Painful menstrual periods in women.

Other Syndromes Related to FMS: Chronic Fatigue Syndrome, Multiple Chemical Sensitivities, Tension/migraine headaches, Depression/affective disorders, Temporomandibular Joint Disorder, Sleep Disorders, Irritable Bowel Syndrome, Esophageal dysmotility, Idiopathic Low Back Pain, Nondermatomal paresthesias, Vestibular Dysfunction, Sicca syndrome, Vasomotor rhinitis, Neurally mediated hypotension, Mitral valve prolapse, Noncardiac chest pain, Interstitial Cystitis, Female urethral syndrome, Chronic Pelvic Pain, Endometriosis (Aaron, Arch Int Med 2000).

FMS Symptoms in Children. Although symptoms are similar in children, some experts suggest that they often have no set number of pain tender points. In one study, children had an average of 9.7 tender point locations compared to the minimum of 11 in adults. In general, children with fibromyalgia most often experience sleep disorders and diffuse pain, and less frequently headache, general fatigue, and morning stiffness.

Who Gets Chronic Fatigue Syndrome & Fibromyalgia?

CFS/ME

In studies of large patient groups, 25% of people complain of fatigue and 4% have a fatiguing illness lasting greater than 6 months and of these only a small number meet CDC criteria for CFS. The CDC performed a national survey in 2004 which revealed that 1-2% of the general population meets criteria for CFS but they were not examined to rule out other causes. All age groups had CFS but adults were most common and women were greater than men by 2-5 times. Minorities were at increase risk along with those in lower socio-economic groups.

Of those people who meet criteria for CFS, 16% also meet criteria for FMS and 41% meet criteria for Multiple Chemical Sensitivity Syndrome.

FMS

Studies report that 4% of the general population meet the diagnostic criteria for fibromyalgia (Wolfe, et al, 1990). Some evidence suggests that a number of  factors may predispose people to fibromyalgia, including being female, having had difficult experiences in childhood, having a psychological vulnerability to stress, and coming from a very stressful culture or environment.

·    Gender. The prevalence of fibromyalgia is higher in women (3.4%) than in men (0.5%). Women's symptoms are also more severe than men's are.

·    Age. The disorder usually occurs in people between 20 to 60 years of age and peaks at age 35. In one study, however, fibromyalgia increased with age and had a prevalence of over 7% in patients between 60 and 79 years of age.

·    A condition called juvenile primary fibromyalgia, which appears in children, is uncommon, but studies indicate that its incidence is increasing. One study found that 1.2% of school children, all girls, met the criteria for fibromyalgia. Other studies have found an even higher prevalence of fibromyalgia in children. A 2000 study reported that in one specialty center it typically developed in children after age 13 and was most commonly diagnosed at 15. Symptoms were similar but outcome appears to be better in young people than adults.

·    Family Factors. Studies report a higher incidence of fibromyalgia among family members. It is not clear if genetic or psychological factors or both are involved. Some studies reporting some relationship are as follows:

o   One reported that 28% of the children of mothers with fibromyalgia also develop the disorder. There were no differences in psychological disorders between offspring who developed fibromyalgia and those who did not, however.

o    Another study noted that 66% of parents of children with fibromyalgia reported some sort of chronic pain, and about 10% had fibromyalgia itself. Close-knit families, oddly enough, were more likely to be associated with severe cases of childhood fibromyalgia.

What Causes These Disorders?

Chronic Fatigue Syndrome/Myalgic Encephalopathy

Theories abound about the causes of chronic fatigue syndrome. Unfortunately, many physicians still doubt that CFS is an actual disease but believe that it is a component of a psychological disorder or a symptom of other problems, similar to anemia and high blood pressure. Indeed, no primary cause has been found that explains all cases of CFS, but a number of experts believe that the chief possible causes of CFS include:

·        Infectious agents (viral, bacterial, other germs)

·        Immune system defects

·        Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction

·        Orthostatic Hypotension

·        Environmental Chemicals- pesticides, solvents, heavy metals

Other factors may include genetic factors and brain abnormalities. Still, although many of these elements appear to be at work in most cases of CFS, it is not clear what sequence of events actually leads to the fatigue and other prominent symptoms of this disorder. And these elements may produce similar symptoms across all individuals but not produce consistent biologic factors that would allow objective testing. Personality and psychological factors do not appear to be a direct cause of CFS but may increase a person's susceptibility to the syndrome after exposure to mental or physical stresses, such as viral infections.

Many experts believe that FMS is not a disease but rather a dysfunctional disorder which is "set" by the genes we are born with but then modified or exacerbated by our environmental influences or stressors. The "Stressors" capable of triggering FMS include (Clauw D. Neuroimmunomodulation 1997):

• Peripheral Pain Syndromes
• Infections (EBV, Parvovirus, Lyme Disease, Q fever)
• Physical trauma (automobile accidents)
• Psychological stress/distress
• Hormonal alterations (hypothyroidism)
• Drugs
• Vaccines
• Certain catastrophic events (war, but not natural disasters)

In our opinion, the underlying cause of these conditions is long-term unremitting stress (we will look at the long list of stressors in more detail later). Where such stress has reduced the vitality of the body it can often only take one or two more severe stress incidents to throw the individual into the full-blown Chronic Fatigue state. While this last stress is the one that usually gets blamed for the condition, it is only the “straw that broke the camel’s back.”

Each of us has our own breaking point dependent upon the vitality of our endocrine (adrenal) glands and immune system. Some individuals have inherited such a weak immune system that they will suffer from this condition no matter what measures they take to prevent it (Even these can be helped, however). On the other hand, there are still a few left whose systems are so strong that they will never develop this condition no matter what may come along. The great majority of us lie somewhere between these two extremes.

In our opinion, the reason that this CFS/FMS is now the fastest growing epidemic in our nation can be laid at the feet of the modern dictum, “Better Living through Chemistry.” The traditional stresses of physical strain, emotional strife, bacterial and viral invaders, trauma, natural poisons, etc. have been with us since the earliest days of mankind and yet we have few verified cases of Chronic Fatigue during these years. What has changed in our lives today is the explosion of man made toxic chemical substances for which the body has had no time to create the needed internal antidotes. A list of these assaulting agents would have to include but are not limited to pesticides, water pollution, air pollution, almost all modern medical drugs including the overuse and abuse of antibiotics, multiple vaccinations and food additives. As each new generation has its collective immune systems assaulted by an increasing number of these “unnatural” substances our children are born with ever-weaker immune systems and so the predisposition to this condition grows exponentially with each new generation.

Causes of Secondary Fibromyalgia

 Secondary Fibromyalgia is a condition with fibromyalgia symptoms that are caused by specific disorders:

• Physical Injury: In one study, for example, secondary Fibromyalgia developed in over 20% of patients who had neck injuries. The symptoms are identical to those of primary Fibromyalgia but are harder to treat. Once study reported a high incidence of Fibromyalgia in workers complaining of repetitive stress injuries, although it is not clear which condition caused the other.

• Ankylosing Spondylitis

• Surgery

• Lyme Disease. According to one study between 10% and 25% of patients with Lyme disease subsequently developed Fibromyalgia, which did not respond to standard Lyme treatment using antibiotics.

• Hepatitis C

 

Body Area and Organ Dysfunctions found in CFS/FMS

Central Nervous System (Brain)

Brain dysfunction appears to be a key abnormality for understanding the features of CFS/FMS. Although IQ does not appear to be affected, cognitive impairment (problems with thinking, memory and attention) has been documented by psychometric testing in both CFS and FMS patients. These include deficiencies in complex information processing (dealing with multiple tasks at the same time), information processing speed, initial acquisition of new information and learning/recalling complex verbal material. It has been shown that these cognitive deficiencies are not the result of depression or other mental health disorders (Tiersky LA, et al. J Clin Exp Neuropsychol 1997). An analysis on reaction times between CFS patients and healthy controls revealed slowed reaction times that worsened and stay worse after exercise (Snell C. IACFS 2007).

 

There are several non-specific abnormalities in the central nervous system, including pinpoint spots of brain inflammation found on MRI (Lange, et al. JNS, 17:3, 1999), decreased regional blood flow to the brain by SPECT and SPET scans, specifically in the temporal lobes, cingulate cortex and frontal lobes (Abu-Judeh 1998, Kuratsune 2002, Garcia A. AICFS 2007), hypometabolism by PET scan, and abnormalities in spinal fluid ( Natelson, BH. Abstract, AACFS, 2003). Furthermore, brain blood flow was demonstrated to be decreased in CFS whether they had depression or not. (Yoshiuchi K, Nateson BH, AACFS, Oct 2004). Brain SPET uptake worsened after performing a physical-mental stress test (Garcia-Quintana A. IACFS 2007).

 

On dynamic neruoimaging studies, CFS patients perform as accurately as healthy controls but their brain activation patterns are different and there is a clear deficit on speed of brain processing (Lange, IACFS 2007). CFS patients demonstrate longer information processing times after controlling for variables (including depression) that confound the interpretation of information processing speed. Simply put, CFS patients have to work harder to do simple tasks and this is not explained by depression (Togo, F. IACFS 2007).

 

Research has reported that some patients with CFS have high levels of serotonin, a neurotransmitter (chemical messenger in the brain); such elevated levels in the brain are associated with fatigue. However, another study revealed low levels of serotonin transporters in the part of the brain (the anterior cingulated cortex) of CFS patients which is very different from the areas involved in depression (Kuratsune H, AACFS, Oct 2004). Other studies have revealed reduced serotonin neurotransmitter system across brain, specifically the hippocampus (Cleare 2005) and anterior cingulate.

 

Some critics of CFS feel that this condition is just a form of primary depression or anxiety. However, CFS patients were found to have elevated lactate in the ventricles and low N-acetyl-aspartate in the hippocampus of their brains compared to healthy individuals and patients with the diagnosis of generalized anxiety disorder (GAD). The elevated lactate suggests oxidative stress and mitochondrial dysfunction are playing a role brain abnormalities in CFS. These findings support that there is biochemical differences in the brains of individuals with "pure" CFS when compared to healthy individuals and those with generalized anxiety disorder.(Nestadt, P. IACFS 2007)

 

Autonomic Nervous System (ANS) Dysfunction

Vagus Nerve Dysfunction: One study found that after CFS patients exercise, they exhibit slight abnormalities in the activity of the vagus nerves on the heart; the vagus nerves run down each side of the neck and end at the intestines and affect many bodily functions.

 

Postural Orthostatic Tachycardia Syndrome (POTS) is the most common form of autonomic imbalance in CFS and occurs frequently in young people with CFS.

 

Neurally Mediated Hypotension (NMH): Some studies have suggested that a subgroup of patients who fit the strict criteria for chronic fatigue syndrome may have a condition known as neurally mediated hypotension (NMH). This is confirmed with a tilt table test. NMH causes a dramatic drop in blood pressure when standing up, even for as short a time as ten minutes. It is the result of an abnormality in the central nervous system that signals the heart to slow down and lower blood pressure when a person stands up; blood pools in the feet and legs before circulating back up to the heart, sometimes causing light-headedness, nausea, and fainting. One 1999 study suggested that such patients tend to be younger and to recover from CFS sooner than patients whose symptoms are not due to NMH. Some experts believe that in these cases, a virus or infection may cause injury to the central nervous system that results in the hypotension abnormality. This could help explain why so many patients report a viral infection before developing chronic fatigue syndrome. Major studies need to be done and the results repeated with larger patient groups before they can be applied to the majority of CFS patients.

 

Low Blood Volume

Some (a subset) of patients with CFS have low blood volume (low blood cell mass) that adds to the orthostatic intolerance described above. A well designed placebo controlled, double-blinded study was performed at the University of Miami examining the role of an injectable drug, Epoetin Alpha in CFS patients with documented low blood volume. This injectable treatment relieved the symptoms of dizziness and the suspectibility to orthostatic syncope but it did not improve the fatigue severity in these patients (Hurwitz B. Miami Epoetin Alpha Clinical Trial, IACFS 2007).

 

Chronic Sleep Disturbance

Although there is not one specific sleep disturbance that is purely defining of CFS or FMS, both CFS and FMS patients have non-restorative sleep, which means that they do not have normal deep sleep. Other abnormalities include difficulty in initiating and maintaining sleep (DIMS), apnea, periodic limb movement of sleep (PLMS), nocturnal myoclonus (NM), vivid nightmarish dreams, "tired but wired", phase shifting, and dysania (Lapp, C. IACFS 2007).  Scientific studies have reveal sleep abnormalities 88-95% of CFS patients (Reeves, BMC neurol 2006, Fossey M. J Behavo Med 2004; May KP, Am J MEd 2004, Drupp L, J Psychsom Res 1993). OSA was the most common sleep disturbance found in these studies. Poor sleep quality was found in CFS patients (but not in healthy controls) and was associated with weakness in the parasympathetic nervous system during sleep (Tajima, S. IACFS 2007).

 

FMS patients have been shown to have decreased amount of the deep stages of sleep (stage III and IV) and increased incidence of sleep apnea, restless legs syndrome, periodic limb movement disorder (PLMD) which is a form of restless legs syndrome during sleep and bruxism (jaw clenching and teeth grinding) (Shaver, J. IACFS 2007).

Upper Airway Resistance Syndrome- UARS is chracterized by erratic breathing but not meeting criteria for Obstructive Sleep Apnea (OSA), oxygenation drops, frequent arousals and is associated with daytime fatigue, headaches, Irritable Bowel Syndrome and low BP (Lario BA Am J Med 1996; Sergi Eur Resp J 1999). This syndrome may be involved in FMS as of 28 subjects with FM, 26 were found to have UARS by a sleep study and CPAP treatment resulted in 40% improvement in their daytime symptoms (Gold AR Sleep 2004). UARS is more common in women.

Some experts believe that fibromyalgia does not cause disturbed sleeping patterns, but that sleep disturbances may be the precipitating factor for many cases of fibromyalgia pain. In one study, non-fibromyalgia volunteers reported fibromyalgia-like pain after they had been subjected to disrupted deep sleep. Disturbed sleep appears to trigger factors in the immune system that cause inflammation, pain, fatigue, and decreased pain threshold.

 

Abnormal Pain Perception

Some studies have suggested that the lowered pain thresholds experienced by fibromyalgia patients may represent a central defect in the way fibromyalgia patients process pain. Brain scans of fibromyalgia patients have, in fact, suggested abnormalities in pain processing centers (Gracely, R. et al. fMRI analysis in fibromyalgia and chronic fatigue syndrome. Abstracts, AACFS, 2003). Of particular interest is research that has detected up to three times the normal level of substance P (a neurotransmitter associated with increased pain perception) in the cerebrospinal fluid of fibromyalgia patients. Such abnormalities along with other factors (such as chronic sleep deprivation or physical injury) may produce a state called generalized hyper vigilance, which is an amplification of sensation. People with this condition are oversensitive to external stimulation and are preoccupied with the sensation of pain.

For example one study compared three groups of individuals: fibromyalgia patients, rheumatoid arthritis patients, and people without these disorders. They were given a questionnaire to assess their response to pain and noise. Of the three groups, the fibromyalgia patients were least tolerant and most attentive to such stimuli.

 

Hormonal Abnormalities & The Hypothalamic-Pituitary-Adrenal (HPA) Axis

Adrenal Stress Hormones. Strong adrenal glands are key to optimum energy. The adrenal glands regulate the body's minerals as well as work with the thyroid gland to produce and maintain energy levels. We are exposed daily to many different kinds of stress including emotional, physical, environmental and work-related stress. Dietary factors such as refined and over-processed foods, preservatives, and pesticides are also stressors. These stresses make the adrenals over respond by producing extra amounts of hormones for energy. However, long periods of stress cause the adrenals to work overtime, eventually robbing the body’s reserve of energy and nutrients – which can create adrenal fatigue and chronic tiredness. Of particular interest to researchers are possible abnormalities in the brain system known as the hypothalamus-pituitary-adrenal axis (HPA), which controls important functions, including sleep, response to stress, and depression.

·        A number of studies on CFS patients have observed deficiencies in cortisol levels, a stress hormone produced in the hypothalamus (Cleare AJ, et al. Constrasting neuroendocrine responses in depression and chronic fatigue syndrome. Journal of Affective Disorders. 1995; 35: 283-289). Cortisol is a powerful suppressor of the immune system. One central hypothesis for CFS suggests that after a person with cortisol deficiency (hypoadrenalism) is exposed to a viral infection or some other physical or emotional stress, the immune system over responds and causes symptoms typical of chronic fatigue syndrome/FMS.

·        Riccardo Baschetti, M.D., states “Chronic Fatigue Syndrome (CFS) shares 39 features with primary adrenal insufficiency, including all the physical and neuropsychological symptoms listed in both the original and the revised criteria for CFS, as well as many other abnormalities.” Dr. Baschetti concludes, “I believe that adrenal insufficiency, rather than alteration in cardiac function, may primarily account for the reduction in exercise capacity in CFS.” (Riccardo Baschetti, M.D. Editor’s Correpsondence regarding: De Becker P, Roeykens J, Reynders M, Mc Gregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 2000;160:3270-3277)

·        DHEA response to stimulation- One study investigated the response of the adrenal glands in 22 patients with CFS and 14 healthy controls. In both groups, they measured DHEA in serum after ACTH stimulation during 60 minutes. Although the researchers found normal basal (pre-stimulation) DHEA levels, they noted a ‘blunted’ serum DHEA response curve to the ACTH injection. This observation adds to the large amount of evidence of endocrinological abnormalities in CFS. (De Becker et al, Horm Metab Res 1999 Jan;31 (1):18-21)

·        Small Adrenal Glands in CFS- The first study to use imaging methods to measure adrenal gland size in CFS revealed significant adrenal atrophy in a group of 8 CFS patients with abnormal endocrine parameters. The right and left adrenal gland bodies were reduced by over 50% in the CFS subjects compared to those from a group of 55 healthy subjects. (Scott et al, Psychoneuroendocrinology 1999 Oct;24 (7):759-68)

·        Abnormalities in the hypothalamus-pituitary-adrenal gland (HPA) axis have also been reported in fibromyalgia patients. Studies have revealed an impaired ability to activate the hypothalamic-pituitary portion of the hypothalamic-pituitary-adrenal axis as well as the sympathoadrenal system, leading to reduced ACTH and epinephrine responses to hypoglycemia (Adler GK, et al, "Reduced Hypothalamic-Pituitary and Sympathoadrenal Responses to Hypoglycemia in Women With Fibromyalgia Syndrome," Am J Med, May, 1999;106:534-543.)

 

Low Growth Hormone Levels. A third of FMS patients have low insulin growth factor (IGF) levels. Low levels of growth hormone have been associated with impaired mental functioning, lack of energy, muscle weakness, and intolerance to cold. See the medical therapy section for more information on growth hormone therapy in FMS/CFS.

 

Female Menses. Dr. Rowe reported in a small study that severe dysmenorrhea (painful menses) was more common in young women with CFS/ME and additionally, their CFS symptoms were worse during the time of their menses (Rowe K. IACFS 2007). Female hormone levels (estrogen, progesterone, testosterone) did not correlate directly with pain severity in 74 FMS women when compared to women without FMS (Okifuji 2006)

 

Infections

In up to 80% of cases, chronic fatigue syndrome starts suddenly with a flu-like condition. Because most of the features of CFS resemble those of a lingering viral illness, many researchers have focused on the possibility that a virus or some other infectious agent causes the syndrome. Most cases of CFS occur sporadically, cropping up individually without appearing to be contagious, and there is no evidence that CFS is spread through casual contact, such as shaking hands or coughing, or by intimate sexual contact. It is likely that a subset of CFS/FMS patients have infection as a major reason for their illness, especially those with significant neuro-cognitive (brain) symptoms (Peterson, D. Abstract, AACFS, 2003).

Although over 30 infectious germs have been suggested to cause CFS over the years, no single germ agent have been proven to cause CFS including Lyme disease, candida ("yeast infection"), herpesvirus type 6 (HHV-6), human T cell lymphotropic virus (HTLVs), Epstein-Barr, measles, coxsackie B, cytomegalovirus, or parvovirus. Specifically, most studies (9 of them) suggest HHV6 as the most common infectious trigger to this disorder, but other studies (2) have failed to confirm this. Some researchers are suggesting that changes in normally harmless bacteria found in the intestine may play a role in the development of CFS symptoms. Another theory referred to as "hit and run" suggests that chronic fatigue syndrome might be the result of a virus or bacteria that infects the body, causes immune abnormalities, and is then eliminated. It leaves behind a damaged imbalanced and dysregulated immune system, however, that continues to cause flu-like symptoms even in the absence of the virus (this is called Th2 activation). Other theories pose that immune system or neurologic abnormalities cause a reactivation of a viral or bacterial infection that had presumably resolved but had persisted in a latent (inactive) stage.

So far, there has been no study proving that CFS is “contagious.” However, one small pilot study suggests the possibility that an infectious agent which can cause CFS may persist in at least some CFS patients and can given to another individual, especially those living closely with the CFS patient (Underhill, O’Gorman, AACFS, Oct 2004).

 

Viral Infections

There have been 20 or more viruses somehow associated with CFS. Of these, two viruses seem to be the most prominent in recent studies: Human Herpes Virus 6 (HHV-6) and Epstein Barr Virus (EBV) (IACFS 2007). Other viruses linked to CFS include Parvovirus B19, enteroviruses (Coxackie B like viruses), Ross River virus, Coxiella burnetti (Q fever virus). In one small sample of 20 CFS patients, 9 (45%) were found positive to either EBV or HHV-6 compared to 12 healthy controls (Levine S. IACFS 2007). More information about HHV-6 can be found at the HHV-6 Foundation, www.hhv-6foundation.org

 

A common symptom found in many CFS patients is chronic stomach pain. Dr. Chia found evidence that 80% of 108 CFS patients had an enterovirus infection of their stomach proven by endoscopic biopsy (Chia J. IACFS 2007).

 

Mycoplasma Infections: Dr. Nicolson and co-workers have been interested in the potential role that chronic infections may play in FMS/CFS. Although the causes of chronic illnesses are for the most part unknown, the complex signs and symptoms that evolve in many FMS, CFS, Gulf War Illness (GWI) patients may be due, in part, to systemic chronic infections (bacteria, viruses, fungi). Such infections can follow acute or chronic chemical, environmental or other insults (trauma, acute viral illness, etc.) that have the potential to suppress the immune system and cause metabolic imbalances (Nicolson, G.L., et al. Mycoplasmal infections in chronic illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War Illness, HIV-AIDS and Rheumatoid Arthritis. Med. Sentinel 1999; 4: 172-176 and Nicolson, N.L. Chronic fatigue illness and Operation Desert Storm. J. Occup. Environ. Med. 1996; 38: 14-16)

 

Dr. Nicolson previously found that more than 60% of patients with Chronic Fatigue Syndrome/ Fibromyalgia Syndrome had mycoplasma blood infections, such as M. fermentans. In a more recent study, patients with chronic Fatigue Syndrome/Fibromyalgia syndrome were examined for multiple mycoplasmal infections in their blood. A total of 91 patients diagnosed with Chronic Fatigue Syndrome/ Fibromyalgia Syndrome and with a positive test for any mycoplasmal infection were investigated for the presence of M. fermentans, M. pneumoniae, M. hominis and M. penetrans infections using forensic polymerase chain reaction. Infections were detected with M. pneumoniae (54/91), M. fermentans (44/91), M. hominis (28/91) and M. penetrans (18/91) of mycoplasma-positive patients, respectively. Multiple mycoplasmal infections were found in 48 of 91 patients, with double infections being detected in 30.8% or triple infections in 22%, but only when one of the species was M. pneumoniae and/or M. fermentans. Patients infected with different Mycoplasma spp. generally had a longer history of illness, suggesting that patients may have contracted additional mycoplasmal infections with time. (Nasralla M, Nicolson G. Multiple Mycoplasmal Infections Detected in Blood of Chronic Fatigue Syndrome and Fibromyalgia Syndrome Patients. European J of Clin Microbiology & Inf Dis 1999; 18: 859-865). Dr. Kamaroff found no evidence of M. fermentens in CFS patients (1993) but another report found evidence of M. fermentens in roughly 30% of CFS patients (Vojdani A. Detection of Mycoplasma genus and Mycoplasma fermentens by PCR in patients with CFS. FEMS Immunol Med Microbiol 1998; 22:355-65). More information on Mycoplasma can be found at http://www.cfsresearch.org/mycoplasma/index.htm

 

Intestinal bacterial overgrowth (Dysbiosis) may also play a role in these disorders. The data from a recent study suggests that bowel symptoms in fibromyalgia may be caused by small intestinal bacterial overgrowth.  There have been associations made between fibromyalgia symptoms and Chlamydia species as well as Borrelia burgdorferi.  In animal models, small intestinal bacterial overgrowth can result in bacterial translocation to mesenteric lymph nodes and can produce systemic effects.  These systemic effects are believed to be mediated by endotoxins from Gram-negative bacteria.  These endotoxin effects may explain the soft tissue hyperalgesia that is seen in fibromyalgia syndrome since injections of the endotoxin into lab animals results in similar hyperalgesia.  The authors conclude that the intestinal symptoms of fibromyalgia patients may be related to small intestinal bacterial overgrowth, and treatment of small intestinal bacterial overgrowth can result in overall improvement in intestinal symptoms. (Pimentel M, et al, "Small Intestinal Bacterial Overgrowth:  A Possible Association With Fibromyalgia,", J Musculoskeletal Pain, 2001;9(3):107-113)

 

Yeast Infections or Overgrowth

Although the “Yeast Over-growth Syndrome” remains controversial in medicine, one researcher found evidence of increased Candida albicans with an abnormal immune response in some CFS patients (Cozon, G. et al. In vivo and in vitro abnormal cellular reactivity to Candida albicans in patients with CFS. Abstract, AACFS, 2003). A small study on 20 CFS patients in an "acute phase of illness" found elevated levels of Candida albicans in stool samples when compared to 19 healthy individuals without CFS (Evengard B. IACFS 2007).

 

Immune System Abnormalities

CFS has been referred to as the "chronic fatigue - immune dysfunction syndrome" because studies have found dysfunction of the immune system, in which some components appear to be over reactive (termed “activated”), whereas other parts of the immune system have impaired function. Researchers have detected a number of chronic immune abnormalities in CFS patients, but no consistent or major abnormality that could indicate a primary cause. Researchers have identified certain auto-antibodies in many Fibromyalgia patients that affect neurologic and hormonal systems.

 

In one study, those patients with severe CFS symptoms, had higher-than-normal numbers of infection-fighting white blood cells known as killer T cells, which launch attacks on invading viruses and other disease-causing microorganisms. These same people had lower-than-normal levels of another white blood cell known as the suppressor T cell, which helps to shut down the immune response once the invading organisms have been killed. In such cases, the immune system becomes persistently overactive (activated) and produces fatigue, muscle aches, and other symptoms of CFS. Other studies have indicated lower amounts of natural killer (NK) cells and cytotoxic T cells in some CFS patients, which might make them more susceptible to viral and other infections. (Maher, K, Klimas, N, Fletcher, MA. Molecular defects associated with chronic fatigue syndrome. Abstract, AACFS, 2003). Abnormal NK cell function was found to be abnormal in both CFS patients and Gulf War Illness patients compared to healthy controls (Fletcher M. Klimas, N. IACFS 2007). Furthermore, these “activated” lymphocytes can pass through the blood-brain barrier and produce inflammatory chemicals called “cytokines” which leads to chronic low-level immune activation and inflammation in the brain (CDC Cold Spring Harbor Conference, Sept 2004)

 

Another area of research involves increase in the immune defense molecules “2-5A Synthetase” and “Rnase L.” Early studies revealed increased levels of these immune markers in CFS patients, in other words, the antiviral defense pathway is working overtime or is "upregulated" (Suhadolnik, R, et al. Clin Inf Dis, 18 (S96), 1994; Vojdani A, J Clin Lab Immunol, 1998; and Suhadolnik R, J CFS, 5,223, 1999). More recently, Dr. Suhadolnik demonstrated abnormalities of the RNase-L pathway and impaired function of natural killer cells in CFS patients but not in healthy “control” subjects or in patients with primary depression. Furthermore, these abnormalities correlated with elevated symptom scores (Suhadolnik R, et al.. Clinical and Biochemical Characteristics Differentiating CFS from Major Depression and Healthy Control Populations: Relation to Dysfunction of RNase L Pathway. J CFS 2004).  

 

To summarize, the evidence is very convincing that CFS patients have increased number of "activated T cells," poorly functioning natural killer (NK) cells, abnormal 2-5A Synthetase and RNase L pathway dysfunction, and elevated pro-inflammatory cytokines (TNF-a, IL-1, IL-6, INF-y) (Komaroff A. IACFS 2007).

 

Allergies and Contributing Environmental Factors

Allergies- are the only consistent immune system abnormality among CFS patients. Some studies have reported that up to 80% of CFS patients have allergies to food, pollen, metals (such as nickel or mercury) or other substances, although other studies have found no greater incidence of allergies in CFS patients than in the general population. In any case, allergies appear to make CFS symptoms worse in those who have them. Elimination diets may help determine whether allergies to specific foods are present. Most allergic people, however, do not have CFS. Some research indicates that in some cases people with both allergies and emotional disorders, such as anxiety or depression, are more vulnerable to the effects of the inflammatory response, which is triggered by allergens. This response triggers the release of a number of immune factors, importantly cytokines, powerful factors that can cause fatigue, joint aches, and fever and which can also affect the hypothalamus-pituitary-adrenal system in the brain. Another study found a similar relationship between depression, allergies, and low back pain.

 

Heavy Metal Toxicity (namely Mercury) has been implicated in CFS/FMS (Clauw DJ, "The pathogenesis of chronic pain and fatigue syndromes: fibromyalgia" Med Hypothesis, 1995, 44:369-78; & Hanson S, Fibromyalgia, glutamate, and mercury. Heavy Metal Bulletin, Issue 4, 1999, p3-6) and (Sterzl I, et al. Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228). In our experience, those patients who test high in mercury need to have this toxicity addressed for optimal treatment of their underlying CFS/FMS.

 

Metabolic (Mitochondrial) Dysfunction

Mutations in Mitochondria- Another theory about the cause of CFS, as well as fibromyalgia and other illnesses, concerns mutations of the mitochondria, the part of each cell that supplies energy. Inherited disorders involving  mutations that affect mitochondria are known to cause fatigue and muscle pain. One study reported that a specific genetic mitochondrial mutation called cytochrome b was associated with intolerance to exercise and aches and pains in a group of patients who had no known family history of mitochondrial genetic disease. Some research suggests that the mutation may be caused by free radicals, damaging particles released by the body's chemical processes. Two recent studies document increased free radicals and oxidant stress in CFS patients compared to healthy control subjects. (Kennedy, G, et al. Increased plasma isoprotanes and other markers of oxidative stress in chronic fatigue syndrome. Abstract, AACFS, 2003 and Vecchiet J, et al. Antioxidiant status in chronic fatigue syndrome, CFS. Abstract, AACFS, 2003). More work is warranted on this interesting observation to determine if such a mutation may account for some cases of CFS, especially concerning the role of antioxidants.

 

A theory that may help tie in the various conditions associated with CFS suggests that a combination of factors, including allergies, stress, and infections, may impair metabolic function by depleting adenosine triphosphate (ATP). This chemical stores energy in cells, and low levels are common in CFS patients. One study showing symptom improvement using a coenzyme called NADH that increased ATP levels lends support to this theory.

Muscle Abnormalities in FMS

·    Patients with CFS sometimes complain that they feel so weak that it seems as if their muscles are no longer working properly. It has been proposed that a defect in skeletal muscle could be the cause of the fatigue. However, physical, chemical, and metabolic studies have not yet been found in the  majority of CFS patients. Some research has detected muscle defects in fibromyalgia patients, which can be classified as follows:

o   Biochemical abnormalities. (Eg, One study reported that fibromyalgia patients had lower levels of the muscle-cell chemicals phosphocreatine and adenosine triphosphate (ATP). Such chemicals regulate the ebb and flow of calcium in muscle cells, an important component in their ability to contract and relax. If ATP levels are low, calcium is not "pushed back" into the cells and the muscle remains contracted. Such abnormal chemical levels could derive from signals in the brain.)

o   Structural abnormalities. (Eg, some researchers have observed overly thickened capillaries in the muscle tissue of fibromyalgia patients, which could produce lower chemical levels as well as reduce the flow of oxygen-rich blood in the muscle tissue.)

o   Functional abnormalities. (Pain and stress of the disease itself can impair muscle function.)

 

Coagulation Abnormalities

Dr. Berg has documented a unique “hypercoagulable state” in patients with CFS, FMS, Gulf War Illness and other conditions like Infertility and Multiple Sclerosis. He has named this abnormality “Immune System Activation of Coagulation (ISAC).” His model proposes that a variety of infectious agents (CMV, HHV6, Mycoplasma, Chlamydia, etc), toxins, allergens, or even vaccine contaminants stimulates the immune system to produce inflammatory chemicals (cytokines) which then results in increased blood viscosity (thickness) and microscopic “clotting” which causes localized decrease in blood flow and oxygenation to varies body tissues including the brain. These markers of hypercoagulation include fibrinogen, prothrombin fragment 1&2, thrombin anti-thrombin complexes and soluble fibrin monomer. He proposes the use of heparin (which must be injected into the skin or vein) for treatment of this abnormality. (Hannan KL, Berg E, et al. Activation of the coagulation system in Gulf War Illness: a potential pathophysiologic link with chronic fatigue syndrome: a laboratory approach to diagnosis. Blood Coag Fibrinolysis 2000, 11:7). A follow up study of these coagulation factors revealed the possibility that a hereditary gene defect combined with the immune system activation of coagulation work together to produce the end result of microscopic clotting and decreased blood flow to the body’s tissues in the CFS/FM patient. (Harrison H, et al. Procoagulant genetic factor in a pooled cohort of 582 chronic fatigue syndrome, fibromyalgia and related chornic illnesses, AACFS, Oct 2004).

Psychological and Social Effects

Although not primary causes, psychological and social factors may contribute to CFS/FMS in three ways:

·        They could make individuals susceptible to CFS/FMS

·        They may play some role in triggering the onset of the condition.

·        They may help perpetuate it by stressing the immune system

 

Studies have reported a greater incidence of severe experiences of victimization from emotional and physical abuse in patients with fibromyalgia than in the general population. Most often the abuse originated from family or partners. This suggests that post-traumatic stress syndrome or chronic stress may play a strong role in the development of this disorder in some patients. Post-traumatic stress disorder (PTSD) is an anxiety disorder that is a reaction to a specific traumatic event. Symptoms of this condition, which can occur for years after the traumatic event, include emotional withdrawal, hopelessness, irritability, mood swings, sleep problems, inability to concentrate, and an excessive startle response to noise. There is some evidence that PTSD actually results in changes in the brain, possibly from long-term overexposure to stress hormones.

Gulf War Illness: Chronic Fatigue-like Symptoms after the Gulf War

Gulf War veterans have been intensively studied because of a high percentage reporting CFS symptoms. One major study reported that 45% of Gulf War veterans met the overall criteria for chronic fatigue syndrome, with 6% having severe cases. Women veterans had three times the risk as men. Interestingly, 15% of the noncombat personnel, representing the general population, reported the same problems, although the cases in general were less severe than in the veterans. Because such symptoms have occurred in other veteran groups, some experts suspect that post-traumatic stress syndrome may be responsible for the symptoms in some cases. After finding that stress weakens the blood-brain barrier, some experts believe that, in extremely stressful situations such as the Gulf War, this weakened barrier may allow agents, such as small viruses, to pass into the brain causing damage and triggering CFS symptoms. Whether uncovering the causes of the syndrome in Gulf War soldiers can be applied to civilian cases of CFS, however, is not known. One 2000 study has heavily implicated multiple vaccinations given to military personnel during the Gulf War (but not those given before). More than a dozen different illnesses have been detected in over 70,000 soldiers examined for this problem. Some researchers identified an unusual bacteria-like organism known as Mycoplasma fermentans in nearly half the veterans who suffered from Gulf War syndrome, and one scientist speculated that it might have been developed for biological warfare. Some researchers suspect that the symptoms were caused by an experimental vaccine that contained a substance called squalene. High levels of antibodies to this compound have been found in the blood of veterans with CFS symptoms. An investigation is underway. Still other studies have found that up to 20,000 troops may have been exposed to low levels of the nerve gas sarin.

How is CFS/FMS Diagnosed?

Diagnostic Criteria

There is no unequivocal objective method for diagnosing these sister conditions. The criteria used for studying CFS and FMS are very helpful, particularly if the patient does not have any accompanying disorder, such as depression or arthritis, that could complicate the diagnosis. Failure to meet the criteria, however, does not rule them out. It should be suspected in any patients with severe fatigue and muscle or pain when no identifiable cause has been found.

Medical and Personal History

A physician should always take a careful personal and family medical history, which would include a psychological profile and a history of any factors that might be indicative of disorders other than fibromyalgia. Such factors might include recent weight change, physical injuries, infectious diseases, muscle weakness, rashes, and any instances of sexual, physical, or substance or alcohol abuse. The patient should report any drugs being taken, including vitamins and over-the-counter or herbal medications.

Physical Examination

Pressure on Tender Spots. Any physical examination for fibromyalgia requires that the physician press firmly on all potential tender spots. They must be painful when pressed, not simply tender. In addition, for a diagnosis of fibromyalgia, these tender sites are not typically accompanied by signs of inflammation, such as redness, swelling, or heat in the joints and soft tissue. The pressure points may also change in location and sensitivity over time. A physician, then, may re-check pressure points that do not respond the first time in patients who have other significant symptoms.

Detection of Other Causes of Symptoms. A physical examination also includes scrutiny of nails, skin, mucous membranes, joints, spine, muscles, and bones to help rule out arthritis, thyroid disease, and other disorders.

Other Tests

There are no blood, urine, or other laboratory tests that can proof the the specific diagnosis of CFS or FMS. Tests for specific diseases depend on family histories and other symptoms. They may include thyroid and liver function tests, blood count, tests of certain antibodies, and sedimentation rate.

Simply measuring blood pressure will not identify CFS patients whose condition might be caused by Neurally Mediated Hypotension (an abnormal drop in blood pressure). A tilt test, whereby an individual lies on a table tilted upright at a 70-degree angle for a prolonged period, may confirm CFS caused by Neurally Mediated Hypotension if the patient feels lightheaded, sick, and faint after several minutes. A specialized test of the autonomic nervous system (ANSAR) can be easily performed in the office and detects abnormalities in the autonomic nervous system without the stress of a tilt table test.

Other specialized tests may include growth hormone, adrenal hormone assay, tests for heavy metal toxicity, stool tests for bacterial/fungal overgrowths, for infections (RNase-L, EBV, HHV6, Mycoplasma, Lyme, etc), and subtle inflammation markers like HS-CRP. Some experts are hoping that this or other markers may reveal a biologic basis for CFS and also establish a method for diagnosing it. Follow-up psychological profile testing may be suggested if laboratory results do not indicate a specific disease.

Cardiac stress tests with oxygen consumption measurements can sometimes be helpful in finding physiologic abnormalities in CFS patients. However, a recent small study of CFS patients versus healthy controls revealed that CFS patients had a significant worsening of their oxygen consumption when the test was repeated 24 hours later whereas healthy individuals had normal results on both the initial and repeat test (Ciccolella, M. IACFS 2007). This two-step cardiac stress test with oxygen consumption analysis appears to document the significant post-exertional exhaustion that is the hall mark of CFS.

How Serious Are These Conditions?

Severity of Symptoms

The severity of chronic fatigue syndrome varies. In extreme cases, patients are bedridden and can do virtually nothing, including even light housework. More often, CFS sufferers can work at least part-time. Most commonly, patients with CFS report that they have trouble fulfilling both home and work responsibilities. Most patients say that while fatigue is the most incapacitating symptom, those of mental impairment, such as an inability to concentrate, are the most distressing. Some studies indicate that although general intelligence is not impaired, CFS patients test lower in certain mental functions, particularly speed and efficiency in processing complex information. In such studies, this impaired mental function occurs regardless of the presence or absence of depression or other psychiatric disorders. One study found that the mental impairment in CFS patients parallels the degree of their physical impairment, indicating that the disease process itself may exert a neurologic effect.

Like CFS, Fibromyalgia can be mild or disabling, and the emotional repercussions can be substantial. About half of all patients have difficulty with or are unable to perform routine daily activities. Estimates of patients who have had to stop work or change jobs range from 30% to 40%. The pain, emotional repercussions, or sleep disturbances may lead to self-medication and overuse of sleeping pills, alcohol, drugs, or caffeine.

 

Long-term Outlook in Adults

Because the illness has been undefined and there are few objective measures for recovery, experts have found it difficult to determine the long-term outlook of CFS. Some physicians have observed that patients whose symptoms began abruptly following a severe viral illness recovered completely after six months to a year, whereas patients whose problems developed slowly and insidiously experienced symptoms for a longer period of time. Patients who report that they can think clearly most of the time, who do not have other physical or emotional complaints beyond CFS symptoms, and who sleep well are more likely than other CFS patients to experience improvements in their fatigue over time. Nevertheless, studies have reported that between 58% and 72% of patients who complain of chronic fatigue (whether CFS or idiopathic fatigue) continue to experience it after a year and in one study nearly 60% were still fatigued at two years. One small 1999 study observed that even after four years few patients with severe CFS had returned to their pre-illness state. Yet another study, however, found that when patients with severe CFS were treated with a multidisciplinary rehabilitation program, nearly all improved significantly and the gains were maintained for at least a year afterward. Many patients with less severe chronic fatigue have reported turning a corner after a year or two and slowly regaining energy despite some setbacks along the way. Some patients get progressively worse, but the disorder is not fatal. Although children with symptoms of chronic fatigue have not been rigorously studied, some studies indicate that children generally have a better prognosis than adults and recover after one to four years in up to 95% of cases.

Some studies indicate that fibromyalgia symptoms remain stable over the long term, while others report a better outlook, with 25% of patients in remission two years after diagnosis. Although the disease is chronic, it is neither progressive nor fatal, and remission can occur in many patients who participate in disease management programs. Patients with secondary fibromyalgia, particularly when it is caused by injury, tend to have a more severe and less easily treated condition than those with primary fibromyalgia.

Outlook in Children

Children with Fibromyalgia tend to have better outlooks than adults do. In adult patients who were studied for four and a half years, those who had adequate exercise had the most promising outcome; those with a significant life crisis or who were on disability had a poorer outcome than others. Outcome was determined by improvements in the patients' capacity to work, their own feelings about their condition, pain sensation, disturbed sleep, fatigue, and depression.

General Treatment Guidelines

Since there is no one cause for CFS/FMS, there is no one treatment! Treatments can be thought of in two distinct categories and are usually given concurrently.

·    Symptomatic therapies that address the worst symptoms in each individual patient (ie. pain medication, sleep agents, antidepressants).

·    Therapies designed to address those specific HPA axis dysfunctions, immune dysfunctions, infections, toxic, hormonal or metabolic disturbances found in each person evaluated in a comprehensive manner.

If the specific underlying factors can be isolated to each given individual patient and targeted with specific therapies for those specific abnormalities, then less symptomatic therapy is required and improvement ensues. Treatments usually involves a combination of a variety of therapies the achieve the maximum results for each person.

The specific tender points and generalized pain suffered by Fibromyalgia patients are most likely the end-points of a disease process that starts in the brain. Therefore, treatments should involve not just dealing with the pain centers but must be a multi-faceted approach. One study found that interdisciplinary treatment programs were effective in significantly improving pain in 42% of patients. After treatment stopped, improvements in pain and other symptoms, including depression and sense of physical capability, persisted for at least six months, although patients tended to become fatigued again. The effectiveness of the treatments tended to depend on how depressed the patients were, the sense of their own disability, personal support networks, and whether the cause was known. The severity of the pain at the start of treatment had little to do with outcome.

Dr. Teitelbaum demonstrated success with the multi-factorial treatment of 72 FMS patients (38 active, 34 placebo; 69 also met CFS criteria). All patients  received all active or all placebo therapies as a unified intervention. Patients were treated, as indicated by symptoms and/or lab testing, for: (1) subclinical thyroid, gonadal, and/or adrenal insufficiency, (2) disordered sleep, (3) suspected Neurally Mediated Hypotension (NMH), (4) opportunistic infections, and (5) suspected nutritional deficiencies. His conclusions: significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS. (Teitlebaum J, et al. Effective Treatment Of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study. J CFS 2001 8:2)

Preparation for Treatment

·        Patients must have realistic expectations about the long-term outlook and their own individual capabilities. It is important to understand that the condition can be managed and patients can live a full life. The following tips may be helpful in embarking on a treatment program for fibromyalgia:

·        Patients must begin all treatments with the attitude that they are trial and error. No physician, even an expert, has a clear treatment solution, because little significant research has been conducted on this disorder. For example, there were no major trials on drug therapies for fibromyalgia reported during 2000. Patients and doctors need to work together to make the best choices for individual symptoms and concerns.

·        Therapies are prolonged, in some cases life-long, and patients should not be discouraged by relapses.

·        Enlisting family, partners, and close friends, particularly with exercise and stretching programs, can be helpful.

·        Becoming involved with support groups of fellow-patients has also benefited many patients. Support groups may also benefit family members, particularly parents of children with fibromyalgia. One study noted that the severity of the disorder increased in children whose parents were less able to cope with their children's pain.

·        Improvement is subjective, and some patients are pleased with only a 10% reduction in pain and other symptoms.

General Treatments Categories

·        Exercise and Physical Therapy

·        Lifestyle Modification: Stress Management, Diet, Sleep Hygeine

·        Psychological Therapies such a Cognitive Behavior Therapy

·        Medical Therapies: Medication, hormone therapies

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