Guest guest Posted March 6, 2004 Report Share Posted March 6, 2004 A Laymen's Guide to Chapter Nine of CHRONIC FATIGUE SYNDROME A BIOLOGICAL: APPROACH by Cort CHRONIC FATIGUE SYNDROME A BIOLOGICAL APPROACH Edited by Englebienne Ph.D., Kenny DeMeirleir M.D, Ph.D., CRC Press. Washington D.C. 2002 Chapter Nine: Current Advances in CFS Therapy By Pascale DeBecker, Neil R. McGregor, De Suet and Kenny DeMeirLeir (This chapter is where the rubber meets the road for CFS patients. Yes, the research is interesting and it is gratifying to see so many aspects of CFS put together in such a coherent manner, but does all this work show up in the doctors office? Does it show up in increased quality of life for CFS sufferers? In so many ways this is the only chapter that matters for most of us. Everything else, as they say, is prelude. For me this chapter was both encouraging and discouraging -encouraging because of all the different treatments out there that can at take at least a nibble at or maybe even take a good bite out of some of the symptoms that dog us. It was encouraging as well in that some of the findings in the book are leading to new therapeutic approaches. I have not heard, for instance, of amino acid supplementation with regard to CFS. It was discouraging in that, aside from Ampligen, there appears to be no answer to the problem of RNase L dysfunction. Nor is there a mention of something designed to halt the rather massive amount of proteolytic cleavage going on. Nor, except for one reference, is there any discussion of regulators of calcium homeostasis or retinoic acid, two treatment possibilities mentioned in the text. Most of the treatments appear to attack the many co-morbid diseases or problems that afflict CFS sufferers. The breadth of these treatments is certainly gratifying.) 9.1 INTRODUCTION The authors begin by lamenting the state of the art of clinical trials in CFS. In short, given the heterogeneity of the patient population and the complexity of the disease origin, a number of factors that need to be taken into account (gradual vs. sudden onset, disease severity, duration, etc.) are not, and on top of that, the studies are too small, too short, too ill defined, etc. Questions regarding study efficacy have precluded the acceptance of some treatments that have demonstrated clinical benefit. Treatments at this stage are mostly symptomatic; no `consistently effective, readily available, safe and affordable pharmacological therapies' have yet been identified for CFS. Against this rather muddled treatment background, the authors note the profound effects CFS has on patient functioning. Less than 10% of CFS patient return to their `premorbid levels of functioning'; i.e. get well. Few patients ever resume an active lifestyle. There clearly is a great need for effective treatments for this illness. PHARMACOLOGICAL THERAPY Drugs Treating the Brain and Nervous System While there does not appear to be an association between RNase L activity or fragmentation and mood changes/psychiatric symptoms, cytokine alterations in CFS can lead to symptoms involving mood. Altered cytokine levels can cause depression and anxiety through changes in brain neurochemistry. Antidepressant use, sometimes at far lower doses than suggested for depression, is therapeutic for some CFS patients. The ability of non-psychiatrically therapeutic doses of antidepressants to confer clinical improvement in CFS patients suggests that the symptom reduction seen is derived from other that an antidepressant effect Benzodiazepenes `may be' used in treatment of anxiety but are not effective in treating sleep disorders. Modafinil has been successfully used in narcolepsy and could have some benefit in CFS. Tricyclic depressants, in particular those able to regulate sleep, have been beneficial for some CFS patients. Nortriptyline reduced symptoms and depression in one double-blinded study. Significant side effects can accrue from using first generation TCA's. The authors suggest sedating tricyclic antidepressants for severe insomnia (amitriptyline) and neutral (desipramine) for hypersomnia. Despite encouraging results from two preliminary `case series', a recent study found that fluoxetine, a serotonin reuptake blocker, offered no benefits. The authors suggest this was because CFS patients exhibit depressed levels of catecholamine not serotonin precursors. (This view was substantiated by a recent study that found high levels of tryptophan, the serotonin precursor, and low levels of tyrosine, the dopamine precursor). Doxepin, another tricyclic antipressant, had a 70% success rate in an uncontrolled study. A tricyclic monamine oxidase inhibitor, moclobeimide, had significant but modest effects in an open study. Because it influences catecholamine levels the authors suggest that it maybe increasing tyrosine availability. Positive benefits from another study using a different catecholamine agent (phenelzine) suggest that antidepressants influencing catecholamine levels may have the greatest efficacy in CFS. Serotonin is involved in sleep and temperature regulation, pain sensitivity, cardiovascular response and mood. All of these are commonly disturbed in CFS. Results from studies investigating serotonin have, however, been mixed. Galantiamine, an acetylcholinesterase inhibitor, showed promising results in an initial study containing some methodological concerns but had no effect in a double-blinded placebo controlled study. Drugs Treating the Endocrine System Growth hormone is of particular interest in CFS because fatigue is common in growth hormone deficiency. An important `anabolic agent', GH is essential for muscle homeostasis. Attempts to increase plasma volume in order to combat neurally mediated hypotension (loss of blood pressure when standing) using fluodrocortisone were no more successful than placebo in two recent studies. CFS patients display reduced DHEA and DHEA sulfate levels and exhibit a blunted DHEA response to ACTH injections. DHEA has significant immune effects; it promotes the Th1 response and can correct disregulated cytokine production. A subset of CFS patients experienced benefits to two preliminary studies of DHEA. Larger, double-blinded studies are needed to assess DHEA's efficacy in CFS. Immunomodulating and Antiviral Drugs Ampligen is a manufactured dsRNA product that enhances antiviral activity and has immunomodulatory and even anti-tumor properties. It is able to modulate 2-5OAS and 2-5A as well as interferons and interleukins, and can modulate both branches of the immune system. Studies have thus far determined that Ampligen is effective against at least 12 viruses. Ampligen is particularly effective at enhancing the functioning of NK cells – whose activity is inhibited in CFS. Ampligen administration to a cohort of severely ill CFS patients resulted in near normal 2-5A/RNase L pathway activity and improved exercise tolerance and reduced neurocognitive symptoms. Ampligen is able to induce the 2-5OAS system in CFS patients to produce bioactive 2-5A trimers rather than the dimers predominantly produced Ampligen has successfully passed phase II clinical trials and is now in phase III trials. Six months of Ampligen therapy resulted in improved quality of life scores, significantly increased activity and cognitive ability. Scores in exercise tests increased 10%. (This drug is obviously not a panacea.) The authors suggest that ampligen therapy may be appropriate for more severely disabled CFS patients. (In a recent paper (JCFS 2003) Dr. Englebienne indicated that while Ampligen can normalize the 2-5OAS-RNase L system, it most unfortunately also upregulates PKR activity.) Immunoglobulins in general, and IgG in particular, appear to commonly occur in CFS. Intravenous immunoglobulin therapy might benefit CFS patients by increasing antibodies against viral infections or by correcting `immunoregulatory disturbances'. CFS patients received benefits from two of four placebo-controlled studies. Adolescents in particular appeared to benefit from immunoglobulins. The cost, limited efficacy, tolerability, and transient nature of the benefits preclude the authors from recommending immunoglobulin therapy. An extract from T lymphocytes, transfer factor contains a wide assortment of `immune modulators', including parts of T helper and cytotoxic cells, interferons, IL-2, etc. No specific (?) benefits, however, were found in a double-blinded, placebo-controlled study. The considerable improvements experienced by CFS patients in a small study of Isoprinosine suggests that larger double-blinded placebo controlled should be undertaken. The authors indicated that about 1/3rd of their CFS patients responded after 1.5 grams of isoprinosine a day for several months. Amantadine is an antiviral agent that elevates dopaminergic activity by releasing norepinephrine and dopamine from central nervous system stores. Amantadine effectively treated fatigue in multiple sclerosis, (a disease that bears some similarities to CFS. See chapter eight.) Despite promising anecdotal reports, not only were no benefits derived from an Amantadine trial, but side effects were common. The frequency of side effects, the authors suggest, probably indicative of a disordered catecholamine metabolism in CFS. A extract of mushrooms, Lentian appears to impact a wide variety of immune responses; it induces multiple cytokines, inhibits Th2 dominance, and enhances cell mediated immune responses. As all these activities would very likely be beneficial to CFS patients, the authors suggest clinical trials should be done. A porcine liver extract, kutapression inhibits HHV6 replication and blocks EBV infection. Despite its antiviral activities, a double-blinded placebo controlled trial of acyclovir gave no more benefit that placebo. A subset of CFS patients with diminished NK cell functioning showed benefits from IFN-a, an interferon with wide antiviral and immunomodulatory properties. The authors note that while CFS patients with known virally associated co-morbid diseases may derive benefit from IFN-a therapy, IFN-therapy has in the past caused many of the symptoms (fatigue, pain, mood change) associated with CFS. Antibiotics - Treatments of the opportunistic infections often found in CFS may significantly effect patient `morbidity " Using a very sensitive and specific PCR procedure, several groups have found mycoplasma spp. (especially M. fermentans) in about 70% of CFS patients (compared, in one study, to 6% of healthy controls.) Mycoplasma appear to be able to more readily invade cells with low RNase L levels. Besides activating B lymphocytes, mycoplasmas produce proteases that degrade immunoglobulins. Mycoplasmas can infect nerve and synovial cells and other cell types. They are very effective at evading the immune system. Nicolson et. al. have found that most patients require multiple cycles (2-6) of 6 week courses of antibiotics to completely recover (@1-3 years! Then again, few other doctors speak of `complete recovery'.) Therapeutic regimes to correct nutritional and vitamen deficiencies are recommended during antibiotic therapy. Antibiotic therapy has also been beneficial, at least in the short term, in combating another common bacterial infection in CFS, toxin producing coagluase negative staphylococci. Relapse unfortunately was common, and different therapeutic regimes are being explored. A staphylococci toxoid vaccination program resulted in significant improvements in pain, sleep, concentration and memory. OTHER IMMUNE AGENTS - Two antihistamine drugs, rantidime and cimetidine, produced significant remissions in patients with chronic EBV infections in short-term studies. These drugs should be more thoroughly assessed with regard to CFS. Various nonsteroidal anti-inflammatory agents such as NSAIDS, paracetomol or orco-codamol may be useful in muscle and joint pain. Amitriptyline was helpful in easing muscle pain, improving sleep and reducing fatigue. In an assessment of 29 medical and alternative therapies, CFS patients ranked anti-allergy and anti-yeast diets very highly. The authors suggest, however, that systemic anti-fungal agents not be used because of possible side effects, unless a fungal condition is present. By inhibiting apoptotic enzymes or relaxing smooth muscles calcium channel blockers potentially can effect a variety of symptoms found in CFS. Their use in CFS, however, has thus far been limited. Nimodipine and amlodipine have been used to alleviate pain. Goldstein reccomends dihydropyridines. NUTRITIONAL FACTORS Vitamins - Folic acid deficiency in several symptoms commonly found in CFS such as fatigue, neuromuscular problems and reduced brain functioning. A subset of CFS patients appear to be deficient in folic acid. A small double blinded study that the authors feel may have been too short and may have used an insufficient dose of folic acid showed no benefits. Hydroxycobalamin injections have been widely used to combat the low central nervous system levels of vitamin B-12 reported in CFS. B-12 successfully treated abnormally shaped red blood cells that researchers believed caused oxygen deficits at micro-circulatory levels. Because two studies have shown elevated levels of neopterin, a nitric oxide indicator, hydroxycobalamin may be useful in scavenging nitric oxide and its oxidizing by-product peroxynitrite in CFS. Riboflavin, thiamine and pyrodoxine levels may also be reduced in CFS. Ten mgs. of NADH, a reduced form of niacin, generated substantial benefits in a double-blinded, placebo controlled study. These benefits may result not from resolving a niacin deficiency but from establishing a more favorable oxidation/reduction environment. Vitamin C boosts immune responses, has anti-viral properties, and at high doses, can enhance NK activity ten fold (!). Kodama et. al. reported that vitamin C infusions `in association with the enhancement of endogenous glucocorticoids' resulted in `clinical control' (?) of CFS. Adding DHEA resulted in greater benefits. Minerals - Several studies have indicated reduced red blood cell magnesium deficiencies in CFS. CFS patients experienced increased energy, decreased pain and improved mood in one placebo controlled study. CFS patients with significant muscle pain or who also have fibromyalgia should incorporate malate, a mitochondrial ATP enhancing substance, into their magnesium regime. Malate/magnesium significantly reduced the sensitivity of tender points in fibromyalgia patients. Low sodium intake can cause fatigue, headache, poor sleep and inability to concentrate. Conversely increased sodium uptake has successfully increased blood pressure in two studies of CFS sufferers experiencing neurally mediated hypotension. The authors suggest that CFS patients increase their sodium intake. Both zinc and iron deficiencies can lead to fatigue and other symptoms associated with CFS. Iron levels may be reduced as well in CFS patients with multiple infections. (Many microorganisms suck up iron stores in the body.) An iron assessment of iron metabolism should be done to determine if iron supplementation is needed. The authors caution that iron overload can occur in CFS patients who have the hemachromatosis gene. Amino Acids - Individually tailored amino acid mixtures can improve symptomology in CFS, particularly with regard to neurocognitive symptoms and muscle pain. Increased cytokine levels result in increased protein breakdown The wide variety of amino acid patterns found necessitate that individualized amino acid regimes be employed in CFS. Single amino acid supplementation, in particular, should be avoided because, due to the nature of the amino acid transport system, it can cause multiple deficiencies. Possibly because of the increased IFN-y produced, tryptophan degradation is enhanced in infectious diseases. It is not clear, however, that tryptophan supplementation enhances immunity. CFS patients exhibited reduced tryptophan levels in two of three studies. The authors once again recommend against supplementation of one amino acid. An important factor in muscle metabolism, L-carnitine deficiency is marked by muscle pain, weakness and fatigue following exercise. L. carnitine helps in fatty acid transport across membranes and optimizes the intracellular `lipid mileu', an environment involved in lymphocyte proliferation and cytokine production. About one third of CFS patients appear to benefit from L-carnitine supplementation. Plasma concentrations of glutamine were significantly lower in CFS patients in one study but not another. Gluatmine supplementation offered no benefits, however, to CFS patients in one study. NUTRITIONAL FACTORS - Fatty acids are essential substrates for many cellular processes including oxidative phosphorylation in muscle mitochondria and neuronal metabolism. Fatty acid levels can fall during viral infections and remain low afterwards. The lipid alterations associated with viral infections were not found in CFS patients, however. Instead, levels of n-6 fatty acids, which are precursors of inflammatory substances such as prostaglandins and leukotrienes, are increased in CFS. Levels of n- 6 fatty acids are positively associated with symptom expression which in turn is associated with increased inflammatory activity and/or viral activity. Viral activity has been associated with reduced EFA levels. A double-blinded placebo controlled study indicated that EFA's (80% EPO, 20% fish oil) reduced muscle pain, dizziness, concentration and depression. 's study, however, indicated that high EPA levels were positively correlated with increased symptom expression. No benefits were seen in another study. The authors suggest EFA supplementation is not indicated in CFS unless a demonstrable defect is shown. Food intolerances are common in CFS. Removing allergens from the diet can result in the complete resolution of gastrointestinal symptoms. Significant improvement of CFS symptoms, exercise tolerance and post exercise fatigue was found in one open study using coenzyme Q10. OTHER THERAPIES - Significant improvements in pain, sleep, concentration and memory were seen in a placebo-controlled study using a Staphylococcus Toxoid Vaccine NON PHARMACOLOGICAL THERAPY - Cognitive Behavior Therapy (CBT) attempts to alter behavior patterns that may either exacerbate CFS or hamper recovery. Such programs are often important facets of rehabilitation for those dealing with chronic illnesses. They focus not on the disease but on the psychological responses to disease, some of which can have physiological effects. In CFS CBT has focused on activity levels, relaxation and breathing patterns. While CBT is beneficial in coping with the psychological effects of CFS it does not appear to alter the organic basis of the disease. Deconditioning has been proposed to account for exercise induced fatigue in CFS. Several studies, however, have failed to find evidence for deconditioning. A subset of CFS patients with evidence of deconditioning, however, improved with graded exercise treatments. Seventy percent of CFS patients in another graded exercise program trial experienced improvements in fatigue, disability and mood. Severely impaired CFS patients, however, do not appear to be good candidates for graded exercise programs. CFS patients experienced significant improvements in sleeping, anxiety, pain, depression, fatigue and somatic symptoms in a randomized controlled trial of Transcutaneous Electrical Stimulation (TENS). FUTURE DEVELOPMENTS - The disease progression in CFS is complex. Treating this disease involves managing the three processes described in these chapters; (1) the disease etiology, (2) the host response to the disease and (3) the co-morbid diseases that accrue as a result of the disruptions caused by the disease. Therapeutic regimes are needed for each component of the disease process. These would include using antivirals, antibiotics, and antifungals to attack the disease etiology and co-morbid pathogens; anti-inflammatories, apoptotic regulators and supplements to manage host responses and pyschological adjuncts, graded exercises and anti-depressants to combat the outcome of the disease process. The interventions may range from treatments designed to reduce cytokine levels (drugs, EFA manipulation, etc.), or alter ion channel activity, or manipulate 2-5A synthetase/RNase L pathways, ABC transporters, or even double stranded RNA aptamers. Promising Treatments the Authors Believe Need More Study: DHEA, amino acids, magnesium, Quote Link to comment Share on other sites More sharing options...
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