation. Surprisingly the low-flow POTS patients displayed normal reactions to all of them (!). Stewart indicates this means they have a normal capability for smooth muscle vasodilation and that their ‘resistance vessel architecture’ was normal; in short the mechanics of their vasodilatory responses was fine. What, then, could be causing the low blood flows found in the extremities of these patients?

A last set of experiments examined how the skin responds to local heating. The body removes excess heat through increasing blood flows to the extremities. Studies have shown that the blood vessels in the skin respond to heat with a two-part vasodilatory response; first an initial peak in blood flow occurs, declines briefly, and then rises again. The first peak is derived from an inflammatory response and the second largely results from NO production. This study found that while both groups had the same initial reaction to heating the low-flow POTS patients had displayed a greatly reduced plateau in blood flow during the second part of response induced by NO. The circulation problems and orthostatic intolerance in low-flow POTS patients, appear then, to be due with abnormalities in the NO mediated vasodilation.

Piecing It All Together; Is– Low Flow Pots (and CFS?) a Disease of Altered Angiotensin II Production? - Several pieces that fall into place with this second paper allow Stewart to introduce a fascinating theory. This theory places increased Ang II levels at the heart of the vascular problems in low-flow POTS patients and perhaps many CFS patients as well.

The adrenals are only one of the organs that Ang II interacts with. Ang II also prompts the smooth muscles lining the blood vessels to constrict and reduce blood flow to the tissues. Stewart, not surprisingly, posits that high Ang II levels cause the increased vasoconstriction and reduced blood flows found in low-flow POTS patients. Ang II’s ability to increase norepinephrine release by binding to the receptors on SNS nerves could result in further vasoconstriction in the blood vessels of the body. Studies have reported decreased blood flows to the brain, muscles and extremities in CFS.

Besides shutting down blood flows Ang II also increases oxidative stress through its activation of NADPH oxidase. NADPH oxidase produces superoxide which is able to readily bind to nitric oxide to produce peroxynyitrite. This can cause a problem with blood flow because if nitric oxide, which is, as we have just seen, an important vasodilator, is taken up then blood vessel diameter will stay constricted. Stewart posits that the induction of NADPH oxidase by Ang II produces enough superoxide to dramatically reduce the NO levels in the blood vessels of these patients. Ang II, thus, is the cause of the impaired vasodilation response.

Increased Ang II levels then could contribute to the low blood flows, orthostatic intolerance and oxidative stress seen in CFS. Ang II also plays a key role in heart failure – a finding Dr. Cheney believes is common in CFS. (To read the Cheney report by Carol Sieverling click here. For more information on cardiac studies in CFS patients click here).

There is on more twist to this story. By reducing the volume of the blood vessels vasoconstriction usually results in increased blood pressure, something neither POTS nor CFS patient normally exhibit. Stewarts explains the lack of high blood pressure in POTS patients (and CFS patients) by noting that the low blood volume in these POTS results in reduced cardiac output and therefore normal blood pressure. Since high blood pressure is a risk factor for heart failure one wonders if low blood volume could be why, if CFS patients do have heart failure, they progress so slowly with it? Patients with heart failure usually have high not low blood volume and commonly take measures to reduce it.

Note that the findings of this paper are limited to those with one kind of POTS – low-flow POTS. A significant number of CFS patients have POTS but it is unclear what percentage have low flow POTS. But what about CFS patients in general – has anyone measured Ang II levels in CFS patients? As a matter of fact someone has. Twelve years ago two sarcoidosis researchers, Lieberman and Bell, found that 80% of CFS patients had elevated levels of the angiotensin converting enzyme (ACE) and suggested that increased serum ACE levels could be a useful marker for CFS! This study, like many other apparently successful ones, was never followed up on (Lieberman and Bell 1993). ACE and angiotensin appear to play a major role in sarcoidosis.

There is, however, one proviso to this paper. The number of low-flow POTS patients were very small (n=10) and only half of them exhibited high angiotensin levels. This study obviously needs to be expanded and replicated, two things given Dr. Stewart’s prolific publishing in the last five years, one imagines and hopes are already underway.

 #2 - Local vasoconstriction in Postural Tachycardia Syndrome; the goal is to determine whether endothelial dependent abnormalities account for local flow disturbances in postural tachycardia syndrome in young people (7/1/04-8/30/09) 

Reports of infectious events shortly preceding cases of temporal mandibular disorder (TMD) have lead researchers to question whether temporal mandibular disorder (TMD), like CFS, can be triggered by a pathogen. Recent studies have found increased rates of TMD in CFS. A 1998 study finding a symptom commonly found in CFS, muscoskeletal pain, was increased in patients with higher levels of coagulase negative staphyloccus bacteria (CoNS), suggested CoNS could be the cause of the jaw pain and TMD found in CFS patients. These findings were buttressed by a 2002 study indicating that staphyloccal vaccine therapy resulted in significantly reduced symptoms in CFS patients (Zachrisson et. al. 2002). The etiology of TMD is unclear but a recent report indicated that levels of methemoglobin, a breakdown product associated with oxidative stress, was associated with jaw muscle pain in CFS patients.

Most coagulase negative staphyloccus bacteria (CoNS) are commensal bacteria that pose no threat to humans. Some, however, including the commensals can be pathogenic under the right conditions. The bacteria examined in these papers are particularly intriguing given the recent findings of increased oxidative stress in CFS. Referred to as ‘membrane damaging toxin producing coagulase-negative Staphyloccus, readers of the last newsletter may remember that cell membranes are a favorite target of free radicals.

These studies examined whether markers of oxidative stress and/or CoNS bacteria were associated with the TMD or facial pain occurring in CFS patients. Besides testing for the presence of CoNS bacteria these studies made various measures of antioxidant capacity (glutathione – GSH) and oxidative stress (malondialdehyde, DPG, methemoglobin, total iron, total iron binding capacity, ferritin) and red blood cell status (hemoglobin, hematocrit, etc.) in the blood of CFS patients. Like cell membranes, red blood cells are frequently attacked by free radicals. Nitric oxide, bacterial toxins and pharmaceutical drugs can all induce MetHb production.

Study Findings – The increased facial pain both in CFS patients and controls was associated with CoNS toxin levels. The studies also found that face pain and TMJ clicking was associated with several markers of increased oxidative stress indicating lipid peroxidation (membrane damage – malondialdehyde) and red blood cell oxidation (methemoglobin, ferritin). Malondialdehyde is a decomposition product formed during lipid peroxidation. A regression analysis indicated methemoglobin was the principal factor associated with jaw pain and TMD. While oxidative stress levels in these patients were increased antioxidant levels (glutathione) were not significantly decreased. (CFS patients with TMJ clicking (but not face pain) had significantly increased glutathione levels).

Red blood cells have long been of interest in CFS. As early as 1987 red blood cell morphology in CFS patients was shown to be altered. Other studies, one as recent as 2000, have confirmed aberrant red blood cell morphology in CFS. Dr. Cheney has demonstrated poor oxygen delivery in erythrocytes in CFS patients.

This report from Portugal by Daniela Martins initiates an occasional series of reports from around the world that look at the conditions CFS patients face in their efforts to become well. These reports examine the prevailing attitudes to CFS, the availability of medical care, government assistance, etc.

A. Well, ME / CFS is becoming something the general population has vaguely heard of, thanks to our National Association’s efforts and, consequently, to media coverage. It's a recent thing; started about 3 years ago but when people do refer to ME / CFS, including doctors, more often than not they’ll just say ‘chronic fatigue’. 

In the 10 years that I've lived in Portugal (I grew up in Australia, where I got ill and also where I was diagnosed) I've found it EXTREMELY difficult to find a doctor who:

a) had actually heard of ME / CFS

b) would take it seriously

c) wouldn't blame all my symptoms on depression

d) wouldn't regard ME / CFS as being an ailment of psychosomatic origin

In contrast to Fibromyalgia awareness, ME / CFS (and consequently those who have it) has greatly been left behind.  Also the name CFS doesn't help:  it so trivialises this illness that I'm quite reluctant to tell people I have Chronic Fatigue Syndrome; they’ll just reduce it to "fatigue". When I do tell people, they will mostly look at me weird, or ask me (as teacher of mine recently did) if I'm getting enough sleep and eating properly, cause that's really important, etc...  Not only does their perception of me totally change, but also they totally do not understand the gravity of my illness. They don’t see the whole; they see very tiny. Again, I really believe the name itself plays an important role in people's perceptions and misconceptions of this serious (therefore not to be taken lightly) condition.  Semantics is a powerful thing.  Overall, I think ME / CFS is not taken seriously in Portugal at all, including amongst great part of the medical population.  We are way behind where this is concerned.

No, Cort.  Sadly, in Portugal even people with illnesses such as Multiple Sclerosis have quite a hard time getting government support.  In order to be able to retire due to disability you have to go through an extremely long, bureaucratic and stressful process often with no guarantee that you will be granted disability support (which in this case, would be permanent).  If you are granted this disability pension, it is ALWAYS calculated according to the number of years you have worked, so if you were never well enough to work in the first place you will get a monthly check that won't cover even food expenses. But this is for conditions that are recognised by our health system as being "legitimate" illnesses.  ME / CFS and Fibromyalgia don't have this status, so there is no government support in our cases. We are not entitled to Sickness Allowance nor are we entitled to Disability Support Pension (I’m using Australian terms because I’m not familiar with the equivalent US terms). What many people do when they are too ill to work, is get a doctor's certificate saying that they are depressed.  This way they get a temporary pension. It's their only option, really. But this goes for any situation; it's not specific to ME / CFS or Fibromyalgia patients.  So, basically depression is recognized as being a disability. ME / CFS isn't at all!

Nonetheless, and to be fair, I have to say that more and more doctors are starting to take ME / CFS seriously and seeing that this is an illness with biological underpinnings and a serious one at that. There are doctors who genuinely want to help, want to alleviate the suffering PWCs / PWMEs go through but may not have the necessary knowledge to do so. In rarer cases, doctors are knowledgeable of this ailment. I’m very lucky to have a family doctor who believes I’m ill and that this is a serious and often very incapacitating illness and who tries to help me.

Overall, I do feel progress is being made but at a snail's pace.

A.  Treatments are almost exclusively aimed at reducing and managing pain, addressing sleep disorders and cognitive issues; so muscle relaxants, sleeping pills, and also antidepressants are often prescribed, among others. I feel there is little knowledge of treatment plans for ME / CFS. Personally, due to previous lack of support and understanding from doctors I have to admit that I've often resorted to self-medication.  I'm aware this is not the best option.  The problem is the range of options available.  I mean I really love that Hippocrates quotation:  "Healing is a matter of time, but it is also sometimes a matter of opportunity".  The big issue is that a great deal of opportunities to heal are not being made available in Portugal, partly because doctors don't know, don't care or don't have time for you and your complaints. Another issue is not having access to some medications and supplements that are being used to treat ME / CFS in countries such as the US.  Not having them be commercialized in Portugal, one might be tempted to order them online from another country.  This is a really bad option!  Customs and our equivalent to the American FDA are so strict and there is just so much bureaucracy involved that the stress of it all is may very well not be worth it!

Where traditional physicians are concerned, a Fibromyalgia or an ME / CFS diagnosis is still too often seen as a "wastebasket" diagnosis.  Fibromyalgia not as much because of the tender points. It tends to be taken more seriously. ME / CFS patients definitely get the worst deal; not only are the diagnosis (when patients are lucky enough to get one in the first place) often treated as a "wastebasket" solution but also patients are kind of seen as being "basket cases" themselves. 

A. No, there isn't really much research going on in Portugal.  There were I think a couple of unsuccessful attempts. We just don't have the resources for proper research. I feel that we desperately need to raise not only awareness but funds. So fund-raising for proper research is key.

Daniela Martins

Coimbra, Portugal

(To contribute your own experiences of life with CFS in another country please e-mail me at phoenixcfs@yahoo.com)

I started my trip in an apt fashion. Feeling rather anxious – I had not driven the car for more than a half-hour in almost 5 months – for the first time in memory I pulled the gas hose from the tank before it was done sending gas cascading over the car. After a break to let the fumes dissipate I was back on the road. I was okay for the first 45 minutes, felt sick at about an hour, was okay at 2 hours and was nauseous but happy as I settled into camp after about three hours.

Bad Night #1 –I wrapped myself up in what linen I had then rolled myself up in a tarp and settled down for a cold and restless night. I was happy, although I had gotten sick the car, I thought, was fixed and my long ordeal with it was over.

Bad Night #2 - Upon starting out the next day the nausea quickly returned, however, and remained present throughout most of the rest of the trip. No the car was not fixed, it was better but still not fixed.

Because my father, like my sister, has made the very bad choice of situating his house near a golf course, I have never been able to tolerate spending the night there and always head out to one of two spots. The one closer to the house is out in the pristine desert but I’ve had troubles sleeping there possibly because of a mine nearby. The further one has been used by several generations of Las Vegans as a dumping site, shooting range and off-road vehicle course but I’ve always done fine there.

I found some linen at the house, bought some more from the thrift store and headed out to the closer more pristine site. I did okay the first night but woke up after the second exhausted with itchy eyes and difficulty taking deep breaths. That day and the families big get together passed in something of a haze. Unfortunately the get together culminated in a dinner in a carpeted room. After about 15 minutes in the room I could the fog settle into my brain; I began having trouble speaking – after starting my sentences I couldn’t get to the end of them and wandered about flailing for words, I had trouble concentrating on what others were saying, my jokes fell flat, sometimes it seemed I was speaking too loudly, other times it seemed like everybody else was too loud. In short I felt awkward and out of place and ended up struggling through yet another difficult family get-together. These get-togethers in my earlier years with CFS sometimes left me near tears with frustration at my mental slowness and awkward behavior. By now my expectations were lowered – something to try and forget and move on.

Bad Night #3 - I headed out to my good site - the beaten up dumping grounds for Las Vegans but had another bad night. After 10 or so hours in the car my clothes had become saturated with whatever bothered me in the car – another entirely foreseeable problem. As I settled into bed my breathing became tight and constricted as the ‘poison’ began seeping into my body.

Bad Night #4 - The next day, spying my cargo carrier in the garage, I put everything in that and on top of the car….and had ANOTHER bad night. Yet again I had made another stupid mistake. During the six months the cargo bag had sat in the garage next to the car and my father’s painting area it had slowly absorbed all the fumes and odors in the garage. The short 25 minute trip in the carrier was all that was needed to contaminate everything in it. I knew better than that!

Bad Nights #5 and 6 - The next day the weather suddenly turned shockingly cold with a vicious wind blowing out of the north. Still lacking in linen I was in no way prepared for a night like that. With the heat turned off I spent the night in the house sleeping fairly well but emerging groggy and wiped out the next day. The next night was even colder but the wind was down and finding more linen I spent the night outside of the house. This seemed to go okay but after two days sleeping at the house I was exhausted and more importantly my sensitivities has risen greatly. It didn’t help that every heating system in the city had jacked up its heating systems permeating them with what was for me, rather toxic product, natural gas. This time, however, fortified with even more linen, I made it out to the desert where I spent a cold but mostly satisfactory night.

Bad Night #7 – Theoretically things should have been fine – I was in a good spot, my linen was clean and I was now pretty warm but 5 months away from the desert had rendered me somewhat stupid. Since I got MCS I have become intensely sensitive to aromatic plants. I can’t spend much time around the eucalyptus trees that dot Southern California, the pine trees in the mountains or the sage brush in the upper desert. I can’t spend more than a day in the mountains or upper desert. Most of the aromatic plants in the lower desert are problems only when it rains but creosote, the main shrub in the southwest is at least mildly aromatic all year long. Although camping near dense stands of creosote has given me headaches and left me exhausted in the past this is just what I did. I camped in a dip (which limited air circulation) containing a moderately dense stand of creosote. The first night was okay but the second left me nauseous and out of it all day long.

Bad Night #7 – After that the trouble seemed to be over. What else could go wrong? I was in a good location with clean linen – I’d basically worked out all the kinks and was finally settled in – I thought. About a week later, however, I made yet another mistake involving my linen. Not wanting to leave my linen in the desert for fear of theft, nor wanting to leave it in the car for long because of the mysterious fumes, I had been driving it to my fathers house and leaving it there. That had worked fine until the golf course or an adjoining yard or somewhere was apparently fertilized. I could feel it when I drove in that day and I knew I risked contaminating it but I still dropped off the linen at the house – it was either that or leave it in the car. The first night was okay but the second time I did this I had another restless night that left me short of breath and tasting fertilizer for half the next day. Now the linen is staying hidden away in the desert hidden - safe at last!

This was a rather unusual series of events in itself but times like this, when I get slammed from one side or another by one unforeseen event after another happens fairly frequently. Life with MCS requires a great deal of attention and scrutiny; it is nothing if not complex.