RESEARCH FORUM REPORT
Adelaide Research Network 3 - 4 June 2005
UNIVERSITY OF ADELAIDE
Convenor: Alison Hunter Memorial FoundationDr Michael Barratt MBBS FRCPA
Medical Adviser, Alison Hunter Memorial Foundation
Forum review: Current perspectives
The keynote speaker was Professor Kenny De Meirleir, Professor of Medicine at the Free University, Brussels, Belgium. His clinic sees 800 CFS patients every three months, coming from many parts of Europe. He has 50 papers awaiting publication about this condition, many dealing with molecular biology as it impinges on aetiology, treatment and prognosis. This article briefly summarizes some of the large amount of current research into CFS presented at the Adelaide forum. Professor De Meirleir presented an epitome of over 5000 research papers on the topic since 1999. This disease has measurable physical abnormalities, contrasting with the dearth of adequate science in psychiatric claims.
- CFS is not primarily a depressive illness, or some sort of psychological problem.
- The abnormalities at the cellular level explain the clinical abnormalities.
- The biochemical and cellular chemistry confirm that CFS is a disorder of immuno-vigilance caused by low grade sepsis and chronic, mostly undiagnosed infection.
- It is a heterogeneous illness, a true syndrome, with a clustering of many symptoms and signs, and a large number of "causes". Especially, it is not a single symptom to be called "chronic fatigue".
- It may turn out that CFS is caused by many different diseases, just as "all that wheezes isn’t asthma".
- There is a chronic over-stimulation of an increasingly dysfunctional immune system: more activity, but less effectiveness.
- Activation of anti-viral pathways plays a central role, especially low molecular weight Ribonuclease L (RNaseL) and Protein Kinase pathways.
- The role of non-viral micro-organisms and even non-biological agents, like insecticides or heavy metal pollution, in activating viral pathways needs to be sorted out.
- The reactivation of latent viruses, and other micro-organisms, involves profound interactions between the brain and immune system.
- The gut is central to the initiation of CFS. Intestinal dysbiosis allows toxins, viruses, bacteria and heavy metals that must not enter the body to do so.
- The blood-brain barrier is defective, allowing molecules that must not enter the brain to do so.
- Herpes viruses play a key role in about 20% of cases with CFS.
- The Final Common Pathway of all the causes of CFS is Dysautonomia, i.e. autonomic nervous system dysfunction.
- CFS is a serious, legitimate illness, devastating to those who have it, with a slow and uncertain recovery for many. The spectrum of disease extends to the wheel chair and the bed bound, and it has a significant mortality, caused both by the often severe effects of the illness and by suicide. The extreme end of the condition is virtually unknown to even the most gifted and caring of the medical profession, who pass the ball to the psychiatrists from where they end up in anorexia or other clinics.
CHRONIC FATIGUE: SYNDROME OR SYMPTOM?
In medicine, a "Case Definition" sets out those symptoms or signs that must be present in a patient to allow a particular diagnosis to be made. Various attempts since 1988 at the Case Definition of abnormal fatigue states have foundered on the vagueness of the word "Fatigue".
Even healthy people get fatigued, physically and mentally, from to time. It is also found in serious illness including AIDS, cancer and major depression. How do we distinguish the pathological fatigue of CFS from ordinary fatigue or numerous fatiguing illnesses?
In 2003, Health Canada convened The Canadian Case Definition Panel for CFS. For the first time, this Expert Panel moved away from making the symptom "Fatigue" the main feature of CFS. Rather, they concentrated on what was unique and central about the fatigue in CFS. It is not that these patients get fatigued. It is that their fatigue, and malaise, is made significantly worse with exercise.
Taking the emphasis away from fatigue as a subjective symptom, one is forced to describe the connection between fatigue and activity. Fatigue also embraces mental fatigue, (impaired cognitive function and alertness), as well as physical fatigue, (lack of energy or strength, often felt in the muscles). However, this specific type of fatigue is always found together with some or many evidences of neuro-cognitive, neuro-endocrine, dysautonomic (e.g. orthostatic intolerance), and immune manifestations, i.e. it is part of a much bigger "Syndrome". (Gk. Syn: together, Dromos: a race track, hence: a running or clustering together, a bit like the Tour de France bicycle pack.) The essential feature of the fatigue of CFS is that the patient becomes worse after even minor exercise, (e.g. putting out the garbage bin), and this persists, usually for at least 24 hours, but sometimes for days or weeks. Interestingly, the onset of the severe fatigue may sometimes occur hours after the trivial exertion, or even the next day, but with the same devastating mental and physical exhaustion.
Sometimes, as a result of earlier Case Definitions numerous diseases were lumped together that had little or nothing to do with each other, apart from exhibiting fatigue to some degree. For example, depression and CFS became, in many peoples mind the reverse and obverse of the same coin.
The Canadian Case Definition also clearly distinguishes between Symptom and Syndrome. Indeed, a symptom may be part of a Syndrome, but a Syndrome may never be reduced to a single Symptom.
According to the Canadian panel, who between them have managed over 20,000 CFS patients, the Syndrome of CFS may be defined as: a significant degree of new onset, unexplained, persistent or recurrent physical and mental fatigue; that significantly reduces ones level of activity; that with trivial exertion causes a disproportionately increased muscular and cognitive fatigability; that, as well, is associated with the worsening of co-existing neuro-immuno-endocrine symptoms; that has a pathologically slow recovery period, usually 24 hours or longer; and that has been present for more than six months.
Though this is not quite the complete Canadian definition, even this should be enough to distinguish, say, an alcoholic hangover from a potentially lethal illness like CFS that sometimes may be confused with multiple sclerosis. Also, thankfully, we can now all be talking about the same illness and not confusing it with "clinical depression".
THE CENTRAL ROLE OF A DYSREGULATED, 2-5 OLIGOADENYLATE SYNTHETASE-RIBONUCLEASE L (2-5A synthetase/ RNaseL), INTERFERON INDUCED, ANTI-VIRAL DEFENSE PATHWAY IN CFS.
In 1957, it was discovered that when a virus infests a cell the "interferon" pathway is activated to destroy (interfere with) the virus. It is now known that at least 200 molecules and cytokines, (immuno-regulatory substances that are secreted by cells of the immune system) are involved in this defensive ploy. The interferon pathway repulses the virus by activating a molecule in peripheral blood monocytes called Ribonuclease L (RNaseL) This destroys viral Ribose Nucleic Acid (RNA) within the cell, and at the same time triggers the removal of the infected cell by inducing programmed cell death (apoptosis, Greek, "meaning a falling away from," i.e. a falling off the planet for that particular cell). RNaseL is normally inactive within the cell, so that it cannot damage the large amount of native RNA essential for normal cell function. (Remember the mantra chanted by students of biochemistry: "DNA makes RNA, RNA makes protein.)
Inactive RNaseL is "up regulated", as the Americans say, by another, smaller, effecter molecule called 2-5 Oligo-Adenylate Synthetase, (2-5 OAS). This newly activated RNaseL enzyme destroys the viral RNA, acting like a pair of scissors snipping a paper streamer. Once its mission is finished, it must immediately "switch off", to avoid damage to the normal cell.
Normally, inactive RNaseL has a molecular weight of 80 kilo Daltons, or 80 kDa, (80,000 in the older terminology). In 1997 it was discovered that in CFS, and only in CFS, the 80 kDa molecule is partially or totally replaced by a different, but defective RNaseL molecule with a molecular weight (MW) of 37 kDa. The more of this low MW 37 kDa molecule that is present, the more severe is the CFS clinically. This is well shown in Figure 1. This, incidentally, is difficult to explain if CFS is primarily a depressive illness.
When 2-5 OAS activates the abnormal LMW 37kDA RNaseL a destructive "rogue molecule" is let loose. This molecule is extra-ordinarily active, more that six times that of the usual, activated 80kDa RNaseL one. Because it resists enzymes that destroy proteins, (proteases) it has a deadly property, it does not switch off! It persists in the cell, "snipping away" at normal protein synthesis, enzyme production and numerous other vital cellular functions. This destructive molecule also consumes enormous amounts of Adenosine Tri-Phosphate, (ATP), the molecule that provides energy for the cell. It has been estimated that 70% of the cells energy production is consumed by this abnormal "up-regulation" of the interferon pathway. This has been described as a "black hole" for ATP. Should anyone be surprised that these patients are fatigued?
Low MW RNaseL fragments also fails to induce apoptosis, keeping the damaged cells alive, and the immune system dysfunctional.
Low MW 37kDa RNaseL was discovered by Dr Bob Suhadolnik and his team at Temple University Medical School, Philadelphia in 1997. This pioneering discovery of a highly abnormal molecule that is not present in patients with cancer, AIDS, multiple sclerosis, clinical depression, malingering, hypochondriasis or normal health has been confirmed independently in five other molecular biological laboratories around the world, (Belgium, France, USAx2, and Tokyo). This work casts serious doubt on commonly held psychological views about the nature of CFS.
Unfortunately, RNaseL assay, performed on peripheral blood monocytes, is a complicated and expensive test. However, it is important to remember that, in 1955, the only method for measuring serum sodium was based on Vogel’s Text Book of Inorganic Chemistry, and took a PhD scientist half a day to perform. Today, a high school, work-experience student can be shown how to get a result in a few minutes. Venite diem, when a nurse can perform a 37 kDa RNaseL dip-stick assay in a side room of a psychiatric ward!
The enzyme that fragments normal 80kDa RNaseL to the low MW 37 kDa RNaseL form is now known to be Elastase. Currently, it is thought that the gene sequence in Low MW RNaseL is normal, but it is only a fragment from the original 80 kDa molecule.
An inflammatory protease (an enzyme that breaks down proteins) that is present in leucocytes and monocytes. The level of elastase activity correlates with fragmentation of RNaseL to an incredibly high degree, (p<10-18, in a series of 50 patients). Professor DeMeirLeir and colleagues have detailed a finding that has exciting implications for the treatment of CFS and multiple sclerosis, which they consider are both chronic immune diseases. Beta-Lactam containing antibiotics such as Cephalosporins and the penicillins are also elastase inhibitors and help restore normal 80 kDa RNaseL levels. The amount of reversion of the 37 kDa molecule is dose dependent. Interestingly, over the years some CFS patients have reported feeling better on antibiotics without any apparent reason. Other antibiotics may have anti-elastase properties. Lycopene, found in tomatoes, besides being useful in prostatic and other carcinomas has an active role in promoting apoptosis, countering the damage done by the 37 kDA molecule.
NATURAL KILLER CELLS (NK CELLS)
These are a subset of lymphocytes that act as a first line of defense against abnormal cells, including damaged and precancerous cells, and cells infected by micro-organisms. Low NK cell numbers are routinely seen in CFS, but may also be seen in a variety of chronic immune diseases including HIV infection, and certain cancers. Again LMW RNaseL assay is a critical discriminator.
PROTEIN KINASE ACTIVITY (PKR)
This is another enzyme specific for RNA destruction, and which is also induced by Interferon. It acts by destroying the continued production of proteins by the virus in an infected cell. It also initiates apoptosis in damaged cells. In CFS, a patient’s continued PKR up-regulation leads to destruction of immune cells, and a dysfunctional immune system. It is an important marker to help differentiate CFS from some forms of multiple sclerosis.
NITRIC OXIDE (NO) DETERMINATION
Nitric oxide is produced by NO synthetase. It is important in regulating certain normal physiological responses such as blood pressure and penile erection. Increased levels over time allow NO to become toxic to cells. In CFS, immune cells produce significantly high NO levels. This is thought to be part of the Elastase story, (see above). There is quite a large group of CFS patients who present with a multiple sclerosis type clinical picture. NO is normal in MS, unlike CFS.
The Belgium researchers believe that damaged fragments of RNaseL and 2-5 OAS impair the transport of ions into and out of cells by interfering with transport protein molecules. Radioactive studies using isotopes of potassium have confirmed that the total body potassium in CFS is significantly lowered in CSF, but not so in clinical depression.
THE LABORATORY INVESTIGATION OF CFS
If DSM IV is correct, it should be possible to diagnose major depression even amongst castaways on a desert island in the absence of sophisticated laboratory testing. However, to diagnose precisely what is going on, if depression is not the primary illness, certainly requires such testing. Even if CFS is strongly suspected it is also essential to exclude certain diseases which would be tragic to miss: Addison’s disease, thyroid deficiency, iron anaemia or iron overload, diabetes mellitus, multiple sclerosis, myasthenia gravis, auto-immune diseases, cardiomyopathy, tuberculosis, sarcoidosis, hepatitis and cancer, to name but a few. Recently discovered mitochondrial based diseases such as MNGIE (Mitochondrial Neuro-Gastric Intestinal Encephalopathy) should remind us that medical science is an exploding universe. Some psychiatrists are advising referring doctors not to investigate CFS patients because this will re-enforce their delusion that they actually have a significant medical condition, rather than a highly elaborated self diagnosis, with symptoms refractory to reassurance, explanation and standard treatment. The question begging behind this dangerously absurd view should be obvious even to a high school student of logic.
A USEFUL DIAGNOSTIC PANEL IN CFS
- LOW MW 37 kDa RNaseL ASSAY
- HUMAN LEUCOCYTE ELASTASE
- PROTEIN KINASE ASSAY
- SERUM NITRIC OXIDE
- SERUM URIC ACID (An index of Purine metabolism)
- NATURAL KILLER CELL (NK) ASSAY
On the basis of these six tests CFS patients tend to fall into three broad groups, sometimes with overlap. These have differing aetiologies, treatment and severities. These are seen in Figure 1, which obviously does not show definite test values, but overall trends. For example, a normal patient has no LMW RNaseL. However the severity of all groups increases as LMW RNase L increases. Levels over 5 units are quite ill. Some patients, moribund with levels of 500 units are still being told their problem is in their heads.
GROUP 1: These have high LMW RNaseL levels, high uric acid, low Protein Kinase, reasonable NK killer cell levels, and low or normal NO.
This group, about 15-20% of CFS sufferers, tends to have a multiple sclerosis type picture. Pain is not a strong feature. They tend to be associated with one or more of a long list of well known suspects, micro-organisms such as, brucellosis, Q fever, cytomegalovirus, glandular fever, Herpes virus 6A, Epstein Barr virus, enteroviruses, Lyme disease, mycobacteria, Leishmaniasis, mycoplasma; and pesticides, and heavy metals, to name but a few members of a vast rogues gallery. A staggering 20% of this group has low grade Herpes virus 6A encephalitis, a little known fact! Treatment is aimed at removing causes, if possible, with antibiotics, and anti-viral therapy, often with the addition of Interferon therapy.
GROUP 2: LMW RNaseL up, PK up or not, Uric acid and NK down a little, NO is up. This group, about 60% of CFS patients, has pain as a predominant feature.
Pain is often generalized and does not follow nerve root distribution. It may be aching, burning, sharp or shooting. Many patients develop many types of new onset headaches, including migraines, tension and pressure headaches. There is often generalized myalgia, and arthralgia. There is an overall reduction in pain threshold, (allodynia). The pain is often triggered by exercise.
This group is referred to as the ME (myalgic encephalopathy) group, in contrast with the Group 1, MS type.
GROUP 3: this severely ill group, about 15% of patients, have very high LMW RNaseL levels, (up to 500 or more), high Protein Kinase activity, very low serum Uric acid, and severely depleted Natural Killer Cell activity.
They usually have severe bowel problems, such as total bowel paresis, or retrograde faecal vomiting. There is a high mortality in this group, sometimes due to suicide. Many of these patients are living in survival mode, and are often abandoned by the medical profession as being in the "too hard basket".
The gut is an important part of the immune system. We must get past the notion that it is only a conveyor belt for nutrients, or some sort of septic tank. If spread out, its surface absorptive area is about the area of the Sydney Cricket Ground! All patients at Professor De Meirleir’s clinic have serum Ig M and Ig A tests against a panel of 12 gut pathogenic bacteria. Any patients with a positive Ig M for any of these are given a cycle of one weeks antibiotics, followed by three weeks probiotics. 58% of patients have improved after three months, and interestingly, the serum Elastase drops.
Group 3 patients also seem to be helped by Isoprinosine, an immuno-stimulator drug which has proved helpful in delaying the onset of AIDS in HIV positive patients.
There is an encouraging support for the validity of these three CFS groupings. Professor De Meirleir took a large number of new CFS patients referred to his clinic and performed all the above six tests before the patients were seen clinically. On the basis of the test results he penciled onto their files his predictions as to their clinical symptoms. He was correct in 95% of the cases! The other 5% had overlap features.
In Sydney in the late 1950's there was an active Flat Earth Society, which used to distribute regular articles outside Sydney University’s main gate trying to convince students that the earth was flat.
At 9.07am, Moscow time, on April 12, 1961, Yuri Gagarin, the son of a rural carpenter, became the first human to be blasted into space. Back on terra firma at 11.55am, in those 168 minutes the Russian had reached an altitude of 381 Kms above the earth and had seen something that no other human being had ever seen, the earth's curvature! The flat earth theorists never recovered from this mortal blow.
Suhadolnik's discovery, in 1997, of a 37 kDa RNaseL molecule, unique to Chronic Fatigue Syndrome, is already changing the common view that CFS is predominantly a psychiatric illness. For some, this may be a difficult adjustment of mind set, like our friends in the Flat Earth Society had to endure. But from this important discovery will come, hopefully, a new era of understanding and treatment of this terrible disease.
1. Suhadolnik RJ, Peterson DL et al. Biochemical Evidence for a novel low molecular weight 2-5A-dependent RNaseL in chronic fatigue syndrome. Journal of Interferon and Cytokine Research 1997; 17:377-385
2. Journal of Chronic Fatigue Syndrome. Myalgic encephalitis/Chronic fatigue syndrome: A clinical working Case Definition. Carruthers, De Meirleir et al. 2003: Vol11, No1: pages 7-116
3. Chronic Fatigue Syndrome: A Biological Approach. De Meirleir K, Engelebienne P. CRC Press
4. R.E.D. Laboratories, Brussels, Belgium. Brochure discussing available diagnostic tests for CFS. (R.E.D. stands for "RNaseL Enzyme Deficiency").
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