Phoenix Rising – An ME/CFS/FM Newsletter by Cort Johnson (April 2006)


Phoenix Rising – An ME/CFS/FM Newsletter by Cort Johnson (April 2006)

NEWS

Reports From the London CFS/ME Conference -Mary Schweitzer and Melanie Jameson have given us reports from the London Conference we’ve been looking forward to for awhile. You can access Mary’s Report at

http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0605c&L=co-cure&T=0&P=777

And Melanie’s report at http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0605c&L=co-cure&T=0&P=3291

Pat Fero Testifies to CFSAC regarding the truly pitiful level of NIH funding for CFS and the layers of obfuscation she has encountered. Why our advocacy groups haven’t taken this on with the vigor Pat has is entirely unclear to me. The NIH funding for CFS is a travesty; thanks to Pat’s work we are uncovering how just how bad things are. There is no more important topic in CFS than public funding. You can find her latest testimony at http://www.co-cure.org/PatFero.htm

HHV-6 drug effective in CFS? - Click here to read a newspaper article that relates the startling effectiveness of an anti HHV-6 drug in a small group of CFS patients. http://chronicfatigue.about.com/od/treatments/a/hhv6drug.htm

Learn more from Dr. Podelll on disability and CFS/FMS athttp://www.co-cure.org/Podell-1.htm

Dr. Nicolson Talks - about his new book ‘Project Day Lily’ . A 1 hour interview, aired on Radio Liberty at 12 May 2006, is available at the CFSResearch Website in both Streaming Real Audio and as MP3. You can find the 1 hour interview here: http://www.cfsresearch.org/mycoplasma/nicolson/17.htm

The CDC will update the gene microrray findings from the recent large CFS research effort at the CAMDA 2006 Conference.The conference notes also state “the CDC has agreed to experimentally validate biomarkers identified in submitted abstracts!” I’m not sure what that means but it sounds exciting! It will be held from June 8-9, 2006 in Durham, North Carolina.

*CF-ALLIANCE NEWSLETTER CONTEST: Write an essay about your journey with chronic illness. The contest winner will have their original essay printed in the CF-Alliance Summer 2006 Newsletter and posted on the CF-Alliance Official Website. The winner will also receive the book, ‘Stricken: Voices from the Hidden Epidemic of Chronic Fatigue Syndrome’ by Peggy Munson and a set of CFS/ME/FM awareness postcards. The Deadline is June 1, 2006. One entry per person/per address. The entry must be 300 words or less. Send your original essay via email, fax or regular mail to the CF-Alliance. Include your name, mailing address and email address with your entry. -Writer retains all copyrights to their original work.

Mail or Email Contest Entry To: CFA, PO Box 9204, Bardonia, NY 10954 USA

Read an excerpt from Dr. Pellegrino’s “Fibromyalgia Up Close & Personal”:Those Dysfunctional Autonomics by Mark Pellegrino, M.D. Read this excerpt at http://www.immunesupport.com/library/bulletinarticle.cfm?ID=7117

RESEARCH

RESEARCH - Unless otherwise noted the research summaries are by Cort Johnson, a CFS patient, whose ‘expertise’ such as it is, extends mostly to subjects of CFS pathophysiology. Submissions from others with knowledge of other fields (psychology, epidemiology, etc). or of any aspect of CFS pathophysiology are gratefully accepted. Comments, suggestions, clarifications, etc, negative or positive, only add to the editors and others understanding of CFS. Please send them to Phoenixcfs@yahoo.com).

Research Summary:

Rating The Months Research - The thesis of this newsletter is that the most important studies deal with the pathophysiology of CFS. Each month is graded according to the following criteria;

A - several difference making papers on CFS pathophysiology

B - a difference making paper on CFS pathophysiology plus several important ones

C – several important 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

Research Rating

Total Number of Papers – 13 Country of Origin
Clinical – 3 United States – 3
Treatment – 3 Iran – 3
Brain/CNS – 1 UK – 2
Immune – 1 Japan – 2
Genes – 1 Australia – 1
Oxidation – 1 Spain – 1
Detoxification – 1 Italy – 1
Hematology – 1
Psychology – 1

THE PAPERS

FOCUS ON FIBROMYALGIA

Part II: The Origin of the Pain in FMS Lies in the Periphery?

This is a fertile time for FMS research. Two decades of research lead many researchers to believe that the cause of FMS lies in the brain. Several recent papers, however, that suggest the pain in FMS originates in the muscles, are causing some to reassess their findings.

Kim, S. Jang, T. and I. Moon. 2006. Increased expression of N-Methyl- D- Aspartate receptor subunit 2D in the skin of patients with Fibromyalgia. J. of Rhuematology 33: 785-8.

This small study has opened a new window in the question of whether peripheral not central sensitization exists in FMS. The last issue of Phoenix Rising discussed how NMDA receptor activation is an integral part of central sensitization. We learned that increased numbers of NMDA receptors on a neuron can make it hypersensitive to glutamate, the substance that ‘opens’ the neuron. When high numbers of NMDA receptors are present, neurons respond to small levels of glutamate; the pain-producing neurons produce large amounts of pain enhancing substances such as substance P and nitric oxide.

Recent studies indicate that glutamate plays a role not only in central sensitization but in sensitization of the peripheral nerves as well. This could be a very important point. Researchers have found that the ‘pain’ neurons in the dorsal horn of the spinal cord respond to continued, repetitive pulses of pain in a rather unusual matter; instead of becoming de-sensitized to them, they become more sensitized to them. A chronic pattern of excitation caused by over-sensitive neurons in the periphery could, therefore, ultimately cause the pain we see in FMS. Some support for this idea comes from the natural history of this disease; FMS often starts with a initial trauma (fall, car accident, etc.) and then spreads to the rest of the body.

Unlike previous studies which limited examination to the spinal cord, this study to examines whether NMDA receptors are abnormally abundant in the periphery, in this case, the skin from the shoulder region. This study found that a particular type of NMDA receptor called NR2D was significantly increased in FMS patients. This receptor has a particularly high affinity for glutamate and exhibits a weaker magnesium MG2+ block than the other NMDA receptors. This indicates it responds more quickly to glutamate and more quickly sheds the agent, Mg, that plugs up the NMDA ion channels (and deactivates) them; i.e. the more abundant NR2D more quickly activates the NMDA ion channels and produces pain.

__________________________

The prevalence of particularly active NMDA receptors in the skin of FMS patients suggests that pro-pain substances associated with NMDA activation might also be increased. The next study examined whether an integral pain factor, brain derived nerve factor (BDNF), was increased in the serum of FMS patients

Laske C, Stransky E, Eschweiler GW, Klein R, Wittorf A, Leyhe T, Richartz E, Kohler N, Bartels M, Buchkremer G, Schott K. 2006. Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. J Psychiatr Res. 2006 Apr 3

As noted in the last issue of Phoenix Rising, BDNF plays a major role in how the CNS processes painful stimuli. It is also, however, quite active in the periphery – its ability to regulate the mechanoreceptors in the skin means it plays an important role in how we respond to fine sensations. This study examined BDNF levels in the serum in order to determine whether it might contribute to the sensitization of the peripheral nerves in FMS.

It found that BDNF levels were indeed significantly increased in FMS compared to controls (p<.0001) (!). But where is the increased BDNF coming from? The authors suggest three possible sources; the endothelial cells, or the smooth muscles lining the blood vessels, or activated monocytes/macrophages. But not the neurons? Perhaps because neurons produce substances that diffuse locally and not into the bloodstream? This suggests, of course, that just as with CFS, an immune disruption could play a role in FMS. The authors note that macrophages could produce BDNF themselves or they could induce BDNF production via production of the pro-inflammatory and pro-pain cytokine, IL-6.

When an injury occurs in the periphery, the nociceptors or pain receptors in that region are activated by various substances that become liberated during trauma (e.g. bradykinins, histamine, prostaglandins. etc.). These substances trigger the production pro-pain substances such as substance P and brain-derived nerve factor (BDNF) that further sensitize the neurons. All this activity contributes to the extreme sensitivity (hyperalgesia) found in an area surrounding a wound.

But where is the wound in FMS? If the pain in FMS originates in the muscles, they must have suffered from some sort of trauma. The lack of a consistently found lesion in the muscles has bedeviled FMS researchers. In the review article below Goff examines the evidence for and against the theory that a muscle disorder is responsible for the pain present in FMS.

Goff, Paul, P. 2006. Is fibroymalgia a muscle disorder? Joint Bone Spine.

Goff believes the Sprott paper in 2004 re-opened the debate on the possibility of muscle trauma in FMS. Sprott et al. found low numbers of often enlarged mitochondria as well as lipid and glycogen accumulations in the muscles of FMS patients. They believed these reflected problems with energy metabolism.

First Goff notes that after more than 30 studies a consensus on the role muscle pathology plays in FMS has still not been reached. Surprisingly, at least part of the reason appears to be the inability of researchers to agree on what constitutes a significant morphological abnormality. Goff cited one paper that concluded no morphological abnormalities were present in FMS but which had, Goff thought, illustrations clearly illustrating morphological abnormalities.

Some problems have to do with the varying types of irregularities thus far found in FMS. Since FMS is a distinctive disease, researchers want to see distinctive abnormalities. While studies have found muscle abnormalities, there has been little consistency in the type found. The fact that some of the irregularities found sometimes also occur in healthy people suggests some of them could be relatively minor.

Goff states, however, that two types of muscle abnormalities are not only consistently found in FMS but appear to be distinctive to it. These are lesions (injuries) in parts of the muscles called the ‘Z lines’ and that suggest mitochondrial problems may be present in FM. . Z line abnormalities were found in subjects suffering from ‘overexertion of the muscles and tendons’ in the late 1980′s but Goff reports that since then they have been found only in FMS patients (four studies). Z lines are bands of muscles that are aligned with each other. When the muscle contracts the Z lines come together; when it relaxes they separate. This appears to suggest there could be a problem with cell-coordinated muscle contraction/relaxation in FMS. The mitochondrial abnormalities seen in FMS (5 studies) have only rarely been found in healthy subjects.

Goff believes that the mitochondrial abnormalities could account for the fatigue that is brought on by exercise in FMS. Since mitochondrial myopathies are usually quite debilitating, Goff believes that the lesser debility usually found in FMS suggests that the type of myopathy found in FMS might be observable only when an individual is exerting himself. This has echoes of Chia’s theory of exercise induced enterovirus activation in CFS. Chia believes the pathogens in CFS become fully active during exercise. He further argues that the kinds of mitochondrial abnormalities seen in FMS are obscured in two ways; first he posits they are most observable only during exercise, and two, the types of muscles usually biopsied in FMS studies are the types where it is difficult to find mitochondrial abnormalities.

Critics of the idea of peripheral trauma in FMS state that many of the lesions found appear to be too minor to satisfactorily account for the extent of debility and pain found in many FMS patients. No signs of muscle degeneration and regeneration have been found. Nor have signs of pathological process involving inflammation. Normal muscle strength suggests no gross abnormalities in muscle functioning are present. Electrical stimulation studies indicate that the muscles are receiving the appropriate inputs from the brain. Most indices of muscle functioning in FMS are normal.

It seems that most evidence would argue against a serious muscle injury in FMS. Examinations of muscle functioning have, have however, led to an intriguing finding that suggests the problem in FMS could be in the muscle circulation. This is the next study we look at.

*Sprott, H., Salem, S., Gay, R., Bradley, L, Alarcon, G., Oh, S., 2004. Increased DNA fragmentation and ultrastructural changes in fibromyalgic muscle fibers. Am. Rheum. Dis. 63: 245-51.

FMS is a microcirculatory disorder?

Morf, S., Amann-Vesti, B., Forster, A., Franzeck, U., Koppensteiner, R.,Uebelhart, D. and H.Sprott. 2005. Microcirculation abnormalities in patients with fibromyalgia – measured by capillary microscopy and laser fluxometry. Arthritis Res Ther. 7:R209-R216 (DOI 10.1186/art459).

Although the presence of overt histological or functional alterations in the muscles of FMS patients is controversial, several studies have now found alterations in microcirculatory blood flows. This study found that it took longer for the blood flow to return to normal in the FMS patients than in the controls after it was shut off by a cuff. It also found low normal levels of capillary density.

The decreased circulation was presumably due to increased sympathetic nervous system activity (tone) causing increased blood vessel vasoconstriction. Because the blood vessels are kept narrower than normal it takes longer for the blood flow to return to normal. Increased sympathetic nervous system activity could also account for the reduced capillary density found.

What might cause this microcirculatory dysfunction in FMS? Mawaka et. al. produced a much discussed paper in 2002 that posited it was due to a widespread sympathetic nervous system dysfunction.

Maekawa, K., Clark, G. and T. Kuboki. 2002. Intramuscular hypoperfusion, adrenergic receptors and chronic muscle pain. The Journal of Pain 3, 251-260.

Three researchers have posited that increased sympathetic nervous system (SNS) activity causes reduced blood flows to the muscles in FMS. Several lines of evidence suggest that an aberration in sympathetic nervous system activity could play a role in the pain found in FMS. Blocking sympathetic nervous system (SNS) activity resulted in a dramatic reduction of pain in 5 of 8 FMS patients in one study. It also returned their ‘muscle relaxation rate’ from slow to near normal. High electromyography readings in tender points in FMS patients may be due to increased muscle sympathetic nerve activity. One research group has proposed that the tender points in FMS are due to intrafusal muscle contractions within the muscle spindle that occur because of SNS overactivation.

The idea that the chronic muscle pain in FMS is caused by low blood flows to the muscles was raised over 30 years ago in a biopsy study that revealed swollen endothelial cells in the muscles of FMS patients. This study, amazingly, has never been repeated. Three studies since then, however, have found indications of low muscle blood flows in FMS. Reduced blood flows have also been found in the jaw muscles of patients with chronic muscle pain.

How could reduced blood flows to a muscle cause muscle pain? One study has shown that states of ischemia (low blood flows) sensitize the pain receptors in muscles. Another has found that hypoxic states (low oxygen content) do the same.

But what could cause obstructed flows of blood to the muscles of FMS patients? One theory suggests an anatomical abnormality present in the blood vessels could, and indeed one study found significantly reduced capillary density in the thigh muscles of FMS patients. A larger study by a different researcher, however, did not.

Because cold stimulates the SNS, the cold pressor test which involves submerging a limb in ice water is commonly used to examine SNS activity. That patients with chronic muscle pain had abnormally reduced blood flows during the cold pressor test suggested they had impaired vasodilation.

Why the impaired vasodilation in these groups? Maekawa posits that chronically increased epinephrine production results in B2 AR desensitization. This suggests that when the signal for vasodilation occurs the receptors largely ignore it. Thus, when muscle contraction during exercise occurs, the signal for increased blood flow (vasodilation) is ignored. This somehow locks the muscles spindles into a contracted position and activates the pain sensors in the muscles. This causes low blood flows to the muscles and pain in FMS and possibly other chronic pain diseases as well.

The sympathetic nervous system is a key regulator of blood flows to the tissues. This system, which uses norepinephrine (NE) and epinephrine (E) (adrenaline) to achieve its effects, operates differently depending on which receptors are present. If receptors called beta adrenoreceptors (B ARs) are present then NE will cause the blood vessels to dilate. If receptors called alpha adrenoreceptors (A ARs) the NE will cause the blood vessels to vasoconstrict. Since B1 ARs are found mostly in the heart and A ARs are found mostly in the muscles, systemically increased NE levels will result in increased blood flows to the heart and decreased blood flows to the muscle tissues.

Ravings of a layman — Whether the blood flows in the brains of CFS/FMS patients are low enough to trigger ‘ischemia’ is unclear. Indeed the definition of ischemia is unclear; Stedman’s Medical Dictionary defines it as ‘local anemia’ due to an obstruction. There is certainly no evidence as yet of an obstruction in CFS brains but several processes perhaps able to produce a low-level chronic ischemic state – e.g. low blood volume, low cerebral blood flows during standing (or otherwise) – have been documented in some CFS patients. Baranuik’s stunning recent paper on the protein composition in the cerebral spinal fluid of CFS patients suggests a process of protein aggregation (amyloidosis) that is enhanced when blood flows are low could be occurring in the blood vessels in the brains of CFS patients. Could reduced blood flows in the brains of FMS/CFS patients cause first increased glutamate, then NMDA receptor activation and finally pain in FMS patients? Are CFS and FMS circulatory conditions?

Even Worse Ravings – There are dramatic differences in the type of heart disease in men and women. Men tend to get heart disease earlier but tend to do better after being diagnosed. Women tend to get heart disease later but are often not diagnosed early and have poorer outcomes. A recent article In the New York Times indicated the differences between the two may lie in the type of circulatory dysfunction they have. While men tend to have problems with the arteries, it is now believed that women have more problems with their microcirculation. Unfortunately the technology is only now being developed that can adequately measure the microcirculation. This may have nothing to do with CFS but what an interesting finding it is given the increased rate of women with CFS. Could women’s susceptibility to microcirculatory problems be the cause of the gender bias present in CFS?

Conclusions – It is difficult to sum up such a complex field. Whereas FMS was for some time largely believed to be a disease of central sensitization several recent studies have suggested it is, in fact, a disease of both peripheral and central sensitization. Research now implicates both the spinal cord and brain in FMS in the central sensitization occurring in FMS. (See March Phoenix Rising). Several lines of evidence including low blood flows to the thalamus and the muscles suggest, just as with CFS, that widespread circulatory problems may contribute to FMS.

FOCUS ON TREATMENT

This section provides overviews of recent treatments trials for CFS. Consult with your physician regarding these. Note that even in several of those studies in which not a great deal of benefit was shown a subset of CFS sometimes showed a great deal of benefit – just a bit more evidence for the presence of subsets in CFS.

Good Vibrations

Saggini R, Vecchiet J, Iezzi S, Racciatti D, Affaitati G, Bellomo RG, Pizzigallo E. 2006. Submaximal aerobic exercise with mechanical vibrations improves the functional status of patients with chronic fatigue syndrome. Eura Medicophys.

This, the only CFS research group in Italy, has been plugging away with innovative studies of neuromuscular physiology in CFS for some time now. They recently completed a study that indicated oxidative stress may impair muscle functioning in CFS (see Phoenix Rising ). This time they turn their attention to a most unusual form of treatment indeed.

The authors begin by citing two theories of CFS pathophysiology pertinent to the neuromuscular studies: deconditioning or, as they posit, neuromuscular dysfunction. They note the improvements seen for some CFS patients in graded exercise programs and the impaired cognition seen in CFS following exhaustive exercise.

Apparently theorizing that high levels of exercise are counterproductive, this team used a submaximal exercise protocol that avoided increasing oxygen consumption. It employed a machine called a Galileo 2000 which produces ‘sinusoidal vertical vibrations’ all over the body.

The below is from the manufacturer’s website

Galileo Whole Body Vibration

The “Galileo” stimulates the whole body by tilting slightly around an axle. The person who stands on the machine tries to keep the head and body steady and upright. All the muscles that keep the body in this position are forced to react to the oscillatory movements provided by Galileo, thus exercising them. This stimulation form is currently known as “Whole Body Vibration” (WBV) training. Many studies show that vibrations at the right dose can lead to faster growth and recovery of all tissues.

Training sessions of only 2-3 minutes twice a week produce measurable effects.

Galileo stimulation induces a post-activation-potentiation of the muscles and improves tendon reflex sensitivity. Galileo stimulation improves the effects of your regular training significantly.

Galileo training improvespower and balance in all people, but especially in low taxable people, neurological patients, and sportsmen who are training at their physical limits.

Galileo training improves power balance and coordination inneurological patients.

Galileo stimulation enhances blood flow significantly, especially in peripheral regions.

The bone quality (noted as Stress Strain Index) improves after Galileo training.

Method - Ten CFS patients in varying positions did the Galileo for short periods every 48 hours for 6 months. They were a given questionnaires that assessed their fatigue, muscle pain, mood, quality of life, and work status. They also underwent a pain threshold test and a muscle performance analysis.

Results - All patients felt worse during the first week and then improved from then on. The CFS patients showed significant reductions in fatigue, muscle pain, mood, quality of life and working activity. Their quadriceps muscle showed an increased pain threshold. Their muscles showed an 18% increase in strength. Interestingly they also showed about a 15% reduction in body mass index and weight.

Conclusions - The authors attributed these results to improved neuromuscular proprioception and increased muscular vascularization.

Proprioception is the process by which the body regulates the position of the muscles and joints to achieve a balance of both. The brain uses proprioception and other processes to make muscle and joint adjustments in order to achieve movement and balance. Also referred to as the sixth sense, proprioception is the nervous system’s means to keep track of and control the different parts of the body. The authors’ mention of proprioception was interesting given the abnormalities seen in several studies of ‘gait analysis’ in CFS. The idea of increased muscular vascularization is intriguing as well given the possible microcirculatory problems in CFS.

The authors linked the improvements seen in part to reduced quadriceps stiffness. The proprioception system interprets signals from the muscle spindles to regulate muscle contraction. If the muscles are too contracted they will be stiff and more painful. They also proposed that the low intensity submaximal exercise stimulated the body’s endorphin system and noted that a prior study had found decreased levels of beta-endorphins in CFS patients. Endorphins are peptides produced by the pituitary gland and the hypothalamus that resemble opiates in their ability to produce analgesia and a sense of well-being.

This study unfortunately did not have a control group. Given the positive results the authors suggested that a larger follow up study with one was in order.

Resetting the Brain’s Clock

Heukelom, R. O., Prins, J., Smits, M. and G. Bleijenberg. 2006. Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome. European Journal of Neurology 13, 55-60.

CFS patients display symptoms similar to people with disturbed circadian rhythms such as jet-lagged travelers, people with seasonal affective disorder and people unable to adjust to night-shift work. Circadian rhythms refer to 24 hour cycles. Melatonin (or N-acetly-5-methoxytryptamine – that’s an easy one!) plays a major role in regulating our sleep-wake times.

Melatonin (adapted from Stedman’s Dictionary)

Melatonin secretion is triggered when diminishing light levels activate the neural pathways leading from the eye to pineal gland. Melatonin secretions increase 10-fold just before sleep and peak around midnight. The decline of melatonin secretion with age has been blamed for the tendency to insomnia in the elderly. Because melatonin acts as an antioxidant in counteracting free radicals, it has been promoted as a means of delaying aging and preventing cancer, heart disease, and Alzheimer dementia. It has also been proposed as an antidepressant because serotonin (5-hydroxytryptamine), whose metabolism is known to be disordered in clinical depression, is a chemical precursor of melatonin. There is experimental evidence that long-term administration can reset the circadian pacemaker. Anecdotal reports suggest that shorter courses can hasten recovery from jet lag and facilitate adaptation to night-shift work. High doses of melatonin result in prolonged elevation of serum melatonin level and increased production of prolactin by the pituitary gland. Unlike most hormones, melatonin is readily absorbed from the digestive tract and is a component of some foods. Testing of commercially available preparations of melatonin has indicated both variation in potency and the presence of possibly harmful contaminants

A subset of CFS patients display delayed ‘Dim Light Melatonin Onset’ (DMLO); that is, the signal for sleep produced by melatonin kicks in later that it should. (DLMO in healthy individuals is between 6 and 9:30pm. DMLO is measured using the saliva; it can be collected at home). What might have caused this delayed onset? The authors posited that damage to the retinal – pineal gland neural pathways caused by a virus could have delayed the signal prompted by the approach of darkness.

Only CFS patients with ‘feelings of insomnia’ and healthy controls participated. Several indices of ‘fatigue’ were assessed (fatigue severity, concentration, motivation, activity) over three months. This study found that all the ‘fatigue’ scores for the CFS patient significantly improved with treatment.

Treatment trials can be ‘successful’, however, without dramatically affecting how a patient feels; the criterion for ‘success’ is a bigger positive difference with the trialed substance than with a placebo or in a control group. Success at a treatment trial doesn’t tell us, then, if an agent is a major breakthrough for CFS patients or just a mildly helpful adjunct.

While CFS patients improved more than did the healthy controls their improvement as determined by their self-assessed fatigue scores, was good; they did about 15-20% better after melatonin, but their fatigue scores were still roughly double those of the healthy controls.

There was one group of CFS patients, however, that derived very significant benefits. The fatigue scores of the CFS patients with late DLMO’s normalized on melatonin, i.e their fatigue was no worse than that of controls (!). Their other scores (concentration, motivation, activity) did not normalize but improved significantly relative to other CFS patients.

Conclusions – Melatonin can be moderately helpful for CFS patients with insomnia but may bring significant benefits to insomniac CFS patients with delayed ‘dim light melatonin onset’.

Dose – 5 mg. melatonin five hours before each individual DLMO. The authors posited that the failure of an earlier study to show a response was due to too late of an administration time. Since healthy DLMO’s range up to 9:30, one would think those with late DLMO’s received melatonin sometime after 4:30 in the afternoon.

Possible Severe Side Effects – none known

Available – Over the counter

Amphetamines For CFS?

Blockmans, D., Persoons, P., Van Houdenhove, B. and H. Bobbaers. 2006. Does Methylphenidate reduce symptoms of Chronic Fatigue Syndrome? The American Journal of Medicine 119, 167-e23-167.e30.

Methylphenidate (Ritalin), the agent under discussion, is an amphetamine derivative, not an actual amphetamine. It is, however, a stimulatory drug. Its effects appear to derive from its ability to increase dopamine and possibly norepinephrine levels in the brain by blocking their reuptake at the nerve synapses.

A nervous system signal is propagated when neurotransmitters fill the gap at the nerve synapse. Once the signal has been produced the neurotransmitters are taken back up into the nerves. By blocking this reuptake Ritalin increases the amount of dopamine available. Dopamine is precursor of the two catecholamines, norepinephrine and epinephrine (adrenaline, noradrenaline). Present in various places in the brain it is centralized basal ganglia.

Methylphenidate (Ritalin)

Intriguingly (given the notable daytime sleepiness present in CFS), before the advent of modafinil (see below), Ritalin used to be used to combat narcolepsy. Ritalin has also been used successfully to relieve fatigue in cancer patients. Its most prominent (and notorious) usage, however, has been in the treatment of attention deficit and hyperactivity disorders in children. Several class action suits have charged its manufacturers with the over promoting its use in young children.

What a seemingly odd conjunction; hyperactivity disorder and CFS. Then again we are all aware of that ‘tired but wired’ feeling and the concentration difficulty found in CFS. Could the concentration difficulties in these disorders be related?

At its prescribed doses Ritalin’s effects are described as being between those of caffeine and amphetamines. Ironically, given its stimulatory nature it is reported to have a calming effect on people with attention deficit and hyperactivity disorders.

Because high dose Ritalin can produce a euphoria-like effect that may become addictive, it is a Schedule II controlled substance. At its prescribed dose, Ritalin is not associated with addiction.

This double-blinded randomized treatment trial (n=60) measured an array of indices including those measured in the melatonin study (fatigue, concentration, activity, motivation) plus body pain, mental health, etc. as well as symptoms found in the Fukuda definition of CFS (i.e. sore throat, joint pain, etc.)

The study found that a clinically significant response occurred in about 15% of the participants. People with less severe fatigue were most likely to benefit. The overall scores were quite similar to those in the melatonin study above; the CFS patients as a group appeared to get about 10% better. A subset of patients (15%), however, had a strongly positive response to Ritalin. Other than dry mouth no significant side effects were seen.

The authors noted that the long term effects of CFS patients taking this amphetamine precursor are still unknown. They were also unclear whether the improvement seen was due to Ritalin’s interactions with the central pathophysiology of CFS or whether, since Ritalin increases the alertness etc. of even healthy people, CFS patients simply displayed a normal response to it.

Conclusions – CFS patients with less severe fatigue may benefit moderately from methylphenidate. A subset of CFS responds to this drug very well. The long term effects of Ritalin on CFS are unknown. Other than dry mouth no side effects were seen.

Dose – 20/mg day for 4 weeks

Potential side effects – dizziness, drowsiness, blurred vision, insomnia, impaired concentration

Available – by prescription

Randall, D., Cafferty, F., Shneerson, J., Smith, I., Llewelyn, M. and S. File. 2005. Chronic treatment with modafinal may not be beneficial in patients with chronic fatigue syndrome. Journal of Psychopharmacology 19, 847-660.

We just saw that methylphenidate appeared to help some CFS patients. In a nice twist, modafinil, the drug that largely replaced methylphenidate as the drug of choice for some disorders, was also recently tested in CFS patients in a double blinded, placebo controlled, crossover study.

Modafinil

Termed a ‘wakefulness promoting’ drug, modafinil has been used to reduce fatigue in multiple sclerosis, daytime sleepiness in Parkinson’s disease and depression in HIV patients and patients with major depression. It has also been used to increase cognition in healthy volunteers and people with sleep deprivation. Unlike some amphetamine-like stimulants, modafinil is not addictive.

Despite its efficacy in other disorders modafinil had no significant effects on cognition or on the CFS patients’ self-rated assessments of physical or mental fatigue, quality of life or mood. The authors, who seemed somewhat surprised at the lack of effect seen, questioned whether the small sample size (14) obscured any significant findings. They noted that the ‘nature of this patient group, which finds research participation difficult…greatly restricted the potential sample size’. (About a quarter of the participants dropped out).

Perhaps a more important problem were the dosages used. The researchers used the recommended dosages for narcolepsy (200/400 mg.) but noted that doses of only 100/200 mg doses were effective in one multiple sclerosis study, and that some MS patients responded positively only to doses as low as 50 mg. They indicted that a kind of ‘inverted U’ response, with low but not high doses conferring positive responses, is common in psychostimulants. These researchers appear to have missed the many anecdotal reports of CFS patients doing better on low doses of many pharmaceutical drugs.

Dosage used – 200/400 mg. one dose for 20 days with a 14 day washout period followed by the other dose for 20 days.

Side effects noted – high dropout rate but no side effects noted.

Antiobiotics for CFS?

Iwakami, E., Arashima, Y., Kato, K., Komiya, T., Matsukawa, Y. Ikeda, T., Arakawa, Y. and A. Oshida. 2005. Treatment of Chronic Fatigue Syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection. Internal Medicine 44, 1258-1263.

Q-fever, a bacterial infection caused by Coxiella burnetii, is known to cause CFS in a subset of those infected. One study found that almost 20% of Q fever patients met the criteria for CFS ten years later.

The primary reservoir for Q-fever is livestock but it has also been found in domesticated pets. Coxiella burnetii can be found in the milk, urine and feces of infected animals but is mostly shed in high numbers during birthing. The resistance of these bacteria to heat, drying and common disinfectants allows them to survive for long periods. Infection in humans usually occurs from the inhalation of barnyard dust contaminated by birth materials and feces of infected animals.

The CDC states that only about one-half of all people infected with C. burnetii show signs of clinical illness. Most acute cases of Q fever begin with sudden onset of one or more of the following: high fevers (up to 104-105° F), severe headache, general malaise, myalgia, confusion, sore throat, chills, sweats, non-productive cough, nausea, vomiting, diarrhea, abdominal pain, chest pain and weight loss. The weight loss can occur and persist for some time. Thirty to fifty percent of patients with a symptomatic infection will develop pneumonia. In general, most patients will recover to good health within several months without any treatment.

A similar symptom presentation in chronic Q-fever and CFS (fatigue, muscle and joint pain and headache) has made it of interest to CFS researchers. Antibody tests indicating increased antibody production to coxiella burnetii in four CFS patients suggested Q-fever infection might be the cause of their CFS. Accordingly these researchers gave them and a large group of chronic Q-fever patients antibiotics (3 months minocycline/doxycycline) designed to clear the infection and compared how the two groups fared.

They found that the antibiotic treatment did eliminate signs of C. burnetii infection (DNA, antibodies) in both groups but that only Q-fever syndrome patients showed significant symptomatic improvement. This indicated, of course, that C. burnetii was an opportunistic pathogen that played little role in the pathophysiology of these CFS patients. They suggested the CFS patients had picked up Coxiella burnetii from their pets.

There has been legitimate concern about opportunistic pathogens that may not cause CFS but contribute to its pathology. That did not appear to be the case here. How strange, though, that such a high percentage of these CFS patients (4 of 8) tested positive for C. burnetii despite they fact they were apparently at low risk for catching it.

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The CDC Studies Part I – Overview: the recent CDC efforts to better characterize CFS using a large data set resulted in the simultaneous publication of 14 research papers in the Journal Pharmacogenomics in April, 2006. This complex effort which involved almost 20 researchers, many of them working for free, is the first to attempt to integrate gene expression with laboratory and clinical data. It could re-orient our thinking on CFS. To read an overview of the studies click here.

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