PHOENIX RISING

Lately some evidence has been indirectly suggesting that the mitochondria – the energy producers of the cell – are indeed affected in CFS. Several gene expression studies have highlighted mitochondrial genes and evidence from the Dubbo studies suggests that the Epstein-Barr virus may be able to interfere with immune cell energy production. Dr. Pall believes free radicals impair mitochondrial functioning in CFS and the noted CFS researcher/advocate Dr. Komaroff has also come to the opinion that problems with cellular metabolism may be present in CFS.

Teitelbaum points out that there are at least two ways to get the mitochondria to function improperly; either they’re dysfunctional because of an inherent (genetic?) problem or they become damaged when subjected to high levels of ‘metabolic stress’. Metabolic stress occurs when cells are hypoxic or in ischemic environments; i.e. in environments in which they don’t get enough oxygen.

What happens to cells in hypoxic and/or ischemic environments is rather technical. Hypoxic/ischemic environments impair ATP production, a problem the cell combats by using two ADP molecules to make ATP. Unfortunately combining two ADP molecules leaves a phosphate group called AMP (adenosine mono-phosphate) behind that the cell must eliminate. As AMP levels accumulate, the cell breaks it down to its adenine nucleotides which are then flushed out of the cell. Adenosine, however, is a key structural component of ATP and flushing it out of the cell deprives the cell of the very elements it needs to build more ATP. This causes the cell to become energy starved over time.

One way to combat this is to help cells reconstitute these adenosine nucleotides and this is what Dr. Teitelbaum is focusing on. The enzyme that does this is formed out of ribose. Interestingly this enzyme is found in low amounts in the muscles and the heart and this may be why they are most affected in FM and/or CFS.

Study Findings – This study found that D-ribose intake resulted in quite significant improvement in sleep patterns, energy levels, mental clarity, pain threshold and well-being. A closer look shows that these patients were helped quite a bit by D-ribose but were nowhere near being cured; on a scale of 1-10 their energy levels increased from 3.8-5.5, sleep from 4.8-6.0, mental clarity from 4.9-5.7, pain from 4.9-5.6 and well-being from 4.3-5.6. A few side effects were experienced by a small number of patients and these were eliminated by lowering the dose.

Through its contribution to ATP production D-ribose, then, doesn’t fix the problems occurring in CFS - it simply helps the cells cope with the mitochondrial difficulties they have. It does appear to help CFS patients symptomatically, however.

Physicians can help patients battle viral infections in one of two general ways; by using antiviral agents to directly knock the virus down, or by using immune enhancers to boost the patient’s immune response. This study attempted to do the second. These researchers administered a probiotic, Lactobaccilus acidophilus, not to CFS patients, but to overtrained and fatigued athletes in an attempt to boost their immune response to a virus believed to be causing their fatigue.

This study is intriguing in a number of ways. Overtraining syndrome is not the same as CFS but the symptoms are remarkably similar (fatigue, reduced cognition, sore throats, post-exertional fatigue), and overtrained athletes face the same general problem that CFS patients do – an inability to exert themselves at levels they are accustomed to.

The virus under discussion is Epstein-Barr virus (EBV)– a virus CFS researchers have been interested in ever since CFS broke onto the scene in the mid-1980’s. Studies have shown that EBV reactivation often occurs under all kinds of increased stressful conditions (astronauts training, Antarctic winter expeditioners!, army cadets, elite runners). Studies indicate that high levels of exercise inhibit the ability of cytotoxic T-cells to control EBV. Most cases of EBV reactivation are benign and cause no symptoms, but some are not; these researchers believe EBV reactivation is responsible for the fatigue and symptoms seen in these athletes.

Lactobaccillus acidophilus has been shown to boost immune function in clearing candida albicans (yeast; fungal rather than viral) infection. L. acidopholus turns on the toll-like receptors on antigen presenting cells (APC’s) that detect pathogens. APC’s are the main pathogen detectors in the body. Once they have identified a pathogen they alert the cytotoxic T-cells that an attack is underway. L. acidophilus, then, appears to boost the immune alert system.

These researchers gave L. acidophilus to overtrained and healthy athletes for a month while measuring cytotoxic T-cell cytokine secretion and EBV levels.

Study Findings – This study found that the fatigued athletes had more upper respiratory infections, evidence of EBV reactivation, and reduced interferon-y secretions from cytotoxic T-cells. L. acidophilus administration was found to significantly increase the levels of this cytokine. IFN-y is a cytokine produced by T-cells that helps regulate the immune response and that plays an important role in controlling EBV reactivation.

This study suggests that defects in T-cell activity may cause the fatigue in overtraining syndrome. We have seen that CFS patients also have impaired T-cell activity. Recent studies from the Miami group have shown that CFS patients have reduced levels of perforin, the main cytotoxic element of both T-cells and natural killer cells.

Two presentations at the 2007 IACFS conference suggested that L. acidophilus is helpful in CFS. This probiotic is relatively cheap and easily available. Several physicians including Dr. De Meirleir and Dr. Chia, believe that poor intestinal health plays an important role in a subset of CFS patients. The authors suggested expanding this study to include other ‘chronic fatigue illnesses’.

Just on a personal note, I have always thought of acidophilus as a minor treatment and have ignored it for years, but I’ve been taking it regularly for the first time and have been very impressed with its results. Many with CFS have probably tried this supplement but if you haven’t I strongly suggest you do so. As with D-ribose we will look more at this topic in the upcoming 2007 Conference Overview.

It’s not often that three CFS researchers produce papers that espouse the same kind of treatment but this is what recently occurred. In the last several months longtime CFS researchers Dr. Garth Nicolson of the U.S., Dr. Basant Puri of the U.K. and a newcomer, Dr. Maes of Belgium, have published papers promoting the use of lipid replacement therapy (LRT) in CFS. Here we take a detailed look at LRT; what it consists of, what it purports to do and how it works. That each researcher, interestingly, uses LRT for a different purpose, suggests it is a multi-dimensional therapy - one that every CFS patient should try.

Dr. Nicholson focuses on using LRT to reduce oxidative stress levels in CFS. Although much has been made recently of the many inconsistent study results in CFS this does not apply to studies of oxidative stress. Higher than normal levels of oxidative stress have been found in the red blood cells, serum, blood and muscles of CFS patients.

As noted above, oxidants or free radicals are highly attracted to the lipids in our cellular membranes. As they rip electrons out of the formerly stable lipids they release products that trigger an inflammatory reaction that causes more free radicals to be produced. High levels of free radical activity can initiate a self-promoting process called lipid peroxidation which could likened to a free radical wildfire. This can cause the affected cells to trigger their apoptotic or suicide programs. We know higher than normal levels of apoptosis are found in CFS.

There are at least two ways to combat this problem. One is to quickly repair the cellular membranes before major damage is incurred and the lipid peroxidation process is initiated. The second is to optimize membrane health by using lipids that make an inflammatory response less likely once membrane damage has occurred.

The study above involved cancer patients. Cancer is not CFS but there are some interesting parallels. Although most people associate chemotherapy with pain, fatigue is actually the most commonly found and often the most disabling symptom cancer patients face. Dr. Nicholson believes that fatigue in chronic illness is largely caused when reactive oxygen species (ROS) inhibit energy production. ROS are the most common form of free radicals.

Free radical production is also a natural by-product of energy production. This means the mitochondria – already subject to high ROS levels – are particularly vulnerable to further ROS increases. Although ROS can damage membranes throughout the cell Dr. Nicolson believes that people with fatiguing disease are particularly vulnerable to mitochondrial damage. He is not alone in this; other physicians such as Dr. Cheney and Dr. Myhill believe that low ATP production (in the mitochondria) is important in CFS.

This study found that supplementation with the Propax NT lipid replacement product resulted in reduced fatigue, nausea, diarrhea, insomnia, etc. in cancer patients. Another study found that fatigue was reduced by 40% in chronically fatigued (but not CFS) patients. Two recent studies found that both mitochondrial function and fatigue were substantially improved in both moderate and severely fatigued patients and in CFS and FMS patients. This looks like it may be an effective product for some CFS patients.

Dr. Basant Puri of Hammermith Hospital in London has published a series of short papers on the effects of fatty acid (lipid) supplementation in chronic fatigue syndrome and other diseases over the past several years. He has also published a book on CFS that outlines for the public his research and treatment plans for CFS. A pioneer in the use of NMR brain scans in CFS, he believes his (and others’) findings of increased choline levels in the cerebral cortex and basal ganglia of CFS patients probably indicate a central nervous system infection is present. (see Choline on the Brain).

Dr. Puri believes these high choline levels reflect viral interference with the enzyme responsible for putting together the lipids found in our membranes. These phospholipids should have either N-6 or N-3 longchain polyunsaturated fatty acids should be attached to them. If I am reading this correctly, a ‘polar head’ made up of choline, serine, or inositol should be attached at the end of these phospholipids chains.

The enzyme used to synthesize the N-6 and N-3 polyunsaturated acids (delta-6-desaturase) can, however, be inhibited by viruses. Dr. Puri believes that viral activity in the central nervous system of CFS patients leaves choline molecules that would otherwise be attached to these polyunsaturated chains free, and it is these free choline particles are being picked that by these brain scans. This, of course, also suggests that the cellular membranes in these areas may have lower than normal levels of essential fatty acids.

Consequences of low fatty acid levels - why is it important to have adequate levels of polyunsaturated fatty acids in our cellular membranes? It turns out that not all lipids are the same; some lipids are more apt to promote an inflammatory reaction than others. The fatty acid evening primrose oil (EPO) is rich in, for instance, y-linolenic acid, is less likely to be transformed into arachidonic acid (AA) which sits at the beginning of the inflammatory reaction.

Building up levels of ‘good’ lipids that are less likely to be converted to AA could therefore lead to reduced inflammation, oxidative stress, immune activation, etc. Dr. Puri believes this could explain why EPO was reported to be helpful in rheumatoid arthritis patients. Interestingly, the y-linolenic or ‘good’ fatty acid pathway appears to be inhibited in many chronic diseases including viral infections, diabetes, and cardiovascular diseases, as well as aging.

Dr. Puri’s protocol, then, helps CFS patients recover from the damage caused by viral activity in their central nervous system by providing the essential fatty acids the viruses inhibit; it does not bring a halt to the viral activity.

This is not, however, the end of the LRT story. Dr. Puri’s analyses of unrefined evening primrose oil, a source of omega 6 fatty acids, indicate that it contains substances called tripertenes are a) free radical scavengers, and b) inhibit two inflammatory enzymes called cyclo-oxygenase and neutrophil elastase. EPO supplementation, then, appears to be able to reduce inflammation in several ways; by repairing cell membrane damage, by building healthy cell membranes that are less likely to initiate the inflammatory processs when injured, by reducing free radical levels and by inhibiting the inflammatory enzymes.

The Treatment Regime - Dr. Puri uses high-dose eicosapentaeonic (EP) fatty acid supplementation in CFS (10-12 capsules of eye q; 930 mg. EPA (omega 3), 290 mg. docahexanoic acid (omega 6), 100 mg. gamma linolenic acid (omega 6) + 16 mg. Vit. E daily. The sources of these fatty acids are fish oils (omega 3s) and unrefined, cold pressed evening primrose oil (omega 6).

Treatment results - one CFS patient with high fatigue, poor sleep, muscle pain, and ‘low mood’ who was almost totally confined to a wheelchair after six years of CFS began to go into remission about six to eight weeks into the program. At 16 weeks her depression score had dropped from 27 to 3 (!) and she reported that her sleep was much improved. Her muscle pain, however, was unchanged.

Comments from a group of four CFS patients after 12 weeks of therapy ranged from the startling ‘the fogginess of the brain was gone completely’ and the ‘for the first time a feeling of well being was experienced’ to the beneficial ‘I am able to communicate during a relapse.’

Dr. Puri also tells a remarkable story of a 20 year old who in the seven years after the appearance of his depressive symptoms, had not only not responded to anti-depressants, antipsychotics, lithium, paroxetine and hypnosis but had over time become severely suicidal. One month after starting 4 g of eicosapentoaenoic acid a day his unceasing suicidal thoughts had disappeared. Nine months later all his symptoms had disappeared, his depression rating, formerly at 32, was now zero and a brain scan indicated that substantial changes had occurred.

Eye Q – is made by a U.K. company, Equazen. It contains high levels of omega 3 and low levels of omega 6 fatty acids (from evening primrose oil) as well as an antioxidant, vitamin E. You can learn more about Eye Q at http://www.equazen.com/default.aspx?pid=23

Serotonin - Dr. Maes believes the benefits depressed patients derive from LRT come from its ability to re-normalize serotonin activity. Cellular membranes with low omega 3 fatty acids have been shown to have low ‘membrane fluidity’, a condition that can impair the functioning of the many receptors, ion channels, etc. present on them. Maes believes that low omega 3 fatty acid levels in both depression and CFS probably result in reduced serotonin activity.

Fatty Acids and Inflammation – Maes also believes that omega 3 fatty acids have anti-inflammatory effects as well. His 2000 study found that people with low omega 3 fatty acid levels displayed increased production of pro-inflammatory cytokines when they were stressed. Omega 6 fatty acids are known to accelerate the production of the pro-inflammatory cytokines that play a role in increasing oxidative stress levels.

Zinc, Fatty Acids and CFS – Dr. Maes has also found that low omega 3 fatty acid levels and depression are also associated with low zinc levels. Zinc is an important co-factor in the production of the desaturase enzymes that produce the polyunsaturated fatty acids. We have just seen that Dr. Puri believes that central nervous system viruses inhibit these enzymes in CFS patients. Dr. Maes, here, gives us another cause of desaturase inhibition in CFS.

The Study – This study examined a wide range of fatty acids in CFS patients and controls. They included omega 3’s (a-linolenic, eicosapentaenoic, docosahexaenoic), omega 6’s (linoleic, gamma-linolenic, arachidonic), omega 9’s, saturated fatty acids (myristic, palmitic, stearic), monounsaturated fatty acids (palmitoleic, oleic-eladic). He also measured zinc levels and a marker of immune activation (CD 69) found on T-cells.

The study found that CFS patients had low zinc levels, low omega 3/6 ratios and high omega 6 levels relative to healthy controls. All of these findings could be associated with increased inflammation in CFS.

A correlation between low omega 3 levels and a marker (CD 69) indicating a defect in the early T-cell response suggested that low omega 3 levels could play a role in the immune dysfunction seen in CFS. Reduced omega 3 levels were associated with increased fatigue, pain and memory problems. Increased omega 6 levels were associated with irritability, memory problems and muscular tension.

Two studies of the efficacy of LRT therapy in CFS have had mixed results. This studies’ findings suggested why this was so. The high omega 6 levels found in CFS patients suggested they should avoid LRT’s involving high omega 6 levels. The failed LRT study, however, used Efamol, an LRT high in omega 6 fatty acids. The successful trial (Puri’s) used a formulation (‘Eye Q’) which has reduced omega 6 fatty acid levels. Dr. Maes suggests that CFS patients use only LRT formulations that have low or no omega 6 fatty acid levels in them.

The immune system is a finely honed and very complex machine. One part of it increases the powerful immune response called inflammation while another part inhibits inflammation. Too much of one kind of immune response can result in tissue damage and even death while too much of another kind of immune response can result in increased allergy and hypersensitivity reactions. Immunomodulators such as Isoprinosine can play an important role in CFS patients protocols.

Several studies suggest that increased rates of bacterial infection are present in CFS patients. The few antibiotic studies in CFS have had mixed results with some showing real success and others not. Anecdotal reports of antibiotic usefulness are not uncommon. Azithromycin’s immunomodulatory and antibiotic properties make it particularly interesting.

This was a ‘retrograde study’; in it a group of Dutch physicians at a CFS clinic examined the clinical records of 99 CFS patients over a period of five years who had taken Azithromycin (500 mgs. on three consecutive days a week/6 weeks). If found that about 60% of those patients had, in a clinical interview following the treatment, reported ‘improvement’. Except for bowel distress, which was resolved by halving the dose, side effects were negligible. The authors reported that patients reported to recover to approximately 80% of their ‘pre-morbid capacity’. This study seemed a strong validation of the role antibiotics could play in treating CFS.

Despite its positive results there were a number of problems with this study. Although the physicians employed a variety of measures designed to quantitatively assess the extent of CFS disability at the beginning of the study they did not use those tests to assess how effective the antibiotic treatment was at the end of it. Our only assessment of that came in a clinical interview in which the patient rated the change as positive, neutral or negative. The authors report that their patients improved to 80% of capacity but they gave no indication where that number came from and its statistical validity is unclear.

Most antibiotic studies focus their efforts on CFS patients who have clear evidence of bacterial infection. The criteria for inclusion in this study - the ineffectiveness of counseling and L-carnitine therapy - did not screen for infection. Since it is fairly clear that only a subset of patients with CFS have bacterial infections, one would think that this heterogeneity would weaken their protocol’s effectiveness. In fact the high effectiveness reported in this study does not gibe with other reports. Nicolson - who does screen for bacterial infection - has reported the need for, at times, multiple periods of antibiotic use in CFS and GWS, and this is echoed in anecdotal reports.

The CAMDA and Pharmacogenomics CFS studies again and again focused our attention on the adrenal stress hormone cortisol and its triggering agent, corticotropin releasing hormone (factor) (CRH/F). Now this study examines CRH’s relevance to CFS’s sister disorder, fibromyalgia.

This study found that increased CRH levels were associated with increased levels of depression, anxiety and poor motivation (but not pain) in FM. Twelve weeks of massage therapy (30 minutes of stroking, kneading, friction and shaking twice a week), however, reduced both urinary CRH levels and pain and the number of ‘emotional reactions’ (? but not depression or motivation?). There were a wide range of Individual responses with some patients reacting very well and others not. Encouragingly, the effects of the massage were still present a month after it had been discontinued.

Studies have indicated that a good number of CFS patients either suffer from depression or have suffered from depression at one time. This makes it odd that the research community has given so little attention to the efficacy of antidepressants in CFS. Two studies have shown no beneficial effects and one study found positive effects but they have all been short-term. This long term study (3 years) evaluated how effective two general types of antidepressants – Tricycle and Selective Serotonin Reuptake Inhibitors (SSRI’s) – were in ameliorating CFS.

This is another rather crude study. It followed CFS patients for three years who were on antidepressants at the time they were admitted to a CFS clinic and compared their progress to CFS patients not on antidepressants. Since they were on a variety of antidepressants, no information on specific antidepressant type and dosage was available. There was obviously no placebo group. Other than increased levels of depression in the antidepressant group, the two groups were similar symptomatically and demographically.

Study Findings – The antidepressant taking group had improved symptoms at the end of the three year period (but not after 6 or 18 months). They were actually significantly worse at baseline. Sixty-four percent of those taking antidepressants considered themselves at least partially recovered compared to 45% of those not taking antidepressants. Antidepressant-taking CFS patients reported significantly less fatigue and aching joints although the levels of these were still quite high. One area of distinct improvement was sleep; four times as many antidepressant-taking CFS patients reported improved sleep as did those not taking them (29 versus 7%).

Overall SSRIs appeared to be more effective than Tricyclic antidepressants with a remarkably high number of CFS patients (43%) reporting themselves to be ‘almost recovered’ at three years. It was the SSRI group that largely accounted for the reduced symptom levels seen in those taking antidepressants.