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

A – several difference making papers on CFS pathophysiology

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

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

F – no important papers on CFS

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.

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.

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.

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.

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.

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.

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.

Galileo Whole Body Vibration

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.

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.

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’.

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.

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.

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.

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.

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.

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.

WEBSITE UPDATES

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.

Days of the Bloggers - After two severe crashes both Jessica and Sue take a look back and reflect on the good and bad of their struggles and their efforts to maintain a healthy outlook on life. After several decades of this illness Zona is less than thrilled that newspapers are finally telling her her disease is a real one. Betsy charts her very slow but steady progress since seeing Dr. Lapp . To check out the bloggers click here.